CN111349077B - Pyridazine derivative and preparation method and medical application thereof - Google Patents
Pyridazine derivative and preparation method and medical application thereof Download PDFInfo
- Publication number
- CN111349077B CN111349077B CN202010078837.3A CN202010078837A CN111349077B CN 111349077 B CN111349077 B CN 111349077B CN 202010078837 A CN202010078837 A CN 202010078837A CN 111349077 B CN111349077 B CN 111349077B
- Authority
- CN
- China
- Prior art keywords
- group
- compound
- radical
- hif
- hydrocarbyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to pyridazine derivatives shown in formula (I) and application thereof in preparing medicaments for preventing and/or treating indications related to HIF regulation. The pyridazine derivatives of the present invention are desirable high-potency HIF-PHD inhibitors, useful for treating or preventing conditions or diseases associated with HIF modulation, such as anemia and ischemia,
Description
Technical Field
The invention relates to a pyridazine derivative and application thereof in preparing a medicament for preventing and/or treating indications related to HIF regulation and a pharmaceutical composition.
Background
Anemia is a clinical syndrome of lower than normal peripheral red blood cell or hemoglobin volume caused by various causes, including weakness, dizziness, fatigue, and shortness of breath. The main function of red blood cells is to carry oxygen to the tissues and organs of the body. When anemia occurs, the oxygen-carrying effect is affected by a decrease in the number of red blood cells or hemoglobin concentration, resulting in a series of manifestations of hypoxia in the tissues and organs.
The early response to tissue Hypoxia is the induction of Hypoxia-inducible factor (HIF). HIF is an α/β heterodimeric gene transcription factor that is associated with erythropoiesis, angiogenesis, glycolytic energy metabolism, and apoptosis. Cellular levels of HIF are regulated metabolically by hydroxylation of proline residues on their alpha subunits by prolyl hydroxylases (HIF-PHDs). The half-life of HIF under aerobic conditions is short because the alpha subunit of HIF is oxidatively degraded by HIF-PHD, which uses molecular oxygen as a substrate; hypoxic conditions or inhibition of the three isoforms of HIF-PHD (PHD-1, PHD-2, PHD-3) stabilize HIF, thereby stimulating the production of red blood cells.
Thus, inhibition of HIF-PHD stabilizes HIF cell levels, which in turn can prevent and/or treat conditions or disorders associated with HIF regulation, such as anemia and ischemia. There is a need in the art to develop agents with potent inhibitory effects on HIF-PHD.
Disclosure of Invention
The present invention provides pyridazine derivatives, which are desirable high-potency HIF-PHD inhibitors.
The invention also provides application of the pyridazine derivative in preparing medicines for preventing and/or treating indications related to HIF regulation.
The pyridazine derivatives of the present invention are desirable high-potency HIF-PHD inhibitors, and are useful for treating or preventing conditions or diseases associated with HIF modulation, such as anemia and ischemia.
In order to solve the technical problems, the invention adopts the following technical scheme:
a pyridazine derivative having a structure represented by the general formula (I),
wherein:
R1selected from hydrogen, C1-6Alkyl or substituted C1-6An alkyl group;
R2is selected from C1-6Alkyl, substituted C1-6Alkyl, carboxyl or-CH2COOH；
R3、R4Independently selected from hydrogen, C1-6Alkyl, substituted C1-6Alkyl, fluoro, chloro, bromo, iodo, hydroxy;
R5is unsubstituted or selected from fluorine, chlorine, bromine, iodine, hydroxy, carboxy, nitro, C1-6Hydrocarbyl radical, C1-6C substituted with one, two, three, four or more substituents selected from alkoxy, cyano, ester, amido and sulfonyl 1-20Alkyl radical, C5-20Aryl or C5-20A heteroaryl group;
x is selected from N or CH;
y is selected from NH and CH2、O、CO、SO2、SO。
According to some preferred aspects of the invention, R1Is hydrogen, R2Is carboxyl or-CH2COOH，R3Is a hydroxyl group.
