CN108623528A - A kind of substituted pyrimidine trione compound and the composition and application thereof comprising the compound - Google Patents
A kind of substituted pyrimidine trione compound and the composition and application thereof comprising the compound Download PDFInfo
- Publication number
- CN108623528A CN108623528A CN201810494949.XA CN201810494949A CN108623528A CN 108623528 A CN108623528 A CN 108623528A CN 201810494949 A CN201810494949 A CN 201810494949A CN 108623528 A CN108623528 A CN 108623528A
- Authority
- CN
- China
- Prior art keywords
- compound
- deuterium
- pharmaceutically acceptable
- acceptable salt
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 [O-][N+]=C(CC(*1C2CCCCC2)=O)*(C2CCCCC2)C1=O Chemical compound [O-][N+]=C(CC(*1C2CCCCC2)=O)*(C2CCCCC2)C1=O 0.000 description 4
- WRIRWRKPLXCTFD-UHFFFAOYSA-N NC(CC(N)=O)=O Chemical compound NC(CC(N)=O)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
A kind of composition and application thereof the present invention provides substituted pyrimidine trione compound and comprising the compound, the invention discloses the pyrimidine trione compounds as shown in formula (I), or its crystal form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate or solvated compounds.Pyrimidine trione compound of the present invention and the composition comprising the compound can be used for adjusting hypoxia inducible factor (HIF) and/or endogenous erythropoietin (EPO), can be used for preparing the drug of regulation and control human body anaemia.
Description
Technical field
The invention belongs to pharmaceutical technology field more particularly to a kind of substituted pyrimidine trione compound and include the compound
Composition, and the stability of hypoxia inducible factor (HIF) subunit can be adjusted and increase external and internal endogenous and promoted
The method and compound of erythropoietin(EPO).
Background technology
Hypoxia inducible factor (HIF) is that a kind of basic helix-loop-helix (bHLH) PAS (Per/Arnt/Sim) transcription is sharp
Agent living, regulates and controls the change of the gene expression changed with cell oxygen concentration.HIF is a kind of containing there are one oxygen to adjust alpha subunit
The heterodimer of (HIF- α) and a constructive expression β subunit (HIF- β), also referred to as aryl hydrocarbon receptor importin
(ARNT).In oxygen closes (normal oxygen) cell, HIF- alpha subunits inhibit albumen (pVHL) E3 connections by being related to retinal angiomatous
The mechanism of multienzyme complex ubiquitination is degraded rapidly.Under anoxic conditions, HIF- α are non-degradable, and a kind of activity HIF- α/β compounds
Accumulate and activate the expression of several genes in nucleus, including glycolytic ferment, glucose transporter (GLUT) -1, promote it is red thin
Born of the same parents generate plain (EPO) and vascular endothelial growth factor (VEGF).(Maxwell et al., naturally, 1999,399,271-
275)。
Hematopoietin (EPO) is with HIF- α and the hormone of a kind of naturally occurring that generates, stimulation delivery oxygen
Through the generation of the red blood cell of whole body.EPO is usually by renal secretion, and endogenous EPO increases under conditions of oxygen reduces (anoxic).
All types anaemia is characterized in that the ability of blood-borne oxygen is reduced, and thus with similar sign and symptom, including skin
And mucosal pallor, weakness, dizziness, fatiguability and drowsiness, lead to the decline of quality of life.Subject with severe anemia situation
It shows to be difficult to breathe and heart malformations.Anaemia usually with leiphemia is related in red blood cell or in hemoglobin.
The main reason for ischaemic and anoxic illness are morbidities and are dead.Cardiovascular disease causes at least 1,500 every year
Ten thousand death and be the reason for causing the death of the whole world 30%.In a variety of cardiovascular diseases, ischemic heart disease and cerebrovascular disease
Cause about 17% death.Annual report has the case of 1,300,000 non-lethal acute myocardial infarctions, constitute every about
The incidence of 300 people in 100,000 people.On the other hand, estimation has 5,000,000 Americans to suffer from Venous Thrombosis every year, and about
600,000 these cases lead to pulmonary embolism.The Pulmonary Embolism Patients of about one third are finally dead so that pulmonary embolism becomes American
Dead third most common reason.
Currently, the treatment of ischaemic and anoxic illness concentrates in the mitigation of symptom and the treatment of pathogenic disorders.Example
Such as, the treatment of myocardial infarction includes to the nitroglycerin and antalgesic of control pain and mitigation heart working load.Use it
Its drug, including digoxin (digoxin), diuretics, amrinone (amrinone), beta blocker, lipid lowering agent and vasotonia
Plain converting enzyme inhibitor stablizes the patient's condition, but no one of these therapies can be done directly on by ischaemic and anoxic generation
Tissue damage.
(chemical name is N- [(1,3- dicyclohexyl -2,4,6- trioxy- -5- hexahydropyrimidines base) carbonyls to Daprodustat
Base] glycine, have following structure formula) it is a kind of oral HIF- α prolyl hydroxylases suppression that GlaxoSmithKline PLC company is researched and developed
Preparation is currently in the III clinical trial phase stages for treating chronic kidney disease anemia associated.
Known poor absorption, distribution, metabolism and/or excretion (ADME) property are to lead to many drug candidate clinical tests
The main reason for failure.The many drugs currently listed are also due to poor ADME properties limit their application range.Medicine
The tachymetabolism of object can cause many drugs that can efficiently treat disease originally fallen from internal metabolite clearance due to too fast and
It is difficult to patent medicine.Frequently or high dose medication is although it is possible to solve the problems, such as that drug is quickly removed, but this method can be brought such as
The problems such as side effect and treatment cost caused by patient dependence is poor, high dose is taken medicine rise.In addition, the drug of tachymetabolism
Patient may be made to be exposed in undesirable toxicity or reactive metabolin.
There are still serious clinical unmet demands in the field, and find there is treatment HIF correlations and EPO relevant diseases
And with good oral administration biaavailability and there is the new compound of druggability to be also challenging work.
Invention content
For the above technical problem, the invention discloses a kind of compound and comprising the composition of the compound, can be used
In adjusting hypoxia inducible factor (HIF) and/or endogenous erythropoietin (EPO) and/or there is more preferable pharmacodynamics/medicine generation
Dynamic performance.
In this regard, the technical solution adopted by the present invention is：
The object of the present invention is to provide it is a kind of it is novel can be used for adjusting hypoxia inducible factor (HIF) and/or endogenous promote it is red
Erythropoietin (EPO) and/or with more preferable pharmacodynamics/pharmacokinetics performance compound.
In the first aspect of the present invention, a kind of formula (I) compound represented or its crystal form, pharmaceutically acceptable are provided
Salt, hydrate or solvated compounds.
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、
R22、R23、R24、R25It is each independently hydrogen, deuterium, halogen or trifluoromethyl；
Additional conditions are R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、
R20、R21、R22、R23、R24And R25In it is at least one be deuterated or deuterium.
In another preferred example, R24And R25It is each independently deuterium or hydrogen.
In another preferred example, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10And R11It is each independently deuterium or hydrogen.
In another preferred example, R12、R13、R14、R15、R16、R17、R18、R19、R20、R21And R22Be each independently deuterium or
Hydrogen.
In another preferred example, deuterium isotopic content of the deuterium in deuterated position is at least more than natural deuterium isotopic content
(0.015%), it is preferably greater than 30%, even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, more preferably
More than 99%.
Specifically, R in the present invention1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、
R17、R18、R19、R20、R21、R22、R23、R24And R25Deuterium isotopic content is at least 5% in each deuterated position, is preferably greater than
10%, even more preferably greater than 15%, even more preferably greater than 20%, even more preferably greater than 25%, even more preferably greater than 30%, even more preferably greater than
35%, even more preferably greater than 40%, even more preferably greater than 45%, even more preferably greater than 50%, even more preferably greater than 55%, even more preferably greater than
60%, even more preferably greater than 65%, even more preferably greater than 70%, even more preferably greater than 75%, even more preferably greater than 80%, even more preferably greater than
85%, even more preferably greater than 90%, even more preferably greater than 95%, even more preferably greater than 99%.
