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WO2013020440A1 - Dérivés d'amide et son procédé de préparation, composition pharmaceutique et son utilisation - Google Patents

Dérivés d'amide et son procédé de préparation, composition pharmaceutique et son utilisation Download PDF

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WO2013020440A1
WO2013020440A1 PCT/CN2012/078691 CN2012078691W WO2013020440A1 WO 2013020440 A1 WO2013020440 A1 WO 2013020440A1 CN 2012078691 W CN2012078691 W CN 2012078691W WO 2013020440 A1 WO2013020440 A1 WO 2013020440A1
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trans
carboxamide
substituted
methylpyrrole
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夏广新
余建鑫
沈竞康
郑常春
许振民
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Shanghai Pharmaceuticals Holding Co Ltd
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    • C07—ORGANIC CHEMISTRY
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D211/92—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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention particularly relates to an amide derivative, a process for its preparation, a pharmaceutical composition and use. Background technique
  • Glucocorticoids play an important role in sugar, protein, fat, water and salt metabolism and stress response. Excessive or lack of glucocorticoids can cause abnormalities in the body. Glucocorticoids induce insulin resistance, which is central to the onset of type 2 diabetes.
  • the level of glucocorticoids in local tissues and organs is related to the activity of 11 ⁇ -hydroxysteroid dehydrogenase (l lBHSD) and the ratio of the two subtypes.
  • the change in the activity of type 1 11 ⁇ -hydroxysteroid dehydrogenase (l lBHSD1) is closely related to the development of insulin resistance (IR) and type 2 diabetes.
  • 11BHSD1 is a specific reductase that enhances glucocorticoid activity, while glucocorticoids have key enzymes that activate gluconeogenesis in hepatocytes such as phosphoenol 1 ⁇ 4 pyruvate carboxykinase (PEPCK) and glucose.
  • PEPCK phosphoenol 1 ⁇ 4 pyruvate carboxykinase
  • the action of 6-phosphatase accelerates gluconeogenesis; it also directly inhibits the secretion function of islet G cells by down-regulating the expression of intracellular receptor proteins, thereby causing insulin resistance and impairing islet B cell function.
  • the use of corticosteroids in diabetic patients can aggravate the patient's hyperglycemia. About 20% of patients with Cushing syndrome have impaired glucose tolerance or diabetes.
  • the pathophysiology is that excessive glucocorticoids can cause hyperinsulinemia and impaired glucose tolerance. High blood pressure, abdominal obesity, and finally develop into diabetes.
  • adipose tissue such as subcutaneous adipose tissue and visceral adipose tissue in obese people
  • elevated levels of lBHSD1 mRNA may be an important factor in the pathogenesis of metabolic syndrome.
  • the use of 11BHSD1 inhibitors can down-regulate the concentration of glucocorticoids in different tissues and achieve treatment for metabolic diseases such as diabetes, obesity, and metabolic syndrome without affecting circulating glucocorticoid levels.
  • 11BHSD1 is also present in brain tissue, which plays an important regulatory role in neuronal development, metabolism, secretion and structure of neurotransmitters. Glucocorticoids in the brain regulate their secretion through negative feedback In the aspects of learning, memory and fear behavior, 11BHSD1 inhibitors were given, and cognitive dysfunction caused by excessive glucocorticoids was restored.
  • the inventors have found a new class of amide derivatives which have an inhibitory effect on 11BHSD1 after a lot of arduous experimental research, and completed the present invention.
  • the technical problem to be solved by the present invention is to provide an amide derivative, a pharmaceutically acceptable salt or solvate thereof, a preparation method thereof, a pharmaceutical composition and use thereof which are completely different from the prior art.
  • the amide derivative of the present invention is an inhibitor of ll- ⁇ hydroxysteroid dehydrogenase type I (llBHSD1), which can be used for the treatment of various diseases associated with the expression or activity of 11BHSD1.
