WO2023160004A1 - Composé à cycle fusionné ayant une activité analgésique, son procédé de préparation et son utilisation - Google Patents

Composé à cycle fusionné ayant une activité analgésique, son procédé de préparation et son utilisation Download PDF

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WO2023160004A1
WO2023160004A1 PCT/CN2022/129152 CN2022129152W WO2023160004A1 WO 2023160004 A1 WO2023160004 A1 WO 2023160004A1 CN 2022129152 W CN2022129152 W CN 2022129152W WO 2023160004 A1 WO2023160004 A1 WO 2023160004A1
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alkoxy
alkyl
alkylamino
hydrogen
aryl
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张哲峰
张爱琴
杨谋伟
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南京知和医药科技有限公司
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present application relates to the technical field of medicines, in particular to a class of condensed ring compounds and their compositions as active ingredients, and the use of such compounds and their compositions for preparing analgesic drugs.
  • Pain is a self-protective reaction caused by tissue damage or potential tissue damage, accompanied by physiological conditions such as emotional anxiety and tension, and is a common symptom or accompanying symptom of many clinical diseases. Pain is divided into acute pain and chronic pain. Acute pain is mainly caused by surgery, severe physical trauma, etc. Chronic pain is usually caused by nociceptive pain, inflammation, neuropathic pain, migraine, etc.
  • Analgesics are a class of drugs that act on the central nervous system and can effectively relieve or eliminate pain without affecting other sensations. They are of great significance in first aid.
  • opioid alkaloids Opioids
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • Opioid receptors include the classical mu, delta, kappa and nonclassical nociceptin (NOP) receptors.
  • ⁇ receptor agonists have the strongest analgesic effect, but usually increase addiction and even cause respiratory depression; ⁇ receptor agonists are less addictive, but the analgesic effect is far less than ⁇ receptor agonists; The analgesic effect of receptor agonists is between the two, but it is easy to cause side effects such as hallucinations, mydriasis, and irritability.
  • the current mainstream opioid receptor agonists mainly include morphine, oxycodone, fentanyl, sufentanil, remifentanil, and methadone. Worryingly, the current abuse of opioids has also led researchers to expand into new research directions, but most of them are in the early clinical stage.
  • Antipyretic and analgesic drugs are a class of drugs that can relieve fever and relieve local pain. They exert antipyretic and analgesic effects by inhibiting the synthesis and release of prostaglandins (PGs) in the hypothalamus, and usually have anti-inflammatory effects. These drugs are better for local pain, neuralgia, joint pain, menstrual pain and other dull pain, but less effective for other kinds of pain. At present, the commonly used ones are: aspirin, ibuprofen, voltaren, and chinoli, etc., but the use of such drugs needs to be considered in different situations.
  • PGs prostaglandins
  • Analgesics currently have relatively large side effects. Therefore, the development of high-quality analgesics is still imminent.
  • the invention provides a novel condensed ring compound and its composition.
  • the compound has strong stability and significant analgesic activity, and is suitable for being developed into various dosage forms.
  • the compound provided by the present invention can overcome the deficiencies of the prior art, has high efficacy in vivo, has long-lasting analgesic effect, and has no obvious side effects.