In another preferred example, in formula (I) compound R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、
R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24And R25, at least one of which R is containing deuterium, and more preferably two R are containing deuterium, more
Good three R in ground contain deuterium, and more preferably four R contain deuterium, and more preferably five R contain deuterium, and more preferably six R contain deuterium, and more preferably seven R contain
Deuterium, more preferably eight R contain deuterium, and more preferably nine R contain deuterium, and more preferably ten R contain deuterium, and more preferably 11 R contain deuterium, and more preferably ten
Two R contain deuterium, and more preferably 13 R contain deuterium, and more preferably 14 R contain deuterium, and more preferably 15 R contain deuterium, more preferably 16 R
Containing deuterium, more preferably 17 R contain deuterium, and more preferably 18 R contain deuterium, and more preferably 19 R contain deuterium, and more preferably 20 R contain deuterium,
More preferably 21 R contain deuterium, and more preferably 22 R contain deuterium, and more preferably 23 R contain deuterium, and more preferably 24 R contain
Deuterium, more preferably 25 R contain deuterium.
In another preferred example, the compound does not include non-deuterated compound.
In the second aspect of the present invention, a kind of method preparing pharmaceutical composition, including step are provided：It will pharmaceutically
Compound or its crystal form, pharmaceutically acceptable salt, hydrate described in acceptable carrier and first aspect present invention or
Solvate is mixed, to form pharmaceutical composition.
In the third aspect of the present invention, provide a kind of pharmaceutical composition, it contain pharmaceutically acceptable carrier and
Compound described in first aspect present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate.
The pharmaceutically acceptable carrier that can be used in pharmaceutical composition of the present invention includes but not limited to any glidant, increasing
Edulcorant, preservative, dyestuff/colorant, flavoring reinforcing agent, surfactant, wetting agent, dispersant, disintegrant, helps diluent
Suspension, stabilizer, isotonic agent, solvent or emulsifier.
Pharmaceutical composition of the present invention can be configured to solid-state, semisolid, liquid or gaseous state preparation, such as tablet, pill, capsule
Agent, pulvis, granule, paste, emulsion, suspending agent, solution, suppository, injection, inhalant, gelling agent, microballoon and aerosol
Deng.
The classical pathway for giving pharmaceutical composition of the present invention includes but not limited to oral, rectum, saturating mucous membrane, through enteral administration,
Or part, percutaneous, sucking, parenteral, sublingual, intravaginal, intranasal, intraocular, in peritonaeum, intramuscular, subcutaneous, intravenous administration.
It is preferred that oral medication or drug administration by injection.
The pharmaceutical composition of the present invention may be used method manufacture well known in the art, such as conventional mixing method, dissolution method,
Granulation, dragee method processed, levigate method, emulsion process, freeze-drying etc..
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Herein, unless otherwise instructed, " halogen " refers to F, Cl, Br and I.More preferably, halogen atom is selected from F, Cl and Br.
Herein, unless otherwise instructed, " deuterated " refers to one or more of compound or group hydrogen and is replaced by deuterium；Deuterium
Generation can be a substitution, two substitutions, polysubstituted or full substitution.Term " one or more deuterated " and " one or many deuterated "
It is used interchangeably.
Herein, unless otherwise instructed, " non-deuterated compound " refers to that ratio containing D-atom is not higher than the same position of natural deuterium
The compound of cellulose content (0.015%).
The invention also includes the compounds of isotope labelling, are equal to original chemical and are disclosed.This hair can be classified as
The example of bright compound isotope includes hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, respectively such as2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F and36Cl.Compound in the present invention or enantiomer, diastereomer, isomers or medicine
Acceptable salt or solvate on, wherein containing the isotope of above compound or other other isotope atoms all at this
Within the scope of invention.Certain compound isotopically labelleds in the present invention, such as3H and14The radioactive isotope of C also wherein,
It is useful in the experiment of the Tissue distribution of drug and substrate.Tritium, i.e.,3H and carbon-14, i.e.,14C, their preparation and detection are compared
It is easy, is the first choice in isotope.The compound of isotope labelling can use general method, by with the isotope mark being easy to get
Note reagent replaces with non isotopic reagent, can be prepared with the scheme in example.
Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is that the compounds of this invention is formed with acid
Salt.The acid for suitably forming salt includes but is not limited to：The inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid；
Formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,
The organic acids such as citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, naphthalene sulfonic acids；And dried meat ammonia
The amino acid such as acid, phenylalanine, aspartic acid, glutamic acid.Another kind of preferred salt is the salt that the compounds of this invention is formed with alkali,
Such as alkali metal salt (such as sodium salt or sylvite), alkali salt (such as magnesium salts or calcium salt), ammonium salt (such as rudimentary alkanol ammonium salt
And other pharmaceutically acceptable amine salt), such as methylamine salt, ethylamine salt, propylamine salt, dimethyl amine salt, trismethylamine salt, two
Ethyl amine salt, triethyl amine salt, tert-butylamine salt, ethylenediamine salt, oxyethylamine salt, dihydroxy ethylamine salt, three oxyethylamine salt, Yi Jifen
The amine salt not formed by morpholine, piperazine, lysine.
Term " solvate " refers to the compounds of this invention and is coordinated the complex to form special ratios with solvent molecule." hydration
Object " refers to the complex that the compounds of this invention carries out coordination formation with water.
The present invention provides the method for adjusting HIF and/or EPO, by inhibiting HIF α hydroxylatings to stablize HIF and activation
The expression of HIF controlling genes.The method can also be applied to prevent, treat or treat HIF and/or EPO related conditions, packet in advance
Include anaemia, ischaemic and the anoxic patient's condition.
Ischaemic and anoxic are two kinds of patient's condition related with HIF and including but not limited to myocardial infarction, liver locally lack
Blood, kidney ischaemic and apoplexy；Peripheral vascular disorders, ulcer, burn and chronic wounds；Pulmonary embolism；It is damaged with ischemia-reperfusion
Wound, including for example with operation and the relevant ischemia reperfusion injury of organ transplant.
One aspect of the present invention provides the method for treating a variety of ischaemics and the anoxic patient's condition, especially with this
Compound described in text.In one embodiment, when being administered after ischaemic or anoxic, method of the invention generates
Treatment benefit.For example, after myocardial infarction, the reduction that method of the invention makes morbidity and mortality surprising, and show
Writing improves cardiac structure and performance.On the other hand, of the invention when being administered after hepatogenotoxicity-ischemic injury
Method improves liver function.Anoxic is an important component of liver diseases, especially with hepatotoxic compound, such as ethyl alcohol
In related chronic liver disease.Additionally, it is known that the gene expression induced by HIF α increases in alcoholic liver disease, such as nitric oxide
Synzyme and glucose transporter-1.
Therefore, the present invention provides treatment ischaemic or the method for anoxic related conditions, and the method includes that will treat to have
The compound of effect amount or its pharmaceutically acceptable salt individually or with pharmaceutically acceptable excipient composition administer subject.
In one embodiment, the compound is administered immediately after the patient's condition for generating ischaemic, for example, myocardial infarction, pulmonary embolism,
Intestinal obstruction, ishemic stroke and Renal Ischemia Reperfusion Injury.In another embodiment, compound administering is diagnosed as
With the patient of the relevant patient's condition of generation of Chronic ischemia, such as cardiac cirrhosis, macular degeneration, pulmonary embolism, acute exhale
Inhale failure, congenital alveolar dysplasia and congestive heart failure.
Another aspect of the present invention, which provides to have using compound described herein treatment, occurs ischaemic or anoxic
The method of the patient of patient's condition danger, such as atherosclerosis high-risk individuals.The risk factor of atherosclerosis includes, such as
Hyperlipidemia, smoking, hypertension, diabetes, hyperinsulinemia and abdominal obesity.Therefore, the present invention, which provides, prevents local lack
The method of courageous and upright tissue damage, the method include by the compound of therapeutically effective amount or its pharmaceutically acceptable salt individually or
The patient needed with the administering of pharmaceutically acceptable excipient composition.In one embodiment, the predisposed patient's condition can be based on to administer
The compound, such as hypertension, diabetes, arterial occlusive disease, chronic venous insufficiency, Raynaud's disease, chronic skin
Skin ulcer, hardening, congestive heart failure and systemic sclerosis.