  • the present invention relates to an amide derivative of the formula (I), a pharmaceutically acceptable salt or solvate thereof;
  • Ar is a substituted or unsubstituted C 6 -C 1Q aryl group or a substituted or unsubstituted C 3 -C 12 heteroaryl group, Said substitution is substituted by 1, 2 or 3 substituents R 1 ;
  • R 1 is selected from halogen (such as F, C1 or Br), -OR', -OC(0)R', -OC(0)NR'R", -NR'R" (if Ar is naphthyl, - NR'R" at the 5 position of the naphthyl group, -NR'C(0)R", -C(0)OR', -C(0)NR'R", -C(O) R', -SR ', -S(0)R', -S(0)NR'R", -S(0) 2 NR'R", substituted or unsubstituted ⁇ .
  • halogen such as F, C1 or Br
  • R a and R b and their linked 1-position N atom and 2 quaternary carbon atom together form a 4 to 8 membered saturated heterocyclic ring;
  • the carbon at position 2 is an achiral carbon, a chiral carbon in the R configuration or a chiral carbon in the S configuration;
  • R 2 is a substituted or unsubstituted linear or branched ⁇ 0 Hydryl group, a substituted or unsubstituted linear, or branched ( ⁇ -6 fluorohydrocarbyl group; the substituent is selected from -OR', -OC ( 0) R', -OC(0)NR'R", -NR'R” or -NR'C(0)R";
  • 1 3 is 11, ( ⁇ 4 hydrocarbon group or ( ⁇ 4 fluorohydrocarbon group;
  • R 4 is a substituted or unsubstituted C 3 -C 12 cycloalkyl group, a substituted or unsubstituted C 3 -C 12 heterocycloalkyl group, or a substituted or unsubstituted C 5 -C 2 .
  • a bridged cyclic hydrocarbon group the substitution being a fluorine, -OR' (such as a 1-OR' group substituted on the adamantyl group, a 4-OR' substituted on the cyclohexyl group, or a 3 substituted on the adamantyl group) -OR'), -OC(0)R', -OC(0)NR'R", -NR'R", -NR'C(0)R", -C(0)OR'
  • amide derivative represented by the formula (I) as defined above does not include a compound having the following chemical structure:
  • the C 6 -C 1Q aryl group is preferably a phenyl group or a naphthyl group (such as 1). -naphthyl);
  • the C 3 -C 12 heteroaryl group is preferably a thienyl group (e.g., 2-thienyl group), a pyridyl group. (such as pyridin-3-yl), quinolyl (such as 8-quinolinyl) or isoquinolyl (such as 8-isoquinolinyl or 5-isoquinolinyl).
  • the R 1 is preferably selected from the group consisting of halogen, -OR', -OC(0)R', -OC(0)NR'R", -NR'R", -NR'C(0 ) R", -C(0)OR', -C(0)NR'R", -C(0) R', Ci ⁇ C4 hydrocarbon group, ( ⁇ C 4 fluorohydrocarbyl group, 0-( ⁇ 4 a hydrocarbon group, ( ⁇ 3 hydrocarbyl-C(OR')(CF 3 )- or a cyano group;
  • R 1 when R 1 is selected according to a substituted or unsubstituted hydrocarbon group ⁇ ⁇ 4, ⁇ C 4 hydrocarbon claim is -OR ', C ⁇ Cs alkyl with haloalkyl and one or more of halogen, When substituted, the -OR' is preferably -OH, and the halogen in the halogen or halogenated fluorenyl group is preferably F, Cl, Br or I.
  • the d ⁇ C 3 halofluorenyl group is preferably a trifluoromethyl group;
  • R 1 when R 1 is selected according to a substituted or unsubstituted hydrocarbon group ⁇ ⁇ , preferably, to 4, wherein said hydrocarbon is selected from ⁇ methyl, propyl or tert-butyl, wherein. ⁇ .