According to some preferred aspects of the invention, R4And R3Different.
In some embodiments of the invention, R3Is hydroxy, R4Is hydrogen, C1-6Alkyl, fluoro, chloro, bromo or iodo.
According to the invention, C1-6The hydrocarbon radical comprising C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl.
In some embodiments of the invention, C is1-6Alkyl includes methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl.
In some embodiments of the invention, C is2-6Alkenyl includes CH2＝CH-、CH2＝CH-CH2-、CH2＝CH-CH2-CH2-、CH2＝CH-CH2-CH2-CH2-、CH3-CH＝CH-CH2-、CH3-CH＝CH-CH2-CH2-and the like.
In some embodiments of the invention, C is2-6Alkynyl includes CH.ident.C-, CH.ident.C-CH2-、CH≡C-CH2-CH2-、CH≡C-CH2-CH2-CH2-、CH3-C≡C-CH2-、CH3-C≡C-CH2-CH2-and the like.
In some embodiments of the invention, C is1-6Alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentyloxy, isobutyloxy, t-butoxy and the like.
According to some preferred aspects of the invention, C is5-20The heteroatoms in the heteroaryl group are selected from one or more of nitrogen, oxygen and sulfur.
According to some preferred aspects of the invention, when R5Is substituted C5-20Aryl or C5-20When it is heteroaryl, said C5-20Aryl or C5-20Substituents on heteroaryl being as defined for C5-20Aryl or C5-20The carbon to which the heteroaryl is attached is non-ortho, e.g., meta, para.
According to some specific and preferred aspects of the invention, R5Is unsubstituted, or substituted C1-6Alkyl radical, C5-10Aryl or C5-10A heteroaryl group.
In some embodiments of the invention, R5Is unsubstituted, or substituted monocyclic aryl or monocyclic heteroaryl.
According to some preferred aspects of the invention, R5Is composed of
Wherein R is6Is selected from C1-6Alkoxy radical, R7Selected from fluorine, chlorine, bromine or iodine.
In some embodiments of the invention, the pyridazine derivative has a structure represented by general formula (II):
wherein:
R2is selected from C1-6Alkyl, substituted C1-6Alkyl, carboxyl or-CH2COOH；
R3、R4Independently selected from hydrogen, C1-6Alkyl, substituted C1-6Alkyl, fluoro, chloro, bromo, iodo, hydroxy;
R5is unsubstituted or selected from fluorine, chlorine, bromine, iodine, hydroxy, carboxy, nitro, C1-6Hydrocarbyl radical, C1-6C substituted with one, two, three, four or more substituents selected from alkoxy, cyano, ester, amido and sulfonyl1-20Alkyl radical, C 5-20Aryl or C5-20A heteroaryl group;
x is selected from N or CH;
y is selected from NH and CH2、O、CO、SO2、SO。
According to some preferred aspects of the invention, R is as described in formula (II)2Selected from carboxyl or-CH2COOH；
R3Selected from hydroxyl;
R4selected from hydrogen, C1-6Alkyl, fluoro or chloro;
R5is selected from
X is selected from N or CH;
y is selected from NH or O.
According to some preferred aspects of the invention, the pyridazine derivative has the following structure:
according to some particular and preferred aspects of the invention, the pyridazine derivative is one of the compounds represented by the following structural formula:
according to the invention, the pyridazine derivative compound not only comprises a single compound form, but also comprises a mixture form of a plurality of compounds with the structures meeting the requirements of the general formula (I), and different isomer forms of the same compound, such as raceme, enantiomer, diastereoisomer and the like. "prodrug of a compound having the general formula (I)" means a substance which, when administered by an appropriate method, undergoes a metabolic or chemical reaction in the subject to convert into at least one compound of the general formula (I).