In a particular embodiment, it is used for the method to increase the vascularization in damaged tissues, wound and ulcer
And/or granulation tissue is formed.For example, have been shown in wound healing can effective stimulus granulation tissue shape for the compound of the present invention
At.Granulation tissue contains the leakage blood vessel newly formed and interim plasma protein matrix, such as fibrinogen and plasma fiber knot
Hop protein.From inflammatory cell, blood platelet and the release of the growth factor of endothelium is activated to stimulate fibroblast and endothelial cell
Migration in granulation tissue and proliferation.If vascularization or nerve stimulation weaken, ulcer can occur.The method of the present invention has
Effect promotes the formation of granulation tissue.Thus, the present invention is provided to treat have due to for example blocking caused by tissue damage, tool
Have by such as wound or wound inducement wound or with due to certain illness (such as diabetes) and generate chronic wounds or
The method of the patient of ulcer.The method include by the compound of therapeutically effective amount or its pharmaceutically acceptable salt individually or with
The patient that pharmaceutically acceptable excipient composition administering needs.
The another aspect of invention is provided treats subject to reduce or prevent and ischaemic in advance using the compound
Or the method that the relevant tissue damage of anoxic occurs.When being administered immediately before being related to the patient's condition of ischaemic or anoxic, this
The method of invention generates treatment benefit.For example, before induced myocardial infarction using the present invention method show cardiac structure and
Performance obtains the improvement of statistically significance.On the other hand, when before ischemia reperfusion injury and between immediately
When administering, method of the invention generates treatment benefit, substantially reduces and the relevant Diagnostic parameters of kidney failure.
Therefore, the present invention provide in advance treatment subject to reduce or prevent and ischaemic or anoxic relevant tissue damage
Bad method, the method include by the compound of therapeutically effective amount or its pharmaceutically acceptable salt individually or with pharmaceutically may be used
Patient of the excipient composition administering with ischemic conditions medical history of receiving, such as myocardial infarction, or lacked with approaching part
The patient of mass formed by blood stasis shape, such as angina pectoris.It in another embodiment, can be based on the physical parameter administering for implying possible ischaemic
The compound, such as the individual under general anesthesia or temporarily working under High aititude.In another embodiment, may be used
The compound is used in organ transplant, to advance treating organs donor or before being implanted into receptor, to maintain certainly
The organ that body removes.
Previous research are it has been shown that the certain compounds used in the method for the invention are procollagen prolyl 4- hydroxylations
Effective inhibitor of enzyme.Although it is recognized that initially the recovery of infraction or wound needs connective tissue to be deposited in necrotic zone, but
It is present invention demonstrates that the treatment for cicatrization is without side-effects.Thus, certain compounds based on the present invention are in treatment and in advance
The benefit provided in oxygen deficit proof tissue damage and fibrosis, the present invention cover a kind of treat or prevent and are related to ischaemic or lack
" double treatment " method of the oxygen patient's condition, including obstruct with the relevant ischaemic of concurrent reaction fibrosis or anoxic, such as cardiac muscle
Plug and thing followed congestive heart failure.A kind of compound can be used in the method, inhibits more than one with identical
Specificity or the not 2-oxoglutaric acid dioxygenase of homospecificity, such as HIF prolyl hydroxylases and procollagen prolyl 4- hydroxyls
Change enzyme.Alternatively, the combination of compound can be used in the method, wherein each compound specifically inhibits only a kind of 2-oxoglutaric acid double
Oxygenase, such as a kind of compound specifically inhibit HIF prolyl hydroxylases and second of compound specifically to inhibit procollagen dried meat ammonia
Acyl 4- hydroxylases.
In one aspect, the compound of the present invention inhibits one or more kinds of 2-oxoglutaric acid dioxygenases.At one
In embodiment, the compound inhibits at least two 2-oxoglutaric acid dioxygenases with phase homospecificity or non-homospecificity
Family member, such as HIF prolyl hydroxylases and HIF asparagine-hydroxylases (FIH-1).In another embodiment, describedization
Close object has specificity, such as HIF prolyl hydroxylases for a kind of 2-oxoglutaric acid dioxygenase, and for other families
Member shows seldom specificity or does not show specificity.
The compound can combine administering with a variety of other therapies.In one embodiment, the compound and another
A kind of 2-oxoglutaric acid dioxygenase inhibitor administers together, wherein both compounds for a other 2-oxoglutaric acid it is double plus
Oxygenase family member has different specificity.Described two compounds can be thrown with a ratio relative to another simultaneously
It gives.For the ratio suitable for giving therapeutic process or particular subject measurement within the technical merit in the field.Alternatively,
Described two compounds can continuously administer in treating time-histories, such as after myocardial infarction.In a particular embodiment, one
Kind compound specifically inhibits the activity of HIF prolyl hydroxylases, and second of compound specifically inhibits procollagen prolyl 4- hydroxyls
Change the activity of enzyme.In another particular embodiment, a kind of compound specifically inhibits the activity of HIF prolyl hydroxylases, and second
Kind compound specifically inhibits the activity of HIF asparaginyl-hydroxylase enzymes.In another embodiment, the compound and another tool
There is the therapeutic agent of different role pattern to administer together, such as Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe (ACEI), angiotensin-II receptor blocking agent
(ARB), inhibin, diuretics, digoxin, carnitine etc..
The present invention provides the method for increasing endogenous erythropoietin (EPO).These methods can be applied in vivo, example
It in blood plasma, or applies in vitro, such as in cell culture medium after the adjustment.The present invention further provides increase endogenous
The method of EPO contents, to prevent, in advance treat or treat EPO related conditions, including for example with anaemia and nerve problems
The relevant patient's condition.Anaemia related conditions include for example acute or chronic kidney trouble, diabetes, cancer, ulcer, virus infection
The illness of (such as HIV, bacterium or parasite), inflammation etc..The anaemia patient's condition can further comprise and program or treatment-related disease
Condition, described program or treatment include such as radiotherapy, chemotherapy, dialysis and operation.Anaemia associated disease also comprises different
Normal hemoglobin and/or red blood cell, such as be found in as microcytic anemia, hypochromic anemia, aplastic are poor
In the illnesss such as blood.
The endogenous EPO that the present invention can be used in subject that is preventative or increasing experience particular treatment or program simultaneously,
Such as ring is just contained with the infected by HIV Anemic patients of retrovir (Zidovudine) or the treatment of other reverse transcriptase inhibitor, receiving
The anaemia or non-poor of the anemic cancer patient or plan experience operation of neoplatin or cyclic chemical therapy without neoplatin
Blood patient.The method for increasing endogenous EPO can also be used for preventing, treat or treat in advance and degenerate with neuronal damage or nerve fiber
Relevant EPO related conditions, including but not limited to apoplexy, wound, epilepsy, spinal cord injury and neurodegenerative disorders.
In addition, the method can be used for the anaemia of increase plan experience operation or the endogenous EPO in non-Anemic patients contains
Amount, to reduce the needs transfused blood to external source or with the storage in order to operation consent blood.After usual blood supply self before surgery
A small amount of reduction not erythropoietic increases of stimulation of endogenous EPO or compensatory of the blood hematocrit of generation.However,
The operation consent stimulation of endogenous EPO will be effectively increased mass of red blood cells and self blood supply volume, while maintain higher haemocyte
Specific volume is horizontal, and the method specificity covers in this article.In some operations crowd, especially operation, which is lost blood, is more than
2 liters of individual, the method that can apply the present invention expose to the open air to reduce heterologous blood.
The method of the present invention can also be used for enhancing movenent performance, improve exercising ability and promotion or the aerobic adjusting of enhancing.Example
Such as, the method can be used to promote training and soldier that the method can be used to improve such as endurance and restrain oneself in sportsman
Power.
The method of the present invention has been displayed in the culture medium that can increase external treatment culture cell and the animal blood of interior therapeutic
Endogenous erythropoietin content in slurry.Although kidney is the main source of internal hematopoietin, once suitable
Can and hematopoietin can really be synthesized by working as stimulation, other organs, including brain, liver and marrow.Use the method for the present invention
The expression of endogenous erythropoietin in multiple organs, including brain, kidney and liver can be increased.In fact, of the invention
Method even increase the content of the endogenous erythropoietin in the double animals for surveying nephrectomies of experience.
Even if the method for the present invention can increase the content of hematopoietin if proof when kidney function damage.Although
The mechanism that the present invention is not generated by hematopoietin limits, but usually visible promoting erythrocyte during kidney failure
The reduction for generating element secretion is attributable to flowing in nephridial tissue/caused hyperoxia of perfusion increase.