  • the hydrocarbon group is a propyl group and it is substituted by -OR' and/or a halogen
  • the substituted propyl group is further preferably 1,1,1-trifluoro-2-hydroxy-2-propyl group.
  • R 1 is an unsubstituted ⁇ ⁇ hydrocarbyl group
  • the unsubstituted hydrocarbyl group is a tert-butyl group
  • the tert-butyl group is further preferably a 4-tert-butyl group.
  • R a and R b and their associated N-position and 2-position are identical to R a and R b and their associated N-position and 2-position.
  • the straight-chain or branched-chain hydrocarbon group is preferably 6 ⁇ ⁇ is methyl, ethyl or Allyl.
  • the R 3 is preferably hydrogen
  • the C 3 -C 12 cycloalkyl group is preferably a C 5 -C 1Q cycloalkyl group such as a cyclohexyl group.
  • the cyclohexyl group may be a racemic cyclohexyl group or a chiral cyclohexyl group in which both the 1 and 4 positions are chiral carbons.
  • the C 3 -C 12 heterocycloalkyl group is preferably a C 5 -C 1Q heterocycloalkyl group, and the hetero atom may be 0, such as a heterocycloalkyl group, preferably 3-oxobicyclo[3.3.1]fluorene.
  • the bridged cyclic hydrocarbon group is preferably a C 5 -C 1Q bridged cyclic hydrocarbon group such as adamant-4-yl, adamant-2-yl or adamant-1-yl.
  • R 4 is a substituted or unsubstituted C 3 -C 12 cycloalkyl group, a substituted or unsubstituted C 3 -C 12 heterocycloalkyl group, or a substituted or unsubstituted C 5 -C 2 .
  • the substitution is preferably carried out by a hydroxyl group, OC(0)R', OC(0)NR'R", C(0)OR', C(0)NR'R", C( 0)
  • R' and R" are independently H, ⁇ 4 hydrocarbyl (such as methyl or ethyl) or ( ⁇ 4 fluorohydrocarbyl (such as trifluoromethyl or trifluoro) Ethyl).
  • a more preferred compound (I) is: (R)-l-(3-chloro-2-methylphenylsulfonyl)-N-(adamant-2-yl:)-2-methylpyrrole-2-carboxamide; (Preparation of Example 1 compound of)
  • the invention also provides a preparation method of the compound of the formula (I), which is any one of the following methods: Method 1: The compound II or its acid salt and ArS0 2 X are subjected to a condensation reaction as shown below,
  • X is a halogen such as C1; the definitions of the other groups are as described above.
  • the methods and conditions of the reactions in the methods 1 and 2 can be the conventional methods and conditions for the two types of reactions in the field.
  • the compounds of the present invention can be prepared in a variety of ways well known in the art of organic synthesis and by those skilled in the art; the methods described in this application can also be used, along with synthetic methods known in the art of organic synthesis or as understood by those skilled in the art. The changes on the synthesis.
  • the compounds of the present invention can be prepared from the readily available starting materials using the following general methods and procedures. It will be understood that when typical or preferred process operating conditions (gp, reaction temperature, time, mole ratio of reactants, solvent, pressure, etc.) are given; other process operating conditions may also be used unless otherwise stated .
  • the reaction of the process described herein can be carried out in a suitable solvent, which is readily selected by those skilled in the art of organic synthesis.
  • a suitable solvent does not substantially react with the starting materials, intermediates or products at the temperature at which the reaction is carried out, the temperature at which the reaction can be carried out at a temperature ranging from the freezing point of the solvent to the boiling temperature of the solvent.
  • a given reaction can be carried out in a solvent or a mixture of solvents.
  • a solvent suitable for the particular reaction step can be selected.
  • the preparation of the compounds can involve the protection and deprotection of multiple chemical groups.
