CN106146404B

CN106146404B - Pyridazinone derivative and application thereof

Info

Publication number: CN106146404B
Application number: CN201510179782.4A
Authority: CN
Inventors: 张桂森; 曹旭东; 邱印利; 赵松; 徐祥清; 刘欣; 刘笔锋; 张译芳
Original assignee: WUHAN JIAYU TECHNOLOGY Co Ltd; Nhwa Pharmaceutical Corp
Current assignee: WUHAN JIAYU TECHNOLOGY Co Ltd; Nhwa Pharmaceutical Corp
Priority date: 2015-04-15
Filing date: 2015-04-15
Publication date: 2020-03-20
Anticipated expiration: 2035-04-15
Also published as: CN106146404A; CN111153859A; CN111153859B

Abstract

The invention relates to the field of medicines, in particular to a pyridazinone derivative and application thereof, and more particularly relates to a pyridazinone derivative, a pharmaceutical composition containing the pyridazinone derivative, and application of the composition and the pyridazinone derivative in preparation of drugs for preventing or treating pain diseases. The pyridazinone derivative has a structure shown in a formula (I). Experiments show that the compounds can be used for preventing or treating pain diseases.

Description

Pyridazinone derivative and application thereof

Technical Field

The invention relates to the field of medicines, in particular to a pyridazinone derivative and application thereof, and more particularly relates to a pyridazinone derivative, a pharmaceutical composition containing the pyridazinone derivative, and application of the composition and the pyridazinone derivative in preparation of drugs for preventing or treating pain diseases.

Background

Pain is the basic sensation that human beings have naturally, and has important significance in the aspects of protecting the human body from being injured, maintaining the internal environment of the human body and the like. Chronic or excessive pain can seriously affect the normal physiology and life of a person, and chronic pain and neuropathic pain have been medically defined as diseases that seriously compromise human health. Of these, neuralgia is a disease that is a serious hazard to the life of patients among pain-like diseases, and about 8% of the world is affected by this disease. Despite much work done by researchers in the areas of basic and clinical research, there remains a significant challenge to clinically studying the pathogenesis of neuropathic pain and its analgesic mechanisms. At present, no broad-spectrum and specific targeted medicine for neuralgia exists. The medicament for treating neuralgia in clinic is mainly a medicament which has neuralgia analgesic activity and is used for treating diseases such as depression, epilepsy and the like.

sigma-1 receptor (sigma)₁Receptors) are emerging drug targets in recent years, and particularly show excellent potential in neuralgia analgesia. Sigma₁Receptors are distributed primarily in the central nervous system and also widely in peripheral organs. About sigma₁The study of receptor-mediated human pain began in the 90 s, when sigma was found₁The receptor antagonist can enhance the analgesic activity of opioid analgesics₁Agonists would reduce this phenomenon. In acute pain experiments, σ₁The antisense oligodeoxynucleotide of the receptor can obviously enhance the analgesic effect of morphine and opiate mu receptor agonist. More experiments prove that the sigma₁The receptors act by interacting directly with opioid μ receptors. On the other hand, σ has been demonstrated₁The receptor antagonist itself also has analgesic effects on pain, particularly neuropathic pain. The leading edge in the current study of sigma-1 receptor antagonists is S1RA, which is directed against sigma₁The receptor has high affinity and simultaneously has the function of binding to sigma₁The receptor has high selectivity. S1RA is currently used in trials for the treatment of various pains and is in the clinical stage, where trials for the treatment of neuropathic pain alone have already entered clinical stage II.

Thus, find the pair σ₁Sigma of receptor selectivity₁The receptor antagonist is used for anti-pain treatment, and has important scientific value and social significance for clinical treatment of pain and neuralgia.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art. To this end, an object of the invention is to propose a pair σ that can be used for anti-pain treatment₁Sigma of receptor selectivity₁A receptor antagonist.

According to one aspect of the present invention, there is provided a compound which is a compound of formula I or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula I

Wherein the content of the first and second substances,

R₁is optionally substituted C_1～5Alkyl, optionally substituted C_3～7Cycloalkyl, optionally substituted aryl, optionally substitutedThienyl, optionally substituted indolyl selected from the group consisting of alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of;

z is optionally substituted-R_c-R_d-，R_cIs O, S, NH or CH₂，R_dIs a C1-10 linear chain or branched chain alkyl or heterocarbon group, wherein, the C1-10 linear chain or branched chain alkyl or heterocarbon group contains at least one oxygen atom or ethylene, the substituted substituent is selected from alkyl, cyano, hydroxyl, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of;

q is N or CH, R_aAnd R_bEach independently is an optionally substituted straight or branched chain alkyl group containing 1 to 5 carbon atoms, the substituted substituents being selected from alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of the above-mentioned (B),

or Q together with Ra and Rb to which it is attached form a five-to seven-membered ring containing at least one O, N or carbonyl group, said five-to seven-membered ring being optionally substituted alkyl having 1-5 carbon atoms, optionally substituted aryl, optionally substituted thiophene, C_1～10Alkyl formate group, said substituted substituent being selected from the group consisting of alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of (a).

The inventors have surprisingly found that the compounds of the invention are directed towards sigma₁The receptors have selective antagonism and have the potential to have analgesic activity, i.e. the potential to treat pain, particularly neuropathic pain. Further, through animal experiments, the inventors found that the compound of the present invention can be effectively applied to the treatment and prevention of various pain-like diseases including acute pain, chronic pain, intractable pain, cancer pain, and special pain.

According to another aspect of the present invention, there is also provided a pharmaceutical composition. According to an embodiment of the invention, the pharmaceutical composition comprises a compound as described above. The inventors have surprisingly found that₁The pharmaceutical composition of the present invention of the aforementioned compounds, which has selective antagonism to receptors, can be effectively applied to the treatment and prevention of various pain-like diseases including acute pain, chronic pain, intractable pain, cancer pain and special pain.

According to a further aspect of the present invention, there is also provided the use of a compound or pharmaceutical composition as hereinbefore described in the manufacture of a medicament for the prophylaxis or treatment of pain-like disorders.

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.

Definitions and general terms

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and with the handbook of chemistry and Physics (75 th edition, 1994). In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The term "patient" as used herein refers to humans (including adults and children) or other animals. According to some embodiments of the invention, the "patient" refers to a human.

The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

The term "enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

The term "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The term "chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "optional" or "optionally" means 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, "optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" is 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 optional substituent 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, 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 invention as "…" independently means "that the specific items expressed between the same symbols in different groups do not affect each other, and that the 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 "C_1-5Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl and C₅An alkyl group.

The term "alkyl" or "alkyl group" as used herein, unless specifically described, refers to a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. According to one embodiment of the invention, the alkyl group contains 1 to 12 carbon atoms; according to another embodiment of the invention, the alkyl group contains 1 to 6 carbon atoms; according to one embodiment of the invention, the alkyl group contains 1 to 4 carbon atoms; according to another embodiment of the invention, the alkyl group contains 1 to 3 carbon atoms. 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 group (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) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like.

The term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", denotes- (C ═ O) -.

The term "H" represents 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 "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. According to one embodiment of the invention, the alkoxy group contains 1 to 6 carbon atoms; according to one embodiment of the invention, the alkoxy group contains 1 to 4 carbon atoms; according to one embodiment of the invention, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group is optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

The term "ring" includes carbocycles, heterocycles, aromatic rings, heteroaromatic rings, and the like, wherein the carbocycles, heterocycles, aromatic rings, heteroaromatic ring groups have the meaning as described herein.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused, bridged and spiro rings. According to one embodiment of the invention, the cycloalkyl group contains 3 to 10 carbon atoms; according to one embodiment of the invention, the cycloalkyl group contains 3 to 8 carbon atoms; according to one embodiment of the invention, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, at least one of which is aromatic. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. Examples of the aryl group may include phenyl, naphthyl, and anthracene. The aryl group is optionally substituted with one or more substituents described herein.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. For a detailed discussion of prodrugs, reference may be made to the following: higuchi et al, Pro-drugs as Novel delivery systems, vol.14, a.c.s.symposium Series; roche et al, ed., Bioreversible Carrier Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; rautio et al, primers: Design and Clinical Applications, Nature Reviews drug discovery,2008,7, 255-.

The term "metabolite" as used herein refers to a product obtained by the metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: s.m.berge et al, j.pharmaceutical Sciences, 66: 1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations to combat formation of counterionsExamples of the organic compounds are halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

When the solvent is water, the term "hydrate" may be used. According to one embodiment of the invention, a molecule of the compound of the invention may be associated with a molecule of water, such as a monohydrate; according to one embodiment of the invention, one molecule of the compound of the invention may be associated with more than one water molecule, such as a dihydrate, and according to one embodiment of the invention, one molecule of the compound of the invention may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

The term "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., arresting the development of at least one clinical symptom of a disease in a subject that may be facing or predisposed to facing such a disease, but does not yet experience or exhibit symptoms of the disease).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002) may find some additional lists of suitable salts.

