CN113429390A - Quinazoline derivatives and uses thereof - Google Patents

Quinazoline derivatives and uses thereof Download PDF

Info

Publication number
CN113429390A
CN113429390A CN202110297107.7A CN202110297107A CN113429390A CN 113429390 A CN113429390 A CN 113429390A CN 202110297107 A CN202110297107 A CN 202110297107A CN 113429390 A CN113429390 A CN 113429390A
Authority
CN
China
Prior art keywords
oxy
methylquinazolin
propyl
methyl
ethyl
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
CN202110297107.7A
Other languages
Chinese (zh)
Other versions
CN113429390B (en
Inventor
陈科
蒋钰
季明华
王小华
黄从报
金雪梅
张长青
万泽红
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou Enhua Biomedical Technology Co Ltd
Original Assignee
Suzhou Enhua Biomedical Technology Co Ltd
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 Suzhou Enhua Biomedical Technology Co Ltd filed Critical Suzhou Enhua Biomedical Technology Co Ltd
Publication of CN113429390A publication Critical patent/CN113429390A/en
Application granted granted Critical
Publication of CN113429390B publication Critical patent/CN113429390B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to the field of chemical medicine, in particular to quineThe specific structure of the oxazoline derivative is shown as a formula I, the series of oxazoline derivatives have good sigma 1 receptor affinity and selectivity, are strong selective inhibitors of sigma 1 receptors,
Figure DDA0002984745370000011