On the other hand, hematocrit and blood-hemoglobin water in the animal of method of the invention increase interior therapeutic
It is flat.The increasing of the blood plasma EPO, hematocrit and blood-hemoglobin that are generated as compound uses in the method for the invention
Add with dosage susceptibility, however can determine dosage to generate the level of response of constant, controllable the compounds of this invention.Separately
On the one hand, anaemia can be cured using the treatment of the compounds of this invention, such as by toxic chemical, such as chemotherapeutant is along chlorine ammonia
The anaemia of platinum induction, or the anaemia caused by losing blood, such as wound, damage, parasite or operation.
It is blood before hematocrit and blood-hemoglobin increase in animal with the compound of the present invention treatment
The increase of middle cycle immature erythrocyte (granulophilocyte) percentage.Thus, the present invention covers the compounds of this invention and is increasing
In animal blood the content of granulophilocyte to generate cell-free reticulocyte lysate method (such as Pelham and
Jackson exists《European journal of biological chemistry》(Eur.J.Biochem.)67:Described in 247-256 (1976)) in purposes.
By be used individually with the compound of the present invention or with the combined therapies such as another compound, such as acetylphenylhydrazine, animal (such as
Rabbit etc.) in cycle granulophilocyte content increase.
Compared with prior art, beneficial effects of the present invention are：The compounds of this invention can be used for adjusting hypoxia inducible factor
(HIF) and/or endogenous erythropoietin (EPO).By deuterate, this technology changes generation of the compound in organism
It thanks, makes compound that there is better pharmacokinetic parameter characteristic.In such a case, it is possible to change dosage and form long-acting system
Agent improves applicability.Compound can be improved dynamic due to its deuterium isotope effect with the hydrogen atom in deuterium substituted compound
Drug concentration in object, to improve curative effect of medication.With the hydrogen atom in deuterium substituted compound, since certain metabolites are pressed down
System, may improve the safety of compound.
Specific implementation mode
Compound
The present invention provides a kind of formula (I) compound represented or its crystal form, pharmaceutically acceptable salt, hydrate or
Solvated compounds.
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、
R22、R23、R24、R25It is each independently hydrogen, deuterium, halogen or trifluoromethyl；
Additional conditions are R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、
R20、R21、R22、R23、R24And R25In it is at least one be deuterated or deuterium.
In a particular embodiment, " R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、
R18、R19、R20、R21、R22、R23、R24、R25It is each independently hydrogen, deuterium, halogen or trifluoromethyl " include R1Selected from hydrogen, deuterium, halogen
Element or trifluoromethyl, R2Selected from hydrogen, deuterium, halogen or trifluoromethyl, R3Selected from hydrogen, deuterium, halogen or trifluoromethyl, and so on, directly
To R25Selected from hydrogen, deuterium, halogen or trifluoromethyl, R3Technical solution selected from hydrogen, deuterium, halogen or trifluoromethyl.More specifically, packet
Include R1For hydrogen, R1For deuterium, R1For halogen (F, Cl, Br or I) or R1For trifluoromethyl, R2For hydrogen, R2For deuterium, R2For halogen (F, Cl,
Br or I) or R2For trifluoromethyl, R3For hydrogen, R3For deuterium, R3For halogen (F, Cl, Br or I) or R3For trifluoromethyl, and so on,
Until R25For hydrogen, R25For deuterium, R25For halogen (F, Cl, Br or I) or R25For trifluoromethyl.
In preferred embodiments, the present invention relates to a kind of compound of formula (I) or its crystal forms, pharmaceutically acceptable
Salt, hydrate or solvated compounds, wherein R23For hydrogen, and R1-R22And R24-R25As defined above, additional conditions are described
Compound is at least containing there are one D-atoms.
In preferred embodiments, the present invention relates to a kind of compound of formula (I) or its crystal forms, pharmaceutically acceptable
Salt, hydrate or solvated compounds, wherein R23For hydrogen, and R1-R22And R24-R25It is each independently selected from hydrogen or deuterium, is added
Condition is D-atom there are one the compound at least contains.
In preferred embodiments, the present invention relates to a kind of compound of formula (I) or its crystal forms, pharmaceutically acceptable
Salt, hydrate or solvated compounds, wherein R23For hydrogen, R1-R22And R24-R25It is each independently selected from hydrogen or deuterium, and R1And R2
It is identical, additional conditions are D-atoms there are one the compound at least contains.
In preferred embodiments, the present invention relates to a kind of compound of formula (I) or its crystal forms, pharmaceutically acceptable
Salt, hydrate or solvated compounds, wherein R1-R6、R14、R15、R17、R18、R21-R23For hydrogen, R7-R11、R12、R13、R16、
R19、R20And R24、R25It is each independently selected from hydrogen or deuterium, additional conditions are D-atoms there are one the compound at least contains.
In preferred embodiments, R7-R10It is identical.
In preferred embodiments, R12、R13、R19、R20It is identical.
In preferred embodiments, R24、R25It is identical.
In preferred embodiments, R1、R2It is identical.
As the preferred embodiments of the invention, the compound is following any structure or its is pharmaceutically acceptable
Salt, but it is not limited to having structure：
Embodiment
The preparation method of formula (I) structural compounds of the present invention is described more particularly below, but these specific methods are not to this
Invention constitutes any restrictions.The compounds of this invention can also optionally will be describing or known in the art various in the present specification
Synthetic method combines and is easily made, such combination can by those skilled in the art in the invention easily into
Row.
In general, in preparation flow, each reaction is usually in atent solvent, in room temperature to reflux temperature (such as 0 DEG C~100
DEG C, preferably 0 DEG C~80 DEG C) under carry out.Reaction time is usually -60 hours 0.1 hour, preferably 0.5-24 hours.
1 N- of embodiment [(1,3- dicyclohexyl -2,4,6- trioxy- -5- hexahydropyrimidines base) carbonyl] glycine -2,2-
d2, i.e. compound T-1, molecular formula be as follows：
Using following synthetic route：
Step 1：The synthesis of compound 2.
Under nitrogen protection, anhydrous chloroform (20mL) solution of malonyl chloride (1.30mL, 13.39mmol) is added drop-wise to 1,3-
In anhydrous chloroform (80mL) solution of bis- (cyclohexyl) ureas (3.00g, 13.39mmol), after being added dropwise, reaction solution is warming up to 50
4.5hrs is reacted at DEG C.It is cooled to room temperature, reaction is quenched with the dilute hydrochloric acid of 1M, organic layer is dried with anhydrous sodium sulfate, and decompression is dense
Contracting, filtrate decompression concentration, concentrate carry out post separation (eluant, eluent：Petrol ether/ethyl acetate (v/v)=10:1) 1.50g is obtained
White solid, yield：38.4%, LC-MS (APCI):M/z=293.2 (M+1)+。
Step 2：The synthesis of compound 3.
At room temperature, isocyanide ethyl acetoacetic acid ethyl ester (0.70g, 5.50mmol) is added to compound 2 (1.50g, 5.50mmol)
In anhydrous methylene chloride (80mL) solvent of DIPEA (1.40g, 11.00mmol), reaction solution is stirred at room temperature overnight, and is used
Washing reaction liquid is quenched in the dilute hydrochloric acid (30mL x 2) of 1M, and organic layer is concentrated under reduced pressure to give white solid and is directly used in next step instead
It answers.LC-MS(APCI):M/z=422.3 (M+1)+。
Step 3：The synthesis of compound 4.
Above-mentioned crude Compound 3 is dissolved in ethyl alcohol (10mL) under greenhouse, adds the sodium hydroxide (5mL) of 1M, reaction exists
It is stirred to react 3hrs at room temperature, with the dilute hydrochloric acid acidification reaction liquid of 1M.Ethyl acetate extracts (50mL x 2), merges organic layer and uses
The dilute hydrochloric acid of 1M washs, and organic layer is concentrated under reduced pressure to give white solid, with ether and the mashing purifying of n-hexane mixed solvent, solid
Filtering, washs filter cake, solid is dried in vacuo to obtain the white solid of 2.0g, two steps with a small amount of ether and n-hexane mixed solvent
Total recovery is 92.0%.LC-MS(APCI):M/z=394.2 (M+1)+.Purity 99.21% (HPLC).1H NMR(400MHz,
DMSO-d6) δ 10.18 (t, J=5.7Hz, 1H), 4.64 (t, J=12.0Hz, 2H), 4.08 (d, J=5.6Hz, 2H), 2.28
(q, J=12.3Hz, 4H), 1.78 (d, J=12.5Hz, 4H), 1.69-1.49 (m, 6H), 1.27 (q, J=12.9Hz, 4H),
1.18-1.04(m,2H).