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H，³H，¹¹C，¹³C，¹⁴C，¹⁵N，¹⁷O，¹⁸O，¹⁸F，³¹P，³²P，³⁵S，³⁶Cl and¹²⁵I。

in another aspect, the compound package of the present inventionIncluding isotopically enriched compounds defined herein, e.g. in which a radioisotope, e.g. is present³H，¹⁴C and¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³C. the isotopically enriched compounds can be used for metabolic studies (use)¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.¹⁸F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

Compound (I)

Wherein the content of the first and second substances,

R₁is optionally substituted C_1～5Alkyl, optionally substituted C_3～7Cycloalkyl, optionally substituted aryl, optionally substituted thienyl, optionally substituted indolyl, said substituted substituent being selected from the group consisting of alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of;

z is optionally substituted-R_c-R_d-，R_cIs O, S, NH or CH₂，R_dIs a C1-10 linear chain or branched chain alkyl or heterohydrocarbon group, wherein, the C1-10 linear chain or branched chain alkyl or heterohydrocarbon group is optionalContaining at least one oxygen atom or ethylene group, said substituted substituents being selected from alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of;

Wherein, the expression "R" used herein is₁Is optionally substituted C_1～5Alkyl, optionally substituted C_3～7Cycloalkyl, optionally substituted aryl, optionally substituted thienyl, optionally substituted indolyl, said substituted substituent being selected from the group consisting of alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃In "at least one of (1), the term" substituted substituent "means when C is_1～5Alkyl radical, C_3～7When cycloalkyl, aryl, thienyl, indolyl is substituted, for C_1～5Alkyl substituents, for C_3～7Cycloalkyl substituents, substituents for aryl substituents, and useThe substituent for the substituted thienyl group and the substituent for the substituted indolyl group are each independently selected from the group consisting of alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of (a).

As used herein, the expression "Z is optionally substituted-R_c-R_d-，R_cIs O, S, NH or CH₂，R_dIs a C1-10 linear chain or branched chain alkyl or heterocarbon group, wherein, the C1-10 linear chain or branched chain alkyl or heterocarbon group contains at least one oxygen atom or ethylene, the substituted substituent is selected from alkyl, cyano, hydroxyl, halogen, -CN, -N (CN)₂and-C (CN)₃In "at least one of (1), the term" substituted substituent "means when-R_c-R_dWhen substituted, for substitution of-R_c-R_d-substituents selected from alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of (a).

The expression "Q is N or CH, R" as used herein_aAnd R_bEach independently is an optionally substituted straight or branched chain alkyl group containing 1 to 5 carbon atoms, the substituted substituents being selected from alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃In the above-mentioned "at least one of (1) and (b), the term" substituted substituent "means that when a straight-chain or branched alkyl group having 1 to 5 carbon atoms is substituted, a substituent for substituting the straight-chain or branched alkyl group having 1 to 5 carbon atoms is selected from the group consisting of alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of (a).

As used herein, the expression "or Q together with Ra and Rb to which it is attached forms a five-to seven-membered ring containing at least one O, N or carbonyl group, said five-to seven-membered ring being optionally substituted alkyl containing 1-5 carbon atoms, optionally substituted aryl, optionally substituted thiophene, C_1～10Alkyl formate group, said substituted substituent being selected from the group consisting of alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃In at least one of (1), the termThe term "substituted substituent" refers to an alkyl group having 1 to 5 carbon atoms, an aryl group, a thiophene, and C_1～10When the alkyl formate group is substituted, a substituent for substituting an alkyl group having 1 to 5 carbon atoms, a substituent for substituting an aryl group, a substituent for substituting a thiophene, a substituent for substituting C_1～10The substituents of the alkyl formate group are each independently selected from the group consisting of alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of (a).

With respect to "alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃"unless explicitly stated otherwise, definitions are as commonly understood by those of skill in the art and defined herein.

According to an embodiment of the invention, R₁Is optionally substituted cyclopentyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted thienyl, optionally substituted indolyl selected from the group consisting of alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of (a). The term "substituted substituent" as used herein means that when cyclopentyl, phenyl, naphthyl, thienyl, indolyl are substituted, the substituent used to substitute cyclopentyl, the substituent used to substitute phenyl, the substituent used to substitute naphthyl, the substituent used to substitute thienyl, the substituent used to substitute indolyl are each independently selected from alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of (a).

According to an embodiment of the invention, Z is an optionally substituted alkoxy group containing 1 to 5 carbon atoms, the substituted substituent being selected from the group consisting of alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of (a). The term "substituted substituent" as used herein means that when an alkoxy group having 1 to 5 carbon atoms is substituted, the substituent for substituting the alkoxy group having 1 to 5 carbon atoms is selected from the group consisting of alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of (a).

According to an embodiment of the present invention, Q is in conjunction withTo which it is attached to_aAnd R_bCo-form

Or

Wherein R is₂And R₃Each independently is optionally substituted C_1-5Alkyl radical, R₄And R₅Each independently is selected from hydrogen, optionally substituted C_1-5One or more of alkyl, hydroxyl, tert-butyloxycarbonyl and carbonyl, wherein the substituted substituent is selected from alkyl, cyano, hydroxyl, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of;

m is 0, 1 or 2; and

x is one of oxygen, nitrogen or CH.

The substituted substituent is selected from alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of (a).

In addition, R is the same as R₂And R₃As used herein, the term "substituted substituent" means when C is_1-5When alkyl is substituted, for C_1-5The substituents for alkyl are selected from alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of; for R₄And R₅When R is₄And R₅Is optionally substituted C_1-5When alkyl, the term "substituted substituent" as used herein means when C is_1-5When alkyl is substituted, for C_1-5The substituents for alkyl are selected from alkyl, cyano, hydroxy, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of; for R₅When R is₅Is optionally substituted C_1-5The term "substituted substituent" as used herein when it is one or more of alkyl, hydroxy, t-butyloxycarbonyl, carbonyl means when C is_1-5Alkyl, hydroxy, tert-butoxycarbonyl, or substituted carbonylFor substitution of C_1-5The substituent of the alkyl, the substituent used for substituting the hydroxyl, the substituent used for substituting the tert-butyloxycarbonyl and the substituent used for substituting the carbonyl are respectively and independently selected from the group consisting of alkyl, cyano, hydroxyl, halogen, -CN, -N (CN)₂and-C (CN)₃At least one of (a).

According to the embodiment of the invention, the halogen is fluorine, chlorine, bromine or iodine.

According to an embodiment of the invention, R₁Is phenyl, dichlorophenyl, benzyl, fluorophenyl, chlorophenyl, naphthyl or cyclopentyl;

z is ethoxy, propoxy or butoxy;

q is N, CH, and Ra and Rb are each independently methyl, ethyl, propyl, isopropyl, or

Q together with Ra and Rb to which it is attached form a five-to seven-membered ring containing at least one O, N or carbonyl group, said five-to seven-membered ring being optionally substituted with methyl, propyl, phenyl, tert-butyl formate.

According to an embodiment of the present invention, the compound of the present invention is a compound represented by the general formula (I):

wherein the content of the first and second substances,

z is substituted or unsubstituted-O (CH)₂)_n-n is an integer of 2 to 4, the substituted substituent hydroxyl or methyl, or the carbon chain in Z contains a double bond or an oxygen atom;

R₁is hydrogen, substituted or unsubstituted C_1-5Alkyl, substituted or unsubstituted C_3-7Cycloalkyl, substituted or unsubstituted aryl, wherein the substituted substituent is selected from one or more of alkyl, cyano, hydroxyl or halogen;

q is N or CH, R_aAnd R_bEach independently is an optionally substituted straight chain or branched alkyl group containing 1-5 carbon atoms, and the substituted substituent is selected from alkyl, cyano, hydroxyl and halogen、-CN、-N(CN)₂and-C (CN)₃At least one of the above-mentioned (B),

According to an embodiment of the invention, in the compounds of general formula (I), said unsubstituted C_1-5Alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl, substituted C_1-5Alkyl is selected from halogen substituted C_1-5And the halogen is fluorine, chlorine, bromine or iodine.

According to an embodiment of the invention, in the compounds of general formula (I), said unsubstituted C_3-7Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted C_3--7Cycloalkyl is selected from halogen substituted C_3--7Cycloalkyl radical, C_1—5Alkyl substituted C_3--7Cycloalkyl, wherein halogen is fluorine, chlorine, bromine, iodine; said C_1—5The alkyl is one or more of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl or isoamyl.

According to an embodiment of the present invention, in the compound of the general formula (I), the substituted or unsubstituted aryl group is selected from substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthyl, and the substituent is selected from one or more of alkyl, cyano, hydroxyl, or halogen.

According to the embodiment of the invention, in the compound of the general formula (I), the halogen is fluorine, chlorine, bromine or iodine.

According to an embodiment of the present invention, in the compound of the general formula (I), the substituted phenyl is methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl; the substituted benzyl group is a methoxybenzyl group.

According to an embodiment of the invention, the compound is at least one of the following compounds, or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of at least one of the following compounds:

according to some embodiments of the invention, the invention also includes a compound of formula (I) and salts of each of the specific compounds described above, said salts comprising a pharmaceutically acceptable salt of an anion: such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate or bisulphate, phosphate or acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulphonate, gluconate, saccharate, benzoate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and the like.

Use of

According to an embodiment of the present invention, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof.

According to an embodiment of the present invention, the pharmaceutical composition of the present invention further comprises an agent for preventing or treating pain-like diseases other than the aforementioned compound, wherein the agent for preventing or treating pain-like diseases other than the aforementioned compound is at least one selected from the group consisting of: non-steroidal anti-inflammatory analgesics, central analgesics, narcotic analgesics, and Chinese herbal compound analgesics.

According to other embodiments of the present invention, the drug for preventing or treating pain diseases other than the aforementioned compound is at least one selected from the group consisting of: aspirin, ibuprofen, indomethacin, paracetamol, phenylbutazone, rofecoxib, celecoxib, tramadol, fentanyl, morphine, dolantin, anisodamine, naproxen, fenbutadine, sertraline, and analgetic.

According to an embodiment of the invention, the pain-like disorder is neuropathic pain.

According to an embodiment of the present invention, the pharmaceutical composition of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients (such as a carrier and/or an excipient, etc.), wherein the pharmaceutical composition is a compound having analgesic activity sufficient to produce pain and neuralgia.