  • the need for protection and deprotection, as well as the selection of suitable protecting groups, can be readily determined by those skilled in the art, for example, in Greene et al, Protective Groups in Organic Synthesis, Second Edition, Wiley & Sons, 1991. Found in , which is hereby incorporated by reference in its entirety.
  • the methods described herein can be monitored according to any suitable method known in the art. For example, nuclear magnetic resonance, infrared spectroscopy, spectrophotometry or mass spectrometry, HPLC or thin layer chromatography to monitor product formation.
  • the compounds of the present invention can be prepared using two reaction routes and procedures as described below, but are not limited to the protecting groups, reagents, and solvents in the reaction conditions.
  • the invention further relates to a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • composition consists of one or more compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable adjuvant.
  • pharmaceutical excipients will vary depending on the route of administration and the characteristics of the action, and are usually fillers, diluents, binders, wetting agents, disintegrating agents, lubricants, emulsifiers, suspending agents, and the like.
  • compositions of the invention may be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical routes.
  • injection intravenous, intramuscular, subcutaneous and intracoronary
  • sublingual buccal
  • rectal transurethral
  • vaginal nasal
  • inhalation topical routes.
  • the preferred route is oral.
  • the invention further relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a package Use of a pharmaceutically acceptable composition containing them for the preparation of a medicament for human use.
  • the present invention also relates to a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable composition comprising the same, for use in the preparation of a medicament for the treatment or prevention of a disease in which 11BHSD1 activity is required to modulate 11BHSD1 the use of.
  • the invention further relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable composition comprising the same, for use in the treatment or prevention of obesity, diabetes, glucose intolerance , insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, depression, senile dementia, glaucoma, osteoporosis, inflammation, atherosclerosis, angina pectoris, heart failure, stroke, adverse dyslipidemia, Uses in human medicines for diseases such as hypercholesterolemia, hypertriglyceridemia, hyperlipoproteinemia, metabolic syndrome, or general aldosterone-related target organ damage.
  • diseases such as hypercholesterolemia, hypertriglyceridemia, hyperlipoproteinemia, metabolic syndrome, or general aldosterone-related target organ damage.
  • the reagents and starting materials used in the present invention are commercially available.
  • a positive progressive effect of the present invention is that the compound of the present invention is an inhibitor of ll- ⁇ hydroxysteroid dehydrogenase type I (llBHSD1), which can be used for the treatment of various diseases related to the expression or activity of 11BHSD1.
  • llBHSD1 ll- ⁇ hydroxysteroid dehydrogenase type I
  • Step 3 Prepare the target product The product of the above step (362 mg, 1 mmol) was dissolved in dichloromethane (5 ml), and 4N hydrogen chloride dioxane solution (1 ml) was added and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give a white solid.
  • Examples 3 to 58 were prepared in the same manner as in Example 1 or 2, using sulfonamides of different amines and/or different substituents as starting materials.
  • the active compound is mixed with microcrystalline cellulose, anhydrous lactose, polyvinylpyrrolidone, and microsilica gel in a mixer, and then mixed with magnesium stearate to obtain a tablet.
  • the active compound, microcrystalline cellulose, lactose, sodium carboxymethyl starch was sieved through an 80 mesh sieve, mixed, 8% starch slurry was used to make soft material, 16 mesh granulation, dried, granulated, and then added with magnesium stearate. Uniformity, determination of particle content, calculation of tablet weight, tableting, that is.
  • the cells were transfected into HEK293 cells, and stably transfected mixed cell clones were obtained by G418 (0.75 g/D screening).
  • the cell clones were digested with trypsin and seeded into 96-well plates with single cells, and conditional cell culture medium (HEK293 cells) was administered simultaneously. The culture supernatant was obtained, and a single cell proliferation clone was obtained after 14-20 days.
  • the cells were collected by trypsinization, sonicated, centrifuged (4 ° C, 1500 rpm, 10 min), and the supernatant was again subjected to ultracentrifugation (4 ° C). , 100000g, lh), phosphate buffer (40mM Na2HP04, lmM EDTA, 5% glycerol) resuspended the mouse or human lpHSD1 or 2 purified enzyme obtained after precipitation, frozen at -80 °C for use.
  • phosphate buffer 40mM Na2HP04, lmM EDTA, 5% glycerol
  • the inhibitory effect of the compound on mouse or human lpHSDl was determined by SPA (Scintillation proximity assay), liquid scintillation proximity assay. Different concentrations of the test compound were added to a 96-well plate, followed by the addition of 80 ul of A reaction solution (1.25 mM NADPH, 25 nM cortisone [l, 2-(n) 3 H] and HEPES buffer), followed by 8 ( ⁇ g/ml mouse or human lpHSD1 purified enzyme was shaken for 1 h at 37 ° C.
  • SPA Scintillation proximity assay
  • a reaction solution (1.25 mM NADPH, 25 nM cortisone [l, 2-(n) 3 H] and HEPES buffer
  • 8 ⁇ g/ml mouse or human lpHSD1 purified enzyme was shaken for 1 h at 37 ° C.
  • Inhibition rate (CPM of the test compound - CPM of the background hole) I (Enzyme control well CPM - Bottom hole CPM) l 00%
  • the compounds of the examples all had 11BHSD1 inhibitory activity by the above test, and the test results are shown in the following table.
  • Prednisone intravenous administration solution Take prednisone 100 mM mother liquor 50.3 ⁇ M, and dilute to 6 mL with physiological saline to prepare a 0.3 mg/mL solution.
  • Inhibition rate of conversion in the drug-administered group (transition rate of blank group - conversion rate of drug-administered group:) conversion rate of ⁇ blank group l 00%
  • Blank solvent solution The ratio of cyclodextrin and normal saline is 1:9, 2:8 and 3:7 respectively. Formulated into 3 different blank solvent solutions.
  • Prednisone intravenous administration solution Take 158.3 L of prednisone lOO mM mother liquor, dilute to 18.9 mL with physiological saline, and prepare a 0.3 mg/mL solution.
  • mice male, 18-22 g. Divided into 3 groups of 8 each. The first four mice in each group were intraperitoneally injected with 3 mg/kg, 10 mg/kg, 30 mg/kg of the compound of Example 16 and the latter four mice were injected with the corresponding blank vehicle. After lh, all mice were injected with prednisone and 0.2 mL of blood was taken from the fundus venous plexus 2 min later. The blood sample was centrifuged at 6000 rpm for 10 min, and 50 blood was collected and stored in the heart tube at 4 ° C for later use.
  • Inhibition rate of conversion in the drug-administered group (transition rate of blank group - conversion rate of drug-administered group:) conversion rate of ⁇ blank group l 00%

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Abstract

L'invention porte sur un dérivé d'amide représenté par la formule (I) et un sel pharmaceutiquement acceptable ou solvate de celui-ci. L'invention porte également sur un procédé de préparation du dérivé d'amide, sur une composition pharmaceutique contenant le dérivé d'amide et sur une utilisation du dérivé d'amide. Le dérivé d'amide de la présente invention est un inhibiteur de la 11-β-hydroxystéroïde déshydrogénase de type I (11βHSD1) et il est applicable dans le traitement d'un grand nombre de maladies liées à l'expression ou l'activité de la 11βHSD1.
PCT/CN2012/078691 2011-08-09 2012-07-16 Dérivés d'amide et son procédé de préparation, composition pharmaceutique et son utilisation Ceased WO2013020440A1 (fr)

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CN109169509A (zh) * 2018-09-21 2019-01-11 浙江海洋大学 一种大鲵人工繁育的方法

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WO2025224168A1 (fr) 2024-04-24 2025-10-30 Idorsia Pharmaceuticals Ltd Dérivés d'arylsulfone et de sulfanone utilisés en tant que modulateurs du récepteur de l'orexine

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