Step 4：The synthesis of compound T-1.
40% deuterium sodium oxide molybdena (0.31mL, 3.05mmol) is added to the heavy water of compound 4 (300mg, 0.76mmol)
In (15mL), for reaction solution at 140 DEG C, tube sealing reaction is overnight.It is cooled to room temperature.With the dilute hydrochloric acid tune pH value 3 or so of 1M, second is used
Acetoacetic ester (30mL x 3) extracts, and organic layer is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, and filtrate decompression concentration, concentrate carries out
Post separation (eluant, eluent：Methylene chloride/methanol (v/v)=10:1) 104mg is obtained, yield is：34.6%.Purity：98.15%.
LC-MS(APCI):M/z=396.2 (M+1)+。1H NMR(400MHz,DMSO-d6)δ12.99(br,1H),10.17(s,1H),
4.62 (t, J=12.2Hz, 2H), 2.26 (dd, J=22.4,12.0Hz, 4H), 1.77 (d, J=12.7Hz, 4H), 1.64-
1.51(m,6H),1.31-1.22(m,4H),1.17-1.07(m,2H).
2 N- of the embodiment [((cyclohexyl -2,2,6,6-d of 1,3- bis-4) -2,4,6- trioxy- -5- hexahydropyrimidines base) carbonyl]
Glycine, i.e. compound T-2, molecular formula are as follows：
Using following synthetic route：
Step 1：The synthesis of compound 7.
Cyclohexanone (1.0g, 10.00mmol) and 40%NaOD (0.27mL) are added to 10 milliliters of D2In O, heat up back
Stream reaction 2 days.It is cooled to room temperature, hydroxylamine hydrochloride (2.0g) and sodium acetate (4.0g) is then added under the conditions of 0 DEG C, is warming up to 70
DEG C it is stirred to react 20min.Then it cools down, there is solid precipitation, filter, be dissolved in the ether of 160mL, be slowly added to after filtration cakes torrefaction
Lithium aluminium hydride reduction (2.0g), then mixed solution be heated to reflux 45 minutes.It is cooled to room temperature, the carbonic acid of saturation is then slowly added dropwise
Hydrogen sodium solution, it is dilute go out a large amount of solids, filtering, filter cake with ether elute twice, organic phase merge drying, be concentrated to give 400mg yellow
Liquid.Yield：40%.LC-MS(APCI):M/z=104.2 (M+1)+。
Step 2：The synthesis of compound 8.
By compound 8 (3.90g, 37.86mmol) and vinylethylene carbonate (1.67g, 18.93mmol) and 1,5,7-
Bicyclic (4.4.0) the decyl- 5- alkene (53mg) of three nitrine is added in the single port bottle of 50mL, is heated to 120 DEG C of stirring 2hrs, there is solid
It generates.It is cooled to room temperature, the water of 10mL is added, stir ten minutes, then filter, filter cake is washed three times with DCM, and then baking oven dries
Do to obtain 1.2g white solids.Yield：13.6%.LC-MS(APCI):M/z=233.2 (M+1)+。
Step 3：The synthesis of compound 9.
Under nitrogen protection, anhydrous chloroform (0.3mL) solution of malonyl chloride (365mg, 2.59mmol) is added drop-wise to chemical combination
In anhydrous chloroform (16mL) solution of object 8 (600mg, 2.59mmol), after being added dropwise, reaction solution, which is warming up at 50 DEG C, to react
4.5hrs.It is cooled to room temperature, reaction is quenched with the dilute hydrochloric acid of 1M, organic layer is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, and filtrate subtracts
Pressure concentration, concentrate carry out post separation (eluant, eluent：Petrol ether/ethyl acetate (v/v)=10:1) 190mg white solids are obtained,
Yield：24.5%, LC-MS (APCI):M/z=301.2 (M+1)+。
Step 4：The synthesis of compound 10.
At room temperature, by isocyanide ethyl acetoacetic acid ethyl ester (82mg, 0.63mmol) be added to compound 9 (190mg, 0.63mmol) and
In anhydrous methylene chloride (10mL) solvent of DIPEA (164mg, 1.26mmol), reaction solution is stirred at room temperature overnight, with 1M's
Washing reaction liquid is quenched in dilute hydrochloric acid (10mL x 2), and organic layer is concentrated under reduced pressure to give white solid and is directly used in react in next step.
LC-MS(APCI):M/z=430.3 (M+1)+。
Step 5：The synthesis of compound T-2.
Above-mentioned crude product is dissolved in ethyl alcohol (10mL) under greenhouse, adds the sodium hydroxide (5mL) of 1M, is reacted also at room temperature
It is stirred to react 3 days, with the dilute hydrochloric acid acidification reaction liquid of 1M.Ethyl acetate extracts (20x 2), merges the dilute hydrochloric acid of organic layer 1M
Washing, organic layer are concentrated under reduced pressure to give white solid, with ether and the mashing purifying of n-hexane mixed solvent, solid filtering, with less
The ether and n-hexane mixed solvent of amount wash filter cake, and solid is dried in vacuo to obtain the white solid of 159mg, and two step total recoverys are
62.6%.LC-MS(APCI):M/z=402.2 (M+1)+；Purity：99.67% (HPLC).1H NMR(400MHz,DMSO-d6):
δ 10.18 (t, J=5.6Hz, 1H), 4.60 (s, 2H), 4.11 (d, J=5.7Hz, 2H), 1.76 (d, J=12.9Hz, 4H),
1.62 (d, J=12.4Hz, 2H), 1.25 (t, J=12.7Hz, 4H), 1.12 (t, J=12.9Hz, 2H)
3 N- of the embodiment [((cyclohexyl -2,2,6,6-d of 1,3- bis-4) -2,4,6- trioxy- -5- hexahydropyrimidines base) carbonyl]
Glycine -2,2-d2, i.e. compound T-3, molecular formula be as follows：
Using following synthetic route：
40% deuterium sodium oxide molybdena (0.1mL) is added to the heavy water (1mL) of T-2 (90mg, 0.22mmol) and deuterated ethyl alcohol
In (2mL) mixed solution, reaction solution, which is warming up to after reacting stirring at room temperature 2 days at 60 DEG C, to react 4 days.It is cooled to room temperature.With
The dilute hydrochloric acid acidification reaction liquid of 1M is extracted with ethyl acetate (20mL x 3), and organic layer is dried with anhydrous sodium sulfate, and organic layer subtracts
Pressure is concentrated to give white solid, with ether and the mashing purifying of n-hexane mixed solvent, solid filtering, with a small amount of ether and just oneself
Alkane mixed solvent washs filter cake, and solid is dried in vacuo to obtain the white solid of 50mg, yield 55.6%.LC-MS(APCI):m/
Z=404.1 (M+1)+, purity：97.12% (HPLC)1H NMR(400MHz,DMSO-d6):δ12.92(br,1H),10.17
(s,1H),4.60(s,2H),1.83-1.55(m,6H),1.-1.21(m,4H),1.16-1.08(m,2H).
4 N- of embodiment [(1,3- bis- (cyclohexyl -1-d) -2,4,6- trioxy- -5- hexahydropyrimidines base) carbonyl] glycine,
I.e. compound T-4, molecular formula are as follows：
Using following synthetic route：
Step 1：The synthesis of compound 11.
It at room temperature, will be fresh activatedMolecular sieve (5.0g) is added to cyclohexanone (2.5mL, 23.9mmol) and benzyl
In anhydrous methylene chloride (24mL) solution of amine (2.6mL, 23.9mmol), reaction solution is being to be stirred to react at room temperature overnight, directly
Concentration is connect for reacting in next step.LC-MS(APCI):M/z=188.2 (M+1)+。
Step 2：The synthesis of compound 12.
Above-mentioned crude product is dissolved in absolute methanol (24mL), 0 DEG C by deuterated sodium borohydride (1.0g, 23.9mmol) in batches
It is added, reaction 1.5hrs is stirred at room temperature in reaction, and decompression removal methanol obtains crude product, with ether dissolution, filtering.Filtrate decompression
Concentration, concentrate carry out post separation (eluant, eluent：Methylene chloride/methanol (v/v)=10:1) pale yellow oil, LC-MS are obtained
(APCI):M/z=191.2 (M+1)+。
Step 3：The synthesis of compound 13.
Under greenhouse, Pd/C (10%, 250mg) will be with Pd (OH)2(250mg) is added to the absolute methanol of compound 12
In (50mL) solution, reaction 72hrs, diatomite filtering is stirred at room temperature in reaction, and filtrate decompression is concentrated to give 1.2gColourless liquid
Body, total recovery：50%, LC-MS (APCI):M/z=101.2 (M+1)+.
Step 4：The synthesis of compound 14.
By compound 13 (2.0g, 20mmol) and vinylethylene carbonate (0.88g, 10mmol) and 1,5,7- tri- nitrine
Bicyclic (4.4.0) decyl- 5- alkene (28mg) is added in the single port bottle of 50mL, is heated to 120 DEG C of stirring 2hrs, there is solid generation.
It is cooled to room temperature, the water of 5mL is added, stir ten minutes, then filter, filter cake is washed three times with DCM, and then baking oven is dried
185mg white solids.Yield：4.07%.LC-MS(APCI):M/z=227.1 (M+1)+。
Step 5：The synthesis of compound 15.
Under nitrogen protection, anhydrous chloroform (0.2mL) solution of malonyl chloride (115mg, 0.82mmol) is added drop-wise to chemical combination
In anhydrous chloroform (10mL) solution of object 14 (185mg, 0.82mmol), after being added dropwise, reaction solution, which is warming up at 50 DEG C, to react
4.5hrs.It is cooled to room temperature, reaction is quenched with the dilute hydrochloric acid of 1M, organic layer is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, and filtrate subtracts
Pressure concentration, concentrate carry out post separation (eluant, eluent：Petrol ether/ethyl acetate (v/v)=10:1) 135mg white solids are obtained,
Yield：56.0%, LC-MS (APCI):M/z=295.2 (M+1)+。
Step 6：The synthesis of compound 16.
At room temperature, isocyanide ethyl acetoacetic acid ethyl ester (61mg, 0.48mmol) is added to compound 15 (135mg, 0.48mmol)
In anhydrous methylene chloride (10mL) solvent of DIPEA (122mg, 0.96mmol), reaction solution is stirred at room temperature overnight, and uses 1M
Dilute hydrochloric acid (10mL x 2) be quenched washing reaction liquid, organic layer be concentrated under reduced pressure to give white solid be directly used in it is anti-in next step
It answers.
LC-MS(APCI):M/z=424.1 (M+1)+。
Step 7：The synthesis of compound T-4.
Above-mentioned crude product is dissolved in ethyl alcohol (5mL) under greenhouse, adds the sodium hydroxide (2mL) of 1M, is reacted also at room temperature
It is stirred to react 3 days, with the dilute hydrochloric acid acidification reaction liquid of 1M.Ethyl acetate extracts (20mL x 2), and merging organic layer is dilute with 1M's
Salt acid elution, organic layer are concentrated under reduced pressure to give white solid, and with ether and the mashing purifying of n-hexane mixed solvent, solid filters,
Filter cake is washed with a small amount of ether and n-hexane mixed solvent, solid is dried in vacuo to obtain the white solid of 120mg, and two steps are always received
Rate is 63.1%.
LC-MS(APCI):M/z=396.0 (M+1)+, purity：94.46% (HPLC)1H NMR(400MHz,DMSO-
d6):δ 10.16 (t, J=5.5Hz, 1H), 4.04 (d, J=5.6Hz, 2H), 2.27 (t, J=11.2Hz, 4H), 1.77 (d, J=
12.6Hz,4H),1.65-1.49(m,6H),1.30-1.22(m,4H),1.17-1.05(m,2H).
5 N- of embodiment [(1- cyclohexyl -3- (cyclohexyl -2,2,6,6-d4) -2,4,6- trioxy- -5- hexahydropyrimidines base)
Carbonyl] glycine, i.e. compound T-5, molecular formula be as follows：
Using following synthetic route：
Step 1：The synthesis of compound 18 and 19.
Cyclohexylamine (500mg, 5.04mmol) and vinylethylene carbonate (443mg, 5.04mmol) and 1,5,7- tri- is folded
Bicyclic (4.4.0) the decyl- 5- alkene (10mg) of nitrogen is added in the single-necked flask of 50mL, heats 120 DEG C of reaction 4hrs.It is subsequently cooled to
Room temperature adds compound 7 (519mg, 5.04mmol), then is warming up to 120 DEG C of reaction 4.5hrs.It is cooled to room temperature, 5mL is added
Water has solid precipitation, and filtering, filter cake is washed twice with a small amount of DCM, and vacuum drying obtains 293mg white solid products.
LC-MS(APCI):M/z=229.1 (M+1)+；Yield：25.4%.
Step 2：The synthesis of compound 20.
Under nitrogen protection, anhydrous chloroform (0.4mL) solution of malonyl chloride (181mg, 1.29mmol) is added drop-wise to chemical combination
In anhydrous chloroform (16mL) solution of object 19 (293mg, 1.29mmol), after being added dropwise, reaction solution, which is warming up at 50 DEG C, to react
4.5hrs.It is cooled to room temperature, reaction is quenched with the dilute hydrochloric acid of 1M, organic layer is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, and filtrate subtracts
Pressure concentration, concentrate carry out post separation (eluant, eluent：Petrol ether/ethyl acetate (v/v)=10:1) 238mg white solids are obtained,
Yield：56.0%,
LC-MS(APCI):M/z=297.2 (M+1)+。
Step 3：The synthesis of compound 21.
At room temperature, isocyanide ethyl acetoacetic acid ethyl ester (104mg, 0.80mmol) is added to compound 20 (238mg, 0.80mmol)
In anhydrous methylene chloride (10mL) solvent of DIPEA (207mg, 1.60mmol), reaction solution is stirred at room temperature overnight, and uses 1M
Dilute hydrochloric acid (10mL x 2) be quenched washing reaction liquid, organic layer be concentrated under reduced pressure to give white solid be directly used in it is anti-in next step
It answers.LC-MS(APCI):M/z=426.1 (M+1)+.
Step 4：The synthesis of compound T-5.
Above-mentioned crude product is dissolved in ethyl alcohol (10mL) under greenhouse, adds the sodium hydroxide (5mL) of 1M, is reacted also at room temperature
It is stirred to react 3 days, with the dilute hydrochloric acid acidification reaction liquid of 1M.Ethyl acetate extracts (20mL x 2), and merging organic layer is dilute with 1M's
Salt acid elution, organic layer are concentrated under reduced pressure to give white solid, and with ether and the mashing purifying of n-hexane mixed solvent, solid filters,
Filter cake is washed with a small amount of ether and n-hexane mixed solvent, solid is dried in vacuo to obtain the white solid of 218mg, and two steps are always received
Rate is 68.5%.
LC-MS(APCI):M/z=398.2 (M+1)+；Purity：98.98% (HPLC),1H NMR(400MHz,DMSO-d6)
δ 10.16 (t, J=5.4Hz, 1H), 4.70-4.47 (m, 2H), 4.07 (d, J=5.7Hz, 2H), 2.25 (q, J=11.8Hz,
2H), 1.75 (d, J=10.1Hz, 4H), 1.58 (t, J=14.2Hz, 4H), 1.24 (t, J=12.7Hz, 4H), 1.11 (t, J=
12.7Hz,2H).
6 N- of embodiment [(1- cyclohexyl -3- (cyclohexyl -2,2,6,6-d4) -2,4,6- trioxy- -5- hexahydropyrimidines base)
Carbonyl] glycine -2,2-d2, i.e. compound T-6, molecular formula be as follows：
Using following synthetic route：
40% deuterium sodium oxide molybdena (0.1mL) is added to the heavy water (1mL) of compound T-5 (100mg) and deuterated
In ethyl alcohol (2mL), reaction solution, which is warming up to after reacting stirring at room temperature 2 days at 60 DEG C, to react 4 days.It is cooled to room temperature.With 1M's
Dilute hydrochloric acid acidification reaction liquid is extracted with ethyl acetate (20mL x 3), and organic layer is dried with anhydrous sodium sulfate, and organic layer decompression is dense
Contracting obtains white solid, and with ether and the mashing purifying of n-hexane mixed solvent, solid filtering is mixed with a small amount of ether and n-hexane
Bonding solvent washs filter cake, and solid is dried in vacuo to obtain 80mgFaint yellow solid, yield 79.8%.LC-MS(APCI):m/z
=400.2 (M+1)+；Purity：99.17% (HPLC),1H NMR(400MHz,DMSO-d6):δ13.03(br,1H),10.15(s,
1H),4.73–4.44(m,2H),2.30–2.18(m,2H),1.82–1.68(m,4H),1.64–1.52(m,4H),1.26–1.18
(m,4H),1.15–1.05(m,2H).
7 N- of embodiment [(bis- (cyclohexyl-the 1-d) -2,4,6- trioxy- -5- hexahydropyrimidines bases of 1,3-) carbonyl] glycine -
2,2-d2, i.e. compound T-7, molecular formula be as follows：
Using following synthetic route：
40% deuterium sodium oxide molybdena (0.1mL) is added to compound T-4 (80mg) heavy water (1mL) and deuterated second
In alcohol (2mL), reaction solution, which is warming up to after reacting stirring at room temperature 2 days at 60 DEG C, to react 4 days.It is cooled to room temperature.It is dilute with 1M
Hydrochloric acid acidizing reaction liquid is extracted with ethyl acetate (20mL x 3), and organic layer is dried with anhydrous sodium sulfate, and organic layer is concentrated under reduced pressure
White solid is obtained, with ether and the mashing purifying of n-hexane mixed solvent, solid filtering is mixed with a small amount of ether and n-hexane
Solvent washs filter cake, and solid is dried in vacuo to obtain 70mgYellow solid, yield 87.5%.LC-MS(APCI):M/z=
398.2(M+1)+；Purity：94.35% (HPLC),1H NMR(400MHz,DMSO-d6) δ 10.15 (s, 1H), 2.24 (t, J=
11.3Hz, 4H), 1.76 (d, J=12.6Hz, 4H), 1.63-1.53 (m, 6H), 1.25-1.19 (m, 4H), 1.13-1.04 (m,
2H).
Biological activity test.
(1) mouse tissue HIF western blot analysis.
The mortar and pestle being stored under -80 DEG C of mouse tissue liquid nitrogen frozen smash.Nucleus extraction object uses
NE-PER kits (Pierce Biotechnology) prepare.To carry out immune precipitation, by nucleus extraction object with group
It is 200 to knit than antibody：1 ratio is added to HIF-1αIn monoclonal antibody.By the suspension at 4 DEG C in cone it is miniature from
It is cultivated 4 hours in heart pipe.Then albumin A/G is coupled sepharose 4B (40μThe suspension of L50%) it is added in the pipe.At 4 DEG C
After rotation overnight, the pearl is washed 3 times with ice-cold phosphate buffer.Then 40 μ L Laemmli samples of the pearl are buffered
Prepared by solution is used for SDS-PAGE.The Protein transfer detached from SDS-PAGE is to XCell-II Blot Module systems
On the nitrocellulose plate of system.Trace is closed with 5% BSA, then uses HIF-1 α rabbit antibodies with 1：100 diluted ratio trainings
It educates.Then the goat-anti rabbit two washed trace with Tris buffered salines/Tween-20 buffer solutions and be conjugated with horseradish peroxidase
Grade antibody development.Trace is imaged with ECL reagents.Print image is captured with 1600 scanners of Epson Expression.
(2) mice serum EPO is tested.
Using the mouse Quantikine hematopoietin ELISA kits of R＆DSystems according to operation instructions
Mice serum EPO is detected.
The experimental results showed that the compounds of this invention has response to mice serum EPO detections, illustrate that the compounds of this invention is available
In the drug for preparing regulation and control human body anaemia.
(3) metabolic stability is evaluated.
Microsomal assay：Rat liver microsomes：0.5mg/mL, Xenotech；Coenzyme (NADPH/NADH)：1mM, Sigma
LifeScience；Magnesium chloride：5mM, 100mM phosphate buffer (pH 7.4).
The preparation of storing solution：Precision weighs a certain amount of untested compound powder, and DMSO is used in combination to be dissolved to 5mM respectively.
The preparation of phosphate buffer (100mM, pH7.4)：Take the 0.5M potassium dihydrogen phosphates 150mL for preparing in advance and
The 0.5M dipotassium hydrogen phosphate solutions of 700mL mix, then adjust mixed liquor pH value to 7.4 with 0.5M dipotassium hydrogen phosphate solutions, use
It is preceding to dilute 5 times with ultra-pure water, magnesium chloride is added, phosphate buffer (100mM) is obtained, wherein potassium phosphate containing 100mM, 3.3mM
Magnesium chloride, pH 7.4.
It prepares NADPH regenerative systems solution and (contains 6.5mM NADP, 16.5mM G-6-P, 3U/mL G-6-P D, 3.3mM
Magnesium chloride), using it is preposition in it is wet on ice.
Prepare terminate liquid：Acetonitrile containing 50ng/mL Propranolol Hydrochlorides and 200ng/mL orinases (internal standard) is molten
Liquid.It takes in 25057.5 μ L phosphate buffers (pH7.4) to 50mL centrifuge tubes, is separately added into 812.5 μ L SD rat liver microsomes
Body, mixing obtain the hepatomicrosome dilution of a concentration of 0.625mg/mL of albumen.
The incubation of sample：The storing solution of respective compound is diluted to 0.25mM respectively with the aqueous solution containing 70% acetonitrile,
It is spare as working solution.It takes the rat liver microsomes dilution of 398 μ L that 96 holes are added respectively to be incubated in plate (N=2), add respectively
In the working solution for entering 2 μ L 0.25mM, mixing.
The measurement of metabolic stability：The terminate liquid of 300 μ L precoolings is added in every hole of 96 hole deep-well plates, is placed in ice
On, as termination plate.96 holes are incubated plate and NADPH regenerative systems are placed in 37 DEG C of water baths, 100 revs/min of concussions are incubated in advance
5min.80 μ L Incubating Solutions addition termination plate is taken out per hole from plate is incubated, mixing is supplemented 20 μ L NADPH regenerative system solution, made
For 0min samples.Again to the NADPH regenerative system solution for being incubated plate 80 μ L of addition per hole, start reaction, starts timing.Correspondingization
The reaction density for closing object is 1 μM, a concentration of 0.5mg/mL of albumen.When reaction 10,30,90min, 100 μ L reactions are respectively taken
Liquid is added in termination plate, and vortex 3min terminates reaction.Termination plate is centrifuged into 10min under the conditions of 5000 × g, 4 DEG C.Take 100 μ L
For supernatant to being previously added in 96 orifice plates of 100 μ L distilled water, mixing carries out sample analysis using LC-MS/MS.
Data analysis：By LC-MS/MS system detectios respective compound and interior target peak area, calculate compound with it is interior
Mark peak area ratio.Slope is measured with time mapping by the natural logrithm of the percentage of compound surplus, and according to following
Formula calculates t1/2And CLint, wherein V/M is i.e. equal to 1/ albumen concentration.
Metabolic stability experimental result is as shown in table 2 below：
Metabolic stability in 2 rat liver microsomes of table
| Compound | T1/2(min) | Rate elongation |
| Darprodustat | 267.2 | -- |
| T-1 | 315.1 | 17.9% |
| T-3 | 479.8 | 79.5% |
| T-4 | 449 | 68.0% |
| T-5 | 1151.2 | 330.8% |
| T-6 | 483.5 | 80.9% |
| T-7 | 485.7 | 81.7% |
Should the experimental results showed that, the compound of the present invention can be obviously prolonged half-life period compared with original grinds medicine Daprodustat,
It is metabolized more stable, especially compound T-3 to compound T-7, Increased Plasma Half-life 60% or more.
(4) Pharmacokinetic Evaluation in rat.
6 male Sprague-Dawley rats, 7-8 week old, weight about 210g are divided into 2 groups, every group 3, through vein or
The compound (through vein 3mg/kg, taking orally 10mg/kg) of oral single dosage, compares its pharmacokinetic difference.
Rat is raised using standard feed, gives water.Experiment is fasted for first 16 hours.Drug is sub- with PEG400 and diformazan
Sulfone dissolves.Eye socket is taken a blood sample, and time point of blood sampling is 0.083 hour after administration, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4
Hour, 6 hours, 8 hours, 12 hours and 24 hours.
Rat sucks of short duration anesthesia after ether, and eye socket acquires 300 μ L sample of blood in test tube.There are 30 μ L1% heparinates in test tube
Solution.Before use, test tube is stayed overnight in 60 DEG C of drying.After being completed with the latter time point blood specimen collection, rat etherization
After put to death.
After blood specimen collection, test tube is leniently overturned immediately to 5 times, is positioned on ice after ensureing mixing fully.Blood sample is at 4 DEG C
5000rpm is centrifuged 5 minutes, and blood plasma is detached with red blood cell.100 μ L blood plasma are sucked out to clean plastic centrifuge tube with pipettor
In, show title and the time point of compound.Blood plasma is stored in -80 DEG C before being analyzed.It is measured in blood plasma with LC-MS/MS
The concentration of the compounds of this invention.Pharmacokinetic parameter is based on every animal blood concentration in different time points into calculating.
The experimental results showed that relative to control compound AKB-6548, the compounds of this invention has more preferable in animal body
Pharmacokinetics, thus have better pharmacodynamics and therapeutic effect.
It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention, in embodiment not
The experimental method of actual conditions is indicated, usually according to normal condition, or according to the normal condition proposed by manufacturer.Unless in addition saying
Bright, otherwise parts and percentages are parts by weight and weight percent.
The above content is a further detailed description of the present invention in conjunction with specific preferred embodiments, and it cannot be said that
The specific implementation of the present invention is confined to these explanations.For those of ordinary skill in the art to which the present invention belongs, exist
Under the premise of not departing from present inventive concept, a number of simple deductions or replacements can also be made, all shall be regarded as belonging to the present invention's
Protection domain.
Claims (7)
1. a kind of substituted pyrimidine trione compound, it is characterised in that：The pyrimidine trione compound as shown in formula (I) or its crystalline substance
Type, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate or solvated compounds,
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、
R23、R24、R25It is each independently hydrogen, deuterium, halogen or trifluoromethyl；
Additional conditions are R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、
R21、R22、R23、R24And R25In it is at least one be deuterated or deuterium.
2. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that：R24And R25It is respectively independent
Ground is deuterium or hydrogen.
3. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that：R1、R2、R3、R4、R5、
R6、R7、R8、R9、R10And R11It is each independently deuterium or hydrogen.
4. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that：R12、R13、R14、R15、
R16、R17、R18、R19、R20、R21And R22It is each independently deuterium or hydrogen.
5. compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that：The compound is selected from
The following group compound：
6. a kind of pharmaceutical composition, it is characterised in that：It contains pharmaceutically acceptable carrier and as Claims 1 to 5 is arbitrary
It is substituted pyrimidine trione compound or its crystal form, pharmaceutically acceptable salt, hydrate or solvate described in one, vertical
The pharmaceutical composition of body isomers, prodrug or isotopic variations.
7. a kind of compound as described in claim 1 or its crystal form, pharmaceutically acceptable salt, hydrate or solvent chemical combination
The purposes of object, it is characterised in that：It is related to prepare prevention and treatment study on anemia of chronic disease, poor glucose tolerance and/or nephrosis
Purposes in anaemia and anemia of cancer or haemocyte associated disease drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010484114.3A CN111518038B (en) | 2017-05-26 | 2018-05-22 | Substituted pyrimidinetrione compound, composition containing same and application thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2017103833400 | 2017-05-26 | ||
| CN201710383340 | 2017-05-26 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010484114.3A Division CN111518038B (en) | 2017-05-26 | 2018-05-22 | Substituted pyrimidinetrione compound, composition containing same and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108623528A true CN108623528A (en) | 2018-10-09 |
| CN108623528B CN108623528B (en) | 2020-07-07 |
Family
ID=63694018
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010484114.3A Active CN111518038B (en) | 2017-05-26 | 2018-05-22 | Substituted pyrimidinetrione compound, composition containing same and application thereof |
| CN201810494949.XA Active CN108623528B (en) | 2017-05-26 | 2018-05-22 | Substituted pyrimidinetrione compound, composition containing same and application thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010484114.3A Active CN111518038B (en) | 2017-05-26 | 2018-05-22 | Substituted pyrimidinetrione compound, composition containing same and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN111518038B (en) |
| WO (1) | WO2018214872A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT202200008693A1 (en) * | 2022-04-29 | 2023-10-29 | Dipharma Francis Srl | METHOD FOR THE PREPARATION AND PURIFICATION OF AN AGENT FOR THE TREATMENT OF ANEMIA |
| IT202100020609A1 (en) * | 2021-07-30 | 2023-01-30 | Dipharma Francis Srl | METHOD OF PREPARATION OF AGENT SUITABLE FOR THE TREATMENT OF ANEMIA |
| WO2023006986A1 (en) * | 2021-07-30 | 2023-02-02 | Dipharma Francis S.R.L. | Method for preparing and purifying an agent suitable for treating anemia |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101505752A (en) * | 2006-06-23 | 2009-08-12 | 史密丝克莱恩比彻姆公司 | Prolyl hydroxylase inhibitors |
| CN105377251A (en) * | 2013-03-01 | 2016-03-02 | 马特医疗研究中心有限公司 | Mobilizing agents and uses therefor |
-
2018
- 2018-05-22 CN CN202010484114.3A patent/CN111518038B/en active Active
- 2018-05-22 CN CN201810494949.XA patent/CN108623528B/en active Active
- 2018-05-22 WO PCT/CN2018/087821 patent/WO2018214872A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101505752A (en) * | 2006-06-23 | 2009-08-12 | 史密丝克莱恩比彻姆公司 | Prolyl hydroxylase inhibitors |
| CN105377251A (en) * | 2013-03-01 | 2016-03-02 | 马特医疗研究中心有限公司 | Mobilizing agents and uses therefor |
Non-Patent Citations (2)
| Title |
|---|
| BRENDAN M. JOHNSON ET AL.: "Effect of Food and Gemfibrozil on the Pharmacokinetics of the Novel Prolyl Hydroxylase Inhibitor GSK1278863", 《CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT》 * |
| SIMON BEUCK ET AL.: "Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis", 《DRUG TESTING AND ANALYSIS》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108623528B (en) | 2020-07-07 |
| CN111518038A (en) | 2020-08-11 |
| WO2018214872A1 (en) | 2018-11-29 |
| CN111518038B (en) | 2022-04-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106083720B (en) | A kind of substituted heteroaryl compound and the composition and application thereof comprising the compound | |
| CN105793253A (en) | Autotaxin inhibitor compounds | |
| CN105518008B (en) | Amino pyrans ring derivatives and combinations thereof and application | |
| CA2673038A1 (en) | Substituted tricyclic heteroaryl compounds as janus kinase inhibitors | |
| US10231973B2 (en) | Salts of quinazoline derivative and method for preparing the same | |
| CN108623528A (en) | A kind of substituted pyrimidine trione compound and the composition and application thereof comprising the compound | |
| CN110092779B (en) | Substituted phenyl compound and application thereof | |
| CN101951776A (en) | Tetrahydro-1H-pyrrolo fused pyridones | |
| CN105985357A (en) | Substituted six-component saturated heteroalicyclic long-acting DPP-IV inhibitor | |
| BR112021015544A2 (en) | 1-((2-(2,2,2-TRIFLUOROETOXY)PYRIDIN-4-YL)METHYL)UREA DERIVATIVES AS KCNQ POTENTIALS | |
| JP2020527535A (en) | How to Make and Use PDE9 Inhibitors | |
| JP2022533879A (en) | Use of phosphodiesterase inhibitors | |
| CN102887889B (en) | Heterocyclic substitute dpyrimidines | |
| CN105367565B (en) | Piperazine (pyridine) cyclohexyl derivatives and its application for treating Mental disease | |
| AU2019311121B2 (en) | Fused ring derivative used as FGFR4 inhibitor | |
| CN103360342B (en) | 3-cyano-aniline alkylaryl bridged piperazine derivatives and preparing the application in medicine | |
| JP4464560B2 (en) | Substituted isoindolones and their use as cyclic GMP modulators in medicine | |
| CN106866652A (en) | Bit derivant of jamaicin 12 with insulin-sensitizing activity and preparation method thereof | |
| CN108401429A (en) | A kind of substituted heteroaryl amide compounds and the composition and application thereof comprising the compound | |
| WO2019233366A1 (en) | Selective a2a receptor antagonist | |
| CN106279136B (en) | Compound and its application for treating central nervous system degenerative disease or brain tumor | |
| JP7261349B2 (en) | Pyrimidine-5-carboxamide compound | |
| CN117343064B (en) | Preparation and application of pyrimidine derivative with antiviral effect | |
| CN102757444A (en) | Benzofuran compound with nitrous oxide donor property | |
| WO2023174235A1 (en) | Mutant idh1 and idh2 inhibitor and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |