WO2022227743A1 - Dérivé de mémantine-urée, son procédé de préparation et son application - Google Patents

Dérivé de mémantine-urée, son procédé de préparation et son application Download PDF

Info

Publication number
WO2022227743A1
WO2022227743A1 PCT/CN2022/073961 CN2022073961W WO2022227743A1 WO 2022227743 A1 WO2022227743 A1 WO 2022227743A1 CN 2022073961 W CN2022073961 W CN 2022073961W WO 2022227743 A1 WO2022227743 A1 WO 2022227743A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
reaction
dimethyladamantan
ureido
group
Prior art date
Application number
PCT/CN2022/073961
Other languages
English (en)
Chinese (zh)
Inventor
陈国良
杜芳瑜
刘中博
曹若琳
孙健文
陈峰杨
李啸虎
Original Assignee
沈阳药科大学
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 沈阳药科大学 filed Critical 沈阳药科大学
Publication of WO2022227743A1 publication Critical patent/WO2022227743A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms

Definitions

  • the present invention relates to the technical field of medicine, in particular to memantamide derivatives and a preparation method and application thereof.
  • Pain sensation is mediated through the action of a specialized subset of sensory afferent neurons (nociceptors), which are activated in response to thermal, mechanical, and chemical stimuli through a variety of mechanisms.
  • nociceptors which are activated in response to thermal, mechanical, and chemical stimuli through a variety of mechanisms.
  • ion channel modulation includes transient receptor potential (TRP) channels, G protein-coupled receptor (GPCR) activation, and changes in cell membranes, all of which demonstrate the mechanism of lipid mediator signaling in nociceptors (Nature, 2001, 413(6852):203-210).
  • lipid mediators in pain signaling are demonstrated on the basis of studies showing that cyclooxygenase and lipoxygenase metabolites prostaglandins and leukotrienes can contribute to pain and inflammation.
  • Specific long-chain polyunsaturated fatty acids PUFAs
  • CYP450 cytochrome P450 enzymes
  • EpFA epoxidized fatty acids
  • Investigators have found that these metabolites mediate analgesic effects in several types of pain pathologies such as acute pain, chronic pain, cancer pain, or intractable pain.
  • Arachidonic acid is a 20-carbon PUFA containing four unsaturated double bonds, which can be metabolized by CYP450 enzymes to epoxide metabolites (EETs) of any one or several of the four double bonds , including 5,6-EET, 8,9-EET, 11,12-EET and 14,15-EET.
  • EpFAs, including EETs limit pain and inflammation through multiple direct and indirect mechanisms, including nuclear receptor agonism, limiting endoplasmic reticulum stress, and blocking mitochondrial dysfunction.
  • small-molecule inhibitors of soluble epoxide hydrolase have shown potent analgesic effects (Neurotherapeutics, 2020, 17, 900–916).
  • EETs are easily inactivated by soluble epoxide hydrolase (sEH) metabolism in vivo, and EETs metabolite dihydroxy metabolite DHETs have pro-inflammatory effects, and small molecule inhibitors of soluble epoxide hydrolase can stabilize in vivo EpFA, therefore, increases the amount of EETs in the body by inhibiting the activity of sEH, becoming a new approach for the treatment of EETs-related diseases.
  • sEH soluble epoxide hydrolase
  • EpFA exerts analgesic effects through various mechanisms, such as reducing endoplasmic reticulum (ER) stress, preventing or reversing endothelial cell dysfunction (ECD), and stabilizing mitochondrial function (Cell Physiol Biochem, 2015, 36, 474-486).
  • EpFA can modulate cellular stress induced by reactive oxygen species and divert the ER stress response to maintain homeostasis instead of activating inflammatory pathways leading to cellular senescence and cell death.
  • EpFA can reduce ER stress response and limit reactive oxygen species (ROS), indirectly maintaining mitochondrial function stability.
  • ROS reactive oxygen species
  • EpFA can also directly block the effects of mitochondrial dysfunction. Inhibition of sEH activity can stabilize EpFA and also limit the production of some pro-inflammatory diol metabolites.
  • EpFA mediates beneficial effects in all of these processes, shifting the ER stress response to homeostasis and reducing pain.
  • EpFA EpFA in nociception
  • sEH inhibitors and mimetics of EpFA have great potential for pain relief in humans.
  • NSAIDs are divided into non-selective NSAIDs and selective cyclooxygenase-2 (COX- 2) Inhibitors, although they also have good analgesic effects, non-selective non-steroidal anti-inflammatory drugs have more severe gastrointestinal irritation, easily lead to gastric ulcers, and often have adverse reactions to coagulation and hematopoietic systems.
  • COX-2 inhibitors have no adverse effects of gastrointestinal irritation, they are likely to cause an imbalance between prostacyclin and thromboxane, leading to cardiovascular disease.
  • sEH inhibitors and EpFA In view of the importance of sEH inhibitors and EpFA in the occurrence and development of inflammation and pain, and their protective effects on the heart, kidney, brain and other organs, inhibition of sEH activity can increase and stabilize the content of EpFA in the body, such as EETs, thereby Play analgesic, anti-inflammatory and protective effects on various organs. Therefore, it is urgent and necessary to develop new and efficient sEH inhibitors for the treatment of pain.
  • the purpose of the present invention is to provide a memantine derivative, a preparation method and application thereof.
  • the memantamide derivative provided by the present invention has high inhibitory activity on human sEH (HsEH), and has few side effects, and can be used as sEH inhibitor
  • the agent is used in the preparation of a medicament for the treatment of soluble cyclooxygenase-mediated diseases.
  • the present invention provides a memantine derivative, which has the structure shown in formula A, formula B, formula C or formula D:
  • R 1 and R 2 are independently selected from -H, -OH, -NH 2 , -SH, -CN, a halogen group, an alkyl group, an alkoxy group or a heterocyclic group;
  • R3 is selected from -H, -OH, -NH2 , -SH, -CN, halogen group, alkyl or alkoxy;
  • R 4 is selected from -OH, -NH 2 , hydroxylamine, alkyl, alkoxy, alkylamine, alkoxyamine, alcoholamine, anilino, naphthylamino or heterocyclic;
  • X is selected from -NH 2 ,
  • Y is selected from -H
  • R 5 is selected from alkyl or heterocyclyl
  • Z and M are independently selected from -O-, -NH- or -S-;
  • the halogen group selected from the R 1 and R 2 is independently -F, -Cl or -Br
  • the alkyl group is independently methyl, ethyl, propyl, butyl, pentyl, isobutyl , isopropyl, isoamyl or tert-butyl
  • alkoxy is independently methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclohexyloxy , phenoxy or benzyloxy.
  • the R 1 and R 2 are methyl groups.
  • the halogen group selected by the R 3 is -F, -Cl or -Br;
  • the alkyl group is an unsubstituted or substituted C1-C6 alkyl group;
  • the alkoxy group is an unsubstituted or substituted C1-C6 alkyl group oxy;
  • the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl.
  • the R 3 is -H, -F or -Cl.
  • the alkoxy group selected by R 4 is an unsubstituted or substituted C1-C6 alkoxy group;
  • the alkylamine group is an unsubstituted or substituted C1-C6 alkylamine group;
  • the alkoxyamine group is Unsubstituted or substituted C1-C6 alkoxyamine group;
  • aniline group is unsubstituted or substituted aniline group;
  • naphthylamino group is unsubstituted or substituted naphthylamino group;
  • heterocyclic group is unsubstituted or substituted 5-10 A membered heterocyclic group;
  • the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl.
  • the R 4 is -OH, -NH 2 , -OCH 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHOCH 3 or -NHOH.
  • the alkyl group selected from the R 5 is a chain alkyl group or a cycloalkyl group
  • the alkyl group selected by the R 5 is an unsubstituted or substituted C1-C6 chain alkyl group, and the substituent in the substituted C1-C6 chain alkyl group is selected from -OH, -NH 2 or C1-C6 alkyl group ;
  • the cycloalkyl group selected from the R 5 is an unsubstituted or substituted C3-C6 cycloalkyl group, and the substituents in the substituted C3-C6 cycloalkyl group are selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl;
  • the heterocyclic group selected from the R 5 is an unsubstituted or substituted C3-C6 saturated or unsaturated heterocyclic group, and the substituents in the substituted C3-C6 saturated or unsaturated heterocyclic group are independently selected from -F , -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl.
  • the R 5 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , cyclopropyl or -CH(NH 2 )CH(CH 3 ) 2 .
  • the memantine derivatives include 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ benzyl Acyl)piperidine-4-carboxylic acid, 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ benzoyl)piperidine Ethyl pyridine-4-carboxylate, 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ benzoyl)piperidine -4-Carboxamide, 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ benzoyl)-N-methyl ylpiperidine-4-carboxamide,
  • the present invention provides the preparation method of the memantamide derivatives described in the above technical solution,
  • the compound b is subjected to a first reduction reaction to obtain compound c;
  • the compound d and the compound III are subjected to the first aminolysis reaction to obtain the compound e; when the R 6 in the compound e is -H, the compound e is the memantine having the structure shown in formula A in which R 4 is -OH Urea derivatives;
  • R 6 in compound e is a C 1 -C 6 alkyl group
  • the compound e is subjected to hydrolysis reaction, and then mixed with compound IV, in 1-(3-dimethylaminopropyl)-3-ethyl
  • the fifth acylation reaction is carried out in the presence of carbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain the memantamide derivatives having the structure shown in formula A;
  • the sixth acylation reaction is performed on the compound c and the compound V to obtain the first intermediate compound; the first intermediate compound and the compound III are subjected to the first nucleophilic reaction Substitution reaction to obtain compound e;
  • the compound c, N-Boc-thiourea, NaH and trifluoroacetic anhydride are mixed to carry out a second aminolysis reaction to obtain a second intermediate compound;
  • the second intermediate Compound, compound III and HgCl 2 are mixed, and a desulfurization carbonyl reaction is carried out to obtain a third intermediate compound;
  • the third intermediate compound is subjected to a first deprotection group reaction under acidic conditions to obtain compound e;
  • the compound IV is: NH 3 , R 7 -NH 2 , R 7 -OH, R 7 -O-NH 2 or wherein, R 7 is a substituted or unsubstituted C1-C6 alkyl group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N( CH 3 ) 2 or an alkyl group of C1-C6;
  • Described compound V is solid phosgene or thiophosgene
  • R 6 is selected from -H or an alkyl group of C 1 -C 6 ;
  • the seventh acylation reaction is carried out with compound VI and compound a to obtain compound f;
  • the compound f is subjected to a second reduction reaction to obtain compound g;
  • the compound i is subjected to the second deprotection group reaction under acidic conditions to obtain a memantamide derivative having a structure represented by formula B, where X is -NH 2 , which is denoted as compound j;
  • the fourth intermediate compound and compound III are subjected to a second nucleophilic substitution reaction to obtain compound h;
  • the preparation method comprises the following steps:
  • the compound k is subjected to a third reduction reaction to obtain compound 1;
  • the compound 1 and compound II are subjected to a tridecacylation reaction to obtain compound m;
  • n is subjected to the third deprotection group reaction under acidic conditions to obtain a memantamide derivative with the structure represented by formula C, wherein Y is -H, which is denoted as compound o;