According to embodiments of the invention, an effective amount of a compound of the invention may be administered orally, e.g., with an inert diluent or with some carrier. According to some embodiments of the invention, the compounds of the invention may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral treatment, the compounds of the present invention may be used with excipients and in the form of tablets, troches, capsules, suspensions, syrups and the like. According to an embodiment of the invention, the above-mentioned formulations should contain at least 0.5% by weight of the active compound according to the invention, but may vary depending on the particular dosage form, wherein 4% to about 70% by weight of the unit is convenient. The amount of active compound in such pharmaceutical compositions should be such that a suitable dosage is achieved. Preferred oral unit doses of the pharmaceutical compositions and formulations of the invention contain 1.0-300 mg of the active compound of the invention.

According to the embodiment of the present invention, the compound provided by the present invention and the pharmaceutically acceptable salt, solvate and hydrate thereof can be used in combination with a pharmaceutically acceptable carrier or diluent to constitute a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.

According to an embodiment of the invention, the amount of the compound of the invention used depends on the type and severity of the disease or condition and also on the characteristics of the subject, such as general health, age, sex, body weight and drug tolerance. The skilled person will be able to determine the appropriate dosage based on these and other factors. Effective dosages of the cns drug generally employed are well known to the skilled artisan. The total daily dose is usually between about 0.05mg and 2000 mg.

According to an embodiment of the invention, the invention relates to a pharmaceutical composition capable of providing about 0.01 to 1000mg of active ingredient per unit dose. The compositions may be administered by any suitable route, for example orally in the form of capsules, parenterally in the form of injection solutions, topically in the form of ointments or lotions, rectally in the form of suppositories, transdermally in the form of a patch delivery system.

According to embodiments of the present invention, the compounds provided herein may be combined with suitable solid or liquid carriers or diluents to form capsules, tablets, pills, powders, syrups, solutions and the like. Tablets, pills, capsules and the like contain from about 0.01 to about 99 weight percent of the active ingredient plus a binder such as gelatin, corn starch, gum arabic; excipients such as dibasic calcium phosphate; disintegrating agents such as corn starch, potato starch or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose. When the formulation is in the form of a capsule, it may contain, in addition to the above-mentioned types of raw materials, a liquid carrier such as a fat.

According to embodiments of the invention, when used for parenteral administration, the compounds provided herein may be combined with sterile water or an organic medium to form an injectable solution or suspension.

In vitro receptor binding assays indicate that the compounds of the invention are directed to sigma₁The receptor has higher affinity with sigma₂The affinity of (a) is low. To sigma₁The receptor has selective antagonism, and shows that the receptor has the potential of analgesic activity.

In addition, animal test results also show that the compound can obviously improve phase I and phase II pain induced by formalin. Due to the in vitro action targets, in vivo pharmacological models and sigma₁Receptor-mediated nervous system-mediated responses, particularly pain, are closely related, and therefore the compounds to which the invention relates have potential in the treatment of pain, particularly neuropathic pain.

Furthermore, according to other embodiments of the present invention, the compounds provided herein, as well as pharmaceutical compositions comprised of the compounds, are useful in the treatment and prevention of pain; the pain refers to acute pain, such as acute injury pain of soft tissues and joints, postoperative pain, obstetrical pain, acute herpes zoster pain, gout and the like; chronic pain such as soft tissue and joint strain or degenerative pain, discogenic pain, neurogenic pain, etc.; intractable pain such as trigeminal neuralgia, postherpetic neuralgia, prolapse of intervertebral disc, intractable headache, etc.; cancer pain such as late tumor pain, tumor metastasis pain, and the like; the special pain can be thromboangiitis, intractable angina pectoris, idiopathic chest pain and abdominal pain, etc.

General synthetic schemes

The general synthetic method of the compound is that the pyridazinone parent body is firstly synthesized and then is connected with the nitrogenous structure through a carbon chain. For example:

wherein, the values of R1, R2, R3 and R R, n are defined as above.

Synthetic examples

The following synthetic examples 1 to 47, all based on the above general method, wherein each example preparation of compounds are shown in Table 1. EXAMPLE 1 preparation of 6- (2-Morpholinoethoxy) -2-phenylpyridazin-3 (2H) -one (Compound 1)

The 6- (2-morpholinoethoxy) -2-phenylpyridazin-3 (2H) -one is prepared by the synthetic scheme shown in the reaction formula, and the specific steps are as follows:

1) 14.5g of phenylhydrazine hydrochloride and 9.8g of maleic anhydride are dissolved in 200ml of purified water. Then, 40ml of concentrated hydrochloric acid was slowly added to the solution under stirring to obtain a reaction system. The resulting reaction system was heated under reflux and allowed to react for 6 hours. After the reaction was completed, the reaction mixture was cooled in an ice-water bath to precipitate a yellow solid. The cooled reaction mixture was then filtered with suction and the filter cake was washed twice with water. The washed filter cake was then removed and washed with saturated NaHCO₃Dissolving, filtering insoluble substances, adjusting the pH value of clear liquid to 2-3 by using concentrated hydrochloric acid to separate out white solid, and performing suction filtration and drying to obtain 17.3g of product with the yield of 92.0%.

2) A reaction system was obtained by adding 100ml of acetone to 9.4g of the product of the first step, 13.8g of anhydrous potassium carbonate and 18.8g of 1, 2-dibromoethane. The resulting reaction was heated under reflux for 4 hours and then cooled to room temperature. Subsequently, the reaction mixture was filtered and the solvent was evaporated to dryness to give a pale yellow oil. Then, the pale yellow oil was subjected to flash chromatography to give 8.5g of a white solid, a melting point of 77 to 79 ℃ and a yield of 61.3%.

3) 1.40g of the second-step product, 0.8g of morpholine and 2g of potassium carbonate were taken and added with 50ml of acetonitrile to obtain a reaction system. The resulting reaction was heated under reflux for 6 hours and then cooled to room temperature. Subsequently, the reaction mixture was evaporated to dryness, and an appropriate amount of dichloromethane was added, followed by washing with water, separating the aqueous layer, drying the organic layer over anhydrous magnesium sulfate, and evaporating the solvent to dryness to obtain a yellow oil. Then, the pale yellow oil was subjected to flash chromatography to obtain the objective compound, i.e., 1.21g of a pale yellow oil, in a yield of 80.6%.

¹H NMR(600MHz,CDCl₃)δ7.64(d,J＝7.7Hz,2H),7.47–7.42(m,2H),7.33(t,J＝7.4Hz,1H),7.01(q,J＝9.7Hz,2H),4.31(t,J＝5.6Hz,2H),3.72(t,J＝3.9Hz,4H),2.78(t,J＝5.6Hz,2H),2.56(s,4H).MS(ESI)m/z 302.6([M+H]⁺)

Example 2, 6- (3-Morpholinopropoxy) -2-phenylpyridazin-3 (2H) -one (Compound 2)

The title compound was prepared by converting 1, 2-dibromoethane to 1, 3-dibromopropane, in the same manner as in example 1.

¹H NMR(600MHz,CDCl₃)δ7.65–7.63(m,2H),7.45(t,J＝7.9Hz,2H),7.34(t,J＝7.4Hz,1H),7.02–6.95(m,2H),4.32–4.17(m,2H),3.77–3.57(m,4H),2.80–2.62(m,1H),2.53–2.42(m,5H),2.00–1.88(m,2H).

MS(ESI)m/z 316.4([M+H]⁺)

Example 3, 6- (4-Morpholinobutoxy) -2-phenylpyridazin-3 (2H) -one (Compound 3)

The title compound was prepared by converting 1, 2-dibromoethane to 1, 4-dibromobutane as in example 1.

¹H NMR(600MHz,CDCl₃)δ7.66(d,J＝7.6Hz,2H),7.46(t,J＝7.9Hz,2H),7.35(t,J＝7.4Hz,1H),7.05–6.95(m,2H),4.18(t,J＝6.4Hz,2H),3.72(t,J＝4.6Hz,4H),2.53–2.37(m,6H),1.82–1.73(m,2H),1.68-1.63(m,2H).MS(ESI)m/z 330.8([M+H]⁺)

Example 4, 6- (3- (piperidin-1-yl) propoxy) -2-phenylpyridazin-3 (2H) -one (Compound 4)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to piperidine.

¹H NMR(600MHz,CDCl₃)δ7.64(d,J＝7.7Hz,2H),7.44(dd,J＝10.8,5.0Hz,2H),7.35–7.30(m,1H),7.00–6.94(m,2H),4.19(t,J＝6.4Hz,2H),2.49–2.32(m,6H),2.00–1.90(m,2H),1.64–1.54(m,4H),1.43(s,2H).MS(ESI)m/z 314.3([M+H]⁺)

Example 5, 6- (3- (4-Methylpiperidin-1-yl) propoxy) -2-phenylpyridazin-3 (2H) -one (Compound 5)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to 4-methylpiperidine.

¹H NMR(600MHz,CDCl₃)δ7.66(d,J＝7.7Hz,2H),7.44(t,J＝7.9Hz,2H),7.33(t,J＝7.4Hz,1H),7.01–6.95(m,2H),4.20(t,J＝6.4Hz,2H),2.90(d,J＝11.4Hz,2H),2.52–2.39(m,2H),2.01–1.85(m,4H),1.66–1.56(m,2H),1.41–1.30(m,1H),1.24(qd,J＝12.5,3.6Hz,2H),0.92(d,J＝6.5Hz,3H).MS(ESI)m/z 328.4([M+H]⁺)

Example 6, 6- (3- (4-Methylpiperazin-1-yl) propoxy) -2-phenylpyridazin-3 (2H) -one (Compound 6)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to N-methylpiperazine.

¹H NMR(600MHz,CDCl₃)δ7.62(dd,J＝8.5,1.0Hz,2H),7.43(dd,J＝11.3,4.6Hz,2H),7.35–7.31(m,1H),6.98(q,J＝9.7Hz,2H),4.19(t,J＝6.3Hz,2H),2.90–2.66(m,8H),2.63–2.54(m,2H),2.50(s,3H),1.99–1.88(m,2H).MS(ESI)m/z 329.4([M+H]⁺)

Example 7, 6- (3- (4-ethylpiperazin-1-yl) propoxy) -2-phenylpyridazin-3 (2H) -one (Compound 7)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to N-ethylpiperazine.

¹H NMR(600MHz,CDCl₃)δ7.61(dd,J＝8.5,1.0Hz,2H),7.41(t,J＝7.9Hz,2H),7.33–7.29(m,1H),7.01–6.93(m,2H),4.39–4.10(m,2H),2.81–2.39(m,12H),2.02–1.81(m,2H),1.14(t,J＝7.3Hz,3H).

MS(ESI)m/z 343.5([M+H]⁺)

Example 8, 6- (3- (3, 5-dimethylpiperidin-1-yl) propoxy) -2-phenylpyridazin-3 (2H) -one (Compound 8)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to 3, 5-dimethylpiperidine.

¹H NMR(600MHz,CDCl₃)δ7.68–7.60(m,2H),7.42(t,J＝7.0Hz,2H),7.31(t,J＝7.4Hz,1H),7.00–6.93(m,2H),4.23–4.15(m,2H),2.97–2.87(m,2H),2.59–2.51(m,2H),2.01(dd,J＝14.5,7.1Hz,2H),1.81–1.66(m,2H),1.56(t,J＝11.2Hz,2H),0.83(d,J＝6.6Hz,6H),0.64–0.49(m,2H).MS(ESI)m/z 342.3([M+H]⁺)

Example 9, 6- (3- (4-methyl-1, 4-diazepan-1-yl) propoxy) -2-phenylpyridazin-3 (2H) -one (Compound 9)

¹H NMR(600MHz,CDCl₃)δ7.68–7.65(m,2H),7.49(t,J＝7.4Hz,2H),7.38(t,J＝7.4Hz,1H),7.05(d,J＝9.9Hz,1H),7.01(d,J＝9.8Hz,1H),4.25(t,J＝6.2Hz,2H),3.39–3.09(m,6H),2.95(t,J＝5.9Hz,2H),2.82(dd,J＝15.2,8.0Hz,2H),2.75(s,3H),2.29(s,2H),2.06–1.98(m,2H).MS(ESI)m/z 343.4([M+H]⁺)

Example 10, 6- (3- (dimethylamino) propoxy) -2-phenylpyridazin-3 (2H) -one (Compound 10)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to dimethylamine.

¹H NMR(600MHz,CDCl₃)δ7.66–7.59(m,2H),7.47–7.41(m,2H),7.37–7.31(m,1H),7.07–6.98(m,2H),4.32–4.20(m,2H),3.24–3.17(m,2H),2.80(s,6H),2.35–2.21(m,2H).MS(ESI)m/z 274.3([M+H]⁺)

Example 11, 6- (3- (diethylamino) propoxy) -2-phenylpyridazin-3 (2H) -one (Compound 11)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to diethylamine.

¹H NMR(600MHz,CDCl₃)δ7.67–7.63(m,2H),7.49–7.44(m,2H),7.35(dd,J＝10.7,4.2Hz,1H),7.04–6.98(m,2H),4.25(t,J＝6.1Hz,2H),2.96–2.84(m,6H),2.22–2.08(m,2H),1.24(t,J＝7.2Hz,6H).MS(ESI)m/z 302.4([M+H]⁺)

Example 12, 6- (3- (diisopropylamino) propoxy) -2-phenylpyridazin-3 (2H) -one (Compound 12)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to diisopropylamine.

¹H NMR(600MHz,CDCl₃)δ7.63(d,J＝7.6Hz,2H),7.37(t,J＝7.9Hz,2H),7.25(t,J＝7.4Hz,1H),6.96–6.86(m,2H),4.15(t,J＝6.4Hz,2H),2.49(t,J＝7.1Hz,2H),2.35–2.28(m,4H),1.86–1.78(m,2H),1.44–1.32(m,4H),0.80(t,J＝7.4Hz,6H).MS(ESI)m/z 330.3([M+H]⁺)

Example 13, 6- (3- (4-Oxopiperidin-1-yl) propoxy) -2-phenylpyridazin-3 (2H) -one (Compound 13)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to 4-piperidone.

¹H NMR(600MHz,CDCl₃)δ7.68–7.63(m,2H),7.49–7.42(m,2H),7.36-7.32(m,J＝11.9,5.4,1.0Hz,1H),7.05–6.93(m,2H),4.46–4.20(m,4H),3.76-3.72(m,4H),2.54–2.37(m,2H),2.26–2.09(m,2H),2.02–1.91(m,2H).MS(ESI)m/z 328.5([M+H]⁺)

Example 14, 6- (4- (piperidin-1-yl) butoxy) -2-phenylpyridazin-3 (2H) -one (Compound 14)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 4-dibromobutane and morpholine to piperidine.

¹H NMR(600MHz,CDCl₃)δ7.65(d,J＝7.6Hz,2H),7.48(t,J＝8.2Hz,2H),7.33(t,J＝7.3Hz,1H),7.05–7.02(m,2H),4.25–4.21(m,2H),3.15–3.06(m,2H),2.97–2.88(m,2H),2.78–2.70(m,2H),1.98–1.53(m,10H).

MS(ESI)m/z 328.5([M+H]⁺)

Example 15, 6- (4- (4-Methylpiperazin-1-yl) butoxy) -2-phenylpyridazin-3 (2H) -one (Compound 15)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 4-dibromobutane and morpholine to N-methylpiperazine.

¹H NMR(600MHz,CDCl₃)δ7.61(t,J＝8.8Hz,2H),7.42(dt,J＝13.1,5.8Hz,2H),7.31(dd,J＝10.1,4.5Hz,1H),7.00–6.94(m,2H),4.13(dd,J＝11.6,5.4Hz,2H),2.77(t,J＝50.6Hz,8H),2.61–2.42(m,5H),1.82–1.50(m,4H).

MS(ESI)m/z 343.9([M+H]⁺)

Example 16, 6- (4- (4-ethylpiperazin-1-yl) butoxy) -2-phenylpyridazin-3 (2H) -one (Compound 16)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 4-dibromobutane and morpholine to N-ethylpiperazine.

¹H NMR(600MHz,CDCl₃)δ7.65–7.61(m,2H),7.43(t,J＝7.9Hz,2H),7.32(t,J＝7.4Hz,1H),6.95–6.90(m,2H),4.43(s,2H),4.13(t,J＝6.4Hz,2H),3.77(t,J＝7.1Hz,2H),3.64–3.56(m,2H),2.62-2.54(m,4H),2.46–2.37(m,2H),2.25(s,2H),1.78–1.68(m,2H),1.12(t,J＝7.2Hz,3H).

MS(ESI)m/z 357.5([M+H]⁺)

Example 17, 6- (4- (diethylamino) butoxy) -2-phenylpyridazin-3 (2H) -one (Compound 17)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 4-dibromobutane and morpholine to diethylamine.

¹H NMR(600MHz,CDCl₃)δ7.68(d,J＝8.1Hz,2H),7.47(t,J＝7.8Hz,2H),7.37(t,J＝7.4Hz,1H),7.03(d,J＝9.7Hz,2H),6.98(d,J＝9.7Hz,2H),4.25(s,2H),1.94(s,2H).MS(ESI)m/z316.8([M+H]⁺)

Example 18, 6- (4- (4-methyl-1, 4-diazepan-1-yl) butoxy) -2-phenylpyridazin-3 (2H) -one-pyridine (Compound 18)

¹H NMR(600MHz,CDCl₃)δ7.84(d,J＝2.4Hz,2H),7.60(d,J＝2.4Hz,2H),7.47(d,J＝8.7Hz,1H),7.00-6.95(m,2H),4.23(t,J＝6.1Hz,4H),3.51(s,2H),2.85–2.74(m,4H),2.52(s,7H),2.18–2.05(m,4H).MS(ESI)m/z 357.3([M+H]⁺)

Example 19, 6- (4- (4-oxopiperidin-1-yl) butoxy) -2-phenylpyridazin-3 (2H) -one (Compound 19)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 4-dibromobutane and morpholine to 4-piperidone.

¹H NMR(600MHz,CDCl₃)δ7.69–7.63(m,2H),7.49–7.43(m,2H),7.37–7.32(m,1H),7.04–6.96(m,2H),4.27–4.09(m,2H),3.10–2.89(m,2H),2.74(t,J＝6.1Hz,2H),2.55–2.39(m,4H),1.88–1.59(m,6H).

MS(ESI)m/z 342.5([M+H]⁺)

Example 20, 6- (4- (3, 5-dimethylpiperidin-1-yl) butoxy) -2-phenylpyridazin-3 (2H) -one (Compound 20)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 4-dibromobutane and morpholine to 3, 5-dimethylpiperidine.

¹H NMR(600MHz,CDCl₃)δ7.66-7.63(m,2H),7.46–7.42(m,2H),7.34(t,J＝7.4Hz,1H),7.01–6.96(m,2H),4.29–4.16(m,2H),4.16–4.10(m,2H),3.10(t,J＝20.3Hz,2H),2.74–2.64(m,2H),2.07–1.86(m,2H),1.85–1.61(m,2H),0.97(d,J＝8.9Hz,3H),0.83(d,J＝6.6Hz,3H).MS(ESI)m/z 356.7([M+H]⁺)

Example 21 2- (3, 4-dichlorophenyl) -6- (3-morpholinepropoxy) pyridazin-3 (2H) -one (Compound 21)

The target compound was prepared by the method of example 1, substituting phenylhydrazine hydrochloride for 3, 4-dichlorophenylhydrazine hydrochloride.

¹H NMR(600MHz,CDCl₃)δ7.88(d,J＝2.4Hz,1H),7.65(dd,J＝8.7,2.5Hz,1H),7.53–7.49(m,1H),7.05–6.94(m,2H),4.24(t,J＝6.4Hz,2H),3.73(t,J＝4.5Hz,4H),2.51(dd,J＝16.9,9.4Hz,6H),2.02–1.92(m,2H).

MS(ESI)m/z 384.8([M+H]⁺)

Example 22, 2- (3, 4-dichlorophenyl) -6- (3- (4-methylpiperazin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 22)

The title compound was prepared in the same manner as in example 1, except that phenylhydrazine hydrochloride was changed to 3, 4-dichlorophenylhydrazine hydrochloride, 1, 2-dibromoethane was changed to 1, 3-dibromopropane, and morpholine was changed to N-methylpiperazine.

¹H NMR(600MHz,CDCl₃)δ7.85(d,J＝2.4Hz,1H),7.62(dd,J＝8.7,2.4Hz,1H),7.49(d,J＝8.7Hz,1H),7.06–6.93(m,2H),4.21(t,J＝6.3Hz,2H),2.64(d,J＝25.3Hz,8H),2.57–2.53(m,2H),2.42(s,3H),1.99–1.90(m,2H).

MS(ESI)m/z 397.7([M+H]⁺)

Example 23, 2- (3, 4-dichlorophenyl) -6- (3- (piperidin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 23)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorohydrazinehydrochloride, 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to piperidine.

¹H NMR(600MHz,CDCl₃)δ7.88(d,J＝2.4Hz,1H),7.65(dd,J＝8.7,2.5Hz,1H),7.50(d,J＝8.7Hz,1H),7.04–6.96(m,2H),4.22(t,J＝6.4Hz,2H),2.53–2.38(m,6H),2.02–1.92(m,2H),1.66–1.58(m,4H),1.43(d,J＝30.4Hz,2H).

MS(ESI)m/z 382.8([M+H]⁺)

Example 24, 2- (3, 4-dichlorophenyl) -6- (3- (4-methylpiperidin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 24)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorohydrazinehydrochloride, 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to 4-methylpiperidine.

¹H NMR(600MHz,CDCl₃)δ7.88(d,J＝2.5Hz,1H),7.65(dd,J＝8.7,2.5Hz,1H),7.50(d,J＝8.7Hz,1H),6.99(d,J＝10.0Hz,2H),4.22(t,J＝6.4Hz,2H),2.91(d,J＝11.4Hz,2H),2.49–2.45(m,2H),2.02–1.90(m,4H),1.63(d,J＝12.8Hz,2H),1.41–1.33(m,1H),1.29-1.22(m,3H),0.93(d,J＝6.5Hz,3H).MS(ESI)m/z 396.9([M+H]⁺)

Example 25, 2- (3, 4-dichlorophenyl) -6- (3- (pyrrolidin-1-yl) propoxy) pyridazin-3 (2H) -one (compound 25)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorohydrazinehydrochloride, 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to pyrrolidine.

¹H NMR(600MHz,CDCl₃)δ7.85(d,J＝2.5Hz,1H),7.61(dd,J＝8.7,2.5Hz,1H),7.46(d,J＝8.7Hz,1H),6.95(q,J＝9.8Hz,2H),4.21(t,J＝6.4Hz,2H),2.62–2.58(m,2H),2.53(dd,J＝8.5,3.3Hz,4H),2.01–1.94(m,2H),1.81–1.74(m,4H).

MS(ESI)m/z 368.6([M+H]⁺)

Example 26, 2- (3, 4-dichlorophenyl) -6- (3- (4-oxopiperidin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 26)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorohydrazinehydrochloride, 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to 4-piperidone.

¹H NMR(600MHz,CDCl₃)δ7.87(d,J＝2.4Hz,1H),7.64(dd,J＝8.7,2.5Hz,1H),7.49(d,J＝7.4Hz,1H),7.02–6.96(m,2H),4.26(t,J＝6.3Hz,2H),2.78(dd,J＝13.4,7.4Hz,4H),2.62(t,J＝7.2Hz,2H),2.45(t,J＝6.0Hz,4H),2.05–1.96(m,2H).MS(ESI)m/z 396.5([M+H]⁺)

Example 27, 2- (3, 4-dichlorophenyl) -6- (3- (4-ethylpiperazin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 27)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorohydrazinehydrochloride, 1, 2-dibromoethane to 1, 3-dibromopropane, and morpholine to N-ethylpiperazine.

¹H NMR(600MHz,CDCl₃)δ7.84(d,J＝2.4Hz,1H),7.61(dd,J＝8.7,2.5Hz,1H),7.47(d,J＝8.7Hz,1H),7.00–6.94(m,2H),4.19(t,J＝6.4Hz,2H),2.73–2.41(m,12H),1.98–1.88(m,2H),1.12(t,J＝7.2Hz,3H).MS(ESI)m/z 411.4([M+H]⁺)

Example 28, 2- (3, 4-dichlorophenyl) -6- (3- (4-methyl-1, 4-diazepan-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 28)

The title compound was prepared by substituting phenylhydrazine hydrochloride for 3, 4-dichlorophenylhydrazine hydrochloride, 1, 2-dibromoethane for 1, 3-dibromopropane, and morpholine for N-methylpiperazine according to the procedure of example 1.

¹H NMR(600MHz,CDCl₃)δ7.82(d,J＝2.4Hz,1H),7.59(dd,J＝8.7,2.4Hz,1H),7.47(d,J＝8.7Hz,1H),7.01–6.95(m,2H),4.17(t,J＝6.1Hz,2H),3.33–3.22(m,4H),3.06(d,J＝3.9Hz,2H),2.87(t,J＝6.1Hz,2H),2.78–2.73(m,4H),2.23–2.17(m,2H),1.99–1.91(m,3H).MS(ESI)m/z 411.6([M+H]⁺)

Example 29, 2- (3, 4-dichlorophenyl) -6- (3- (3, 5-dimethylpiperidin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 29)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorophenylhydrazine hydrochloride, 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to 3, 5-dimethylpiperidine.

¹H NMR(600MHz,CDCl₃)δ7.87(t,J＝2.9Hz,1H),7.65–7.61(m,1H),7.48(d,J＝8.7Hz,1H),7.02–6.94(m,2H),4.27–4.17(m,2H),2.88(d,J＝10.0Hz,2H),2.53–2.48(m,2H),2.06–1.98(m,2H),1.77–1.65(m,2H),1.50(t,J＝11.0Hz,2H),0.85(d,J＝6.5Hz,6H),0.54(q,J＝12.3Hz,2H).MS(ESI)m/z 410.6([M+H]⁺)

Example 30 tert-butyl 4- (3- ((1- (3, 4-dichlorophenyl) -6-oxo-1, 6-dihydropyridazin-3-yl) oxy) propoxy) piperazine-1-carboxylate (Compound 30)

The title compound was prepared as in example 1 by replacing phenylhydrazine hydrochloride with 3, 4-dichlorophenylhydrazine hydrochloride, 1, 2-dibromoethane with 1, 3-dibromopropane, and morpholine with N-Boc piperazine.

¹H NMR(600MHz,CDCl₃)δ7.79(d,J＝2.4Hz,1H),7.55(dd,J＝8.7,2.4Hz,1H),7.38(dd,J＝8.7,2.4Hz,1H),6.92–6.85(m,2H),4.13(t,J＝6.3Hz,2H),3.39–3.28(m,4H),2.40(t,J＝7.2Hz,2H),2.30(s,4H),1.90–1.81(m,2H),1.36(s,9H).

MS(ESI)m/z 483.7([M+H]⁺)

Example 31 2- (3, 4-dichlorophenyl) -6- (3- (4-phenylpiperazin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 31)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorohydrazinehydrochloride, 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to 4-phenylpiperazine.

¹H NMR(600MHz,CDCl₃)δ7.82(d,J＝2.4Hz,1H),7.57(dd,J＝8.8,2.4Hz,1H),7.38(d,J＝8.8Hz,1H),6.89(q,J＝9.7Hz,2H),4.13(t,J＝6.4Hz,2H),2.52–2.43(m,6H),1.86–1.78(m,2H),0.93(t,J＝7.2Hz,6H).MS(ESI)m/z 370.9([M+H]⁺)

Example 32, 2- (3, 4-dichlorophenyl) -6- (3- (dimethylamino) propoxy) pyridazin-3 (2H) -one (32)

The objective compound was prepared in the same manner as in example 1 except that phenylhydrazine hydrochloride was changed to 3, 4-dichlorophenylhydrazine hydrochloride, 1, 2-dibromoethane was changed to 1, 3-dibromopropane, and morpholine was changed to dimethylamine.

¹H NMR(600MHz,CDCl₃)δ7.82(d,J＝2.4Hz,1H),7.57(dd,J＝8.8,2.4Hz,1H),7.38(d,J＝8.8Hz,1H),6.89(q,J＝9.7Hz,2H),4.13(t,J＝6.4Hz,2H),2.50(m,2H),1.86–1.78(m,2H),0.93(t,J＝7.2Hz,6H).MS(ESI)m/z 342.6([M+H]⁺)

Example 33, 2- (3, 4-dichlorophenyl) -6- (3- (diethylamino) propoxy) pyridazin-3 (2H) -one (Compound 33)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorohydrazinehydrochloride, 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to diethylamine.

¹H NMR(600MHz,CDCl₃)δ7.82(d,J＝2.4Hz,1H),7.57(dd,J＝8.8,2.4Hz,1H),7.38(d,J＝8.8Hz,1H),6.89(q,J＝9.7Hz,2H),4.13(t,J＝6.4Hz,2H),2.52–2.43(m,6H),1.86–1.78(m,2H),0.93(t,J＝7.2Hz,6H).MS(ESI)m/z 370.5([M+H]⁺)

Example 34 2- (3, 4-dichlorophenyl) -6- (3- (dipropylamino) propoxy) pyridazin-3 (2H) -one (Compound 34)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorohydrazinehydrochloride, 1, 2-dibromoethane to 1, 3-dibromopropane and morpholine to dipropylamine.

¹H NMR(600MHz,CDCl₃)δ7.90(d,J＝2.5Hz,1H),7.67(dd,J＝8.7,2.5Hz,1H),7.51(d,J＝8.7Hz,1H),7.04–6.97(m,2H),4.24(t,J＝6.4Hz,2H),2.57(t,J＝7.1Hz,2H),2.42–2.35(m,4H),1.95–1.85(m,2H),1.51–1.41(m,4H),0.88(t,J＝7.4Hz,6H).MS(ESI)m/z398.6([M+H]⁺)

Example 35, 2- (3, 4-dichlorophenyl) -6- (4-morpholinyloxy) pyridazin-3 (2H) -one (Compound 35)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorohydrazinehydrochloride and 1, 2-dibromoethane to 1, 4-dibromobutane.

¹H NMR(600MHz,CDCl₃)δ7.75(d,J＝2.3Hz,1H),7.50(dd,J＝8.8,2.3Hz,1H),7.30(d,J＝8.8Hz,1H),6.80(dt,J＝9.8,8.3Hz,2H),4.02(t,J＝6.4Hz,2H),3.54–3.48(m,4H),2.22(dd,J＝20.1,12.6Hz,6H),1.66–1.59(m,2H),1.50–1.43(m,2H).MS(ESI)m/z 398.3([M+H]⁺)

Example 36, 2- (3, 4-dichlorophenyl) -6- (4- (4-methylpiperidin-1-yl) butoxy) pyridazin-3 (2H) -one (compound 36)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorohydrazinehydrochloride, 1, 2-dibromoethane to 1, 4-dibromobutane and morpholine to 4-methylpiperidine.

¹H NMR(600MHz,CDCl₃)δ7.89(d,J＝2.4Hz,1H),7.65(dd,J＝8.7,2.4Hz,1H),7.51(d,J＝8.7Hz,1H),7.01–6.97(m,2H),4.19(t,J＝6.4Hz,2H),2.91(d,J＝11.4Hz,2H),2.41–2.32(m,2H),1.93(dd,J＝20.6,8.6Hz,2H),1.82–1.75(m,2H),1.71–1.57(m,4H),1.37(ddd,J＝14.6,10.5,5.2Hz,1H),1.30–1.22(m,2H),0.93(d,J＝6.5Hz,3H).MS(ESI)m/z 410.4([M+H]⁺)

Example 37, 2- (3, 4-dichlorophenyl) -6- (4- (piperidin-1-yl) butoxy) pyridazin-3 (2H) -one (Compound 37)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 3, 4-dichlorohydrazinehydrochloride, 1, 2-dibromoethane to 1, 4-dibromobutane and morpholine to piperidine.

¹H NMR(600MHz,CDCl₃)δ7.90-7.88(m,1H),7.68-7.66(m,1H),7.53(dd,J＝8.7,4.8Hz,1H),7.08–6.97(m,2H).4.25–4.21(m,2H),3.15–3.06(m,2H),2.97–2.88(m,2H),2.78–2.70(m,2H),1.98–1.53(m,10H).MS(ESI)m/z 396.7([M+H]⁺)

Example 38, 6- (3- (4-Methylpiperidin-1-yl) propoxy) -2- (p-tolyl) pyridazin-3 (2H) -one (Compound 38)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to p-tolylhydrazine hydrochloride, 1, 2-dibromoethane to 1, 3-dibromopropanealkane, and morpholine to 4-methylpiperidine.

¹H NMR(600MHz,CDCl₃)δ7.52(d,J＝8.3Hz,2H),7.23(d,J＝8.2Hz,2H),6.95(q,J＝9.7Hz,2H),4.18(t,J＝6.4Hz,2H),2.88(d,J＝11.3Hz,2H),2.45–2.42(m,2H),2.37(s,3H),1.97–1.86(m,4H),1.60(d,J＝12.8Hz,2H),1.39–1.31(m,1H),1.28–1.18(m,2H),0.91(d,J＝6.5Hz,3H).MS(ESI)m/z 342.7([M+H]⁺)

Example 39 6- (3- (piperidin-1-yl) propoxy) -2- (p-tolyl) pyridazin-3 (2H) -one (compound 39)

The title compound was prepared by substituting phenylhydrazine hydrochloride for p-tolylhydrazine hydrochloride, 1, 2-dibromoethane for 1, 3-dibromopropanealkane, and morpholine for piperidine according to the procedure of example 1.

¹H NMR(600MHz,CDCl₃)δ7.48(d,J＝8.3Hz,2H),7.22(d,J＝8.1Hz,2H),6.98–6.93(m,2H),4.17(t,J＝6.2Hz,2H),2.59(dd,J＝18.2,10.4Hz,6H),2.35(s,3H),2.09–1.97(m,2H),1.71–1.61(m,4H),1.46(s,2H).MS(ESI)m/z 328.7([M+H]⁺)

Example 40 2- (4-fluorophenyl) -6- (3- (4-methylpiperidin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 40)

The objective compound was prepared in the same manner as in example 1, except that phenylhydrazine hydrochloride was changed to p-fluorophenylhydrazine hydrochloride, 1, 2-dibromoethane was changed to 1, 3-dibromopropanealkane, and morpholine was changed to 4-methylpiperidine.

¹H NMR(600MHz,CDCl₃)δ7.68–7.63(m,2H),7.15–7.09(m,2H),7.01–6.95(m,2H),4.19(t,J＝6.4Hz,2H),2.88(d,J＝11.1Hz,2H),2.48–2.40(m,2H),1.98–1.84(m,4H),1.61(d,J＝12.8Hz,2H),1.35(d,J＝6.0Hz,1H),1.23(q,J＝11.4Hz,2H),0.91(d,J＝6.5Hz,3H).MS(ESI)m/z 346.5([M+H]⁺)

Example 41, 2- (4-fluorophenyl) -6- (3- (piperidin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 41)

The objective compound was prepared by the procedure of example 1, substituting phenylhydrazine hydrochloride for p-fluorophenylhydrazine hydrochloride, 1, 2-dibromoethane for 1, 3-dibromopropane, and morpholine for piperidine.

¹H NMR(600MHz,CDCl₃)δ7.65–7.61(m,2H),7.14–7.07(m,2H),6.99(d,J＝9.7Hz,2H),4.20(t,J＝6.2Hz,2H),2.66(dd,J＝17.3,9.3Hz,6H),2.15–2.00(m,2H),1.75–1.68(m,4H),1.50(s,2H).MS(ESI)m/z 332.5([M+H]⁺)

Example 42, 2- (4-chlorophenyl) -6- (3- (piperidin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 42)

The title compound was prepared by substituting phenylhydrazine hydrochloride for p-chlorophenylhydrazine hydrochloride, 1, 2-dibromoethane for 1, 3-dibromopropane, and morpholine for piperidine according to the procedure of example 1.

¹H NMR(600MHz,CDCl₃)δ7.68–7.64(m,2H),7.42–7.38(m,2H),6.97(s,2H),4.20(t,J＝6.4Hz,2H),2.42(dd,J＝22.1,14.4Hz,6H),2.04–1.86(m,2H),1.65–1.53(m,4H),1.43(s,2H).MS(ESI)m/z348.7([M+H]⁺)

Example 43, 2- (4-chlorophenyl) -6- (3- (4-methylpiperidin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 43)

The title compound was prepared by substituting phenylhydrazine hydrochloride for p-chlorophenylhydrazine hydrochloride, 1, 2-dibromoethane for 1, 3-dibromopropanealkane, and morpholine for 4-methylpiperidine in the same manner as in example 1.

¹H NMR(600MHz,CDCl₃)δ7.68–7.65(m,2H),7.43–7.39(m,2H),7.01–6.96(m,2H),4.21(t,J＝6.4Hz,2H),2.89(d,J＝11.4Hz,2H),2.49–2.43(m,2H),1.99–1.87(m,4H),1.62(d,J＝12.9Hz,2H),1.42–1.33(m,1H),1.28-1.21(m,3.6Hz,2H),0.92(d,J＝6.5Hz,3H).MS(ESI)m/z 362.8([M+H]⁺)

Example 44, 6- (3- (piperidin-1-yl) propoxy) -2- (naphthalen-2-yl) pyridazin-3 (2H) -one (Compound 44)

The title compound was prepared by substituting phenylhydrazine hydrochloride for 2-naphthylhydrazine hydrochloride, 1, 2-dibromoethane for 1, 3-dibromopropanealkane, and morpholine for piperidine according to the procedure of example 1.

¹H NMR(600MHz,CDCl₃)δ8.20(d,J＝1.7Hz,1H),7.95–7.85(m,3H),7.79(dd,J＝8.8,2.1Hz,1H),7.54–7.49(m,2H),7.03(dd,J＝22.4,9.7Hz,2H),4.25(t,J＝6.4Hz,2H),2.45(dd,J＝24.5,16.7Hz,6H),2.05–1.92(m,2H),1.66–1.55(m,4H),1.45(s,2H).MS(ESI)m/z 364.5([M+H]⁺)

Example 45, 6- (3- (4-methylpiperidin-1-yl) propoxy) -2- (naphthalen-2-yl) pyridazin-3 (2H) -one (Compound 45)

The title compound was prepared in the same manner as in example 1 except for changing phenylhydrazine hydrochloride to 2-naphthylhydrazine hydrochloride, 1, 2-dibromoethane to 1, 3-dibromopropanealkane and morpholine to 4-methylpiperidine.

¹H NMR(600MHz,CDCl₃)δ8.20(d,J＝1.8Hz,1H),7.89(ddd,J＝16.8,11.9,6.1Hz,3H),7.79(dd,J＝8.8,2.1Hz,1H),7.54–7.47(m,2H),7.03(dd,J＝23.3,9.7Hz,2H),4.25(t,J＝6.4Hz,2H),2.90(d,J＝11.4Hz,2H),2.53–2.43(m,2H),2.01–1.89(m,4H),1.62(d,J＝12.8Hz,2H),1.43–1.18(m,3H),0.93(d,J＝6.5Hz,3H).MS(ESI)m/z 378.8([M+H]⁺)

Example 46, 2-cyclopentyl-6- (3- (piperidin-1-yl) propoxy) pyridazin-3 (2H) -one (Compound 46)

The title compound was prepared as in example 1 by substituting phenylhydrazine hydrochloride for cyclopentylhydrazine hydrochloride, 1, 2-dibromoethane for 1, 3-dibromopropane, and morpholine for piperidine.

¹H NMR(600MHz,CDCl₃)δ6.67–6.50(m,2H),5.19–5.00(m,1H),3.93(dd,J＝14.8,8.5Hz,2H),2.19(dd,J＝22.9,15.5Hz,6H),1.82–1.51(m,8H),1.35(dd,J＝23.9,18.4Hz,6H),1.18(s,2H).MS(ESI)m/z 306.5([M+H]⁺)

Example 47, 6- (4- (dimethylamino) butoxy) -2-phenylpyridazin-3 (2H) -one (Compound 47)

The title compound was prepared as in example 1 by converting 1, 2-dibromoethane to 1, 4-dibromobutane and morpholine to dimethylamine.

TABLE 1 numbering of the preferred compounds prepared in the examples and structural formulas thereof

Pharmacological examples

In the following embodiment, the employed homogenate includes two kinds of homogenate of a homogenate and a homogenate of B, and the configuration methods are respectively as follows:

a homogenate contained Tris-HCl buffer at a final concentration of 0.01M and sucrose solution at a final concentration of 0.32M, pH 7.4.

The B homogenate was 0.01M Tris-HCl buffer, pH 7.4.

The C homogenate was 50mM Tris buffer, pH 7.4.

Example 48. sigma₁Preparation of acceptor membranes and determination of ligand affinity (Ki values)

σ₁Preparation of acceptor membranes

After decapitation of guinea pigs, brain tissue was rapidly removed by working on ice, and the resulting brain tissue was added to a centrifuge tube. 5ml of A homogenate was added to the centrifuge tube and homogenized. The centrifuge tubes were then continued to add a homogenate to 10ml a homogenate/g brain tissue. The homogenized tubes were centrifuged at 1000rpm for 10 min. After centrifugation, the supernatant was taken, and the homogenate of A was added to the supernatant to adjust to 2ml/g, centrifuged, and the supernatant was taken, centrifuged at 1000rpm for 10min at 4 ℃ and the supernatant was taken, and centrifuged at 11500rpm for 25min at 4 ℃. Collecting precipitate, adding A homogenate to the obtained precipitate to adjust to 3ml A homogenate/g precipitate, incubating at 25 deg.C for 15min, centrifuging at 4 deg.C 11500rpm for 25min, and collecting precipitate as sigma₁Acceptor membranes.

Receptor binding assay materials

Isotope ligand [ alpha ], [ alpha³H]- (+) -tebuconazole (250. mu. Ci, NET-1056250UC) from Perkin- -Elmer;

haloperidol was purchased from Sigma-Aldrich;

GF/C glass fiber filter paper from Whatman;

PPO, POPOPOP and fat-soluble scintillation liquid are purchased from Shanghai reagent factory I.

Laboratory apparatus

Wallace 1450Microbeta TriLux scintillation counter, product of Perkin Elmer

Experimental methods

1. Bradford method for quantitative determination of protein

Refer to commercially available kit instructions.

2. Receptor saturation binding assay.

(1) Will obtain sigma₁Mixing the receptor membrane with the homogenate B, uniformly dispersing by using a homogenizer, and continuously adding the homogenate B to determine the suspension of the quantitative membrane by reference protein for later use;

(2) adding 100 mu L of membrane preparation into each reaction tube;

(3) add 100. mu.L of homogenate B to total bound Tube (TB) and 100. mu.L of haloperidol (Final concentration) to non-specific bound tube (NB)Degree 10^-5M)；

(4) Adding 10 mu L of radioligand [3H ] - (+) -tebuconazole into each reaction tube respectively, wherein the final concentration is 32.00, 16.00, 8.00, 4.00, 2.00, 1.00, 0.50 and 0.25nM in sequence;

(5) incubating each reaction tube at 25 ℃ for 3h, after the reaction is finished, rapidly filtering the ligand combined in each reaction tube under reduced pressure, fully washing with ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 2ml scintillation cup, adding 1ml of toluene scintillation solution, and uniformly mixing;

(6) and (5) putting the scintillation vial into a liquid scintillation counter for counting.

3、σ₁Competitive receptor binding assays

(1) Firstly, the sigma prepared₁Mixing the acceptor membrane with the homogenate of B, uniformly dispersing by using a homogenizer, and continuously adding the homogenate of B to form 50ml of suspension for later use;

(2) adding 100 μ L of membrane preparation (i.e. the suspension) into each reaction tube;

(3) 100 μ L B solution was added to total binding Tubes (TB) and 100 μ L haloperidol (final concentration 10) was added to non-specific binding tubes (NB)^-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)^-5M)；

(4) Each reaction tube was filled with 10. mu.L (final concentration 4nM) of radioligand [3H ] - (+) -tebuconazole, and each test compound was the compound prepared in examples 1-47;

(5) incubating the reaction tubes at 25 ℃ for 3h, after the reaction is finished, quickly filtering the ligand combined in each reaction tube under reduced pressure (wherein Whatman test paper is saturated by 0.25% PEI (Polyetherimide)) solution for 2h in advance), fully washing the ligand with ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 2ml scintillation cup, adding 1ml toluene scintillation solution, and mixing uniformly;

4. Statistical processing of data

First, the inhibition rate of each test compound was calculated by the following formula:

the inhibition ratio (I%) (TB-SB)/(TB-NB) × 100%,

wherein the content of the first and second substances,

TB: a total binding constant;

NB: a non-specific binding constant;

SB: binding constant of the compound.

Next, IC of each test compound was calculated by the logit method₅₀。

Then, the respective radioligands K were plotted by Scatchard_dThe value and Bmax;

finally, the K of the test compound determined is given by the following formula_iThe value:

Ki＝IC₅₀/(1+C/K_d)，

wherein, C in the formula is the concentration of free isotope.

Some results are shown in table 2.

Example 49 σ₂Preparation of acceptor membranes and determination of ligand affinity (Ki values)

σ₂Preparation of acceptor membranes

After decapitation of guinea pigs, brain tissue was rapidly removed by working on ice, and the resulting brain tissue was added to a centrifuge tube. Adding 0.01M Tris HCl and 0.32M sucrose solution into the centrifuge tube, homogenizing at 4 grades for 3-4s, homogenizing for 4 times, adding 0.01M Tris HCl and 0.32M sucrose solution, adjusting to 10ml/g, adjusting the weight of the homogenized test tube with a balance, and centrifuging at 1000r for 10 min; collecting supernatant, adding 0.01M Tris HCl and 0.32M sucrose solution to adjust to 2ml/g, and centrifuging at 1000r and 4 deg.C for 10 min; taking the supernatant, and centrifuging at 11000r and 4 ℃ for 30 min; suspending the precipitate with 0.01M Tris HCl and 0.32M sucrose solution for 30s, adjusting to 3ml/g, incubating at 25 deg.C for 15min, and centrifuging at 11000g for 30 min; collecting supernatant, storing at-20 deg.C for more than 12h, incubating with 50Mm-Tris, centrifuging, and collecting precipitate as sigma₂Acceptor membranes.

Receptor binding assay materials

Isotope ligand [ alpha ], [ alpha³H]-DTG([³H]-DTG, 250. mu. Ci, NET-986250UC), available from Perkin- -Elmer Corp.; DTG) is di-o-tolylguanidine.

DTG was purchased from Sigma-Aldrich;

(+) -SKF 10047 from Sigma-Aldrich;

GF/C glass fiber filter paper from Whatman;

Laboratory apparatus

Wallace 1450Microbeta TriLux scintillation counter, product of Perkin Elmer

Experimental methods

1. Bradford method for quantitative determination of protein

Refer to commercially available kit instructions.

2. sigma-2 receptor competitive binding assays.

(1) Firstly, the obtained sigma₂Mixing the receptor membrane with the homogenate of C (50 mM Tris buffer solution, pH 7.4) and uniformly dispersing by a homogenizer to obtain a membrane preparation for later use;

(2) adding 100 mu L of membrane preparation and 100 mu L of C homogenate into each reaction tube respectively;

(3) 100 μm L C homogenate was added to total bound Tubes (TB) and 5 μm DTG 100 μ L (final concentration 0.5 × 10) was added to non-specific bound tubes (NB)^-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)^- ⁵M); 100nM (+) -NANM (CAS number: 133005-41-1) masks the sigma-1 receptor; each test compound was the compound prepared in examples 1-47, respectively;

(4) the radioligand 3H-DTG 10. mu.L (final concentration 5nM) was added to each reaction tube (each reaction tube was equipped with 2 parallel tubes, each tube was placed on ice during loading);

(5) incubating each reaction tube at 25 ℃ for 120min, after the reaction is finished, rapidly filtering the ligand combined in each reaction tube under reduced pressure (the whatman test paper is soaked by 0.5% PEI), fully washing the ligand by using ice-cold test buffer solution, taking out a filter disc, putting the filter disc into a 2ml scintillation cup, adding 1ml of toluene scintillation solution, and uniformly mixing;

3. Statistical processing of data

the inhibition ratio (I%) (TB-SB)/(TB-NB) × 100%,

wherein the content of the first and second substances,

TB: a total binding constant;

NB: a non-specific binding constant;

SB: binding constant of the compound.

Next, IC of each test compound was calculated by the logit method₅₀；

Ki＝IC₅₀/(1+C/K_d)，

some results are shown in table 2.

Example 50. sigma₁Determination of the functionality of ligands of receptors

σ₁Preparation of acceptor membranes

According to "σ" in example 48₁Preparation of acceptor film method, preparation of sigma₁Acceptor membranes.

Receptor binding assay materials

haloperidol, phenytoin were purchased from Sigma-Aldrich;

GF/C glass fiber filter paper from Whatman;

PPO, POPOPOP and fat-soluble scintillation liquid are purchased from Shanghai reagent factory I;

laboratory apparatus

Wallace 1450Microbeta TriLux scintillation counter, product of Perkin Elmer

Experimental methods

1. Bradford method for quantitative determination of protein

Refer to commercially available kit instructions.

2、σ₁Functional assay of receptors

(1) Firstly, the obtained sigma₁Mixing the acceptor membrane with the homogenate B, uniformly dispersing by using a homogenizer, and continuously adding the homogenate B to form 50ml of suspension for later use;

(1) adding 100 μ L of membrane preparation (i.e. the suspension) into each reaction tube;

(2) 100 μ L B solution was added to total binding Tubes (TB) and 100 μ L haloperidol (final concentration 10) was added to non-specific binding tubes (NB)^-5M)；

(3) To each test compound-specific binding tube (SB) was added 100. mu.L of test compound (final concentration 10)^-5M), each test compound is a compound prepared as in examples 1-47, respectively;

(4) the radioligand [3H ] - (+) -tebuconazole 10. mu.L (final concentration 4nM) is added to each reaction tube;

(5) incubating the reaction tubes at 25 ℃ for 3h, after the reaction is finished, rapidly filtering the ligand combined in each reaction tube under reduced pressure (wherein Whatman test paper is saturated by 0.25% PEI solution 2h in advance), fully washing with ice-cold test buffer solution, taking out a filter disc, putting the filter disc into a 2ml scintillation cup, adding 1ml toluene scintillation solution, and uniformly mixing;

3. Statistical processing of data

K was calculated for each test compound according to the method of "statistical data processing" in example 48_iThe value is obtained.

Wherein σ₁Functional assays for receptors are by detection of sigma₁Receptor allosteric modulator phenytoin was judged by changes in receptor affinity for the tested compounds. Phenytoin-sigma₁Receptor antagonists have less effect, or weakly decrease the affinity of the compound for the receptor, but significantly increase sigma₁Affinity of receptor agonists to receptors. Sigma for the tested compounds by comparing the addition of phenytoin with the absence of phenytoin₁Changes in receptor affinity (Ki values) can be used to determine σ for the compounds tested₁Receptor functionality.

TABLE 2 partial compound vs. sigma₁Receptor and sigma₂Receptor affinity (Ki value)

Example 51 acute toxicity study

Acute toxicity experiments were carried out on the compounds prepared in examples 1-47, as follows:

sequential limit test

ICR mice, each half of male and female, were randomly divided into several groups, each group containing 2-5 compounds 2000mg/kg and solvent (positive control group: gabapentin group, SIRA group), and administered by intragastric administration at a dose of 0.2ml/10 g. Animals were observed for mortality within 3 days.

Wherein, if 3 or more than 3 animals survive within three days and the life state is not obviously abnormal, the observation is continued until the experiment is finished after 7 days. If an animal dies 3 or more than 3 within three days, its LD50 is determined by the median lethality method.

Half-lethal-dose-method pilot test

ICR mice are divided into a plurality of groups, 4 in each group, 1500mg/kg, 1000mg/kg and 500mg/kg of compounds and solvent groups (positive control groups: gabapentin group and SIRA group are arranged at the same time), and the mice are administrated by intragastric administration according to 0.2ml/10g, and the death condition of the animals within 1-3 days is observed.

Results

As a result, the mice were single drenched LD₅₀Greater than 2000mg/kg, and positive control drug S1RA (>2000mg/kg) was comparable with less acute toxicity. Some results are shown in Table 3.

Example 52 formalin-induced mouse pain model experiment

The compounds prepared in examples 1-47 were subjected to formalin-induced mouse pain model experiments as follows:

laboratory animal

Healthy ICR mice, male, 22-40g, were provided by Nanjing Qinglong mountain animal farming center.

Primary reagent

Test positive drugs: gabapentin, pregabalin, S1RA (E-52862)

Formaldehyde solution, 1002012, chemical industry, Ganshi;

sodium chloride injection, H32026305, xuzhou city, fifth pharmaceutical factory, ltd;

PEG400, 20111202, will chemical.

Laboratory apparatus

Stopwatch

Observation glass device

Experimental methods

ICR mice were randomly divided into a negative control group, a model group, positive drug dose groups (gabapentin, pregabalin, S1RA) and compound dose groups (specific administration dose is shown in Table 3), and each group had 10 mice. And (3) feeding corresponding solvent double distilled water to the negative control group and the model group by intragastric administration, feeding corresponding positive medicine to the positive medicine group by intragastric administration, and feeding corresponding dose of compound to each dose group of compound by intragastric administration, wherein the intragastric volume is 0.1ml/10 g. After gavage for 15min, 20 μ L of formalin 2.5% was injected subcutaneously into the left hind paw of the mouse to form a skin dome as a standard for successful molding, and 20 μ L of physiological saline was injected subcutaneously into the left hind paw of the mouse in the negative control group. And observing the time for licking the injection foot part of the mouse at 0-5 min and 15-45 min after the molding is successfully performed.

Statistical processing of data

The experimental data are expressed as Mean ± standard deviation (Mean ± SD), and the comparison is analyzed by one-way variance; then, ED is calculated using a probabilistic unit regression method₅₀Some results are shown in Table 4.

TABLE 3 influence of gabapentin, SIRA, Compounds 23, 24 on the number of leg lifts in formalin-induced pain rats

Note: p <0.05, P <0.01VS model group.

TABLE 4 in vivo animal model test results for preferred compounds

The in vitro receptor binding assays described above show that the compounds of the invention are directed to sigma₁The receptor has higher affinity with sigma₂The affinity of (a) is low. To sigma₁The receptor has selective antagonism, and shows that the receptor has the potential of analgesic activity.

Formulation examples

Example 53 tablet preparation

The pharmaceutical compositions of the present invention were prepared according to the following formulations, taking the compounds prepared in examples 1-47, respectively, as active ingredients, and taking tablet dosage forms as examples:

sieving raw materials with a 80-mesh sieve for later use, weighing the active ingredients, microcrystalline cellulose, lactose and povidone K30 according to the prescription amount, adding into a high-speed mixing preparation machine, stirring and mixing uniformly at low speed, adding a proper amount of purified water, stirring at low speed, cutting and granulating at high speed, drying the wet granules at 60 ℃ for 3h, granulating with a 24-mesh sieve, adding carboxymethyl starch sodium, silicon dioxide and magnesium stearate according to the prescription amount, mixing totally, and tabletting by using a rotary tablet press to obtain the pharmaceutical composition of the tablet dosage form.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. A compound which is a compound of formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt of a compound of formula I

Wherein the content of the first and second substances,

R₁is an optionally substituted aryl group containing 6 to 14 ring atoms, said substituted substituent being selected from C_1-6At least one of alkyl, cyano, hydroxy and halogen;

z is-R_c-R_d-，R_cIs O, R_dIs a linear or branched alkylene group having 3 to 4 carbon atoms;

q together with R attached thereto_aAnd R_bCo-form

R₄And R₅Each independently is selected from hydrogen and C_1-5One or more of alkyl, hydroxyl and tert-butyloxycarbonyl;

m is 0, 1 or 2;

x is one of oxygen, nitrogen or CH.

2. A compound of claim 1, wherein R is₁Is optionally substituted phenyl or optionally substituted naphthyl, the substituted substituent is selected from C_1-4At least one of alkyl, cyano, hydroxy and halogen.

3. The compound of claim 1, wherein: the halogen is fluorine, chlorine, bromine or iodine.

4. A compound of claim 1, wherein R is₁Is phenyl, dichlorophenyl, tolyl, fluorophenyl, chlorophenyl or naphthyl;

z is-OCH₂CH₂CH₂-or-OCH₂CH₂CH₂CH₂-；

R₄And R₅Are respectively and independently one or more selected from hydrogen, methyl, ethyl, propyl and tert-butyloxycarbonyl.

5. A compound, wherein the compound is at least one of the following compounds, or a stereoisomer, tautomer, or pharmaceutically acceptable salt of at least one of the following compounds:

6. a pharmaceutical composition characterized by containing a compound according to any one of claims 1 to 5.

7. The pharmaceutical composition of claim 6, further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or combination thereof.

8. The pharmaceutical composition of claim 7, wherein the excipient comprises a vehicle.

9. The pharmaceutical composition according to claim 6, further comprising an agent for preventing or treating a pain-related disease other than the compound according to any one of claims 1 to 5, wherein the agent for preventing or treating a pain-related disease other than the compound according to any one of claims 1 to 5 is at least one selected from the group consisting of:

non-steroidal anti-inflammatory analgesics, central analgesics, narcotic analgesics, and Chinese herbal compound analgesics.

10. The pharmaceutical composition according to claim 9, wherein the drug for preventing or treating pain diseases other than the compound according to any one of claims 1 to 5 is at least one selected from the group consisting of:

aspirin, ibuprofen, indomethacin, paracetamol, phenylbutazone, rofecoxib, celecoxib, tramadol, fentanyl, morphine, dolantin, anisodamine, naproxen, fenbutadine, sertraline, and analgetic.

11. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to any one of claims 6 to 10 for the manufacture of a medicament for the prophylaxis or treatment of pain-related disorders.

12. Use according to claim 11, wherein the pain-like disorder is neuropathic pain.