Description

Quinazoline derivatives and uses thereof
the present application claims priority of a prior application entitled "quinazoline derivatives and their use" to the patent application No. 202010206708.8 filed on 23.3.2020 of the present application to the intellectual property office of the chinese country. The entire contents of said prior application are incorporated by reference into the present application.
Technical Field
The invention relates to the field of chemical medicine, in particular to a quinazoline derivative and pharmaceutical application thereof.
Background
The Sigma-1 receptor (Sigma 1 receptor) is an emerging drug target in recent years, is a binding protein of various specific central nervous system drugs, and plays a physiological role as a receptor type molecular chaperone. The main physiological functions of sigma-1 receptors in the central nervous system include analgesia, nerve protection, cognitive regulation, drug addiction improvement, dyskinesia and the like, while peripheral sigma-1 receptors are involved in regulating the immune function of the body.
Sigma 1 receptors are highly expressed in both central nervous system and peripheral nerves, and are mainly distributed in cell membranes, Endoplasmic Reticulum (ER) membranes and mitochondrial membranes in central nerves, and in lymphatic tissues, lung, liver, kidney, pancreas, spleen, adrenal gland, and heart in peripheral nervous system.
Sigma receptors have no homology with opioid receptors, and there are two subtypes, σ 1 and σ 2. They bind to ligands in a very unique way: the affinity of the sigma 1 receptor to dextrorotatory medicaments is stronger than that of levorotatory medicaments; the affinity of sigma 2 receptors for levorotary drugs is higher than for dextrorotary drugs. SKF10047 has nanomolar affinity for the σ 1 site and micromolar affinity for the σ 2 site.
The Sigma-1 receptor (Sigma 1 receptor) was successfully cloned in 1996 as a 29-kDa single-chain protein with 223 amino acid residues and a relative molecular weight of 26000. the active binding site of the Sigma-1 receptor protein is mainly on the amino acid chain from amino acid 116 to amino acid 223, and the long-chain C-terminal hydrophobic moiety often binds to the Sigma-1 receptor ligand together with one or both of the two hydrophobic transmembrane moieties.
σ 1 is a ligand-regulated chaperone that exerts its chaperone effect by interacting with NMDA and opioid receptors. Under normal physiological conditions, the sigma-1 receptor is present in an inactive state in the mitochondrially-associated endoplasmic reticulum membrane, forming a Ca2+ sensitive complex with another chaperone glucose regulatory protein 78(GRP78), also known as immunoglobulin heavy chain binding protein (Bip). In pathological conditions, σ 1 and Bip segregate, dissociate into the cytoplasm and cell membrane, and bind to other proteins, and participate in the regulation of a variety of physiological functions. When Ca is in ER2+When concentration is reduced or specific agonist acts on sigma 1 receptor, sigma 1 receptor is separated from Bip and activated, redistributed to cell membrane lipid raft, and regulates ion channel, protein kinase and G protein coupleThe cognate receptor (GPCR), initiates multiple downstream signaling pathways. The Sigma-1 receptor may exert its physiological effects by the following mechanisms: after the sigma 1 receptor is separated from the Bip, the receptor becomes an excited state, is redistributed and is combined with the IP3 receptor to stabilize the IP3 receptor and cause intracellular Ca2+Enters mitochondria through voltage-gated ion channels, starts tricarboxylic acid circulation in mitochondria and promotes cell metabolism, thereby generating neuroprotection and axon growth promotion effects.
The physiological functions of the sigma-1 receptor (sigma 1 receptor) mainly include analgesia, nerve protection, cognitive regulation, drug addiction improvement and dyskinesia improvement. From biological and functional studies of the sigma receptor, there has been evidence that sigma receptor ligands may be useful in the treatment of psychiatric disorders (e.g., schizophrenia, depression, anxiety, etc.) and neurological disorders (e.g., alzheimer's disease, pain, etc.) and dyskinesias such as dystonia and tardive dyskinesia, dyskinesias associated with huntington's chorea or tourette's syndrome, and parkinson's disease. The known sigma receptor ligand, lincarbazol, has been reported to show clinical efficacy in the treatment of psychosis. The sigma binding site has preferential affinity for certain opiates such as SKF10047, (+) -cycloxazine and (+) -tebuconazole, the dextroisomer of benzomorphan and certain narcolepsy such as haloperidol.
Currently, the prior art discloses different ligands for sigma receptors. Wherein the patent discloses the structure of sigma receptor analogs and the use in CNS related disorders; however, these structures are not the same as the structures of this patent.
In view of the potential applications of sigma receptor antagonists or agonists in the CNS field of pain, psychosis and the like, it is of great importance for clinical use to find compounds with potent and selective pharmacological activity at the sigma 1 receptor and with good "pharmaceutically acceptable" properties, i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion.
Disclosure of Invention
The present invention has been made to solve at least one of the technical problems occurring in the prior art, and therefore it is an object of the present invention to provide a quinazoline compound which has good affinity and selectivity for sigma 1 receptor and is a strong selective inhibitor for sigma 1 receptor.
In one aspect, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt, or solvate thereof:
Figure BDA0002984745350000021
wherein n1 is an integer from 1 to 6; n2 is an integer from 1 to 5;
w is C or S;
R3is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, the substituent is selected from halogen, hydroxyl, nitro, alkoxy;
R2is hydroxyl, double-bonded oxy, substituted or unsubstituted alkyl, and the substituent is selected from halogen, hydroxyl, nitro and alkoxy;
R1is hydrogen, doubly-bound oxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and the substituent is selected from halogen, hydroxyl, nitro and alkoxy;
or, R1And R2Form a
Figure BDA0002984745350000031
Preferably, the alkyl is C1-10 alkyl, more preferably C1-5 alkyl;
preferably, the aryl group is a C5-10 aryl group, more preferably a phenyl group;
preferably, the alkenyl is C2-10 alkenyl, more preferably C2-5 alkenyl;
preferably, the cycloalkyl is C3-10 cycloalkyl, more preferably C3-5 cycloalkyl;
preferably, the alkoxy is C1-10 alkoxy, more preferably C1-5 alkoxy;
preferably, when W is S, R1、R2At the same time being doubly-bound oxy；
Preferably, n1 is an integer of 2-4;
preferably, n2 is an integer of 2 to 3.
In a preferred embodiment of the invention, the compound of formula I, or a pharmaceutically acceptable salt, or solvate thereof, wherein n1 is an integer from 1 to 6; n2 is an integer from 1 to 5;
w is C or S;
R3is methyl; substituted or unsubstituted phenyl, said substituent being halogen; C1-C5 haloalkyl;
R2is a hydroxyl group; double bond oxy; c1-5 straight or branched chain alkyl;
R1is hydrogen; c1-5 straight or branched chain alkyl; alkenyl of C2-5; cycloalkyl of C3-C5; an alkoxy group; C1-C5 haloalkyl; substituted or unsubstituted phenyl, said substituent being halogen; double bond oxy;
or, R1And R2Form a
Figure BDA0002984745350000032
Preferably, n1 is 3, and n2 is an integer of 2-3;
preferably, W is C;
preferably, R3Is methyl or C1-C5 haloalkyl;
preferably, R2Is a hydroxyl group;
preferably, R1Is hydrogen, straight chain or branched chain alkyl of C1-5, alkenyl of C2-5, cycloalkyl of C3-C5, halogenated alkyl of C1-C5, phenyl or halogenated phenyl;
preferably, when W is S, R1、R2And is also doubly bonded oxy.
Further, the halogenated alkyl group of C1-C5 is selected from the group consisting of fluorinated alkyl group of C1-C5, chlorinated alkyl group of C1-C5, brominated alkyl group of C1-C5, and iodoalkyl group of C1-C5.
Further, the alkoxy is selected from methoxy, ethoxy and propoxy.
Further, the cycloalkyl of C3-C5 is selected from cyclopropyl, cyclobutyl and cyclopentyl.
Further, the C1-5 linear or branched alkyl group is selected from methyl, ethyl, isopropyl, isobutyl, and tert-butyl.
Further, the substituted phenyl is chlorophenyl, fluorophenyl or bromophenyl.
Further, the alkenyl of C2-5 is selected from ethenyl, propenyl, butenyl.
Further, the C1-C5 fluoroalkyl is selected from trifluoromethyl and difluoromethyl.
In a preferred embodiment of the invention, the compound of formula I, or a pharmaceutically acceptable salt, or solvate thereof, is of the structure:
Figure BDA0002984745350000041
wherein n1 is an integer from 2 to 5; n2 is an integer from 1 to 4;
R3is methyl, chlorophenyl, difluoromethyl, trifluoromethyl;
when W is C, R2Is hydroxy, doubly-bound oxy or methyl; r1Is hydrogen, methyl, ethyl, isopropyl, isobutyl, tert-butyl, vinyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, phenyl or chlorophenyl; or, R1And R2Form a
Figure BDA0002984745350000042
When W is S, R1、R2And is also doubly bonded oxy.
Further, any of the compounds represented by formula I, or a pharmaceutically acceptable salt or solvate thereof, is selected from any one of the compounds represented by the following formulae, or a pharmaceutically acceptable salt or solvate thereof:
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -4-phenylpiperidin-4-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -4- (4-chlorophenyl) piperidin-4-ol;
4-methyl-1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) piperidin-4-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -4- (trifluoromethyl) piperidin-4-ol;
1- (3- ((2- (difluoromethyl) quinazolin-4-yl) oxy) propyl) -4-methylpiperidin-4-ol;
1- (3- ((2- (difluoromethyl) quinazolin-4-yl) oxy) propyl) -4- (trifluoromethyl) piperidin-4-ol;
1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) -4-phenylpiperidin-4-ol;
4-methyl-1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) piperidin-4-ol;
1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) -4- (trifluoromethyl) piperidin-4-ol;
4-isopropyl-1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) piperidin-4-ol;
4- (tert-butyl) -1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) piperidin-4-ol;
1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) -3-phenylpyrrolidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -3-phenylpyrrolidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) pyrrolidin-3-ol;
3-methyl-1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) pyrrolidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -3- (trifluoromethyl) pyrrolidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -3-vinylpyrrolidin-3-ol;
4- (3- (3-methoxy-3-methylpyrrolidin-1-yl) propoxy) -2-methyl quinazoline;
3-cyclopropyl-1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) pyrrolidin-3-ol;
3-methyl-1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) pyrrolidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -3-phenylazetidin-3-ol;
1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) -3-phenylazetidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) piperidin-4-one;
8- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -1, 4-dioxa-8-azaspiro [4.5] decane;
4- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) thiomorpholine 1, 1-dioxide;
1- (2- ((2- (4-chlorophenyl) quinazolin-4-yl) oxy) ethyl) piperidin-4-ol.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In another aspect, the invention provides the use of a compound of formula I and pharmaceutical compositions thereof in the manufacture of a medicament for the treatment and prevention of sigma receptor related diseases or conditions. Further, the sigma receptor associated disease or condition is pain, preferably neuropathic or inflammatory pain, post-operative pain, cancer pain, trigeminal neuralgia, osteoarthritis pain, burn pain, phantom limb pain.
In the present invention:
the terms "optional," "optionally," or "optionally present" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "an optionally present bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds, and the like.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements. It should be understood that the term "comprising" may encompass the closed meaning, i.e., "consisting of … …".
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as compounds of the general formula above or as specified in the examples, subclasses. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optionally substituted group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be substituted at each position, identically or differently.
In addition, it should be noted that, unless otherwise explicitly indicated, the description of the present invention as "independently" is to be understood in a broad sense and may mean that specific items expressed between the same symbols in different groups do not affect each other, or that specific items expressed between the same symbols in the same groups do not affect each other.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-C5 alkyl" refers specifically to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) And the like.
Ranges (e.g., numerical ranges) recited herein can encompass each value in the range as well as each subrange formed by the respective value. Thus, for example, the expression "n 2 is any integer between 0 and 3" includes, for example, any integer between 0 and 2, any integer between 2 and 3, and the like, such as 1, 2, 3.
The expression "one or more" may denote 1, 2, 3, 4, 5, 6 or more.
The term "hydrogen (H)" denotes a single hydrogen atom. Such radicals may be attached to other groups, such as oxygen atoms, to form hydroxyl groups.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "alkyl" refers to saturated hydrocarbon radicals including straight chain alkyl radicals, branched chain alkyl radicals.
The term "aryl" refers to a monocyclic ring, the ring members being ring carbon atoms, the ring system sharing (4n +2) pi electrons (where n is a positive integer) to comply with the Huckel rule.
The term "alkenyl" refers to a monovalent straight or branched chain hydrocarbon group having at least one double bond.
The term "cycloalkyl" refers to a monocyclic hydrocarbon group that is saturated or contains one or more units of unsaturation, but is not aromatic, the ring being a 3-20 membered ring with a single point of attachment to the rest of the compound.
The term "alkoxy" refers to the group-O-R, where R is alkyl.
Doubly bound oxy is
Figure BDA0002984745350000071
The term "pharmaceutically acceptable salts" includes those salts derived from suitable inorganic as well as organic acids. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid and the like, or by using other methods in the art such as ion exchange and the like. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentylpropionates, gluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, laurates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, embonates, pectinates, persulfates, 3-phenylpropionates, phosphates, pivaloates, propionates, stearates, succinates, salts, Sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, pentanoates, and the like.
Advantageous technical effects of the invention
The compound provided by the invention is a sigma-1 receptor inhibitor with a quinazoline structure, has pharmacological activity and receptor selectivity on a sigma-1 receptor, and preparation methods of the compound and application of the compound in treatment and prevention of central nervous system diseases. The series of compounds have good sigma-1 receptor inhibitory activity, can be used in combination with morphine, can remarkably improve the synergistic effect of morphine, and is effective on I-phase pain and II-phase pain induced by a formalin model.
Drawings
FIG. 1 is a graph of the inhibitory effect of the compound of example 5 (EP0023-C054) in formalin analgesic assay on phase I pain
FIG. 2 is a graph of the inhibitory effect of the compound of example 5 (EP0023-C054) on phase II pain in the formalin analgesic test
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. Unless otherwise indicated, all ratios, percentages, and the like referred to herein are by weight.
General scheme of synthesis:
the following examples are for illustrative purposes only and are not intended to be limiting of the present invention.
Synthesis scheme 1: the compounds of the present invention can be obtained by cyclization and substitution reactions
Reaction scheme 1
Figure BDA0002984745350000081
The term "pharmacological tool" refers to the property of the compounds of the invention by which they are highly selective ligands of the sigma receptor, which indicates that the compounds of formula I according to the invention can be used as a model for testing other compounds as sigma ligands, e.g. radioligands are substituted, and also for establishing physiological activity related to the sigma receptor.
The invention also provides a pharmaceutical composition for administration to a patient, which comprises a compound of the invention, a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
In a preferred embodiment, the pharmaceutical composition is in solid or liquid oral form. Suitable dosage forms for oral administration may be tablets, capsules, syrups or solutions, and may contain conventional excipients known in the art, such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth or povidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricants, such as magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or a pharmaceutically acceptable wetting agent such as sodium lauryl sulfate.
The solid oral compositions may be prepared by conventional methods of mixing, filling, and tableting. Repeated mixing operations can be used to distribute the active agent throughout those compositions that use large amounts of filler. Such operations are conventional in the art. Tablets may be prepared, for example, by wet or dry granulation, optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Suitable excipients, such as fillers, buffers or surfactants, may be used.
The formulations mentioned are prepared using standard methods such as those described or indicated in the spanish and united states pharmacopeia and similar references.
Administration of the compounds or compositions of the present invention may be carried out in any suitable manner, such as intravenous injection, oral formulation, intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience of the patient and the chronic nature of the disease to be treated.
Generally, an effective amount of a compound of the invention to be administered will depend on the relative effectiveness of the compound selected, the severity of the condition being treated and the weight of the patient. However, the active compounds are usually administered once or several times daily, for example 1, 2, 3 or 4 times daily, in a total daily dose of 0.1-1000 mg/kg/day.
The compounds and compositions of the present invention may be used with other drugs to provide combination therapy. The other agents may form part of the same composition, or as separate compositions for simultaneous or non-simultaneous administration.
The following examples are given solely for the purpose of further illustrating the invention and are not to be construed as limiting the scope of the invention.
The following examples are for illustrative purposes only and are not intended to be limiting of the present invention.
Synthesis scheme 1:
the compounds of examples 1-26 can be obtained by this synthesis scheme
Figure BDA0002984745350000091
Example 1:1- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) -4-phenylpiperidin-4-ol hydrochloride EP0023-C036
Step 1.4 Synthesis of (3-chloropropoxy) -2-methyl-quinazoline
Figure BDA0002984745350000092
4-hydroxy-2-methyl quinazoline (2.0g, 12.49mmol), 1-bromo-3-chloropropane (5.90g, 37.47mmol) and K2CO3(3.45g, 24.98mmol) in DMF (10.0mL) and stirred at 60 ℃ for 12 h; the reaction solution was checked by TLC for no significant material remaining, quenched by addition of water (80mL), extracted by EA (80mLx3), the organic phases combined, washed with saturated brine (80mLx3), dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed (PE/EA ═ 10/1) to give 4- (3-chloropropoxy) -2-methyl quinazoline (S1RA-012-C003-a, yield: 81.2%) as a white solid.
Step 2.1 Synthesis of- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) -4-phenylpiperidin-4-ol
Figure BDA0002984745350000101
4- (3-Chloropropoxy) -2-methyl quinazoline (S1RA-012-C003-A, 150.0mg, 0.64mmol), 4-phenyl-4-hydroxypiperidine (126mg, 0.71mmol), KI (10mg, 0.06mmol) and K2CO3(177mg, 1.28mmol) in DMF (4.0mL) and stirred at 70 ℃ for 8 h; the reaction solution was checked by TLC for no significant material remaining, quenched with 50mL of water, extracted with EA, combined organic phases and washed with saturated brine (30mLx3), dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, and chromatographed (DCM/MeOH ═ 20/1) to give 1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -4-phenylpiperidin-4-ol (EP0023-C036-a, 120.0mg, yield: 49.7%).
Step 31- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) -4-phenylpiperidin-4-ol hydrochloride Synthesis
Figure BDA0002984745350000102
1- (3- ((2-Methylquinazolin-4 yl) oxy) propyl) -4-phenylpiperidin-4-ol (EP0023-C036-A, 120.0mg, 0.32mmol) was dissolved in DCM (5mL), followed by addition of a solution of HCl/EA (1.0mL) and drying in vacuo for 2 hours to give 1- (3- ((2-Methylquinazolin-4 yl) oxy) propyl) -4-phenylpiperidin-4-ol hydrochloride (EP0023-C036, 130mg, yield: 98.9%)
1H NMR(400MHz,Methanol-d4)δ8.37(d,J＝8.0Hz,1H),8.07(t,J＝7.7Hz,1H),7.80(t,J＝7.0Hz,2H),7.54(d,J＝7.6Hz,2H),7.38(t,J＝7.5Hz,2H),7.30(d,J＝7.2Hz,1H),4.41(t,J＝6.4Hz,2H),3.61(d,J＝13.3Hz,2H),3.54–3.35(m,4H),3.06(s,3H),2.59–2.30(m,4H),2.05(s,1H),1.99(d,J＝6.8Hz,1H).MS(ESI)m/z 378.2([M+H]+).
Example 2:1- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) -4- (4-chlorophenyl) piperidin-4-ol hydrochloride NH100552
The title compound was prepared by substituting 4-phenyl-4-hydroxypiperidine with 4- (4-chlorophenyl) -4-hydroxypiperidine according to example 1
Figure BDA0002984745350000111
1H NMR(400MHz,Methanol-d4)1H NMR(400MHz,Methanol-d4)δ：δ8.36(dd,J＝8.0,1.4Hz,1H),8.06(td,J＝7.8,1.4Hz,1H),7.83–7.74(m,2H),7.61–7.48(m,2H),7.42–7.34(m,2H),4.40(t,J＝7.4Hz,2H),3.63–3.53(m,2H),3.53–3.35(m,4H),3.04(s,3H),2.53–2.32(m,4H),1.97(d,J＝13.3Hz,2H).MS(ESI)m/z 412.2([M+H]+).
Example 3: 4-methyl-1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) piperidin-4-ol hydrochloride EP0023-C059
The title compound was prepared by substituting 4-phenyl-4-hydroxypiperidine for 4-methyl-4-hydroxypiperidine according to the procedure of example 1
Figure BDA0002984745350000112
1H NMR(400MHz,Chloroform-d)δ8.23(dd,J＝8.0,1.5Hz,1H),7.71(ddd,J＝8.5,7.1,1.5Hz,1H),7.60(dd,J＝8.3,1.1Hz,1H),7.43(ddd,J＝8.2,7.1,1.2Hz,1H),4.22–4.11(m,2H),2.71–2.58(m,5H),2.53(t,J＝7.0Hz,2H),2.48–2.38(m,2H),1.99(p,J＝7.0Hz,2H),1.73–1.58(m,4H),1.23(s,3H).MS(ESI)m/z 316.2([M+H]+).
Example 4:1- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) -4- (trifluoromethyl) piperidin-4-ol hydrochloride EP0023-C047 the title compound was prepared by substituting 4-phenyl-4-hydroxypiperidine for 4-trifluoromethyl-4-hydroxypiperidine in the same manner as in example 1
Figure BDA0002984745350000113
1H NMR(400MHz,Chloroform-d)δ8.23(dd,J＝8.0,1.5Hz,1H),7.72(ddd,J＝8.5,7.1,1.6Hz,1H),7.61(dt,J＝8.1,1.0Hz,1H),7.44(ddd,J＝8.2,7.1,1.2Hz,1H),4.23–4.12(m,2H),2.88(s,2H),2.68(s,3H),2.57(s,2H),2.37(s,2H),2.10–1.84(m,6H),1.74(s,2H).MS(ESI)m/z 370.2([M+H]+).
Example 5:1- (3- ((2- (difluoromethyl) quinazolin-4-yl) oxy) propyl) -4-methylpiperidin-4-ol hydrochloride EP0023-C054
The title compound was prepared by substituting 4-hydroxy-2-methyl quinazoline and 4-phenyl-4-hydroxypiperidine for 4-hydroxy-2- (difluoromethyl) -quinazoline and 4-methyl-4-hydroxypiperidine, respectively, as in example 1
Figure BDA0002984745350000121
1H NMR(400MHz,Methanol-d4)δ8.35(d,J＝8.1Hz,1H),8.11–7.99(m,2H),7.90–7.74(m,1H),6.74(t,J＝54.6Hz,1H),4.83(t,J＝6.0Hz,2H),3.76–3.34(m,6H),2.49(d,J＝4.9Hz,2H),2.10–1.79(m,5H),1.36–1.30(m,4H).MS(ESI)m/z 352.2([M+H]+).
Example 6:1- (3- ((2- (difluoromethyl) quinazolin-4-yl) oxy) propyl) -4- (trifluoromethyl) piperidin-4-ol hydrochloride NH100389
The title compound was prepared by substituting 4-hydroxy-2-methyl quinazoline and 4-phenyl-4-hydroxypiperidine for 4-hydroxy-2- (difluoromethyl) -quinazoline and 4- (trifluoromethyl) -4-hydroxypiperidine, respectively, as in example 1
Figure BDA0002984745350000122
1H NMR(400MHz,Chloroform-d)δ8.20(d,J＝8.8Hz,1H),8.02(d,J＝8.4Hz,1H),7.94–7.86(m,1H),7.65(t,J＝7.6Hz,1H),6.77(s,0.25H),6.63(s,0.51H),6.49(s,0.26H),4.73(t,J＝6.5Hz,2H),2.87(d,J＝11.4Hz,2H),2.68–2.58(m,2H),2.33(t,J＝12.1Hz,2H),2.17–2.07(m,2H),1.93(td,J＝13.3,4.6Hz,2H),1.71(d,J＝14.0Hz,2H).MS(ESI)m/z 406.15([M+H]+).
Example 7:1- (2- ((2-Methylquinazolin-4-yl) oxy) ethyl) -4-phenylpiperidin-4-ol hydrochloride EP0023-C035
The title compound was prepared by substituting 1-bromo-3-chloropropane for 1-bromo-2-chloroethane as in example 1
Figure BDA0002984745350000123
1H NMR(400MHz,Chloroform-d)δ8.25(dd,J＝8.1,1.6Hz,1H),7.72(dd,J＝7.0,1.5Hz,1H),7.65–7.59(m,1H),7.54–7.48(m,2H),7.44(d,J＝1.1Hz,1H),7.37(dd,J＝8.5,6.9Hz,2H),7.28(d,J＝7.3Hz,1H),4.28(s,2H),2.84(d,J＝34.5Hz,4H),2.73(s,3H),2.70–2.58(m,2H),1.79(d,J＝13.5Hz,2H),1.57–1.49(m,2H).
Example 8: 4-methyl-1- (2- ((2)-methyl quinazolin-4-yl) oxy) ethyl) piperidin-4-ol hydrochloride EP0023-C058
The title compound was prepared by substituting 1-bromo-2-chloroethane and 4-methyl-4-hydroxypiperidine for 1-bromo-3-chloropropane and 4-phenyl-4-hydroxypiperidine, respectively, and repeating the procedure of example 1
Figure BDA0002984745350000131
1H NMR(400MHz,Chloroform-d)δ8.22(dd,J＝8.0,1.1Hz,1H),7.72(ddd,J＝8.4,7.2,1.5Hz,1H),7.61(d,J＝8.0Hz,1H),7.48–7.40(m,1H),4.78(s,4H),4.35(s,2H),2.78(d,J＝45.9Hz,9H),1.28(s,3H).MS(ESI)m/z 302.2([M+H]+).
Example 9:1- (2- ((2-Methylquinazolin-4-yl) oxy) ethyl) -4- (trifluoromethyl) piperidin-4-ol hydrochloride EP0023-C060
The title compound was prepared by substituting 1-bromo-3-chloropropane and 4-phenyl-4-hydroxypiperidine for 1-bromo-2-chloroethane and 4- (trifluoromethyl) -4-hydroxypiperidine, respectively, and using the procedures of example 1
Figure BDA0002984745350000132
1HNMR:1H NMR(400MHz,Chloroform-d)δ8.23(dd,J＝8.0,1.5Hz,1H),7.72(ddd,J＝8.5,7.1,1.6Hz,1H),7.61(dd,J＝8.2,1.1Hz,1H),7.44(ddd,J＝8.2,7.1,1.2Hz,1H),4.24(t,J＝7.0Hz,2H),2.94–2.82(m,2H),2.79–2.72(m,2H),2.69(s,3H),2.56–2.46(m,2H),1.93(td,J＝13.2,4.6Hz,2H),1.74–1.68(m,2H).MS(ESI)m/z 356.2([M+H]+).
Example 10: 4-isopropyl-1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) piperidin-4-ol hydrochloride NH100423
The title compound was prepared by substituting 4-phenyl-4-hydroxypiperidine for 4-isopropyl-4-hydroxypiperidine in the same manner as in example 1
Figure BDA0002984745350000133
1H NMR(400MHz,Methanol-d4)δ8.40–8.31(m,1H),8.11–8.01(m,1H),7.78(t,J＝7.6Hz,2H),4.37(t,J＝7.3Hz,2H),3.55–3.42(m,2H),3.34(d,J＝5.7Hz,1H),3.30–3.21(m,2H),3.03(s,3H),2.33(td,J＝7.4,7.0,3.5Hz,2H),1.96(td,J＝14.1,4.2Hz,2H),1.80(d,J＝14.4Hz,2H),1.67(hept,J＝6.9Hz,1H),0.96(d,J＝6.9Hz,6H).MS(ESI)m/z 344.2([M+H]+).
Example 11: 4-tert-butyl-1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) piperidin-4-ol hydrochloride NH100424
The title compound was prepared by substituting 4-phenyl-4-hydroxypiperidine for 4-tert-butyl-4-hydroxypiperidine according to the procedure of example 1
Figure BDA0002984745350000141
Example 12:1- (2- ((2-Methylquinazolin-4-yl) oxy) ethyl) -3-phenylpyrrolidin-3-ol hydrochloride EP0023-C023
The title compound was prepared by substituting 2-bromo-1-chloroethane and 3-phenyl-3-hydroxypyrrolidine for 3-bromo-1-chloropropane and 4-phenyl-4-hydroxypiperidine, respectively, and by the method of example 1
Figure BDA0002984745350000142
1H NMR(400MHz,DMSO-d6)δ8.24(dd,J＝8.0,1.2Hz,1H),7.73(ddd,J＝8.5,7.1,1.5Hz,1H),7.62(d,J＝8.1Hz,1H),7.54–7.48(m,2H),7.47–7.41(m,1H),7.36(td,J＝6.8,6.4,1.6Hz,2H),7.29–7.26(m,1H),4.40–4.22(m,2H),3.33(s,1H),3.18(s,1H),2.99(s,2H),2.86(d,J＝9.7Hz,1H),2.74(s,1H),2.71(s,3H),2.40(ddd,J＝13.8,9.5,5.9Hz,1H),2.27–2.18(m,1H).MS(ESI)m/z 350.2([M+H]+).
Example 13:1- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) -3-phenylpyrrolidin-3-ol hydrochloride EP 0023-C027A reaction of 4-phenyl-4-hydroxypiperidineThe title compound was prepared as described in example 1, substituting 3-phenyl-3-hydroxypyrrolidine
Figure BDA0002984745350000143
1H NMR(400MHz,Chloroform-d)δ8.21(dd,J＝8.0,1.5Hz,1H),7.73(ddd,J＝8.5,7.1,1.6Hz,1H),7.62(dd,J＝8.1,1.0Hz,1H),7.52–7.47(m,2H),7.44(ddd,J＝8.1,7.1,1.2Hz,1H),7.40–7.33(m,2H),7.33–7.27(m,1H),4.25(t,J＝7.4Hz,2H),3.52–3.23(m,3H),2.69(s,3H),2.39(ddt,J＝70.3,13.4,7.3Hz,3H),2.16(t,J＝7.4Hz,3H),2.00(s,1H).MS(ESI)m/z 364.2([M+H]+).
Example 14:1- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) pyrrolidin-3-ol hydrochloride EP0023-C041
The title compound was prepared by substituting 3-hydroxypyrrolidine with 4-phenyl-4-hydroxypiperidine in the same manner as in example 1
Figure BDA0002984745350000151
1H NMR(400MHz,DMSO-d6)δ8.11(dd,J＝8.0,1.5Hz,1H),7.80(ddd,J＝8.5,7.1,1.6Hz,1H),7.60(d,J＝8.1Hz,1H),7.57–7.42(m,1H),5.34(s,1H),4.37(s,1H),4.13(t,J＝7.4Hz,2H),3.13(s,4H),2.64(s,3H),2.06(dd,J＝11.5,5.1Hz,3H),1.82(s,1H).MS(ESI)m/z 288.2([M+H]+).
Example 15: 3-methyl-1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) pyrrolidin-3-ol hydrochloride EP0023-C040
The title compound was prepared by substituting 3-methyl-3-hydroxypyrrolidine with 4-phenyl-4-hydroxypiperidine in the same manner as in example 1
Figure BDA0002984745350000152
1H NMR(400MHz,CDCl3)δ8.21(dd,J＝7.8,1.6Hz,1H),7.72(ddd,J＝8.5,7.1,1.5Hz,1H),7.61(dd,J＝8.3,1.2Hz,1H),7.44(ddd,J＝8.2,7.1,1.2Hz,1H),4.21(t,J＝7.4Hz,2H),3.25(dt,J＝9.9,7.3Hz,1H),3.05(d,J＝10.3Hz,1H),2.85(td,J＝7.5,2.6Hz,2H),2.68(s,3H),2.62–2.50(m,2H),2.16–2.04(m,2H),2.03–1.92(m,2H),1.40(s,3H).MS(ESI)m/z 302.2([M+H]+).
Example 16:1- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) -3- (trifluoromethyl) pyrrolidin-3-ol hydrochloride EP0023-C042
The title compound was prepared by substituting 4-phenyl-4-hydroxypiperidine with 3- (trifluoromethyl) -3-hydroxypyrrolidine as in example 1
Figure BDA0002984745350000161
1H NMR(400MHz,Methanol-d4)δ8.40–8.29(m,1H),8.05(ddd,J＝8.7,7.5,1.5Hz,1H),7.78(ddd,J＝9.3,7.7,1.4Hz,2H),4.37(t,J＝7.4Hz,2H),3.97(s,1H),3.52(s,4H),3.02(s,3H),2.64(s,1H),2.32(d,J＝8.4Hz,3H),2.06–1.96(m,1H).MS(ESI)m/z 356.2([M+H]+).
Example 17:1- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) -3-vinylpyrrolidin-3-ol hydrochloride EP0023-C043 the title compound was prepared by the method of example 1, replacing 4-phenyl-4-hydroxypiperidine with 3-vinyl-3-hydroxypyrrolidine
Figure BDA0002984745350000162
1H NMR(400MHz,Chloroform-d)δ8.19(ddd,J＝7.9,1.6,0.6Hz,1H),7.73(ddd,J＝8.5,7.1,1.5Hz,1H),7.62(ddd,J＝8.2,1.2,0.6Hz,1H),7.44(ddd,J＝8.2,7.1,1.2Hz,1H),5.93(dd,J＝17.2,10.7Hz,1H),5.46(dd,J＝17.2,1.0Hz,1H),5.22(dd,J＝10.7,1.0Hz,1H),4.22(t,J＝7.4Hz,2H),3.49(q,J＝8.7Hz,1H),3.23(d,J＝11.3Hz,1H),3.09(t,J＝7.6Hz,3H),3.00(d,J＝11.2Hz,1H),2.69(s,3H),2.20(ddd,J＝18.5,14.1,8.2Hz,3H),2.14–2.05(m,1H).MS(ESI)m/z314.2([M+H]+).
Example 18: 4- (3- (3-methoxy-3-methylpyrrolidin-1-yl) propoxy) -2-methyl quinazoline hydrochloride EP0023-C048
The title compound was prepared by substituting 3-methyl-3-methoxypyrrolidine for 4-phenyl-4-hydroxypiperidine in the same manner as in example 1
Figure BDA0002984745350000163
1H NMR(400MHz,CDCl3)δ8.23(dd,J＝8.0,1.2Hz,1H),7.71(td,J＝8.4,1.5Hz,1H),7.60(d,J＝8.0Hz,1H),7.47–7.39(m,1H),4.24–4.11(m,2H),3.22(s,3H),2.83–2.74(m,2H),2.67(s,3H),2.59(tt,J＝11.8,6.1Hz,3H),2.45(d,J＝9.8Hz,1H),2.07–1.90(m,4H),1.73–1.65(m,1H),1.32(s,3H).MS(ESI)m/z 316.2([M+H]+).
Example 19: 3-cyclopropyl-1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) pyrrolidin-3-ol hydrochloride EP0023-C037
The title compound was prepared by substituting 3-bromo-1-chloropropane and 4-phenyl-4-hydroxypiperidine for 2-bromo-1-chloroethane and 3-cyclopropyl-3-hydroxypyrrolidine, respectively, and by the method of example 1
Figure BDA0002984745350000171
1H NMR(400MHz,Chloroform-d)δ8.21(ddd,J＝7.9,5.1,1.4Hz,1H),7.70(ddd,J＝7.1,5.1,3.5Hz,1H),7.59(d,J＝8.2Hz,1H),7.49–7.38(m,1H),4.43–4.12(m,2H),3.69–3.59(m,1H),3.29(d,J＝1.7Hz,1H),3.00–2.54(m,9H),2.26(d,J＝7.0Hz,3H),1.84(ddd,J＝11.1,7.8,5.9Hz,1H),1.41–1.16(m,2H),1.15–0.79(m,1H),0.57–0.27(m,2H).MS(ESI)m/z 314.2([M+H]+).
Example 20: 3-methyl-1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) pyrrolidin-3-ol hydrochloride EP0023-C039
The title compound was prepared by substituting 3-bromo-1-chloropropane and 4-phenyl-4-hydroxypiperidine for 2-bromo-1-chloroethane and 3-methyl-3-hydroxypyrrolidine, respectively, and by the method of example 1
Figure BDA0002984745350000172
1H NMR(400MHz,CDCl3)δ8.22(dd,J＝8.0,1.6Hz,1H),7.72(ddd,J＝8.4,7.1,1.6Hz,1H),7.60(dd,J＝8.3,1.1Hz,1H),7.43(ddd,J＝8.2,7.1,1.2Hz,1H),4.27(td,J＝7.1,5.7Hz,2H),3.19–3.10(m,1H),2.95(d,J＝9.7Hz,1H),2.87(t,J＝7.4Hz,2H),2.69(s,3H),2.55(td,J＝9.0,6.7Hz,1H),2.45(d,J＝9.6Hz,1H),1.99–1.86(m,2H),1.38(s,3H).MS(ESI)m/z 288.2([M+H]+).
Example 21:1- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) -3-phenylazetidin-3-ol hydrochloride EP0023-C029
The title compound was prepared by substituting 4-phenyl-4-hydroxypiperidine for 3-phenyl-3-hydroxyazetidine as in example 1
Figure BDA0002984745350000173
1H NMR(400MHz,Chloroform-d)δ8.23(dd,J＝8.1,1.5Hz,1H),7.71(ddd,J＝8.5,7.1,1.6Hz,1H),7.60(dt,J＝8.1,0.9Hz,1H),7.58–7.51(m,2H),7.48–7.34(m,3H),7.34–7.28(m,1H),4.27–4.14(m,2H),3.79–3.63(m,2H),3.49(s,1H),3.47(d,J＝1.1Hz,1H),2.70(t,J＝6.7Hz,2H),2.67(s,3H),1.89–1.84(m,2H).
Example 22:1- (2- ((2-Methylquinazolin-4-yl) oxy) ethyl) -3-phenylazetidin-3-ol hydrochloride EP0023-C024
The title compound was prepared by substituting 3-bromo-1-chloropropane and 4-phenyl-4-hydroxypiperidine for 2-bromo-1-chloroethane and 3-phenyl-3-hydroxyazetidine, respectively, and by the method of example 1
Figure BDA0002984745350000181
1H NMR(400MHz,CDCl3)δ8.23(dd,J＝7.9,1.5Hz,1H),7.72(ddd,J＝8.4,7.0,1.5Hz,1H),7.63–7.58(m,1H),7.55–7.50(m,2H),7.47–7.41(m,1H),7.39–7.34(m,2H),7.32–7.27(m,1H),4.16(t,J＝6.9Hz,2H),3.77–3.71(m,2H),3.59–3.53(m,2H),2.95(t,J＝6.9Hz,2H),2.69(s,3H).
Example 23:1- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) piperidin-4-one hydrochloride EP003-012-C016
The title compound was prepared by substituting 4-phenyl-4-hydroxypiperidine for 4-piperidone according to the procedure of example 1
Figure BDA0002984745350000182
1H NMR(400MHz,Chloroform-d)δ8.34–8.17(m,1H),7.72(ddd,J＝8.5,7.1,1.6Hz,1H),7.61(dt,J＝8.1,1.0Hz,1H),7.44(ddd,J＝8.1,7.0,1.2Hz,1H),4.28–4.18(m,2H),2.76(t,J＝6.1Hz,4H),2.70(s,3H),2.60(t,J＝6.7Hz,2H),2.41(t,J＝6.1Hz,4H),2.04–1.94(m,2H).MS(ESI)m/z 300.15([M+H]+).
Example 24: 8- (3- ((2-Methylquinazolin-4-yl) oxy) propyl) -1, 4-dioxa-8-azaspiro [4.5]Decane hydrochloride EP003-012-C017
The title compound was obtained by substituting 1, 4-dioxa-8-azaspiro [4.5] decane with 4-phenyl-4-hydroxypiperidine
Figure BDA0002984745350000191
1H NMR(400MHz,Chloroform-d)δ8.23(dd,J＝8.1,1.5Hz,1H),7.70(ddd,J＝8.5,7.1,1.5Hz,1H),7.65–7.55(m,1H),7.42(ddd,J＝8.1,7.0,1.2Hz,1H),4.24–4.08(m,2H),3.94(s,4H),2.67(s,3H),2.55(t,J＝5.7Hz,3H),2.49(t,J＝6.8Hz,2H),2.06–1.98(m,1H),1.98–1.91(m,2H),1.73(t,J＝5.7Hz,4H).MS(ESI)m/z 344.2([M+H]+).
Example 25: 4- (2- ((2-Methylquinazolin-4-yl) oxy) ethyl) thiomorpholine 1, 1-dioxide hydrochloride EP003-012-C020
The title compound was prepared by substituting 3-bromo-1-chloropropane and 4-phenyl-4-hydroxypiperidine for 2-bromo-1-chloroethane and thiomorpholine-1, 1-dioxide, respectively, and by the method of example 1
Figure BDA0002984745350000192
1H NMR(400MHz,Chloroform-d)δ8.22(dd,J＝8.0,1.5Hz,1H),7.74(ddd,J＝8.5,7.1,1.6Hz,1H),7.61(dd,J＝8.2,1.1Hz,1H),7.46(ddd,J＝8.2,7.1,1.2Hz,1H),4.23(t,J＝6.8Hz,2H),3.18–3.10(m,4H),3.08–3.00(m,4H),2.86(t,J＝6.8Hz,2H),2.66(s,3H).MS(ESI)m/z322.1([M+H]+).
Example 26:1- (2- ((2- (4-chlorophenyl) quinazolin-4-yl) oxy) ethyl) piperidin-4-ol hydrochloride S1RA-012r-1
Figure BDA0002984745350000193
1H NMR(400MHz,CDCl3)δ：8.32(d,J＝9.1Hz,1H),7.80–7.70(m,2H),7.56–7.48(m,5H),4.14(t,J＝6.9Hz,2H),3.67–3.58(s,1H),2.59–2.49(m,4H),2.11–1.98(m,2H),1.77(dd,J＝12.7,2.9Hz,2H),1.50–1.39(m,2H).
Step 1 Synthesis of 2- (4-chlorophenyl) quinazoline-4-hydroxy group
Figure BDA0002984745350000201
4-chlorobenzaldehyde (2.8g, 20.0mmol), 2-aminobenzamide (2.72g, 20.0mmol) and NaHSO3(2.50g, 24.0mmol) was dissolved in 10mL of DMA and heated to 150 ℃ in an oil bath and stirred for reaction overnight; adding 150mL of water into the reaction solution for quenching, precipitating a large amount of light yellow solid, filtering to obtain a wet solid, and drying by blowing at 50 ℃ to obtain 4.29g of off-white2- (4-chlorophenyl) quinazolin-4-hydroxy (S1RA-012c-A, yield: 83.6%).
Step 2 Synthesis of 1- (2- ((2- (4-chlorophenyl) quinazolin-4-yl) oxy) ethyl) piperidin-4-ol
Figure BDA0002984745350000202
Coupling 2- (4-chlorophenyl) quinazoline-4-hydroxy (S1RA-012c-A, 100mg, 0.39mmol), 1- (2-chloroethoxy) piperidin-4-ol (63.83mg, 0.39mmol), KI (6.5mg, 0.039mmol) and K2CO3(161.7mg, 1.17mmol) was dissolved in 5mL of DMF and the reaction was stirred at 75 ℃ overnight; TLC detection of the reaction solution shows no obvious material residue, 50mL water is added to quench, 60mLEA is added to extract, EA phase is separated, anhydrous sodium sulfate is dried, crude product is obtained by concentration, and 1- (2- ((2- (4-chlorphenyl) quinazoline-4-yl) oxy) ethyl) piperidine-4-alcohol (S1RA-012r-1-A, 18.0mg, yield: 12.0%) is obtained by column chromatography (PE/EA is 10/1)
Step 3 Synthesis of 1- (2- ((2- (4-chlorophenyl) quinazolin-4-yl) oxy) ethyl) piperidin-4-ol hydrochloride
Figure BDA0002984745350000203
Dissolving 1- (2- ((2- (4-chlorophenyl) quinazolin-4-yl) oxy) ethyl) piperidin-4-ol (S1RA-012r-1-A, 18.0mg, 0.047mmol) in DCM (2mL), adding HCl/EA (2M,2.0mL) under magnetic stirring, precipitating a white solid, and performing ultrasonic treatment for 5 mins; concentrating, and drying to obtain 1- (2- ((2- (4-chlorophenyl) quinazolin-4-yl) oxy) ethyl) piperidin-4-ol hydrochloride (S1RA-012r-1, 19.6mg, yield: 99.5%)
Figure BDA0002984745350000211
Figure BDA0002984745350000221
Figure BDA0002984745350000231
Examples of biological activity:
certain representative compounds of the invention were tested for their activity as sigma (sigma-1 and sigma-2) inhibitors, and the specific protocol was as follows:
test Compound preparation: all test samples were dissolved in DMSO at a final concentration of 1%, e.g., poorly dissolved or suspended, HCl (10%, 10. mu.L) was added as appropriate at an initial concentration of 1.0X 10-5M (i.e., 10. mu.M), then 1. mu.M, 333nM, 100nM, 33nM, 10nM, 3.3nM, 1nM, 0.33nM, 0.1nM, 0.01nM in that order for use.
Sigma-1 inhibitor activity assay:
receptor membrane preparation: homogenizing guinea pig whole brain with 10mM Tris-HCl buffer solution containing 320mM sucrose pH 7.4, adjusting weight, centrifuging for 10min at 1000g, collecting supernatant, adding 10mM Tris-HCl buffer solution containing sucrose pH 7.4, homogenizing, centrifuging for 10min at 1000g and 4 deg.C, collecting supernatant, centrifuging for 25min at 50000g and 4 deg.C, collecting precipitate, adding 10mM Tris-HC buffer solution containing no sucrose pH 7.4, homogenizing, centrifuging for 25min at 50000g and 4 deg.C, collecting precipitate, repeating the above operation, and storing at-80 deg.C.
Binding assay: the prepared acceptor membrane was suspended in 10mM Tris-HCl buffer without sucrose pH 7.4 to prepare a 220mg/ml membrane suspension for use. Each reaction tube was filled with 100. mu.L of the membrane preparation. mu.L of 10mM Tris-HC buffer without sucrose pH 7.4 was added to the total binding Tube (TB) and 100. mu.L haloperidol (final concentration 1.0X 10) was added to the non-specific binding tube (NSB)-5M), 100 μ L of test compound was added to each test compound tube (CB). All reaction tubes were each charged with radioligand 4nM [ sic ], [ solution ] respectively3H]10. mu.L of Pentazocine. Incubating each reaction tube at 25 ℃ for 135min, after the reaction is finished, rapidly filtering the combined ligand through decompression, soaking Whatman GF/C test paper in 0.5% PEI for more than 1h in advance, fully washing the paper with ice-cold test buffer solution, taking out a filter disc, putting the filter disc into a 4mL scintillation cup, adding 1mL toluene scintillation solution, uniformly mixing,finally, the scintillation vial was placed in a HIDEX scintillation counter for counting.
Sigma-2 inhibitor activity assay
Receptor membrane preparation: the same as the preparation method of the sigma-1 receptor membrane.
Binding assay: the prepared acceptor membrane is prepared into a membrane suspension of 220mg/mL by using 10mM Tris-HCl buffer solution without sucrose for later use. mu.L of the membrane preparation was added to each reaction tube, 100. mu.L of 10mM Tris-HC buffer solution containing no sucrose and having pH 7.4 was added to the total binding Tube (TB), and 100. mu.L of DTG (final concentration: 1.0X 10) was added to the non-specific binding tube (NSB)-5M), test Compound binding tube (CB) was added with 100. mu.L of test Compound (final concentration 1.0X 10)-5M) and 100nM (+) -NANM is added to screen sigma-1 receptors; adding radioactive ligand into each reaction tube3H-DTG 10. mu.L, final concentration 5 nM. Incubating each reaction tube at 25 ℃ for 135min, after the reaction is finished, rapidly filtering the combined ligand through decompression, soaking Whatman GF/C test paper in 0.5% PEI for more than 1h, fully washing the PEI with ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 4mL scintillation cup, adding 1mL toluene scintillation solution, and uniformly mixing. Finally, the scintillation cup was placed in a HIDEX liquid scintillation counter for counting.
And (3) calculating a Ki value:
Figure BDA0002984745350000241
logic method calculates each compound IC 50;
kd and Bmax of each radioligand were plotted by Scatchard;
Figure BDA0002984745350000251
the following table shows some of the results obtained:
Figure BDA0002984745350000252
Figure BDA0002984745350000261
formalin model experiment
The specific operation is as follows: IP (intraperitoneal injection) administration was performed using physiological saline as a vehicle. The administration volume of the vehicle group was 1.3 ml/vehicle, and the administration volume of each of the other administration groups was 5 ml/kg. The administration time of the test drug is 15min before the molding test. Before experimental testing, rats are adapted in the experimental device for 5-10min after administration. The right hind paw of the acclimatized rat was subcutaneously injected with 100. mu.L of 5% formalin solution (containing 1.85% formaldehyde) to form a skin dome as a standard for successful modeling, and if the paw was injected, the animal was discarded. And the software automatically records the foot lifting times within 1min as a time period between 0 and 60min after the molding. Each group had 8 rats.
And (3) data analysis: phase I, 0-10min, phase II, 10-60min, phase II-a, 10-40min, phase II-b, 40-60 min. Mean ± standard deviation was used to represent the number of foot lifts per group, and statistical differences between the test groups (vehicle and dosing groups) were examined by t-test.
As a result: pregabalin (40mpk) and the compound of example 5 both showed efficacy against I, II phase pain, significantly reduced the number of leg lifts in animals after formalin administration, the efficacy results are shown in fig. 1 and 2, and the compound of example 5 has a dose-response relationship.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A compound of formula I, or a pharmaceutically acceptable salt, or solvate thereof:
Figure FDA0002984745340000011
wherein n1 is an integer from 1 to 6; n2 is an integer from 1 to 5;
w is C or S;
R3is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, the substituent is selected from halogen, hydroxyl, nitro, alkoxy;
R2is hydroxyl, double-bonded oxy, substituted or unsubstituted alkyl, and the substituent is selected from halogen, hydroxyl, nitro and alkoxy;
R1is hydrogen, doubly-bound oxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, and the substituent is selected from halogen, hydroxyl, nitro and alkoxy;
or, R1And R2Form a
Figure FDA0002984745340000012
Preferably, R3Is methyl, substituted or unsubstituted phenyl, and the substituent is halogen, C1-C5 haloalkyl; r2Is hydroxyl, double-bond oxy, C1-5 straight chain or branched chain alkyl; r1 is hydrogen, C1-5 straight chain or branched chain alkyl, C2-5 alkenyl, double bond oxy, C3-C5 cycloalkyl, alkoxy, C1-C5 haloalkyl, substituted or unsubstituted phenyl, and the substituent is halogen; or, R1Or R2Form a
Figure FDA0002984745340000013
Preferably, when W is S, R1、R2Is a double bond oxy group;
preferably, n1 is an integer of 3, and n2 is an integer of 2-3; w is C; r3Is methyl or C1-C5 haloalkyl; r2Is a hydroxyl group; r1Is hydrogen, C1-5 straight chain or branched chain alkyl, C2-5 alkenyl, C3-C5 cycloalkyl, C1-C5 haloalkyl, phenyl or halophenyl.
2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt, or solvate thereof, wherein the haloalkyl group having C1-C5 is a fluoroalkyl group having C1-C5, a chloroalkyl group having C1-C5, a bromoalkyl group having C1-C5, an iodoalkyl group having C1-C5; the alkoxy is selected from methoxy, ethoxy and propoxy; the cycloalkyl of C3-C5 is selected from cyclopropyl, cyclobutyl and cyclopentyl.
3. The compound of formula I, or a pharmaceutically acceptable salt, or solvate thereof, according to claim 1, wherein the C1-5 linear or branched alkyl group is methyl, ethyl, isopropyl, isobutyl, or tert-butyl.
4. The compound of formula I, or a pharmaceutically acceptable salt, or solvate thereof, as claimed in claim 1, wherein said substituted phenyl is chlorophenyl, fluorophenyl, bromophenyl; the alkenyl of C2-5 is ethenyl, propenyl, butenyl.
5. The compound of formula I, or a pharmaceutically acceptable salt, or solvate thereof, as claimed in claim 2, wherein said C1-C5 fluoroalkyl group is selected from trifluoromethyl and difluoromethyl.
6. The compound of formula I, or a pharmaceutically acceptable salt, or solvate thereof, according to claim 1, wherein formula I is of the structure:
Figure FDA0002984745340000021
wherein n1 is an integer from 2 to 5; n2 is an integer from 1 to 4;
R3is methyl, chlorophenyl, difluoromethyl, trifluoromethyl;
when W is C, R2Is hydroxy, doubly-bound oxy or methyl; r1Is hydrogen, methyl, ethyl, isopropyl, isobutyl, tert-butyl, vinyl, cyclopropyl, cyclobutyl, methylOxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, phenyl or chlorophenyl; or, R1And R2Form a
Figure FDA0002984745340000022
When W is S, R1And R2 is simultaneously a doubly-bound oxy group.
7. A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6, selected from any one of the following:
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -4-phenylpiperidin-4-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -4- (4-chlorophenyl) piperidin-4-ol;
4-methyl-1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) piperidin-4-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -4- (trifluoromethyl) piperidin-4-ol;
1- (3- ((2- (difluoromethyl) quinazolin-4-yl) oxy) propyl) -4-methylpiperidin-4-ol;
1- (3- ((2- (difluoromethyl) quinazolin-4-yl) oxy) propyl) -4- (trifluoromethyl) piperidin-4-ol;
1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) -4-phenylpiperidin-4-ol;
4-methyl-1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) piperidin-4-ol;
1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) -4- (trifluoromethyl) piperidin-4-ol;
4-isopropyl-1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) piperidin-4-ol;
4- (tert-butyl) -1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) piperidin-4-ol;
1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) -3-phenylpyrrolidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -3-phenylpyrrolidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) pyrrolidin-3-ol;
3-methyl-1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) pyrrolidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -3- (trifluoromethyl) pyrrolidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -3-vinylpyrrolidin-3-ol;
4- (3- (3-methoxy-3-methylpyrrolidin-1-yl) propoxy) -2-methyl quinazoline;
3-cyclopropyl-1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) pyrrolidin-3-ol;
3-methyl-1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) pyrrolidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -3-phenylazetidin-3-ol;
1- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) -3-phenylazetidin-3-ol;
1- (3- ((2-methylquinazolin-4-yl) oxy) propyl) piperidin-4-one;
8- (3- ((2-methylquinazolin-4-yl) oxy) propyl) -1, 4-dioxa-8-azaspiro [4.5] decane;
4- (2- ((2-methylquinazolin-4-yl) oxy) ethyl) thiomorpholine 1, 1-dioxide;
1- (2- ((2- (4-chlorophenyl) quinazolin-4-yl) oxy) ethyl) piperidin-4-ol.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
9. Use of a compound of formula I according to any one of claims 1 to 7 or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition according to claim 8 in the manufacture of a medicament for the treatment or prophylaxis of a sigma receptor related disease or condition.
10. Use according to claim 9, wherein the sigma receptor related disease or condition is pain, preferably neuropathic or inflammatory pain, post-operative pain, cancer pain, trigeminal neuralgia, osteoarthritis pain, burn pain, phantom limb pain.
CN202110297107.7A 2020-03-23 2021-03-19 Quinazoline derivatives and uses thereof Active CN113429390B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2020102067088 2020-03-23
CN202010206708 2020-03-23

Publications (2)

Publication Number Publication Date
CN113429390A true CN113429390A (en) 2021-09-24
CN113429390B CN113429390B (en) 2022-04-15

Family

ID=77752893

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110297107.7A Active CN113429390B (en) 2020-03-23 2021-03-19 Quinazoline derivatives and uses thereof

Country Status (1)

Country Link
CN (1) CN113429390B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003049740A1 (en) * 2001-12-12 2003-06-19 Pfizer Products Inc. Quinazoline derivatives for the treatment of abnormal cell growth
CN101115736A (en) * 2005-03-14 2008-01-30 神经研究公司 Potassium channel modulating agents and their medical use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003049740A1 (en) * 2001-12-12 2003-06-19 Pfizer Products Inc. Quinazoline derivatives for the treatment of abnormal cell growth
CN101115736A (en) * 2005-03-14 2008-01-30 神经研究公司 Potassium channel modulating agents and their medical use

Also Published As

Publication number Publication date
CN113429390B (en) 2022-04-15

Similar Documents

Publication Publication Date Title
CN109475531B (en) Heterocyclic inhibitors of PTPN11
CN109219604B (en) Tetrahydroisoquinoline estrogen receptor modulators and uses thereof
KR100233323B1 (en) Medical use for tachykinin antagonists
TWI685497B (en) Alkyl derivatives of 1-oxa-4,9-diazaspiro undecane compounds having multimodal activity against pain
CN107849017A (en) The hydroxyl of 1,1,1 trifluoro 3 the third 2 aminocarbamic acid ester derivant and the aminocarbamic acid ester derivant of 1,1,1 trifluoro, 4 hydroxyl fourth 2 as MAGL inhibitor
JP7051853B2 (en) Heteroarylphenoxybenzamide kappa opioid ligand
CN110198944A (en) Heterocyclic ring spiroring compounds as monoacylglycerol lipase inhibitor
EP3227295B1 (en) 6,7-dihydropyrazolo[1,5- ]pyrazin-4(5h)-one compounds and their use as negative allosteric modulators of mglu2 receptors
KR102206321B1 (en) 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine dopamine D3 ligand
CN111655682A (en) High-activity STING protein agonist compound
CN112812061B (en) N-aryl-1, 2,3, 4-tetrahydroisoquinoline-7-amine compound and application thereof
EP4334314A1 (en) Anti-cancer nuclear hormone receptor-targeting compounds
CN114702428B (en) Siama-1 receptor inhibitors of the bicyclic structure
TW201726688A (en) N-[2-(2-amino-6,6-disubstituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3] thiazin-8a(8H)-yl)-1,3-thiazol-4-yl] amides
TW202019923A (en) Tyrosine amide derivatives as Rho-kinase inhibitors
AU2019311121B2 (en) Fused ring derivative used as FGFR4 inhibitor
CA3143367A1 (en) Indazole derivative, preparation method therefor, and pharmaceutical application thereof
CN113429390B (en) Quinazoline derivatives and uses thereof
CN112457329A (en) Preparation and application of aromatic heterocyclic derivative as immunomodulator
JP6884973B2 (en) Oxadiazaspiro compounds that are active against pain
JP2018531949A (en) Substituted morpholine derivatives with activity against pain
JP2018531263A6 (en) Oxadiazaspiro compounds with activity against pain
CN111153859B (en) Pyridazinone derivative and application thereof
JP6337092B2 (en) Tricyclic triazole compounds
CN108409729B (en) Phenyloctahydro-1H-pyrido [1,2-a ] pyrazine derivatives and uses thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CP02 Change in the address of a patent holder

Address after: 215021 Building 6, Tengfei Innovation Park, No. 388, Xinping Street, Suzhou Industrial Park, Jiangsu Province

Patentee after: Suzhou Enhua Biomedical Technology Co.,Ltd.

Address before: Unit 303b, A4 / F, phase I project, biomedical industrial park, 218 Xinghu street, Suzhou Industrial Park, Jiangsu Province, 215000

Patentee before: Suzhou Enhua Biomedical Technology Co.,Ltd.

CP02 Change in the address of a patent holder