  • the compound o and compound VII are mixed, and the fourteenth step is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole Acylation reaction to obtain Y as The memantamide derivatives having the structure described in formula C;
  • Compound 1 was prepared according to (3-1) method
  • the fifth intermediate compound and compound III are subjected to a third nucleophilic substitution reaction to obtain compound n;
  • the molar ratio of the compound I to the compound a is (1.8-2.2):1; the temperature of the first acylation reaction is -40-10° C., and the time is 10-50 min.
  • the temperature of the first reduction reaction is 25-70° C., and the time is 10-15 h.
  • the molar ratio of the compound c and the compound II is 1:(1-2); the second acylation reaction is performed under ice bath conditions, and the time of the second acylation reaction is 10-50 min.
  • the molar ratio of the compound d and the compound III is 1:(0.8-1.3); the first aminolysis reaction is carried out under the reflux condition of the system, and the time of the first aminolysis reaction is 6-10 h.
  • the dosage ratio of the compound e, thionyl chloride and ethanol is (0.5-0.8) mmol: (2-3) mmol: (15-25) mL; the esterification reaction is carried out under the system reflux condition , the time of the esterification reaction is 1.5-2.5h.
  • the molar ratio of the compound e and the compound IV is 1:(1.8-2.2), and the compound e, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the molar ratio of the salt and 1-hydroxybenzotriazole is 1:(1.3-1.7):(1.3-1.7); the temperature of the third acylation reaction is 25-35°C, and the time is 6-10h.
  • the chlorination reaction is carried out under the reflux condition of the system, and the time of the chlorination reaction is 1.5-2.5 h.
  • the molar ratio of the acid chloride intermediate and the compound IV is 1:(1.0-1.5); the temperature of the fourth acylation reaction is -10-40°C, and the time is 1-6h.
  • the temperature of the hydrolysis reaction is 25-70°C, and the time is 30min-6h.
  • the temperature of the fifth acylation reaction is 0 ⁇ 40° C., and the time is 1 ⁇ 8 h.
  • the temperature of the sixth acylation reaction is room temperature, and the time is 1.5-2.5 h.
  • the first nucleophilic substitution reaction is carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
  • the temperature of the second aminolysis reaction is 0-25° C. and the time is 2-24 h.
  • the temperature of the dethiocarbonylation reaction is 0-25° C. and the time is 2-24 h.
  • the temperature of the first deprotection group reaction is 0-40°C, and the time is 30min-4h.
  • the molar ratio of the compound VI to the compound a is 1:(0.8-1.2); the temperature of the seventh acylation reaction is room temperature, and the time is 1.5-2.5 h.
  • the temperature of the second reduction reaction is 25-70° C., and the time is 10-15 h.
  • the molar ratio of the compound g and the compound II is 1:(1-2); the eighth acylation reaction is carried out at room temperature, and the time of the eighth acylation reaction is 5-8h.
  • the molar ratio of the compound h and the compound III is 1:(0.8-1.3); the third aminolysis reaction is carried out under the reflux condition of the system, and the time of the third aminolysis reaction is 6-10 h.
  • the temperature of the second deprotection group reaction is room temperature, and the time is 1.5-2.5 h.
  • the molar ratio of the compound j to the compound VII is 1:(1.5-2.5); the temperature of the ninth acylation reaction is 20-40° C., and the time is 6-10 h.
  • the molar ratio of the compound j and the compound VIII is 1:(1.5-2.5); the temperature of the tenth acylation reaction is room temperature, and the time is 1.5-2.5 h.
  • the temperature of the eleventh acylation reaction is room temperature, and the time is 1.5-2.5 h.
  • the second nucleophilic substitution reaction is carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
  • the molar ratio of the compound IX to the compound a is 1:(0.8-1.2); the temperature of the dodecanoylation reaction is room temperature, and the time is 1.5-2.5 h.
  • the temperature of the third reduction reaction is 70-90° C., and the time is 40-60 min.
  • the molar ratio of the compound I and the compound II is 1:(1-2); the tridecylation reaction is carried out at room temperature, and the time of the tridecaylation reaction is 5-8h .
  • the molar ratio of the compound m and the compound III is 1:(0.8-1.3); the fourth aminolysis reaction is carried out under the reflux condition of the system, and the time of the fourth aminolysis reaction is 6-10 h.
  • the temperature of the third deprotecting group reaction is room temperature, and the time is 3.5-4.5 h.
  • the molar ratio of the compound o to the compound VII is 1:(1.5 ⁇ 2.5); the temperature of the fourteenth acylation reaction is 20 ⁇ 40°C, and the time is 6 ⁇ 10h.
  • the molar ratio of the compound o to the compound VIII is 1:(1.5-2.5); the temperature of the pentadecyl acylation reaction is room temperature, and the time is 1.5-2.5 h.
  • the temperature of the sixteenthylation reaction is room temperature, and the time is 1.5-2.5 h.
  • the third nucleophilic substitution reaction is carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
  • the present invention provides the application of the memantamide derivatives described in the above technical solutions in the preparation of medicines for treating diseases mediated by soluble epoxidase.
  • the soluble cyclooxygenase-mediated disease includes inflammatory disease, pain, cardiovascular disease, neurodegenerative disease, diabetes, diabetic complications, chronic nephritis, renal failure, chronic obstructive pulmonary disease or pulmonary artery Hypertension disease.
  • the inflammatory disease comprises sepsis, cytokine storm, inflammatory bowel disease, chronic peptic ulcer or arthritis.
  • the pain comprises inflammatory pain or neuropathic pain.
  • the cardiovascular disease comprises hypertension, stroke or atherosclerosis.
  • the neurodegenerative disease comprises Parkinson's syndrome or Alzheimer's disease.
  • the invention provides a memantine derivative.
  • the memantine derivative provided by the invention has a typical urea structure as the primary pharmacophore of sEH, and the memantine part acts as a hydrophobic fragment to generate hydrophobicity with the receptor.
  • the interaction force, molecular docking showed that the memantine moiety acts as a hydrophobic fragment to generate a hydrophobic interaction with the receptor, especially when both R 1 and R 2 are methyl (ie, 3,5-dimethyl substituted), which can enhance the van der Waals interaction force. Therefore, the memantine derivatives provided by the present invention have high inhibitory activity on human HsEH, and can be used as sEH inhibitors to prepare medicines for treating diseases mediated by soluble epoxidase.
  • Fig. 1 is the reaction scheme of the memantamide derivatives having the structure shown in formula A when R3 is a group other than a halogen group in the present invention
  • Fig. 2 is the reaction scheme diagram of the memantamide derivatives having the structure shown in formula A when R3 is a halogen group in the present invention
  • Fig. 3 is in the present invention, when R3 is a group other than a halogen group, the reaction scheme of the memantamide derivatives having the structure shown in formula B;
  • Fig. 4 is the reaction scheme diagram of the memantamide derivatives having the structure shown in formula B when R3 is a halogen group in the present invention
  • Fig. 5 is the reaction scheme of the memantamide derivatives having the structure shown in formula C when R3 is a group other than a halogen group in the present invention
  • Fig. 6 is the reaction scheme of the memantamide derivatives having the structure represented by formula C when R3 is a halogen group in the present invention.
  • the present invention provides a memantine derivative, which has the structure shown in formula A, formula B, formula C or formula D:
  • R 1 and R 2 are independently selected from -H, -OH, -NH 2 , -SH, -CN, a halogen group, an alkyl group, an alkoxy group or a heterocyclic group;
  • R3 is selected from -H, -OH, -NH2 , -SH, -CN, halogen group, alkyl or alkoxy;
  • R 4 is selected from -OH, -NH 2 , hydroxylamine, alkyl, alkoxy, alkylamine, alkoxyamine, alcoholamine, anilino, naphthylamino or heterocyclic;
  • X is selected from -NH 2 ,
  • Y is selected from -H
  • R 5 is selected from alkyl or heterocyclyl
  • Z and M are independently selected from -O-, -NH- or -S-;
  • the halogen group selected from R 1 and R 2 is independently -F, -Cl or -Br, and the alkyl group is independently methyl, ethyl, propyl, butyl, Amyl, isobutyl, isopropyl, isoamyl or tert-butyl, alkoxy is independently methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy , cyclohexyloxy, phenoxy or benzyloxy.
  • the R 1 and R 2 are methyl groups.
  • the halogen group selected from the R 3 is -F, -Cl or -Br; the alkyl group is an unsubstituted or substituted C1-C6 alkyl group; the alkoxy group is an unsubstituted or substituted alkyl group C1-C6 alkoxy group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkane
  • the substituted substituent specifically refers to the substituent in the substituted C1-C6 alkyl group and the substituted C1-C6 alkoxy group.
  • the R 3 is -H, -F or -Cl.
  • the alkoxy group selected by R4 is an unsubstituted or substituted C1-C6 alkoxy group;
  • the alkylamine group is an unsubstituted or substituted C1-C6 alkylamine group; an alkoxy group
  • the amino group is an unsubstituted or substituted C1-C6 alkoxyamine group;
  • the aniline group is an unsubstituted or substituted aniline group;
  • the naphthylamino group is an unsubstituted or substituted naphthylamino group;
  • the heterocyclic group is an unsubstituted or substituted 5-10-membered heterocyclic group;
  • the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 Alkyl, the substituted substituent specifically refers to a substituted C1-C6 al
  • the alkyl group selected by the R 5 is a chain alkyl group or a cycloalkyl group; the chain alkyl group selected by the R 5 is an unsubstituted or substituted C1-C6 chain alkyl group, so The substituents in the substituted C1-C6 chain alkyl group are selected from -OH, -NH 2 or C1-C6 alkyl group; the cycloalkyl group selected from the R 5 is an unsubstituted or substituted C3-C6 cycloalkyl group, The substituents in the substituted C3-C6 cycloalkyl are selected from -F, -Cl, -Br, -OH, -NH2 , -NHCH3, -N( CH3 )2 or C1-C6 alkyl; The heterocyclic group selected from the R 5 is an unsubstituted or substituted C3-C6 saturated or unsaturated heterocyclic group, and the
  • the R 5 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , cyclopropyl or -CH( NH2 )CH( CH3 ) 2 .
  • the memantamide derivative when X is substituted at the 3-position of the piperidine ring in the memantamide derivative of the structure shown in formula B, the memantamide derivative is a chiral compound, and the specific structure is as shown in formula E or formula F shows:
  • the memantine derivatives include 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl] Ureido ⁇ benzoyl)piperidine-4-carboxylic acid (GL-B404), 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1- yl]ureido ⁇ benzoyl)piperidine-4-carboxylic acid ethyl ester (GL-B405), 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantine Alk-1-yl]ureido ⁇ benzoyl)piperidine-4-carboxamide (GL-B406), 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-di Methyladamantan-1-yl]ure
  • the present invention provides a method for preparing the memantine derivatives described in the above technical solution, and the present invention selects the preparation method according to the specific structure of the memantamide derivatives, which will be described in detail below.
  • a memantamide derivative having the structure shown in formula A is prepared, as shown in Figure 1. Specifically, (1-1) When R 3 is a group other than a halogen group, the preparation method include the following steps:
  • the compound b is subjected to a first reduction reaction to obtain compound c;
  • the compound d and the compound III are subjected to the first aminolysis reaction to obtain the compound e; when the R 6 in the compound e is -H, the compound e is the memantine having the structure shown in formula A in which R 4 is -OH Urea derivatives;
  • R 6 in compound e is a C 1 -C 6 alkyl group
  • the compound e is subjected to hydrolysis reaction, and then mixed with compound IV, in 1-(3-dimethylaminopropyl)-3-ethyl
  • the fifth acylation reaction is carried out in the presence of carbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain the memantamide derivatives having the structure shown in formula A;
  • the compound IV is: NH 3 , R 7 -NH 2 , R 7 -OH, R 7 -O-NH 2 or wherein, R 7 is a substituted or unsubstituted C1-C6 alkyl group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N( CH 3 ) 2 or an alkyl group of C1-C6;
  • Described compound V is solid phosgene or thiophosgene
  • R 6 is selected from -H or an alkyl group of C 1 -C 6 .
  • compound I and compound a are subjected to the first acylation reaction to obtain compound b.
  • the molar ratio of the compound I and the compound a is preferably (1.8-2.2):1, more preferably 2:1.
  • the first acylation reaction when R 6 is -H, the first acylation reaction is preferably carried out in the presence of potassium carbonate, tetrahydrofuran and water; when R 6 is a C 1 -C 6 alkyl group, the first acylation reaction is performed
  • the monoacylation reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
  • the temperature of the first acylation reaction is preferably -40-10°C, more preferably -25°C, and the time is preferably 10-50 min, more preferably 30 min.
  • the obtained reaction solution is preferably concentrated under reduced pressure to remove the solvent, water is added, the pH value of the system is adjusted to 7 with hydrochloric acid under ice bath conditions, ethyl acetate is added, and hydrochloric acid is used to continue adjusting The pH value of the system was adjusted to 1, then suction filtration, the filter cake was rinsed with water and ethyl acetate successively, and dried to obtain compound b.
  • the present invention performs the first reduction reaction on the compound b to obtain the compound c.
  • the reducing agent used in the first reduction reaction is preferably hydrogen, and the catalyst used is preferably Pd-C; the first reduction reaction is preferably carried out in the presence of anhydrous ethanol.
  • the temperature of the first reduction reaction is preferably 25-70°C, more preferably 60°C, and the time is preferably 10-15h, more preferably 12h.
  • the present invention preferably waits for the reaction solution to be cooled to room temperature, then suction filtration, the filtrate is concentrated under reduced pressure, the obtained residue is mixed with ethyl acetate and then slurried, the system obtained after slurping is subjected to suction filtration, and the filter cake is used Rinse with ethyl acetate and dry to give compound c.
  • the present invention performs the second acylation reaction on the compound c and the compound II to obtain the compound d.
  • the molar ratio of the compound c and the compound II is preferably 1:(1-2), more preferably 1:(1.2-1.7).
  • the second acylation reaction is preferably carried out in the presence of potassium carbonate and tetrahydrofuran.
  • the second acylation reaction is preferably carried out under ice bath conditions, and the time of the second acylation reaction is preferably 10-50 min, more preferably 30 min.
  • the obtained reaction solution is preferably concentrated under reduced pressure to remove the solvent, water is added, the pH value of the system is adjusted to 7 with hydrochloric acid under ice bath conditions, ethyl acetate is added, and the system is continuously adjusted with hydrochloric acid.
  • the pH value was reduced to 1, then suction filtration, the obtained filter cake was washed with ethyl acetate and water in turn, dried to obtain a white solid, the white solid was slurried with ethyl acetate, the system obtained after the slurried beating was subjected to suction filtration, filtered The cake was rinsed with ethyl acetate and dried to give compound d.
  • the present invention performs the first aminolysis reaction on the compound d and the compound III to obtain the compound e.
  • the molar ratio of the compound d and the compound III is preferably 1:(0.8-1.3), more preferably 1:1.1.
  • the first aminolysis reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
  • the first aminolysis reaction is preferably carried out under the reflux condition of the system, and the time of the first aminolysis reaction is preferably 6-10 hours, more preferably 8 hours.
  • the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove the solvent, adds water, adjusts the pH of the system to 1 with hydrochloric acid under ice bath conditions, extracts with ethyl acetate, and then sequentially After washing with water, saturated brine and drying over anhydrous sodium sulfate, suction filtration, the obtained filtrate was concentrated under reduced pressure, acetonitrile was added to the obtained residue and boiled, white granular solid appeared in the system, cooled to room temperature, suction filtration, and the filter cake was used Rinse with acetonitrile and dry to give compound e.
  • the compound e when R 6 in compound e is -H, the compound e is a memantamide derivative having the structure represented by formula A in which R 4 is -OH.
  • compound a when compound a is p-nitrobenzoyl chloride, compound I is 4-piperidinecarboxylic acid, compound II is phenyl chloroformate, and compound III is memantine, the obtained compound is obtained through the first aminolysis reaction.
  • Compound e is compound GL-B404; when compound a is p-nitrobenzoyl chloride, compound I is 3-piperidinecarboxylic acid, compound II is phenyl chloroformate, and compound III is memantine, after the first aminolysis reaction The obtained compound e is compound GL-B411.
  • the present invention mixes compound e, thionyl chloride and ethanol, and carries out esterification reaction to obtain R 4 is -OEt and has the structure shown in formula A memantamide derivatives.
  • the dosage ratio of the compound e, thionyl chloride and ethanol is preferably (0.5-0.8) mmol: (2-3) mmol: (15-25) mL, more preferably 0.66 mmol: 2.65 mmol : 20 mL; the esterification reaction is preferably carried out under the reflux condition of the system, and the time of the esterification reaction is preferably 1.5-2.5 h, more preferably 2 h.
  • the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove ethanol, adds water, extracts with ethyl acetate, and then successively washes with saturated aqueous sodium carbonate solution, washed with water, washed with saturated brine and anhydrous. Dry over sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the obtained residue to make a slurry, filter the obtained system with suction, rinse the filter cake with ether, and dry to obtain R 4 is -OEt and has the formula A. Memantamide derivatives showing the structure.
  • compound GL-B405 is obtained by esterification according to the above method; when compound e is compound GL-B411, it is esterified according to the above method After the reaction, compound GL-B412 was obtained.
  • the present invention mixes said compound e and compound IV, in 1-(3-dimethylaminopropyl)-3-ethylcarbon two
  • the third acylation reaction is carried out in the presence of imine hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A.
  • the molar ratio of the compound e and the compound IV is preferably 1:(1.8-2.2), more preferably 1:2.
  • the molar ratio of compound e, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole is preferably 1:( 1.3-1.7):(1.3-1.7), more preferably 1:1.5:1.5.
  • the third acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
  • the temperature of the third acylation reaction is preferably 25-35° C., more preferably 30° C.; the time is preferably 6-10 h, more preferably 8 h.
  • the present invention preferably pours the obtained reaction solution into water, extracts it with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then sequentially conducts 1 mol/L Washed with hydrochloric acid, washed with 5wt% sodium hydroxide aqueous solution, washed with water, washed with saturated brine and dried with anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, ethyl acetate was added to the obtained residue to make a slurry, and the system obtained after beating was made Perform suction filtration, the filter cake is rinsed with ethyl acetate, and dried to obtain a memantamide derivative having the structure shown in formula A.
  • a dichloromethane-methanol mixed solution the volume ratio of dichloromethane and methanol is preferably 10:1
  • a memantamide derivative having the structure shown in formula A when compound e is compound GL-B404, after the third acylation reaction according to the above method, a memantamide derivative having the structure shown in formula A can be obtained, specifically compound GL-B407 , GL-B408, GL-B409 or GL-B410; when compound e is compound GL-B405, after the third acylation reaction according to the above method, a memantamide derivative having the structure shown in formula A can be obtained. is compound GL-B414, GL-B415, GL-B416 or GL-B417.
  • the compound e is subjected to chlorination reaction in the presence of thionyl chloride to obtain an acid chloride intermediate; the acid chloride intermediate and Compound IV is subjected to the fourth acylation reaction to obtain a memantamide derivative having the structure shown in formula A.
  • the chlorination reaction is preferably carried out in the presence of N,N-dimethylformamide and dichloromethane.
  • the chlorination reaction is preferably carried out under the reflux condition of the system, and the time of the chlorination reaction is preferably 1.5-2.5 h, more preferably 2 h.
  • the obtained reaction solution is preferably cooled to room temperature, concentrated under reduced pressure to remove the solvent, and used for later use.
  • the molar ratio of the acid chloride intermediate and compound IV is preferably 1:(1.0-1.5), more preferably 1:1.1.
  • the fourth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fourth acylation reaction is preferably -10 to 40°C, more preferably 0°C, and the time It is preferably 1 to 6 hours, and more preferably 1 hour.
  • the present invention preferably concentrates the obtained system under reduced pressure to remove the solvent, adds water, extracts with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then Washed with 1mol/L hydrochloric acid, washed with 5wt% sodium hydroxide aqueous solution, washed with water, washed with saturated brine and dried with anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue to make a slurry, The system obtained after beating is subjected to suction filtration, the filter cake is rinsed with ethyl acetate, and dried to obtain a memantamide derivative having the structure shown in formula A.
  • a dichloromethane-methanol mixed solution the volume ratio of dichloromethane and methanol is preferably 10:1
  • Washed with 1mol/L hydrochloric acid washe
  • a memantamide derivative having the structure shown in formula A is obtained after the fourth acylation reaction according to the above method, which can be specifically compound GL-B406 ;
  • a memantamide derivative having the structure shown in formula A can be obtained, specifically compound GL-B413 (racemate).
  • compounds S-GL-B413 and R-GL-B413 are preferably prepared with reference to the method of compound GL-B413 (racemate), and only the raw materials for preparing compound GL-B413 (racemate) are changed to The raw materials corresponding to a single configuration are sufficient, and the details are shown in the examples of the present invention.
  • R 6 in compound e is a C 1 -C 6 alkyl group
  • the compound e is subjected to hydrolysis reaction, and then mixed with compound IV to obtain a 1-(3-dimethylamino group)
  • the fifth acylation reaction is carried out in the presence of propyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A.
  • the hydrolysis reaction is preferably carried out in the presence of sodium hydroxide solution and ethanol, the temperature of the hydrolysis reaction is preferably 25-70°C, and the time is preferably 30min-6h.
  • the fifth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fifth acylation reaction is preferably 0-40° C., and the time is preferably 1-8 h.
  • the obtained system is preferably added to water, extracted with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then washed with 1 mol/L hydrochloric acid successively.
  • a memantamide derivative having a structure shown in formula A is prepared, as shown in Figure 2, specifically, (1-2) when R 3 is a halogen group, the preparation method includes the following steps:
  • the sixth acylation reaction is performed on the compound c and the compound V to obtain the first intermediate compound; the first intermediate compound and the compound III are subjected to the first nucleophilic reaction Substitution reaction to obtain compound e;
  • the compound c, N-Boc-thiourea, NaH and trifluoroacetic anhydride are mixed to carry out a second aminolysis reaction to obtain a second intermediate compound;
  • the second intermediate Compound, compound III and HgCl 2 are mixed, and a desulfurization carbonyl reaction is carried out to obtain a third intermediate compound;
  • the third intermediate compound is subjected to a first deprotection group reaction under acidic conditions to obtain compound e;
  • the present invention prepares compound c according to step (1-1). Specifically, in the present invention, it is preferred to mix compound a, N,N-dimethylformamide, tetrahydrofuran and thionyl chloride, react at 60 to 70° C. for 50 to 70 min, and then concentrate the obtained reaction solution under reduced pressure. , the residue is dissolved in tetrahydrofuran to obtain a solution of acid chloride in tetrahydrofuran; then the tetrahydrofuran solution of acid chloride, compound I, triethylamine and tetrahydrofuran are mixed to carry out the first acylation reaction to obtain compound b.
  • the temperature of the first acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
  • the obtained reaction solution is preferably concentrated under reduced pressure to remove the solvent, added with water, extracted with ethyl acetate, and then washed with 1 mol/L HCl, washed with saturated sodium carbonate solution, and washed with water. , washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, the filtrate obtained was concentrated under reduced pressure, and the obtained residue was directly subjected to the next reaction.
  • the present invention performs the first reduction reaction on the compound b to obtain the compound c.
  • the reducing agent used in the first reduction reaction is preferably iron powder, and the first reduction reaction is preferably carried out in the presence of ammonium chloride, ethanol and water.
  • the temperature of the first reduction reaction is preferably 70-90°C, more preferably 80°C, and the time is preferably 40-60 min, more preferably 50 min.
  • the obtained reaction solution is preferably cooled to room temperature, filtered through diatomaceous earth, the filter cake is rinsed with ethanol, and the filtrate is concentrated to dryness under reduced pressure; water is added to the residue, and ethyl acetate is used. After extraction, washing with water, saturated brine, and drying over anhydrous sodium sulfate in sequence, suction filtration, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is directly subjected to the next reaction.
  • the present invention performs the sixth acylation reaction on the compound c and the compound V to obtain the first intermediate compound; the first intermediate compound and Compound III undergoes a first nucleophilic substitution reaction to obtain compound e.
  • the sixth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
  • the temperature of the sixth acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
  • the obtained reaction solution is preferably concentrated to dryness under reduced pressure, and dichloromethane is added to the residue for dissolution to obtain an intermediate compound solution, which is for later use.
  • the first nucleophilic substitution reaction is preferably carried out in the presence of tetrahydrofuran (or dichloromethane) and triethylamine.
  • the first nucleophilic substitution reaction is preferably carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
  • the present invention mixes the compound c, N-Boc-thiourea, NaH and trifluoroacetic anhydride (TFAA) to carry out the second aminolysis reaction to obtain the second intermediate intermediate compound; mix the second intermediate compound, compound III and HgCl , carry out a dethiocarbonyl reaction to obtain the third intermediate compound; carry out the first deprotection group reaction of the third intermediate compound under acidic conditions , to obtain compound e.
  • the second aminolysis reaction is preferably carried out in the presence of tetrahydrofuran; the temperature of the second aminolysis reaction is preferably 0-25° C., and the time is preferably 2-24 h.
  • the desulfurization carbonylation reaction is preferably carried out in the presence of mercuric chloride, triethylamine and dichloromethane; the temperature of the desulfurization carbonylation reaction is preferably 0-25°C, and the time is preferably 2-24 h.
  • the obtained system is preferably filtered through diatomaceous earth, the filter cake is washed with ethyl acetate, the organic phase is washed with water, washed with saturated brine and dried over anhydrous sodium sulfate, suction filtration, and the obtained filtrate is filtered.
  • the reagent for providing the acidic conditions required for the first deprotection reaction is preferably trifluoroacetic acid (TFA); the first deprotection reaction is preferably carried out in the presence of dichloromethane.
  • the temperature of the first deprotection reaction is preferably 0 to 40° C., and the time is preferably 30 min to 4 h.
  • the present invention based on the compound e, prepares a memantamide derivative having the structure represented by the formula A according to the step (1-1), as follows:
  • the present invention mixes compound e, thionyl chloride and ethanol, and carries out esterification reaction to obtain R 4 is -OEt and has the structure shown in formula A memantamide derivatives.
  • the dosage ratio of the compound e, thionyl chloride and ethanol is preferably (0.5-0.8) mmol: (2-3) mmol: (15-25) mL, more preferably 0.66 mmol: 2.65 mmol : 20 mL; the esterification reaction is preferably carried out under the reflux condition of the system, and the time of the esterification reaction is preferably 1.5-2.5 h, more preferably 2 h.
  • the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove ethanol, adds water, extracts with ethyl acetate, and then successively washes with saturated aqueous sodium carbonate solution, washed with water, washed with saturated brine and anhydrous. Dry over sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the obtained residue to make a slurry, filter the obtained system with suction, rinse the filter cake with ether, and dry to obtain R 4 is -OEt and has the formula A. Memantamide derivatives showing the structure.
  • the present invention mixes said compound e and compound IV, in 1-(3-dimethylaminopropyl)-3-ethylcarbon two
  • the third acylation reaction is carried out in the presence of imine hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A.
  • the molar ratio of the compound e and the compound IV is preferably 1:(1.8-2.2), more preferably 1:2.
  • the molar ratio of compound e, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole is preferably 1:( 1.3-1.7):(1.3-1.7), more preferably 1:1.5:1.5.
  • the third acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
  • the temperature of the third acylation reaction is preferably 25-35° C., more preferably 30° C.; the time is preferably 6-10 h, more preferably 8 h.
  • the present invention preferably pours the obtained reaction solution into water, extracts it with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then sequentially conducts 1 mol/L Washed with hydrochloric acid, washed with 5wt% sodium hydroxide aqueous solution, washed with water, washed with saturated brine and dried with anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, ethyl acetate was added to the obtained residue to make a slurry, and the system obtained after beating was made Perform suction filtration, the filter cake is rinsed with ethyl acetate, and dried to obtain a memantamide derivative having the structure shown in formula A.
  • a dichloromethane-methanol mixed solution the volume ratio of dichloromethane and methanol is preferably 10:1
  • the compound e is subjected to chlorination reaction in the presence of thionyl chloride to obtain an acid chloride intermediate; the acid chloride intermediate and Compound IV is subjected to the fourth acylation reaction to obtain a memantamide derivative having the structure shown in formula A.
  • the chlorination reaction is preferably carried out in the presence of N,N-dimethylformamide and dichloromethane.
  • the chlorination reaction is preferably carried out at room temperature, and the time of the chlorination reaction is preferably 20-40 min, more preferably 30 min.
  • the obtained reaction solution is cooled and concentrated under reduced pressure to remove the solvent, and is for later use.
  • the molar ratio of the acid chloride intermediate and compound IV is preferably 1:(1.0-1.5), more preferably 1:1.1.
  • the fourth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fourth acylation reaction is preferably -10 to 40°C, more preferably 0°C, and the time It is preferably 1 to 6 hours, and more preferably 2 hours.
  • R 6 in compound e is a C 1 -C 6 alkyl group
  • the compound e is subjected to hydrolysis reaction, and then mixed with compound IV to obtain a 1-(3-dimethylamino group)
  • the fifth acylation reaction is carried out in the presence of propyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A.
  • the hydrolysis reaction is preferably carried out in the presence of sodium hydroxide solution and ethanol, the temperature of the hydrolysis reaction is preferably 25-70°C, and the time is preferably 30min-6h.
  • the fifth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fifth acylation reaction is preferably 0-40° C., and the time is preferably 1-8 h.
  • the obtained system is preferably added to water, extracted with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then washed with 1 mol/L hydrochloric acid successively.
  • compound a when compound a is 3-chloro-4-nitrobenzoic acid, compound I is ethyl piperidine-3-carboxylate, compound V is solid phosgene, compound III is memantine, and compound IV
  • the memantamide derivative having the structure shown in formula A obtained by the above reaction is specifically compound GL-B435.
  • a memantamide derivative having the structure shown in formula B is prepared, as shown in Figure 3, specifically, (2-1)
  • R 3 is a group other than a halogen group
  • the preparation method include the following steps:
  • the seventh acylation reaction is carried out with compound VI and compound a to obtain compound f;
  • the compound f is subjected to a second reduction reaction to obtain compound g;
  • the compound i is subjected to the second deprotection group reaction under acidic conditions to obtain a memantamide derivative having a structure represented by formula B, where X is -NH 2 , which is denoted as compound j;
  • compound VI and compound a are subjected to the seventh acylation reaction to obtain compound f.
  • the molar ratio of the compound VI and the compound a is preferably 1:(0.8-1.2), more preferably 1:1.
  • the seventh acylation reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
  • the temperature of the seventh acylation reaction is preferably room temperature, and the time of the seventh acylation reaction is preferably 1.5-2.5 h, more preferably 2 h.
  • the obtained reaction solution is preferably concentrated under reduced pressure to remove most of the solvent, water is added to the obtained residue, extracted with ethyl acetate, and the organic layer is washed with water, saturated brine and dried over anhydrous magnesium sulfate, suction filtered, the filtrate obtained was concentrated under reduced pressure, and the obtained residue was directly subjected to the next reaction.
  • the present invention performs the second reduction reaction on the compound f to obtain the compound g.
  • the reducing agent used in the second reduction reaction, the type of the second catalyst, the conditions of the second reduction reaction and the post-treatment method are preferably the same as the reducing agent used in the first reduction reaction in step (1-1).
  • the type of catalyst, the first reduction reaction and the post-treatment method are the same, and will not be repeated here.
  • the present invention performs the eighth acylation reaction between the compound g and the compound II to obtain the compound h.
  • the molar ratio of the compound g to the compound II is preferably 1:(1-2), more preferably 1:(0.2-1.7).
  • the eighth acylation reaction is preferably carried out in the presence of potassium carbonate and tetrahydrofuran.
  • the eighth acylation reaction is preferably carried out at room temperature, and the time of the eighth acylation reaction is preferably 5-8h, more preferably 6h.
  • the obtained reaction solution is preferably concentrated under reduced pressure to remove most of the solvent, water is added, and ethyl acetate is used for extraction, and the organic layer is washed with water, washed with saturated brine and dried over anhydrous magnesium sulfate. , suction filtration, the obtained filtrate is concentrated under reduced pressure, ether is added to the obtained residue for beating, the system obtained after beating is subjected to suction filtration, the filter cake is rinsed with ether, and dried to obtain compound h.
  • the present invention performs the third aminolysis reaction on the compound h and the compound III to obtain the compound i.
  • the molar ratio of the compound h and the compound III is preferably 1:(0.8-1.3), more preferably 1:1.1.
  • the third aminolysis reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
  • the third aminolysis reaction is preferably carried out under the reflux condition of the system, and the time of the third aminolysis reaction is preferably 6-10 hours, more preferably 8 hours.
  • the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove the solvent, adds water, extracts with ethyl acetate, and then sequentially washes with saturated sodium carbonate, water, and saturated brine. Dry over anhydrous sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the residue for beating, filter the obtained system after beating with suction, rinse the filter cake with ether, and dry to obtain compound i.
  • the present invention performs the second deprotection group reaction on the compound i under acidic conditions to obtain a memantamide derivative having the structure represented by formula B, where X is -NH 2 , which is denoted as compound j.
  • the reagent for providing acidic conditions is preferably trifluoroacetic acid, and the second deprotection reaction is preferably carried out under the condition of dichloromethane.
  • the temperature of the second deprotection group reaction is preferably room temperature, and the time is preferably 1.5-2.5 h.
  • the obtained reaction solution is preferably subjected to vacuum distillation, water and dichloromethane are added to the obtained residue, and the pH value of the system is adjusted to 14 with sodium hydroxide solid under ice-water bath conditions. , the organic layer was separated and removed, the aqueous layer was extracted with dichloromethane (100 mL ⁇ 2), washed with water, washed with saturated brine and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure.
  • the present invention mixes the compound j and compound VII, in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzene
  • the ninth acylation reaction is carried out in the presence of triazole (HOBt) to obtain X as The memantamide derivatives having the structure described in formula B.
  • the molar ratio of the compound j and the compound VII is preferably 1:(1.5-2.5); more preferably, 1:2.
  • the ninth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
  • the temperature of the ninth acylation reaction is preferably 20 ⁇ 40° C., more preferably 30° C., and the time is preferably 6 ⁇ 10 h, more preferably 8 h.
  • the present invention preferably pours the obtained reaction solution into water, extracts with dichloromethane, and the organic layer is washed with 1mol/L hydrochloric acid, washed with 5wt% NaOH aqueous solution, washed with water, washed with saturated brine and anhydrous.
  • the present invention performs tenth acylation reaction on the compound j and compound VIII to obtain X as The memantamide derivatives having the structure described in formula B.
  • the molar ratio of the compound j and the compound VIII is preferably 1:(1.5-2.5); more preferably, it is 1:2.
  • the tenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
  • the temperature of the tenth acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
  • the present invention preferably pours the obtained reaction solution into water, and extracts it with dichloromethane. Dry over sodium sulfate, suction filtration, concentrate the obtained filtrate under reduced pressure, add ether to the obtained residue for beating, filter the obtained system after beating with suction, rinse the filter cake with ether, and obtain X after drying.
  • the memantamide derivatives having the structure described in formula B.
  • a memantamide derivative having the structure shown in formula B is prepared, as shown in Figure 4, specifically, (2-2) when R 3 is a halogen group, the preparation method includes the following steps:
  • the fourth intermediate compound and compound III are subjected to a second nucleophilic substitution reaction to obtain compound h;
  • the present invention prepares compound g according to step (2-1). Specifically, the present invention performs the seventh acylation reaction of compound VI and compound a to obtain compound f.
  • the ratio of the compound VI and the compound a, the conditions of the seventh acylation reaction and the post-treatment method are preferably the same as those in step (2-1), and will not be repeated here.
  • the present invention performs the second reduction reaction on the compound f to obtain the compound h.
  • the reducing agent used in the second reduction reaction is preferably iron powder, and the second reduction reaction is preferably carried out in the presence of ammonium chloride, ethanol and water.
  • the temperature of the second reduction reaction is preferably 70-90° C., more preferably 80° C., and the time is preferably 40-60 min, more preferably 50 min.
  • the obtained reaction solution is preferably cooled to room temperature, filtered through diatomaceous earth, the filter cake is rinsed with ethanol, and the filtrate is concentrated to dryness under reduced pressure; water is added to the residue, and ethyl acetate is used. After extraction, washing with water, saturated brine, and drying over anhydrous sodium sulfate in sequence, suction filtration, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is directly subjected to the next reaction.
  • the present invention performs eleventh acylation reaction with compound g and compound V to obtain a fourth intermediate compound; the fourth intermediate compound and compound III are subjected to a second nucleophilic substitution reaction to obtain compound h .
  • the eleventh acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
  • the temperature of the eleventh acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
  • the obtained reaction solution is preferably concentrated to dryness under reduced pressure, and dichloromethane is added to the residue for dissolution to obtain a fourth intermediate compound solution, which is for later use.
  • the second nucleophilic substitution reaction is preferably carried out in the presence of tetrahydrofuran (or dichloromethane) and triethylamine.
  • the second nucleophilic substitution reaction is preferably carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
  • the present invention prepares the memantamide derivative having the structure represented by the formula B based on the compound h according to step (2-1), which will not be repeated here.
  • a memantamide derivative having the structure shown in formula C is prepared, as shown in Figure 5, specifically, (3-1)
  • R 3 is a group other than a halogen group
  • the preparation method include the following steps:
  • the compound k is subjected to a third reduction reaction to obtain compound 1;
  • the compound 1 and compound II are subjected to a tridecacylation reaction to obtain compound m;
  • n is subjected to the third deprotection group reaction under acidic conditions to obtain a memantamide derivative with the structure represented by formula C, wherein Y is -H, which is denoted as compound o;
  • compound IX and compound a are subjected to dodecanoylation reaction to obtain compound k.
  • the molar ratio of the compound IX to the compound a is preferably 1:(0.8-1.2), more preferably 1:1.
  • the dodecanoylation reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
  • the temperature of the dodecanoylation reaction is preferably room temperature, and the time of the dodecanoylation reaction is preferably 1.5-2.5 h, more preferably 2 h.
  • the obtained reaction solution is preferably concentrated under reduced pressure to remove most of the solvent, water is added to the obtained residue, extracted with ethyl acetate, and the organic layer is washed with water and saturated brine successively. Drying with anhydrous magnesium sulfate, suction filtration, the obtained filtrate was concentrated under reduced pressure, ether was added to the obtained residue for beating, the system obtained after beating was subjected to suction filtration, the filter cake was rinsed with ether, and dried to obtain compound k.
  • the present invention performs the third reduction reaction on the compound 1 to obtain the compound 1.
  • the reducing agent used in the third reduction reaction is preferably hydrogen, and the catalyst used is preferably Pd-C; the third reduction reaction is preferably carried out in the presence of anhydrous ethanol.
  • the temperature of the third reduction reaction is preferably 25-70°C, more preferably 60°C, and the time is preferably 10-15h, more preferably 12h.
  • the present invention performs the tridecacylation reaction of the compound 1 and the compound II to obtain the compound m.
  • the molar ratio of the compound I and the compound II is preferably 1:(1-2), more preferably 1:(0.2-1.7).
  • the tridecylation reaction is preferably carried out in the presence of potassium carbonate and tetrahydrofuran.
  • the tridecylation reaction is preferably carried out at room temperature, and the time for the tridecaylation reaction is preferably 5 to 8 hours, more preferably 6 hours.
  • the present invention preferably concentrates the obtained reaction solution under reduced pressure to remove most of the solvent, adds water, extracts with ethyl acetate, and the organic layer is washed with water, saturated brine and anhydrous magnesium sulfate in turn. Drying, suction filtration, the obtained filtrate is concentrated under reduced pressure, ether is added to the obtained residue for beating, the system obtained after beating is subjected to suction filtration, the filter cake is rinsed with ether, and compound m is obtained after drying.
  • the present invention performs the fourth aminolysis reaction on the compound m and the compound III to obtain the compound n.
  • the molar ratio of the compound m and the compound III is preferably 1:(0.8-1.3), more preferably 1:1.1.
  • the fourth aminolysis reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
  • the fourth aminolysis reaction is preferably carried out under the reflux condition of the system, and the time of the fourth aminolysis reaction is preferably 6-10 hours, more preferably 8 hours.
  • the obtained reaction solution is preferably cooled to room temperature, filtered with suction, the filter cake is rinsed with tetrahydrofuran, and dried to obtain compound n.
  • the present invention performs the third deprotection group reaction on the compound n under acidic conditions to obtain a memantamide derivative with the structure represented by formula C in which Y is -H, which is denoted as compound o.
  • the reagent for providing acidic conditions is preferably trifluoroacetic acid, and the third deprotecting group reaction is preferably carried out under the condition of dichloromethane.
  • the temperature of the third deprotecting group reaction is preferably room temperature, and the time is preferably 3.5-4.5 h, more preferably 4 h.
  • the obtained reaction solution is preferably subjected to vacuum distillation, water and dichloromethane are added to the obtained residue, and the pH value of the system is adjusted to 14 with sodium hydroxide solid under ice-water bath conditions. , the organic layer was separated and removed, the aqueous layer was extracted with dichloromethane, washed with water, washed with saturated brine and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure.
  • the present invention mixes the compound o with the compound VII, in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzene
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the fourteen acylation reaction is carried out in the presence of triazole (HOBt) to obtain Y as The memantamide derivatives having the structure described in formula C.
  • the molar ratio of the compound o to the compound VII is preferably 1:(1.5-2.5); more preferably, it is 1:2.
  • the fourteenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
  • the temperature of the fourteenth acylation reaction is preferably 20-40° C., more preferably 30° C., and the time is preferably 6-10 h, more preferably 8 h.
  • the present invention preferably pours the obtained reaction solution into water, extracts with dichloromethane, and the organic layer is washed with 1 mol/L hydrochloric acid, washed with 5wt% NaOH aqueous solution, washed with water, washed with saturated brine, and washed with water.
  • the present invention carries out the pentadecyl acylation reaction of the compound o and the compound VIII to obtain Y as The memantamide derivatives having the structure described in formula C.
  • the molar ratio of the compound o to the compound VIII is preferably 1:(1.5-2.5); more preferably, it is 1:2.
  • the fifteenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
  • the temperature of the pentadecyl acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
  • the present invention preferably pours the obtained reaction solution into water, extracts with dichloromethane, and the obtained organic layer is washed with 6mol/L hydrochloric acid, washed with 5wt% NaOH aqueous solution, washed with water, washed with saturated brine and washed with water. Dry over anhydrous sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the residue for beating, filter the obtained system after beating with suction, rinse the filter cake with ether, and dry to obtain Y as The memantamide derivatives having the structure described in formula C.
  • the memantamide derivatives having the structure shown in formula C are prepared, as shown in Figure 6, specifically, (3-2) when R 3 is a halogen group, the preparation method comprises the following steps:
  • Compound 1 was prepared according to step (3-1);
  • the fifth intermediate compound and compound III are subjected to a third nucleophilic substitution reaction to obtain compound n;
  • step (3-1) Based on the compound n, according to step (3-1), a memantamide derivative having the structure represented by formula C is prepared.
  • the present invention prepares compound 1 according to step (3-1). Specifically, in the present invention, compound IX and compound a are subjected to dodecanoylation reaction to obtain compound k.
  • the ratio of the compound IX to the compound a, the conditions of the dodecanoylation reaction and the post-treatment method are preferably the same as those in step (3-1), and will not be repeated here.
  • the present invention performs the third reduction reaction on the compound k to obtain the compound l.
  • the reducing agent used in the third reduction reaction is preferably iron powder, and the third reduction reaction is preferably carried out in the presence of ammonium chloride, ethanol and water.
  • the temperature of the third reduction reaction is preferably 70-90° C., more preferably 80° C., and the time is preferably 40-60 min, more preferably 50 min.
  • the obtained reaction solution is preferably cooled to room temperature, filtered through diatomaceous earth, the filter cake is rinsed with ethanol, and the filtrate is concentrated to dryness under reduced pressure; water is added to the residue, and ethyl acetate is used. After extraction, washing with water, saturated brine, and drying over anhydrous sodium sulfate in sequence, suction filtration, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is directly subjected to the next reaction.
  • the present invention After obtaining compound 1, the present invention performs sixteen acylation reaction with compound 1 and compound V to obtain the fifth intermediate compound; the fifth intermediate compound and compound III are subjected to a third nucleophilic substitution reaction to obtain compound 1 .
  • the sixteenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
  • the temperature of the sixteen acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
  • the obtained reaction solution is preferably concentrated to dryness under reduced pressure, and dichloromethane is added to the residue for dissolution to obtain a fifth intermediate compound solution, which is for later use.
  • the third nucleophilic substitution reaction is preferably carried out in the presence of tetrahydrofuran (or dichloromethane) and triethylamine.
  • the third nucleophilic substitution reaction is preferably carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
  • the present invention based on the compound n, prepares a memantamide derivative having the structure represented by the formula C according to the step (3-1), which will not be repeated here.
  • the memantamide derivatives having the structure shown in formula D are prepared. Specifically, the present invention is based on compounds The memantamide derivative having the structure shown in formula D is prepared according to the method of the third case, and will not be repeated here.
  • the present invention provides the application of the memantamide derivatives described in the above technical solutions in the preparation of medicines for treating diseases mediated by soluble epoxidase.
  • the diseases mediated by soluble cyclooxygenase specifically include inflammatory diseases, pain, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications, chronic nephritis, renal failure, chronic obstructive pulmonary disease disease or pulmonary hypertension disease;
  • the inflammatory disease preferably includes sepsis, cytokine storm, inflammatory bowel disease, chronic peptic ulcer or arthritis;
  • the pain preferably includes inflammatory pain or neuropathic pain;
  • the vascular disease preferably includes hypertension, stroke or atherosclerosis;
  • the neurodegenerative disease preferably includes Parkinson's syndrome or Alzheimer's disease.
  • reaction solution was concentrated under reduced pressure to remove THF, Add water (100 mL), adjust the pH of the system to 7 with 2 mol/L hydrochloric acid under ice bath (0°C) conditions, add ethyl acetate (100 mL), continue to adjust the pH of the system to 1 with 2 mol/L hydrochloric acid, and then pump Filtration, the filter cake was rinsed with water and ethyl acetate successively, and a white solid was obtained after drying, namely 1-(4-nitrobenzoyl)piperidine-4-carboxylic acid, the yield was 25.4 g, and the yield was 84%.
  • the obtained system after beating is subjected to suction filtration, the filter cake is rinsed with ethyl acetate, and a white solid is obtained after drying, which is 1-(4-aminobenzoyl)piperidine-4-carboxylic acid, and the output is 15.5 g, the yield is 87%.
  • the white solid was slurried with ethyl acetate.
  • the system obtained after beating was subjected to suction filtration, and the filter cake was rinsed with ethyl acetate and dried. After that, a white solid was obtained, which was 1- ⁇ 4-[(phenoxycarbonyl)amino]benzoyl ⁇ piperidine-4-carboxylic acid, and the yield was 5.28 g and the yield was 30%.
  • Embodiment 6 Carboxylic acid is the first general operation of acylating agent
  • Example 6 Operate according to the method of Example 6, take methylamine hydrochloride as raw material (that is, the hydrochloride of amine in Example 6 is specifically methylamine hydrochloride) to obtain a white solid, which is GL-B407, and the output is 0.27g , the yield is 66%, mp237-240 °C.
  • methylamine hydrochloride as raw material (that is, the hydrochloride of amine in Example 6 is specifically methylamine hydrochloride) to obtain a white solid, which is GL-B407, and the output is 0.27g , the yield is 66%, mp237-240 °C.
  • Example 6 Operate according to the method of Example 6, take methoxymethylamine hydrochloride as raw material (that is, the hydrochloride of amine in Example 6 is specifically methoxymethylamine hydrochloride) to obtain a white solid, which is GL- B410, yield 0.12 g, 28% yield, mp 237-239°C.
  • Example 18 Operate according to the method of Example 18, using methylamine hydrochloride as a raw material (that is, the hydrochloride of the amine in Example 18 is specifically methylamine hydrochloride) to obtain a white solid, which is GL-B414, and the output is 0.19g , the yield is 46%, mp210-212 °C.
  • methylamine hydrochloride as a raw material (that is, the hydrochloride of the amine in Example 18 is specifically methylamine hydrochloride) to obtain a white solid, which is GL-B414, and the output is 0.19g , the yield is 46%, mp210-212 °C.
  • Example 18 Operate according to the method of Example 18, take dimethylamine hydrochloride as a raw material (that is, the hydrochloride of amine in Example 18 is specifically dimethylamine hydrochloride) to obtain a white solid, which is GL-B415, and the output is 0.19g, 45% yield, mp 137-139°C.
  • Example 18 Operate according to the method of Example 18, using methoxymethylamine hydrochloride as a raw material (that is, the hydrochloride of the amine in Example 18 is specifically methoxymethylamine hydrochloride) to obtain a white solid, which is GL- B417, yield 0.28 g, 65% yield, mp 130-132°C.
  • the obtained reaction solution was concentrated under reduced pressure to remove most of the THF, added water (60 mL), extracted with ethyl acetate (60 mL ⁇ 3), combined the organic layers, washed with water (60 mL ⁇ 2), washed with saturated brine ( 60mL) and anhydrous magnesium sulfate, dried, suction filtered, and the obtained filtrate was concentrated under reduced pressure to obtain a yellow oily substance, which was added with ether (15mL) for beating, and the obtained system was subjected to suction filtration after beating.
  • a white solid was obtained, namely phenyl(4- ⁇ 4-[(tert-butoxycarbonyl)amino]piperidine-1-carbonyl ⁇ phenyl)carbamate, the yield was 5.32 g, and the yield was 86%.
  • Example 28 Operate according to the method of Example 28, using methanesulfonyl chloride as a raw material (that is, the acid chloride raw material in Example 28 is specifically methanesulfonyl chloride) to obtain a white solid, namely GL-B419, the yield is 0.19g, and the yield is 40% , mp157-159°C.
  • methanesulfonyl chloride that is, the acid chloride raw material in Example 28 is specifically methanesulfonyl chloride
  • Example 28 Operate according to the method of Example 28, take acetyl chloride as raw material (that is, the acid chloride raw material in Example 28 is specifically acetyl chloride) to obtain a white solid, namely GL-B420, the output is 0.17g, the yield is 39%, mp244 -246°C.
  • Example 28 Operate according to the method of Example 28, take propionyl chloride as raw material (that is, the acid chloride raw material in Example 28 is specifically propionyl chloride) to obtain a white solid, namely GL-B421, the yield is 0.12g, the yield is 27%, mp230 -232°C.
  • Example 29 Operate according to the method of Example 29, take n-butyric acid as a raw material (that is, the carboxylic acid raw material in Example 29 is specifically n-butyric acid) to obtain a white solid, namely GL-B422, the output is 0.12g, and the yield is 26 %, mp236-237°C.
  • Example 29 Operate according to the method of Example 29, using 2-methylbutyric acid as a raw material (that is, the carboxylic acid raw material in Example 29 is specifically 2-methylbutyric acid) to obtain a white solid, namely GL-B423, and the output is 0.35 g, 73% yield, mp 250-252°C.
  • 2-methylbutyric acid that is, the carboxylic acid raw material in Example 29 is specifically 2-methylbutyric acid
  • Boc-valine was used as a raw material (that is, the carboxylic acid raw material in Example 29 was specifically Boc-valine), and 1 mol/L hydrochloric acid was not used for washing in the post-treatment process to obtain half 1 g of the solid crude product was used for the next reaction without purification.
  • N-Boc-piperazine (10.1g, 54.1mmol), triethylamine (16.4g, 0.16mol) and THF (80mL) were added to the there-necked flask, the ice-salt bath was cooled to below 0°C, and p-nitro was added dropwise.
  • the THF solution 50 mL of benzoyl chloride (10.0 g, 54.1 mmol) was added dropwise, and the reaction was carried out at room temperature for 2 h. TLC monitored the completion of the reaction; the obtained reaction solution was concentrated under reduced pressure to remove most of the THF, and water was added.
  • the resulting reaction solution was concentrated under reduced pressure to remove most of the THF, water (100 mL) was added, extracted with ethyl acetate (100 mL ⁇ 3), the organic layers were combined, and washed with water (100 mL ⁇ 2) and saturated brine (100 mL) successively. ) and anhydrous sodium sulfate, suction filtration, and the obtained filtrate was concentrated under reduced pressure to obtain 27.6 g of a yellow oil, which was added with ether (60 mL) to make a slurry, and the obtained system was subjected to suction filtration after beating, and the filter cake was rinsed with ether and dried.
  • the obtained reaction solution was distilled under reduced pressure to remove most of the trifluoroacetic acid, water (80 mL) and DCM (100 mL) were added, and the pH value of the system was adjusted to 14 with sodium hydroxide solid under ice-water bath conditions, and the organic layer was separated and removed, The aqueous layer was extracted with DCM (100 mL ⁇ 2), then washed with water (100 mL), saturated brine (100 mL) and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure to obtain 18.88 g of pale yellow semi-solid , add ether (30mL) to make pulp, filter the obtained system after beating, rinse the filter cake with ether, and dry to obtain a white solid, namely GL-B426, the output is 9.60g, the yield is 80%, mp190-193 °C.
  • Example 43 Operate according to the method of Example 43, using methanesulfonyl chloride as the raw material (that is, the acid chloride raw material in Example 43 is specifically methanesulfonyl chloride), and purified by beating with ether to obtain a white solid, namely GL-B427, the yield is 0.42g, and the yield is 0.42 g. The rate is 88%, mp226-229°C.
  • Example 43 Operate according to the method of Example 43, take acetyl chloride as the raw material (that is, the acid chloride raw material in Example 43 is specifically acetyl chloride), purified by ether beating and then purified by silica gel column chromatography to obtain a white solid, namely GL-B428, Yield 0.23 g, 52% yield, mp 127-129°C.
  • Example 43 Operate according to the method of Example 43, use propionyl chloride as raw material (that is, the acid chloride raw material in Example 43 is specifically propionyl chloride), and purified by ether beating to obtain a white solid, namely GL-B429, the yield is 0.37g, and the yield is 82%, mp234-235°C.
  • n-butyric acid as the raw material (that is, the carboxylic acid raw material in Example 44 is specifically n-butyric acid), purified by beating with ether, and then purified by silica gel column chromatography to obtain a white solid, which is GL -B430, yield 0.33g, 70% yield, mp 222-224°C.
  • 2-methylbutyric acid was used as the raw material (that is, the carboxylic acid raw material in Example 44 was specifically 2-methylbutyric acid), purified by beating with ether, and then purified by silica gel column chromatography to obtain The white solid, GL-B431, yielded 0.33 g, 69% yield, mp 119-122°C.
  • Example 44 Operate according to the method of Example 44, using cyclopropanecarboxylic acid as a raw material (that is, the carboxylic acid raw material in Example 44 is specifically cyclopropanecarboxylic acid), purified by ether beating and then purified by silica gel column chromatography to obtain a white solid, namely GL- B432, yield 0.33 g, 70% yield, mp 231-234°C.
  • cyclopropanecarboxylic acid that is, the carboxylic acid raw material in Example 44 is specifically cyclopropanecarboxylic acid
  • Example 44 using Boc-valine as a raw material (that is, the carboxylic acid raw material in Example 43 is specifically Boc-valine), 1.04 g of a semi-solid crude product was obtained, which was directly used in the next step without purification. one-step reaction.
  • Example 54 The procedure of Example 54 was followed except that ethyl 1-(3-chloro-4-nitrobenzoyl)piperidine-3-carboxylate was replaced by 1-(3-fluoro-4-nitro Benzoyl)piperidine-3-carboxylic acid ethyl ester to finally obtain 1.3 g of pale yellow oil.
  • Example 55 The procedure of Example 55 was followed, except that ethyl 1-(4-amino-3-chlorobenzoyl)piperidine-3-carboxylate was replaced with 1-(4-amino-3-fluorobenzyl) acyl)piperidine-3-carboxylic acid ethyl ester, and finally obtain a light yellow solid 0.8g.
  • Example 56 The procedure of Example 56 was followed, except that 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ -3-Chlorobenzoyl)piperidine-3-carboxylic acid ethyl ester was replaced with 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl ]ureido ⁇ -3-fluorobenzoyl)piperidine-3-carboxylic acid ethyl ester to finally obtain 0.5 g of a white solid.
  • Example 57 The procedure of Example 57 was followed except that 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ -3-Chlorobenzoyl)piperidine-3-carboxylic acid was replaced with 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]urea yl ⁇ -3-fluorobenzoyl)piperidine-3-carboxylic acid, the white solid finally obtained was GL-B434, the yield was 60 mg, and the yield was 11%.
  • Example 60 According to the operation method of Example 60, using (S)-ethyl 1-(4-amino-3-fluorobenzoyl) piperidine-3-carboxylate and memantine as raw materials, the finally obtained white solid is (S) -1-(4- ⁇ 3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido ⁇ -3-fluorobenzoyl)piperidine-3- Ethyl formate, yield 0.64 g, 70% yield.
  • Example 58 According to the operation method of Example 58, using 3-fluoro-4-nitrobenzoic acid and (S)-3-Boc-aminopiperidine as raw materials, 1.98 g of brownish yellow oil was finally obtained. Used directly in the next step without purification.
  • tert-butyl (S)-[1-(3-fluoro-4-nitrobenzoyl)piperidin-3-yl]carbamate was used as raw material to prepare 1.78g
  • Example 60 According to the operation method of Example 60, using tert-butyl (S)-[1-(3-fluoro-4-aminobenzoyl)piperidin-3-yl]carbamate as raw material, a white solid 0.90 was finally obtained. g, 90% yield.
  • the difference is that 3-fluoro-4-nitrobenzenesulfonyl chloride is used as the raw material; the light yellow solid finally obtained is compound GL-B440, the yield is 90 mg, and the yield is 30%. mp147-149°C.
  • Detection principle The specific substrate (3-phenyl-oxy)-acetic acid cyano-(6-methoxy-naphthalen-2-yl) methyl ester, that is, PHOME itself has no fluorescence, but is hydrolyzed under the action of sEH enzyme
  • the generated product 6-methoxy-2-naphthaldehyde, 6-methoxy-2-naphthaldehyde can emit fluorescence with a wavelength of 465nm under the excitation of 330nm light wave, and the detected fluorescence signal intensity is related to the inhibition of sEH enzyme Strength is inversely proportional.
  • the inhibition rates of samples with different concentrations were calculated. SPSS 20 software was used to calculate the IC 50 values of the compounds according to the inhibition rate and concentration.
  • PHOME solution Dissolve 0.79 mg of PHOME in 106 ⁇ L of DMSO to obtain a PHOME solution with a concentration of 20 mM, and use Tris-HCl buffer to dilute to 1/3 mM.
  • sEH solution sEH (5mg/mL) stock solution was stored at -80°C in a refrigerator, and diluted to 4 ⁇ g/mL with 25mM Tris-HCl buffer when used.
  • the sample powder to be tested was dissolved in DMSO into a 20 mM solution, stored in a -20°C refrigerator for later use, and diluted to the corresponding concentration with Tris-HCl buffer during use.
  • the fluorescence signal data was detected by a microplate reader, the excitation wavelength was 330 nm, and the emission wavelength was 465 nm.
  • Table 1 shows the inhibitory activities of compounds GL-B404 to GL-B441 on human sEH (HsEH).
  • the compounds GL-B404 to GL-B441 provided by the present invention have a good inhibitory effect on HsEH IC 50 values between 0.1 nM and 1 ⁇ M.
  • the experimental results showed that 15 compounds had better inhibitory activity on sEH than the lead compound GL-B401, namely compounds GL-B412, GL-B413, GL-B415, GL-B416, GL-B417, GL-B434, GL-B435 , GL-B436, GL-B437, GL-B438, GL-B439, GL-B440, GL-B441, R-GL-B413, S-GL-B413, among which compounds GL-B437 and GL-B440 have strong inhibitory activity , with IC50s of 0.06nM and 0.08nM , respectively, showing a very promising development prospect.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychiatry (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine technique des médicaments, et concerne un dérivé de mémantine-urée, un procédé de préparation de celui-ci, et une application de celui-ci. Le dérivé de mémantine-urée selon la présente invention présente une structure d'urée typique en tant que pharmacophore primaire de sEH, et l'amarrage moléculaire montre qu'un fragment de mémantine agit en tant que fragment hydrophobe pour générer une force hydrophobe avec un récepteur, en particulier lorsque R1 et R2 sont tous deux méthyle (c'est-à-dire, 3,5-diméthyl-substitué), la force de Van der Waals peut être augmentée. Par conséquent, le dérivé de mémantine-urée selon la présente invention présente une activité inhibitrice élevée sur sEH humain (HsEH), et peut être utilisé en tant qu'inhibiteur de sEH pour préparer un médicament pour le traitement de maladies médiées par l'époxydase soluble.
PCT/CN2022/073961 2021-04-28 2022-01-26 Dérivé de mémantine-urée, son procédé de préparation et son application WO2022227743A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110469170.4 2021-04-28
CN202110469170.4A CN113185451B (zh) 2021-04-28 2021-04-28 美金刚脲类衍生物及其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2022227743A1 true WO2022227743A1 (fr) 2022-11-03

Family

ID=76980060

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/073961 WO2022227743A1 (fr) 2021-04-28 2022-01-26 Dérivé de mémantine-urée, son procédé de préparation et son application

Country Status (2)

Country Link
CN (1) CN113185451B (fr)
WO (1) WO2022227743A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024105225A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Combinaisons synergiques d'un antagoniste du récepteur sigma 1 (s1r) et d'un inhibiteur d'époxyde hydrolase soluble (sehi) et leur utilisation dans le traitement de la douleur

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113185451B (zh) * 2021-04-28 2023-09-12 沈阳药科大学 美金刚脲类衍生物及其制备方法和应用
CN113402447B (zh) * 2021-06-22 2022-10-18 沈阳药科大学 一种sEH抑制剂或其药学上可接受的组合物及其制备方法和应用
CN115141123B (zh) * 2022-05-20 2024-05-17 沈阳药科大学 一种化合物及其制备方法和在制备组蛋白去乙酰化酶和环氧化物水解酶双重抑制剂中的应用
CN115819328B (zh) * 2022-11-18 2024-08-27 沈阳药科大学 美金刚脲类衍生物及其制备方法和在制备治疗可溶性环氧化物酶介导的疾病的药物中的应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101495119A (zh) * 2006-08-01 2009-07-29 亚瑞特医疗公司 可溶性环氧化合物水解酶抑制剂
CN101516361A (zh) * 2006-09-28 2009-08-26 亚瑞特医疗公司 可溶性环氧化物水解酶抑制剂
CN101516838A (zh) * 2006-09-28 2009-08-26 亚瑞特医疗公司 可溶性环氧化物水解酶抑制剂
CN102464631A (zh) * 2010-11-08 2012-05-23 中国科学院上海药物研究所 哌嗪取代的1,3-二取代脲类化合物及哌嗪取代的酰胺类化合物及其制备方法和用途
CN111423396A (zh) * 2020-04-30 2020-07-17 沈阳药科大学 一种sEH抑制剂及其制备方法和应用
CN113185451A (zh) * 2021-04-28 2021-07-30 沈阳药科大学 美金刚脲类衍生物及其制备方法和应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101535259A (zh) * 2006-10-20 2009-09-16 亚瑞特医疗公司 作为可溶性环氧化物水解酶抑制剂的苯基脲化合物
MX2018001135A (es) * 2015-07-28 2018-05-23 Univ Barcelona Analogos de adamantilureas como inhibidores de epoxido hidrolasa soluble.
CN105348168B (zh) * 2015-11-06 2018-04-10 厦门大学 1‑(2‑(金刚烷‑1‑基)‑1h‑吲哚‑5‑基)‑3‑取代脲衍生物及制备和用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101495119A (zh) * 2006-08-01 2009-07-29 亚瑞特医疗公司 可溶性环氧化合物水解酶抑制剂
CN101516361A (zh) * 2006-09-28 2009-08-26 亚瑞特医疗公司 可溶性环氧化物水解酶抑制剂
CN101516838A (zh) * 2006-09-28 2009-08-26 亚瑞特医疗公司 可溶性环氧化物水解酶抑制剂
CN102464631A (zh) * 2010-11-08 2012-05-23 中国科学院上海药物研究所 哌嗪取代的1,3-二取代脲类化合物及哌嗪取代的酰胺类化合物及其制备方法和用途
CN111423396A (zh) * 2020-04-30 2020-07-17 沈阳药科大学 一种sEH抑制剂及其制备方法和应用
CN113185451A (zh) * 2021-04-28 2021-07-30 沈阳药科大学 美金刚脲类衍生物及其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANANDAN, S.K. ; GLESS, R.D.: "Exploration of secondary and tertiary pharmacophores in unsymmetrical N,N@?-diaryl urea inhibitors of soluble epoxide hydrolase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 20, no. 9, 1 May 2010 (2010-05-01), Amsterdam NL , pages 2740 - 2744, XP027012824, ISSN: 0960-894X *
HUANG SHAO-XU, CAO BIN, MORISSEAU CHRISTOPHE, JIN YI, HAMMOCK BRUCE D., LONG YA-QIU: "Structure-based optimization of the piperazino-containing 1,3-disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase", MEDCHEMCOMM, ROYAL SOCIETY OF CHEMISTRY, UNITED KINGDOM, vol. 3, no. 3, 1 March 2012 (2012-03-01), United Kingdom , pages 379 - 384, XP055981049, ISSN: 2040-2503, DOI: 10.1039/c2md00288d *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024105225A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Combinaisons synergiques d'un antagoniste du récepteur sigma 1 (s1r) et d'un inhibiteur d'époxyde hydrolase soluble (sehi) et leur utilisation dans le traitement de la douleur

Also Published As

Publication number Publication date
CN113185451B (zh) 2023-09-12
CN113185451A (zh) 2021-07-30

Similar Documents

Publication Publication Date Title
WO2022227743A1 (fr) Dérivé de mémantine-urée, son procédé de préparation et son application
EP1756043B1 (fr) Composes aryl- ou heteroarylamides ortho-substitues
DE69734773T2 (de) Nicht-peptidische Bombesin-Rezeptor-Antagonisten
FR2896798A1 (fr) Derives de sulfonamides, leur preparation et leur application en therapeutique
FR2861074A1 (fr) Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
JP6518789B2 (ja) 精神障害の処置において使用するためのテトラゾール誘導体
WO2008009335A2 (fr) Dérivés d'urée d'aminoindazole
FR2842805A1 (fr) Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide,leur preparation et leur application et therapeutique
EP0647629B1 (fr) 1-Naphtylpyrazole-3-carboxamides substitués actifs sur la neurotensine, leur préparation, les compositions pharmaceutiques en contenant
CN102292321A (zh) 作为前列环素(pgi2)受体调节剂用于治疗该受体相关病症的吡唑基取代的碳酸衍生物
WO2024193129A1 (fr) Composé, son procédé de préparation et son utilisation dans la préparation d'un inhibiteur de seh et d'un agoniste de ppars
TW200305417A (en) Chemical compounds
KR20140091042A (ko) 바닐로이드 수용체 리간드로서의 ｃｏ－함유 그룹으로 치환된 페닐 모이어티를 갖는 치환된 피라졸릴계 카복스아미드 및 우레아 유도체들
JPWO2007148711A1 (ja) Ｎ−（３，４−ジ置換フェニル）サリチルアミド誘導体
JP2011526936A (ja) 癌の処理のための新規オルト−アミノアニリド
EP1244611A1 (fr) Derives d'acide en tant qu'antagonistes d'integrine
JP2020506226A (ja) アミド化合物およびその使用
KR20050101541A (ko) 진통 작용을 가진 인다졸아마이드
JPH06507920A (ja) 心循環器系に作用する２−アミノ−１，２，３，４−テトラヒドロナフタレン誘導体、それらを製造する方法、及びそれらを含む医薬組成物
ES2391371T3 (es) Derivados de la 2-trifluorometilnicotinamida como agentes para aumentar el HDL-colesterol
EP0991650B1 (fr) Nouveaux composes de n-benzenesulfonyl-l-proline, procede de preparation et utilisation en therapeutique
FR2756562A1 (fr) Nouveaux composes de n-benzenesulfonyl-l-proline, procede de preparation et utilisation en therapeutique
WO2015046405A1 (fr) Analgésique
CA2217479C (fr) Derives de la phenoxyethylamine possedant une haute affinite pour le recepteur 5-ht1a, leur procede de preparation, leur application comme medicament et les compositions pharmaceutiques les renfermant
EP2185525B1 (fr) Dérivés de pyrazole 3,5-carboxylates, leur préparation et leur application en thérapeutique

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: 22794224

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22794224

Country of ref document: EP

Kind code of ref document: A1