  • the present invention provides a compound of formula I:
  • Y is selected from CH, or N;
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, Carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6-18 aryl, C 3-12 heteroaryl; the above-mentioned alkyl , alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl can be further optionally replaced by the following One or more groups A are substituted;
  • R4 is selected from
  • T is selected from O, or S;
  • n is selected from 1, 2, or 3;
  • R 5 and R 6 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R 5 and R 6 are connected to form a ring ;
  • R 7 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2-8 heterocyclyl, C 6-18 aryl, C 3-12 heteroaryl; the above - mentioned alkyl , alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl
  • the group and the heteroaryl group can be further optionally substituted by one or more of the following groups A;
  • R 8 and R 9 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R 8 and R 9 are connected to form a ring ;
  • R a and R b are each independently selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or R a and R b are connected to form a ring;
  • R c and R d are each independently selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or R c and R d are connected to form a ring;
  • X1 is selected from O, or N;
  • R 10 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2-8 heterocyclyl, C 6-18 aryl, C 3-12 heteroaryl; the above - mentioned alkyl , alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl
  • the group and the heteroaryl group can be further optionally substituted by one or more of the following groups A;
  • R 11 is selected from hydrogen, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl , C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl, heteroaryl can be further optionally substituted by one or more of the following groups A;
  • X 2 and X 3 are each independently selected from O, NH, or S;
  • R 12 and R 13 are each independently selected from hydrogen, Na, K, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, C 2-8 alkenyl, C 2-8 Alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl, or R 12 , R 13 are connected to form a ring; the above-mentioned alkyl, alkane Oxygen, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl can be further optionally replaced by one or more of the following hydrogen, halogen, hydroxy, hydroxymethyl, hydroxy Ethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl, formalde
  • R 14 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino ;
  • R 15 selected from
  • Z is selected from CH, or N;
  • R 16 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy , C 1-8 alkylamino,
  • R is selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, cyano, trifluoromethyl, methoxy, ethoxy, isopropoxy, methyl Thio, acetyl, methylsulfonyl, ethylsulfonyl;
  • R 18 is selected from C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above carbocyclyl, heterocyclyl, aryl, heteroaryl
  • the group can be further optionally substituted by one or more of the following groups A;
  • Group A is: hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, Methanesulfonyl, ethylsulfonyl, phenyl, benzyl, pyridyl, picolyl, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino.
  • the compound provided by the present invention has the following structure of formula II:
  • the compound provided by the present invention has the following structure of formula III:
  • the compound provided by the present invention has the structure of the following formula IV:
  • the compound provided by the present invention has the following structure of formula V:
  • Y is selected from CH, or N;
  • R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, Cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; wherein, the above-mentioned alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, Heteroaryl can be further optionally substituted by one or more of the following groups A;
  • R 1 is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, cyano, trifluoromethyl , C 1-8 alkyl, C 1-8 alkoxy; more preferably, R 1 is hydrogen .
  • R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, Cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; wherein, the above-mentioned alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, Heteroaryl can be further optionally substituted by one or more of the following groups A;
  • R is selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde Base, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl;
  • R2 is selected from F, Cl, hydroxyl, hydroxyethyl, methoxy, cyano, trifluoromethyl, methylsulfonyl.
  • R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, Cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; wherein, the above-mentioned alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, Heteroaryl can be further optionally substituted by one or more of the following groups A;
  • R is selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde Base, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1 - 8 alkyl, C 1 - 8 alkoxy, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl;
  • R3 is selected from hydrogen, or methyl.
  • L is in
  • R 5 and R 6 are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R 5 and R 6 are connected to form a ring;
  • R 5 and R 6 are each independently selected from hydrogen, or C 1-8 alkyl ;
  • R and R are both hydrogen
  • R 7 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, Aryl and heteroaryl can be further optionally substituted by one or more of the following groups A;
  • R 7 is C 1 - 8 alkyl
  • R 7 is selected from isopropyl or tert-butyl
  • L is in
  • R 8 and R 9 are each independently selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or R 8 and R 9 are connected to form a ring;
  • R 8 and R 9 are each independently selected from hydrogen, or C 1-8 alkyl ;
  • R and R are both hydrogen
  • X 1 is selected from O, or N;
  • X 1 is O, at this time R 11 does not exist;
  • R 10 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, Aryl and heteroaryl can be further optionally substituted by one or more of the following groups A;
  • R 10 is selected from C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino , C 2-8 alkenyl , C 2-8 alkynyl, C 3-8 carbocycle Base, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl;
  • R 10 is selected from methyl, or isopropyl
  • R 11 is selected from C 1 - 8 alkyl, C 1 - 8 alkoxy, C 1 - 8 alkylamino, C 2 - 8 alkenyl, C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above-mentioned alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, Aryl and heteroaryl can be further optionally substituted by one or more of the following groups A; in particular, X is N at this time;
  • L is in
  • R a and R b are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R a and R b are connected to form a ring ;
  • R a and R b are each independently selected from hydrogen, or C 1-8 alkyl ;
  • R a and R b are both hydrogen;
  • R c and R d are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino, or R a and R b are connected to form a ring ;
  • R c and R d are each independently selected from hydrogen, or C 1-8 alkyl ;
  • both R a and R b are hydrogen, or one of R a and R b is hydrogen, and the other is methyl;
  • L is in
  • X 2 and X 3 are each independently selected from O, NH, or S;
  • X 2 and X 3 are each independently selected from O, or NH;
  • R 12 and R 13 are each independently selected from hydrogen, Na, K, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino , C 2-8 alkenyl , C 2 - 8 alkynyl, C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl, or R 12 and R 13 are connected to form a ring; wherein, the above-mentioned alkyl Alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl can be further optionally replaced by one or more of the following hydrogen, halogen, hydroxyl, methylol hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl
  • R 12 and R 13 are each independently selected from hydrogen, Na, C 1-8 alkyl, C 6-18 aryl, or R 12 and R 13 are connected to form a 5-6 membered ring;
  • R 16 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino, or
  • R 4 is in
  • T is selected from O, or S;
  • m is selected from 1, 2, or 3;
  • m is selected from 1, or 2;
  • R 14 is selected from hydrogen, C 1-8 alkyl , C 1-8 alkoxy, C 1-8 alkylamino;
  • R 14 is selected from hydrogen, or C 1-8 alkyl ;
  • R 14 is selected from hydrogen, methyl, or ethyl
  • the above Z is selected from CH, or N;
  • R is selected from hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, cyano, trifluoromethyl, methoxy, ethoxy, isopropoxy, Methylthio, acetyl, methylsulfonyl, ethylsulfonyl;
  • R 17 is selected from hydroxyl, methylthio, isopropoxy, acetyl;
  • R 18 is selected from C 3 - 8 carbocyclyl, C 2 - 8 heterocyclyl, C 6 - 18 aryl, C 3 - 12 heteroaryl; the above carbocyclyl, heterocyclyl, aryl, hetero
  • the aryl group can be further optionally substituted by one or more of the following groups A;
  • R 18 is selected from C 5 - 6 carbocyclyl, or C 2 - 5 heterocyclyl; wherein, the above-mentioned carbocyclyl and heterocyclyl can be further optionally replaced by one or more of the following groups A replace;
  • Group A is: hydrogen, halogen, hydroxyl, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, Methanesulfonyl, ethylsulfonyl, phenyl, benzyl, pyridyl, picolyl, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino.
  • the compound provided by the invention has the following structure:
  • the present invention provides compounds comprising the above compounds, or solvates, pharmaceutically acceptable salts, enantiomers, diastereoisomers, racemic mixtures (as active compounds) Component) and the pharmaceutical composition of inert carrier.
  • composition the applicable composition form comprises: injection, powder, spray, inhalant, tablet, pill, capsule, lozenge, jelly, powder, granule, gel, cream, Ointments, patches, suppositories, suspensions, syrups.
  • composition wherein the active ingredient occupies a unit dose of 0.01 mg-1.0 g of the body weight of the individual in need of treatment.
  • the present invention provides the use of the above-mentioned pharmaceutical composition in the preparation of medicines for treating and/or preventing related diseases or conditions.
  • the related diseases or conditions include neuropathic pain, oral pain, facial pain, internal organ pain, headache, insomnia, cognitive decline, appetite disturbance, emotional disturbance, sunset syndrome, Alzheimer's disease.
  • a method of treating a disease or condition comprises administering to a subject in need thereof a therapeutically effective amount of said compound or said composition.
  • the compound disclosed in the invention has the function of inhibiting the deposition of ⁇ -amyloid protein.
  • the compound disclosed in the present invention has more significant analgesic effect.
  • the compounds disclosed in the present invention have stronger blood-brain barrier penetration and greater in vivo exposure, especially compound RE-33, which is the most excellent in the above aspects.
  • amino group herein refers to a functional group having 1 nitrogen atom and 0, 1, or 2 hydrogen atoms.
  • the halogen herein refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C1-8 alkyl refers to a straight chain, side chain or cyclic hydrocarbon group having 1 to 8 carbon atoms.
  • C1-8 alkoxy refers to a straight-chain, side-chain or cyclic hydrocarbon group having 1 to 8 carbon atoms inserted into an -OH or -O- group at any reasonable position.
  • C1-8 alkylamino refers to a group in which -N-, -NH-, -NH2 atomic groups are inserted at any reasonable position of "C1-8 alkyl". For example, methylamino, ethylamino, diisopropylamino, N-methyl-n-propylamino, di-n-propylamino, N-ethylisopropylamino, 2-(isopropylamino)ethyl and the like.
  • C2-8 alkenyl refers to a straight chain, branched chain or cyclic hydrocarbon group containing at least one carbon-carbon double bond in a molecule having 2 to 8 carbon atoms.
  • C2-8 alkynyl refers to a straight-chain, branched-chain or cyclic hydrocarbon group containing at least one carbon-carbon triple bond in a molecule having 2 to 8 carbon atoms.
  • C3-8 carbocyclyl refers to a saturated or unsaturated alicyclic hydrocarbon group having 3 to 8 carbon atoms.
  • the cyclic hydrocarbon group can be selected from one ring, or polycyclic fused, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, dicyclopentyl, methylcyclohexyl, ethyl Cyclohexyl, decalinyl, 3-cyclopentyl-1-propyl, 1,3-cyclohexadienyl, 1-methyl-1-cyclohexenyl, etc.
  • C2-8 heterocyclic group refers to a saturated or unsaturated monocyclic or polycyclic group with at least one ring containing heteroatoms with 2 to 8 carbon atoms.
  • Each ring of this type of polycyclic heterocycloalkyl group may have Different connection methods, such as fusion, bridging, spiro, etc.
  • pyrrolidinyl piperidinyl, morpholinyl, homopiperazinyl, 4-pyrrolidin-1-yl-piperidinyl, 3-methylpiperidinyl, N-methylpiperidinyl, N-ethyl Piperidinyl, furyl, thienyl, pyrazolyl, oxazolyl, tetrahydro-3-thiol, 4-methyl-1-piperazineethyl, etc.
  • C6-18 aryl refers to a group containing at least one aromatic ring with 6 to 18 carbon atoms.
  • each ring of the polycyclic aryl group can have different connection methods, such as fused , bridging, etc., and the fused rings may be saturated or unsaturated.
  • fused e.g., fused , bridging, etc.
  • the fused rings may be saturated or unsaturated.
  • C3-12 heteroaryl refers to a monocyclic or polycyclic aromatic heterocyclic group with 3 to 12 carbon atoms and containing at least one heteroatom, and each ring of the polycyclic heteroaryl group can have different connections , such as fused, bridged, etc., such as furyl, thienyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, indolyl, pyrazinyl, quinolinyl, pyridazinyl, indenyl, indanyl base, benzofuryl, etc.
  • the double bond-containing compounds of the present invention include all configurational isomers (such as cis and trans isomers).
  • hetero atom in the present invention includes nitrogen atom, oxygen atom, phosphorus atom, boron atom, sulfur atom, selenium atom and the like.
  • the compounds of the present invention possess one or more asymmetric centers and the present invention therefore relates to the use of all optical isomers and stereoisomers of these compounds and mixtures thereof. It also includes the use of compounds with tautomers and their mixtures.
  • the compounds of the present invention contain basic nitrogen atoms (heterocyclic or aliphatic amino groups, etc.), and are easily oxidized by oxidants such as oxygen in the air and hydrogen peroxide to be selected from N-oxides to generate other compounds of the present invention.
  • the converted N-oxide derivatives are therefore part of the group selected from the compounds of the present invention.
  • each instance of a substituent is selected from the available variable definitions independently of other selections to define the variable. Accordingly, each substituent may be the same as or different from the other substituents.
  • Treatment refers to the effect of significantly reversing, alleviating the symptoms of the individual's disease, or causing the reversal of the progress of the disease by administering a drug or a pharmaceutical composition to the individual.
  • “Individuals in need of treatment” in the present invention refer to warm-blooded animals or cold-blooded animals, such as humans, rats, mice, rabbits, dogs, pigs, sheep, chickens, ducks, geese, cats, cows, horses, etc.
  • the “compounds and their salts” mentioned in the present invention refer to the complexes formed by the combination of the compound and the corresponding acid. This property depends on the characteristics of the compound.
  • the addition salt of the compound and the acid for example, an inorganic acid salt such as Hydrochloride, sulfate, hydrobromide, etc.
  • Organic acid salts such as maleate, fumarate, acetate, propionate, malate, tartrate, malonate, succinate, citrate, cinnamate, mandelate , Methanesulfonate, p-toluenesulfonate, salicylate, etc.
  • the “compounds and their salts” mentioned in the present invention also refer to the addition salts of the compounds and bases, salts of inorganic bases such as sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts and the like.
  • Salts of organic amines such as diethylamine salts, ethylenediamine salts, meglumine salts, tromethamine salts, arginine salts, lysine salts, histidine salts, piperidine salts, etc.
  • in the present invention refers to substances that help individuals to take or absorb the active substances in the pharmaceutical composition, and will not cause obvious adverse effects on patients or individuals, including glucose, disintegrants, fillers, Flavoring agent, lubricant, fatty acid ester, hydroxymethyl cellulose, stabilizer, emulsifier, colorant, starch, sodium saccharin, cellulose, etc.
  • the "disease or disease” in the present invention refers to neuropathic pain, joint pain, postoperative pain, obstetrical pain, herpes zoster pain, gout, joint degeneration pain, discogenic pain, trigeminal neuralgia, intractable headache , tumor pain, angina pectoris, idiopathic chest and abdominal pain, oral pain, facial pain, internal organ pain, etc.
  • the “disease or disease” mentioned in the present invention also includes insomnia, Alzheimer's disease, sunset syndrome, Parkinson's disease, memory loss, inattention, mental retardation, addiction and the like.
  • composition refers to a specific amount of the compound provided by the present invention, or any product obtained directly or indirectly from the specific amount of the compound provided by the present invention.
  • the compounds of the present invention can be used alone or in combination with one or more other drugs for the treatment and prevention of diseases or symptoms described by the compounds of the present invention. Combined use can have more significant curative effect.
  • the compound of the present invention occupies a unit dose of 0.01 mg to 1.0 g, more preferably 0.1 mg to 0.5 g, of the body weight of an individual in need of treatment.
  • Figure 1 shows the results of the analgesic test of the compounds of the present invention and TM.
  • Fig. 2 shows the ⁇ -amyloid deposition inhibitory activity of the compounds of the present invention.
  • Embodiment one the preparation of intermediate E
  • Embodiment two the preparation of compound RE-01
  • intermediate H 2.5g, 0.01mol, 1.0eq
  • dichloromethane 100mL
  • HOBt 1.g, 0.01mol, 1.0eq
  • EDCI 1.9g , 0.01mol, 1.0eq
  • intermediate E stirred at room temperature for 6 hours
  • concentrated under reduced pressure washed with water (2*50mL)
  • Embodiment three the preparation of compound RE-22 and compound RE-23
  • Embodiment four the preparation of compound RE-24
  • Embodiment five the preparation of compound RE-25
  • Embodiment six the preparation of compound RE-28
  • Embodiment seven the synthesis of compound TM
  • Dissolve SM01 (7.5g, 45.28mmol) in a mixed solvent of acetonitrile (45mL) and water (75mL), add triethylamine (13.75g, 135.85mmol), the system exotherms, cool the reaction system to 10°C, add Boc Acetonitrile solution (15 mL) of acid anhydride (14.83 g, 67.93 mmol) was added dropwise, stirred at room temperature for 70 h, and the reaction was detected by TLC.
  • Dissolve IM01 (8.88g, 38.73mmol) in dichloromethane (60mL), add benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 14.69g, 38.73mmol) and N,N-diisopropylethylamine (DIPEA, 13.02g, 100.7mmol), stirred for 0.5h, then added DCM solution (40mL) dissolved in SM02 (10.00g, 63.85mmol), and reacted overnight at room temperature , TLC detected that the reaction was complete.
  • HBTU benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • IM03 (6.0 g, 17.16 mmol) was dissolved in dioxane (50 mL), and trifluoroacetic acid (TFA, 9.78 g, 85.82 mmol) was added under ice cooling, stirred overnight, and the reaction was detected by TLC.
  • TFA trifluoroacetic acid
  • reaction solution was concentrated to dryness to obtain a brown oil, namely the crude compound IM04 (6.5 g), which was fed to the next step according to 100% without further treatment.
  • SM03 (8.08g, 29.06mmol) was dissolved in N,N-dimethylformamide (DMF, 70mL), the solution was khaki, and 1H-1,2,3-triazole (4.01g, 58.12mmol ) and cesium carbonate (18.94g, 58.12mmol), the temperature was raised to 40°C, a small amount of gas was released, and cuprous iodide (0.277g, 1.45mmol) was added, the solution gradually turned green, and the temperature rise was not obvious, and the temperature was raised to 70°C, and stirred After 1 h, TLC detected that the reaction was complete.
  • DMF N,N-dimethylformamide
  • IM04 (3.0g, 10.48mmol) was dissolved in dichloromethane (30mL), and IM05 (2.30g, 10.48mmol), DIPEA (6.77g, 52.40mmol), HBTU (3.98g, 10.48mmol) were added successively in an ice bath , start the reaction (as the reaction proceeds, the solution color gradually turns brownish red), the reaction is stirred overnight, and TLC detects that the reaction is complete.
  • Embodiment 8 Preparation of compound RE-31
  • Embodiment 9 Preparation of compound RE-32
  • Embodiment 10 Preparation of compound RE-33
  • Embodiment 11 Preparation of compound RE-37
  • Embodiment 12 Preparation of compound RE-38
  • Embodiment 14 The influence of acetic acid writhing method to measure the pain of mice
  • the concentrations of the above compounds were 0.26mg/mL, 0.33mg/mL, 0.33mg/mL, 0.32mg/mL, 0.33mg/mL, 0.35mg/mL, 0.44mg/mL, 0.46mg/mL, 0.35mg/mL, 0.32mg/mL, 0.33mg/mL, 0.31mg/mL, 0.33mg/mL, 0.32mg/mL, 0.34mg/mL, 0.43mg/mL, 0.46mg/mL, 0.32mg/mL and 0.36mg/mL ( The molar concentration of each compound is the same).
  • mice Sixty 18-22g female KM mice were divided into 20 groups with 3 mice in each group.
  • the administration group and the TM control group were injected intraperitoneally with 0.4 mL of the newly prepared compound solution, and the model group was injected with the same volume of water for injection intraperitoneally.
  • each mouse was intraperitoneally injected with 0.2 mL of 0.6% glacial acetic acid solution, and at the same time recorded the times of writhing in each mouse within 20 minutes, and calculated the average value. The result is shown in Figure 1.
  • Example 15 ⁇ -amyloid deposition inhibitory activity
  • Accelerated aging mice (SAMP8), 63 males (8 months old at the start of the study), were divided into 9 groups with 7 mice in each group.
  • the non-intervention group drank tap water normally; experimental group 1-experimental group 8 respectively drank tap water containing compounds (RE-01, RE-23, RE-31, RE-32, RE-33, RE-37, RE-45 , RE-47) solution, the dosage is 0.1mg/kg/day.
  • Sections were immunostained with streptavidin-biotin using the VECTASTATIN ABC kit. After incubation in 10% normal goat serum for one hour, the anti- ⁇ -amyloid (A ⁇ ) antibody was diluted 10-fold with PBS and incubated overnight at 4°C. The next day, wash with PBS, incubate with biotinylated anti-rabbit secondary antibody for 1.5 hours, wash with PBS, and incubate with peroxidase-labeled streptavidin for 1.5 hours. Immunoreactions were visualized and samples prepared with DAB.
  • Immunoreactive A ⁇ -like granules in the hippocampus were counted under a microscope. A ⁇ -like immunoreactive granules were observed as brown deposits in the hippocampus. Each individual was counted using one slice.
  • ⁇ -amyloid-like immunoreactivity in the hippocampus was observed in the untreated group of accelerated aging mice (SAMP8).
  • SAMP8 accelerated aging mice
  • SAM8 experimental groups 1 to 8 of accelerated aging mice
  • Embodiment 16 Compound Parallel Artificial Membrane Permeation Model (PAMPA) test disclosed by the present invention
  • the compound was diluted into a 25 ⁇ g/mL solution with a buffer solution with a pH of 7.4; the pig brain lipid extract (PBL) was dissolved in dodecane to form a 20 mg/mL solution as a phospholipid film; Add 4 ⁇ L of PBL solution dropwise on the vinyl fluoride membrane to form a phospholipid membrane simulating the environment in the brain; add 300 ⁇ L/well buffer solution above the phospholipid membrane as an acceptor tube, and add 150 ⁇ L/well of 25 ⁇ g/mL compound to another 96-well plate
  • the solution is used as a donor tube, and each drug has three parallel holes; the two plates are stacked so that the phospholipid membrane can contact the donor solution to form a sandwich structure, and placed in a constant temperature environment at 37°C for 18 hours; the 96-hole filter plate
  • the medium solution was taken out and transferred to a blank 96-well plate, and the OD value was measured at 340 nm.
  • the data show that the compounds disclosed in the present invention have stronger ability to penetrate the blood-brain barrier than the reference compound TM, wherein compounds RE-31, RE-32, RE-33, RE-35, RE-38 and RE-45 pass through the blood-brain barrier
  • the ability is 11 to 16 times that of TM. It shows that the compounds disclosed in the present invention can more advantageously pass through the blood-brain barrier and reach the brain, so as to more effectively play the role of treating brain diseases.
  • mice 12 male SD rats, 180g-220g, were fed adaptively for 3 days before the experiment.
  • Preparation of the test product Weigh the appropriate amount of the test product TM, RE-33, RE-37 and RE-38 respectively, place them in reagent bottles, add an appropriate amount of 0.5% carboxymethyl cellulose solution, and prepare TM, RE-33 , RE-37 and RE-38 concentrations are respectively 2.0mg/mL, 2.4mg/mL, 2.5mg/mL and 2.6mg/mL (molar concentration of each compound is the same) of the test solution.
  • Test method Rats were randomly divided into 4 groups, including TM group, RE-33 group, RE-37 group and RE-38 group, with 3 rats in each group. Each animal was given the newly prepared corresponding test solution by gavage respectively. The dosage was 4 mg/kg in TM group, 4.8 mg/kg in RE-33 group, 5.0 mg/kg in RE-37 group and 5.2 mg/kg in RE-38 group. Fast for 16-17 hours before administration, and 4 hours after administration, and water is not allowed during the whole process.
  • Observation of general clinical symptoms During the whole process of the experiment, observe the general state of the experimental animals. The observation contents include: changes in food intake and water intake of rats, changes in body weight, abnormality in coat color, abnormality in behavior and mental state, eye, Whether there are abnormal secretions in the ears, mouth and nose, and whether there is any abnormality in urine and stool. If there is an abnormality, it will be recorded immediately and the cause of the abnormality will be analyzed.
  • the maximum blood drug concentration of the compounds disclosed in the present invention is more than 120%, and the exposure is more than 130% of it, especially RE-33, which is the best in terms of maximum blood drug concentration and in vivo exposure prominent, and there is no abnormality in the observation of general clinical symptoms, indicating that the compounds disclosed in the present invention have higher bioavailability.
  • Embodiment 18 Rat brain tissue distribution experiment
  • mice 12 male SD rats, 180g-220g, were fed adaptively for 3 days before the experiment.
  • Preparation of the test product Weigh the appropriate amount of the test product TM, RE-33, RE-37 and RE-38 respectively, place them in reagent bottles, add an appropriate amount of 0.5% carboxymethyl cellulose solution, and prepare TM, RE-33 , RE-37 and RE-38 concentrations are respectively 2.0mg/mL, 2.4mg/mL, 2.5mg/mL and 2.6mg/mL (molar concentration of each compound is the same) of the test solution.
  • Test method Rats were randomly divided into 4 groups, including TM group, RE-33 group, RE-37 group and RE-38 group, with 3 rats in each group. Each animal was given the newly prepared corresponding test solution by gavage respectively. The dosage is 4 mg/kg in TM group, 4.8 mg/kg in RE-33 group, 5.0 mg/kg in RE-37 group and 5.2 mg/kg in RE-38 group; Eat for 4 hours, the whole process can not help water.
  • Sampling and detection Animals in each group were sacrificed 3.0 hours after intragastric administration, the brain tissue was separated, homogenized, and analyzed by LC-MS/MS to detect TM. The results are shown in the table below. The results are shown in Table 3.

Abstract

L'invention concerne un composé à cycle fusionné ayant une activité analgésique telle que représentée dans la formule I, ainsi que son procédé de préparation et son utilisation. Le composé a une activité analgésique remarquable, peut être développé en médicaments pour le traitement de diverses maladies telles que les symptômes de douleur et la maladie d'Alzheimer, et est également approprié pour être développé sous diverses formes posologiques.
PCT/CN2022/129152 2022-02-25 2022-11-02 Composé à cycle fusionné ayant une activité analgésique, son procédé de préparation et son utilisation WO2023160004A1 (fr)

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