The preparation method of the pyridazine derivative comprises the following steps:
(1) performing Suzuki coupling on the compound A and the compound B to obtain a compound C;
(2) Hydrolyzing the compound C under alkaline conditions to obtain a carboxylic acid compound D;
(3) carrying out esterification reaction on the carboxylic acid compound D and the compound E, and removing the protecting group to obtain a target compound; wherein, the first and the second end of the pipe are connected with each other,
z is selected from Cl, Br, I and OTf;
PG is benzyl;
n is 0 or 1;
other groups are defined as follows:
R4selected from hydrogen, C1-6Alkyl, substituted C1-6Alkyl, fluoro, chloro, bromo, iodo, hydroxy;
R5is composed of
X is selected from N or CH;
y is selected from NH and CH2、O、CO、SO2、SO。
The invention also relates to the use of the pyridazine derivatives described above for the preparation of a medicament for the prevention and/or treatment of indications related to HIF regulation.
The disorders or diseases associated with HIF regulation include anemia and ischemia, and the indications associated with HIF regulation also include other diseases associated with the mechanism of HIF-PHD inhibition.
The invention adopts another technical scheme that: a preventive and/or remedy for an indication relating to HIF-PHD inhibition, which comprises the above pyridazine derivative.
The invention also relates to the use of the pyridazine derivatives described above as medicaments.
Due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the pyridazine derivative provided by the invention has a strong inhibiting effect on HIF-PHD, so the compound can be used for preparing medicaments for treating or preventing various indications related to HIF regulation.
Definition of terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The term "unsubstituted" when used to define a group means that the defined group is not substituted with another group other than a hydrogen atom, when the group has a structure according to the general knowledge of one of ordinary skill in the art to which the invention pertainsThe same meaning is commonly understood. E.g. unsubstituted C1-6Alkyl groups are methyl, ethyl, and the like as is commonly understood by those skilled in the art.
The term "substituted" when used to define a group means that one or more hydrogen atoms of the defined group are replaced with a substituent, in which case the meaning of the group is to be understood in conjunction with the substituent. In the present invention, unless otherwise specified, "substituted" when referring to a group defined thereby means that the hydrogen atom in the group is substituted by one or more substituents selected from the group consisting of:
deuterium, cyano, halogen, hydroxyl, carboxyl, ester group, sulfone group, sulfonamide group, amide group, carbonyl group (-C (═ O) -), C1-6Hydrocarbyl S (═ O) (═ NH) -, amino, hydrazinoacyl, C 1-6Hydrocarbyl, halogenated C1-6Hydrocarbyl, hydroxy-substituted C1-6Hydrocarbyl, amide substituted C1-6Hydrocarbyl radical, C1-6Alkoxy, halogenated C1-6Alkoxy, C1-6Hydrocarbyloxy C1-6Hydrocarbyl radical, C1-6Hydrocarbyloxy group C1-6Hydrocarbyloxy, C1-6Hydrocarbylamino, C1-6Mercapto group of hydrocarbon, C1-6Hydrocarbyl carbonyl group, C1-6Hydrocarbyl amine acyl, C1-6Hydrocarbyl amido, halo C1-6Hydrocarbyl amide group, C1-6Hydroxyoxyacyl group, C1-6Hydrocarbyl amine amido, C1-6Hydrocarbyl sulfone group, C1-6Hydrocarbyl sulfonamide, C3-6Cycloalkyl, halo C3-6Cycloalkyl radical, C3-6Cycloalkoxy, halo C3-6Cycloalkoxy, C3-6Cycloalkyl radical C1-6Hydrocarbyl radical, C3-6Cycloalkanoxy C1-6Hydrocarbyl radical, C3-6Cycloalkyl radical C1-6Hydrocarbyloxy, C3-6Cycloalkyl radical C1-6Hydrocarbyloxy group C1-6Hydrocarbyloxy, C3-6Cycloalkylamino radical, C3-6Cycloalkyl radical C1-6Hydrocarbylamino, C3-6Cycloalkanemercapto, halogeno C3-6Cycloalkanemercapto group, C3-6Cycloalkyl radical C1-6Mercapto group of hydrocarbon, C3-6Cycloalkyl sulfone group, C3-6Cycloalkyl radical C1-6Hydrocarbon sulfone group, C3-6Cycloalkylsulfonamide, C3-6Cycloalkyl radical C1-6Hydrocarbyl sulfonamide, C3-6Cycloalkanecarbonyl group, C3-6Cycloalkyl radical C1-6Hydrocarbyl carbonyl group, C3-6Cycloalkaneaminoacyl radical, C3-6Cycloalkyl radical C1-6Hydrocarbyl amine acyl, C3-6Cycloalkaneamide group, C3-6Cycloalkyl radical C1-6Hydrocarbyl amide group, C3-6Cycloalkaneamine amido group, C4-8Heterocycloalkyl radical, C4-8Heterocycloalkyloxy, halo C4-8Heterocycloalkyloxy, C4-8Heterocycloalkyloxy C1-6Hydrocarbyl, halo C 4-8Heterocycloalkyloxy C1-6Hydrocarbyl radical, C4-8Heterocycloalkyl radical C1-6Alkoxy, halo C4-8Heterocycloalkyl radical C1-6Hydrocarbyloxy, C4-8Heterocycloalkyl radical C1-6Hydrocarbyl radical, C4-8Heterocycloalkyl radical C1-6Hydrocarbyloxy group C1-6Hydrocarbyl radical, C4-8Heterocyclic alkylamino radical, C4-8Heterocycloalkylmercapto group, C4-8Heterocycloalkyl radical C1-6Hydrocarbyl mercapto group, C4-8Heterocyclylalkylsulfone radical, C4-8Heterocycloalkyl radical C1-6Hydrocarbon sulfone group, C4-8Heterocyclylalkylsulfonamide group, C4-8Heterocycloalkyl radical C1-6Hydrocarbyl sulfonamide, C4-8Heterocycloalkylcarbonyl radical, C4-8Heterocycloalkyl radical C1-6Hydrocarbyl carbonyl group, C4-8Heterocycloalkyl substituted by carbonyl groups, C4-8Heterocyclic alkylamine acyl, C4-8Heterocyclylalkylamide radical, C4-8Heterocycloalkyl radical C1-6Hydrocarbyl amide group, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Aryloxy radical C1-6Hydrocarbyl radical, C5-10Aryl radical C1-6Hydrocarbyl radical, C5-10Aryl radical C1-6Hydrocarbyloxy, C5-10Arylamine group, C5-10Aromatic mercapto group, C5-10Aryl radical C1-6Mercapto group of hydrocarbon, C5-10Aryl sulfone group, C5-10Aryl radical C1-6Hydrocarbon sulfone group, C5-10Arylsulfonamide group, C5-10Aryl radical C1-6Hydrocarbyl sulfonamide, C5-10Aryl carbonyl, C5-10Aryl radical C1-6Hydrocarbyl carbonyl group, C5-10Arylaminoyl, C5-10Aryl amide group or C5-10Acyl arylaminesAn amine group.
Preferably, the substituent is selected from deuterium, cyano, halogen (preferably F, Cl, Br), hydroxyl, carboxyl, ester, sulfone, sulfonylamino, carbonylamino, carbonyl, C1-6Alkyl sulfinyl amino, hydrazinoacyl, C 1-6Hydrocarbyl, halogenated C1-6Hydrocarbyl, hydroxy-substituted C1-6Hydrocarbyl, amide substituted C1-6Hydrocarbyl radical, C1-6Alkoxy, halo C1-6Hydrocarbyloxy, C1-6Hydrocarbyloxy group C1-6Hydrocarbyl radical, C1-6Hydrocarbyloxy group C1-6A hydrocarbyloxy group.
More preferably, the substituent is selected from deuterium, cyano, F, Cl, Br, hydroxyl, carboxyl, ester group, sulfone group, sulfonamide group, amide group, carbonyl group, methylsulfinylamino, ethylsulfinylamino, isopropylsulfinylamino, tert-butylsulfinylamino, amino group, hydrazino group, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, tert-butyl group, cyclobutyl group, n-pentyl group, isopentyl group, neopentyl group, cyclohexyl group, halomethyl group (specifically, trifluoromethyl group), haloethyl group, halo-n-propyl group, haloisopropyl group, halocyclopropyl group, halo-n-butyl group, haloisobutyl group, halo-tert-butyl group, halocyclobutyl group, hydroxymethyl group, hydroxyethyl group, hydroxy-n-propyl group, hydroxyisopropyl group, hydroxycyclopropyl group, hydroxy-n-butyl group, hydroxyisobutyl group, hydroxy-tert-butyl group, hydroxycyclobutyl group, hydroxyisopropyl group, hydroxycyclopropyl group, hydroxyisopropyl group, hydroxybutyl group, hydroxyisopropyl group, hydroxybutyl group, etc, Hydroxy-n-pentyl, hydroxy-isopentyl, hydroxy-neopentyl, hydroxy-cyclohexyl, methoxy, ethoxy, propoxy.
The term "hydrocarbyl" refers to alkyl, alkenylalkyl, and alkynylalkyl groups.
The term "alkyl" refers to a straight, branched, or cyclic saturated substituent consisting of carbon and hydrogen. Alkyl includes in particular, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, 2, -methylbutyl and 2, 3-dimethylbutyl, 16-alkyl, 18-alkyl. The term "C1-20Alkyl "refers to straight, branched chains containing 1 to 20 carbon atomsOr a cyclic saturated hydrocarbon group. When the alkyl group is substituted, the substituent may be substituted at any available point of attachment, and the substituent may be mono-or poly-substituted. For example, the substituent may be alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxyl, ester group, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo.
When specific nomenclature is referred to, the substituent is usually placed before the group being substituted, e.g. "C1-3Alkoxy radical C3-8Cycloalkyl radical C1-6Alkyl "means C1-6Alkyl radical, which is substituted by C 3-8Cycloalkyl is substituted, and the C3-8Cycloalkyl radicals being further C1-3Alkoxy substitution, examples being: the structural formula of the methoxycyclobutylmethyl group is as follows:
the terms "alkenyl" and "alkynyl" refer to straight, branched or cyclic unsaturated hydrocarbon groups containing double and triple bonds, preferably 2 to 20 carbon atoms, more preferably 2 to 12 carbon atoms, respectively. When substituted, the substituents may be substituted at any available point of attachment, and the substituents may be mono-or polysubstituted. For example, the substituent may be selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxy, nitro, carboxy, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo.
The term "aryl" is carbocyclic aryl and the term "heteroaryl" refers to groups of heteroaromatic systems containing 1 to 10 heteroatoms, including monocyclic and fused ring heteroaryls. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like. Wherein monocyclic heteroaryl groups include, but are not limited to, furan, thiophene, pyrrole, thiazole, imidazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 3-thiadiazole, oxazole, 1,2, 4-oxadiazole, 1,3, 4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, isoxazoline, and the like. Fused ring heteroaryl groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromene, fluorenone, quinoxaline, 3, 4-dihydronaphthalenone, dibenzofuran, hydrogenated dibenzofuran, benzoxazolyl, and the like. Heteroaryl groups may be substituted and unsubstituted. The substituent is, for example, selected from alkyl, cycloalkyl (e.g., cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl and the like), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkylsilyl and the like.
The term "deuterium" is an isotope of hydrogen with an atomic mass 2 times higher than the latter, and binds stronger to carbon. Deuteration "and" deuterium "mean that hydrogen is replaced with deuterium at the indicated position. One "deuterated substituent" is a substituent wherein at least one hydrogen is replaced with deuterium enriched to the specified percentage.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the following examples.
The starting materials or reagents used in the present invention can be synthesized by conventional methods or commercially available.
Example 1
This example provides compounds of formula Ia, which are the following chemical structures:
the compounds of formula Ia can be obtained by the following synthetic route:
the process for the preparation of the compound of formula Ia comprises the following steps:
preparation of compound a': compound a (40g,0.124mol) was added to 400mL1, 4-dioxane, pinacol diboron (47.4g,0.186mol), potassium acetate (24.4g, 0.249mol) and finally Pb (dppf) Cl2(4g, 10% W) was heated to 80 ℃ under nitrogen for 2 hours. And concentrating under reduced pressure to remove the solvent to obtain a crude compound a'.
Preparation of compound c: the crude compound a' (0.124mol) was added to a mixture of 400mL toluene and 100mL water, followed by compound b (48g, 0.186mol), sodium carbonate (26.4g, 0.249mol), and finally (PPh) 3)4Pd (4g, 10% W). The mixture was heated to 100 ℃ under nitrogen for overnight reaction. The reaction solution was cooled to room temperature, filtered through celite, and concentrated under reduced pressure, and the residue was purified by column chromatography to give 26g of crude compound c, with a yield of 50.3% in two steps.
Preparation of compound d: compound c (26g, 0.0628mol) was added to 300mL of MeOH/H2Adding LiOH & H into the mixed solution of O2O (3.2g, 0.075mol), heated to 40 ℃ and reacted overnight. The reaction was poured into water, the system was adjusted to pH 3 with 3M hydrochloric acid, a solid precipitated, filtered, and the solid was decompressed to remove residual solvent to give compound d (16g, 64%) as an off-white powder.
Preparation of compound f: compound d (7.2g, 18.04mmol) was added to 70mL of DCM, followed by addition of compound e (4.3g, 21.64mmol), EDCI (5.2g, 27.06mmol), HOBT (3.6g, 27.06mmol), and finally triethylamine (5.5g, 54.12mmol), respectively, and reaction was carried out at room temperature for 3 hours. The reaction was poured into water, extracted with DCM, the organic phase was concentrated under reduced pressure and the residue was purified by column chromatography to give compound f (7g, 71.4%) as a white powder.
Preparing a compound of formula Ia: compound f (5g, 9.1mmol) was added to 500mL of methanol, and Pd/C (500mg, 10% W) was further added, followed by reaction under normal pressure with hydrogen at room temperature for 48 hours. The reaction solution was filtered through celite, concentrated under reduced pressure, and slurried with methanol 2 times to give compound Ia (2g, yield 60.6%) as a white powder.
The obtained target product Ia is subjected to hydrogen nuclear magnetic resonance1H-NMR (500MHz, DMSO) and mass spectrometry tests, the results are as follows:
1H-NMR spectraAbsorption peaks in the figure: δ is 12.81(s,1H),12.43(s,1H),9.47(t, J is 6.1Hz,1H),8.91(d, J is 1.8Hz,1H),8.51(d, J is 9.3Hz,1H),8.09(d, J is 1.8Hz,1H),7.65(d, J is 9.3Hz,1H), 7.53-7.45 (m,2H), 7.34-7.25 (m,3H),4.02(d, J is 6.1Hz,2H).
m/z[MH]+:367.1. The product has molecular formula C18H14N4O5The exact molecular mass (exact mass) was 366.096.
Other compounds of the present application can be prepared by the method of example 1 or a similar method.
Test for drug efficacy or the like
Firstly, testing the activity of a compound:
1. test method
Half-inhibitory concentration IC of test compound on PHD1, PHD2 and PHD3 respectively by using FP assay method50(concentration of compound required to inhibit enzyme activity to 50%).
2. Test results
The results show that the target compound (Ia) has very strong inhibitory effect on PHD1, PHD2 and PHD3, IC50Values were all less than 100 nM. This strong inhibitory effect is of great therapeutic importance in the treatment of conditions or diseases associated with HIF-PHD modulation, such as anemia and ischemia.
Second, pharmacokinetic experiments
1. The experimental method comprises the following steps:
Experimental animals: male mice, body weight 21-22 g;
preparing a test article: the object compound Ia was formulated to 0.4mg/mL (for intravenous administration) and 1.0mg/mL (for oral administration) for use. The administration route is as follows: oral/intravenous injection. Dose volume and frequency: 5mL/kg (intravenous) or 10mL/kg (oral), single dose.
Collecting samples: blood was collected at the following time points, and blood was taken 5min, 15min, 30min, 1hr, 2hr, 4hr, 8hr and 24hr after administration.
2. Sample analysis and results
And (3) sample analysis: the collected samples were tested using LC-MS/MS method. The instrument model number LCMSMS-035(triple quadruple, 6500+) was used.
Pharmacokinetic data analysis: the resulting plasma concentration data were fitted and calculated using WinNolin according to a non-compartmental model and part of the results are summarized in the following table.
Pharmacokinetic parameters of a target compound calculated according to a non-compartmental model
The test result shows that the compound of the invention has good pharmacokinetic characteristics.
The above embodiments are merely representative. As can be seen from the above examples, the compounds of the present invention are ideal high-potency HIF-PHD inhibitors, which are expected to be useful for the treatment or prevention of conditions or diseases associated with HIF-PHD regulation, such as anemia and ischemia, with excellent efficacy, and which can be formulated into oral preparations (tablets, capsules, etc.). Tablets or capsules made with the compounds of the present invention may be administered one or more times daily. The compound of the invention can also be combined with other medicines to prepare a compound preparation.
The above embodiments are only for illustrating the technical idea and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention by this means. All equivalent changes and modifications made according to the spirit of the present invention should be covered in the protection scope of the present invention.
Claims (5)
1. A pyridazine derivative having the structure:
2. a process for the preparation of the pyridazine derivative of claim 1 comprising the steps of:
(1) performing Suzuki coupling on the compound A and the compound B to obtain a compound C;
(2) hydrolyzing the compound C under alkaline conditions to obtain a carboxylic acid compound D;
(3) carrying out esterification reaction on the carboxylic acid compound D and the compound E, and removing the protecting group PG to obtain a target compound;
wherein the content of the first and second substances,
z is selected from Cl, Br, I or OTf;
PG is selected from benzyl;
n is 1;
R4is H;
R5is phenyl;
x is N;
y is O.
3. Use of a pyridazine derivative according to claim 1 in the manufacture of a medicament for the prevention and/or treatment of indications related to HIF regulation.
4. Use according to claim 3, characterized in that: the indications associated with HIF modulation are selected from anemia and ischemia.
5. A medicament for the prevention and/or treatment of indications associated with HIF modulation, wherein: comprising the pyridazine derivative according to claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2019101060464 | 2019-02-02 | ||
| CN201910106046 | 2019-02-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111349077A CN111349077A (en) | 2020-06-30 |
| CN111349077B true CN111349077B (en) | 2022-06-28 |
Family
ID=71194460
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010078837.3A Active CN111349077B (en) | 2019-02-02 | 2020-02-03 | Pyridazine derivative and preparation method and medical application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN111349077B (en) |
| WO (1) | WO2020156571A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116472266A (en) * | 2020-10-16 | 2023-07-21 | 苏中药业集团股份有限公司 | Compounds as prolyl hydroxylase inhibitors and methods of making the same |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101506149A (en) * | 2006-06-26 | 2009-08-12 | 宝洁公司 | Prolyl hydroxylase inhibitors and methods of use |
| CN102718708A (en) * | 2003-06-06 | 2012-10-10 | 菲布罗根有限公司 | Novel nitrogen-containing heteroaryl compounds and methods of use thereof |
| CN102802628A (en) * | 2009-06-30 | 2012-11-28 | 默沙东公司 | Substituted 4-hydroxypyrimidine-5-carboxamides |
| CN102036981B (en) * | 2008-03-18 | 2015-04-08 | 默沙东公司 | Substituted 4-hydroxypyrimidine-5-carboxamides |
| CN105492433A (en) * | 2013-03-29 | 2016-04-13 | 武田药品工业株式会社 | 6-(5-hydroxy-1h-pyrazol-1-yl)nicotinamide derivatives and their use as phd inhibitors |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10010422A1 (en) * | 2000-03-03 | 2001-09-06 | Bayer Ag | New 6-(4-carboxy-phenyl)-dihydropyridazinone esters or amides, having erythropoietin sensitizing and erythropoiesis stimulating activity, useful for treating anemia |
| CA2468083C (en) * | 2001-12-06 | 2016-02-23 | Fibrogen, Inc. | Use of heterocyclic carboxamides to treat anemia |
| CN107417605A (en) * | 2017-08-02 | 2017-12-01 | 江苏艾立康药业股份有限公司 | Act on the pyridine derivative compound of prolyl hydroxylase |
-
2020
- 2020-02-03 WO PCT/CN2020/074212 patent/WO2020156571A1/en active Application Filing
- 2020-02-03 CN CN202010078837.3A patent/CN111349077B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718708A (en) * | 2003-06-06 | 2012-10-10 | 菲布罗根有限公司 | Novel nitrogen-containing heteroaryl compounds and methods of use thereof |
| CN101506149A (en) * | 2006-06-26 | 2009-08-12 | 宝洁公司 | Prolyl hydroxylase inhibitors and methods of use |
| CN102036981B (en) * | 2008-03-18 | 2015-04-08 | 默沙东公司 | Substituted 4-hydroxypyrimidine-5-carboxamides |
| CN102802628A (en) * | 2009-06-30 | 2012-11-28 | 默沙东公司 | Substituted 4-hydroxypyrimidine-5-carboxamides |
| CN105492433A (en) * | 2013-03-29 | 2016-04-13 | 武田药品工业株式会社 | 6-(5-hydroxy-1h-pyrazol-1-yl)nicotinamide derivatives and their use as phd inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| RN号1163267-11-5等;CAS;《REG》;20090715;全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020156571A1 (en) | 2020-08-06 |
| CN111349077A (en) | 2020-06-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2964223B1 (en) | Compounds inhibiting leucine-rich repeat kinase enzyme activity | |
| KR102029951B1 (en) | Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof | |
| CN113767103B (en) | Novel spirocyclic K-Ras G12C inhibitors | |
| WO2021129824A1 (en) | New-type k-ras g12c inhibitor | |
| US9688654B2 (en) | Compounds inhibiting leucine-rich repeat kinase enzyme activity | |
| WO2021190467A1 (en) | Spiro ring-containing quinazoline compound | |
| WO2022105855A1 (en) | Kras g12d inhibitors | |
| KR20200086385A (en) | Cap-dependent endonuclease inhibitors | |
| CN115315427B (en) | HPK1 inhibitor and preparation method and application thereof | |
| EP3210969B1 (en) | Kcnq2-5 channel activator | |
| CN111094265B (en) | Pyrazole derivative compound and use thereof | |
| WO2023061406A1 (en) | Parp inhibitor containing fused tri-cyclic structure, and preparation method therefor and medical use thereof | |
| TW201006468A (en) | Use of indole derivatives as NURR-1 activators | |
| TW479058B (en) | 2,7-substituted octahydro-pyrrolo[1,2-a]pyrazine derivatives | |
| CN111349077B (en) | Pyridazine derivative and preparation method and medical application thereof | |
| CN108884099B (en) | Crystal form of free base of imidazo isoindole derivative and preparation method thereof | |
| CN109384785B (en) | Pyrrolopyridinone derivatives, preparation method and medical application thereof | |
| EP3805212A1 (en) | 3-oxazolinone compound, preparation method therefor and pharmaceutical application thereof | |
| TW201922690A (en) | Inhibitors of cyclic-AMP response element-binding protein | |
| TW201910330A (en) | Sulfonamide derivatives, preparation method thereof and use thereof in medicine | |
| KR20230157471A (en) | Polymorphs of compounds and their preparation methods and uses | |
| CN113166148B (en) | Heterocyclic compounds as CDK-HDAC dual pathway inhibitors | |
| WO2023206655A1 (en) | PI3Kδ INHIBITOR AND USE THEREOF | |
| CN109280028B (en) | Quinoline compound and application thereof in DPP-4 enzyme inhibitor | |
| WO2009153897A1 (en) | Stemonamide synthesis intermediate and pharmaceutical composition for prevention and/or treatment of cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |