CN108401429A - A kind of substituted heteroaryl amide compounds and the composition and application thereof comprising the compound - Google Patents

A kind of substituted heteroaryl amide compounds and the composition and application thereof comprising the compound Download PDF

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CN108401429A
CN108401429A CN201780004842.6A CN201780004842A CN108401429A CN 108401429 A CN108401429 A CN 108401429A CN 201780004842 A CN201780004842 A CN 201780004842A CN 108401429 A CN108401429 A CN 108401429A
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chlorphenyl
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organic layer
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王义汉
任兴业
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Shenzhen Targetrx Inc
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

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Abstract

A kind of composition and application thereof the present invention provides substituted heteroaryl amide compounds and comprising the compound, the invention discloses such as formulas（I）Shown in heteroaryl amide compounds or its crystal form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate or solvated compounds.Heteroaryl amide compounds of the present invention and 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

A kind of substituted heteroaryl amide compounds and the composition comprising the compound and application thereof Technical field
The invention belongs to pharmaceutical technology fields, more particularly to a kind of substituted heteroaryl amide compounds and the composition comprising the compound, and the stability of hypoxia inducible factor (HIF) subunit can be adjusted and increase the method and compound of external and internal endogenous erythropoietin.
Background technique
Hypoxia inducible factor (HIF) is a kind of basic helix-loop-helix (bHLH) PAS (Per/Arnt/Sim) transcription activation factor, regulates and controls the change of the gene expression changed with cell oxygen concentration.HIF is a kind of heterodimer that alpha subunit (HIF α) and a constructive expression β subunit (HIF β) are adjusted containing an oxygen, also referred to as aryl hydrocarbon receptor importin (ARNT).It is closed in (normal oxygen) cell in oxygen, HIF alpha subunit is degraded rapidly by being related to the mechanism that retinal angiomatous inhibits albumen (pVHL) E3 connection multienzyme complex ubiquitination.Under anoxic conditions, HIF α is non-degradable, and the expression of several genes, including glycolytic ferment, glucose transporter (GLUT) -1, hematopoietin (EPO) and vascular endothelial growth factor (VEGF) are accumulated in nucleus and activated to a kind of activity HIF α/β compound.(Maxwell et al., naturally, 1999,399,271-275).
Hematopoietin (EPO) is the hormone of a kind of naturally occurring that generates, generation of the stimulation delivery oxygen through the red blood cell of whole body with HIF α.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 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 1,005,000,000 death every year and is 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, constitutes the disease incidence every about 300 people in 100,000 people.On the other hand, estimation has 5,000,000 Americans to suffer from Venous Thrombosis, and about 600 every year, and 000 these cases lead to pulmonary embolism.The Pulmonary Embolism Patients of about one third are finally dead, so that pulmonary embolism becomes the third most common reason of American deaths.
Currently, the treatment of ischaemic and anoxic illness concentrates in the mitigation of symptom and the treatment of pathogenic disorders.For example, the treatment of myocardial infarction includes the nitroglycerin and antalgesic to control pain and mitigation heart working load.Use other medicines, stablize the patient's condition including digoxin (digoxin), diuretics, amrinone (amrinone), beta blocker, lipid lowering agent and angiotensin converting enzyme inhibitor, but no one of these therapies can be done directly on by the tissue damage of ischaemic and anoxic generation.
Due to the deficiency in Current therapeutic and in production and use recombinant epo, so still needing effectively to treat the compound of following disease: hematopoietin related conditions, such as anaemia, including anaemia relevant to diabetes, anaemia, ulcer, kidney failure, cancer, infection, dialysis, operation and chemotherapy and it is related to the patient's condition of ischaemic and anoxic, such as arterial occlusive disease, angina pectoris, intestinal obstruction, lung infraction, cerebral ischaemia and myocardial infarction.It is also required to effectively prevent the compound of the tissue damage as caused by ischaemic, the ischaemic occurs due to such as lung conditions of atherosclerosis, diabetes and such as pulmonary embolism and its similar conditions.In short, needing to adjust HIF and/or endogenous erythropoietin in the art, and it can be used for treating and preventing the method and compound of HIF correlation and EPO associated disease, the illness includes being related to the patient's condition of anaemia, ischaemic and anoxic.
Summary of the invention
Against the above technical problems, the invention discloses a kind of compound and comprising the composition of the compound, it can be used for adjusting hypoxia inducible factor (HIF) and/or endogenous erythropoietin (EPO) and/or there is more preferable pharmacodynamics/pharmacokinetics performance.
In this regard, the technical solution adopted by the present invention are as follows:
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 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 salt, hydrate or solvated compounds are provided.
Wherein, R1、R2、R3、R4、R5、R6、R7、R8It is each independently hydrogen, deuterium, halogen；
Additional conditions are R1、R2、R3、R4、R5、R6、R7And R8In at least one be deuterated or deuterium.
In another preferred example, R1And R2It is each independently deuterium or hydrogen.
In another preferred example, R1、R2It is deuterium.
In another preferred example, R3And R4It is each independently deuterium or hydrogen.
In another preferred example, R5、R6、R7、R8It is each independently deuterium or hydrogen.
In another preferred example, the compound can be selected from the following group compound or its pharmaceutically acceptable salt, but be not limited to following compound:
In another preferred example, deuterium isotopic content of the deuterium in deuterated position is at least greater than natural deuterium isotopic content (0.015%), is preferably greater than 30%, even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, even more preferably greater than 99%.
Specifically, R in the present invention1、R2、R3、R4、R5、R6、R7And R8Deuterium isotopic content is at least 5% in each deuterated position, it 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%, more preferably Ground is 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、R7And R8, at least one of which R containing deuterium, more preferably two R contain deuterium, and more preferably three R contain deuterium, and more preferably four R contain deuterium, and more preferably five R contain deuterium, and more preferably six R contain deuterium containing deuterium, more preferably seven R, and more preferably eight R contain deuterium.
In another preferred example, the compound does not include non-deuterated compound.
In the second aspect of the present invention, provide a kind of method for preparing pharmaceutical composition, comprising steps of by compound described in pharmaceutically acceptable carrier and first aspect present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate are mixed, to form pharmaceutical composition.
In the third aspect of the invention, a kind of pharmaceutical composition is provided, it contains compound described in pharmaceutically acceptable carrier and 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 is not limited to any glidant, sweetener, diluent, preservative, dyestuff/colorant, flavoring reinforcing agent, surfactant, wetting agent, dispersing agent, disintegrating agent, suspending agent, 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, pulvis, granule, paste, emulsion, suspending agent, solution, suppository, injection, inhalant, gelling agent, microballoon and aerosol.
The classical pathway for giving pharmaceutical composition of the present invention includes but is not limited to oral, rectum, saturating mucous membrane, through enteral administration, or part, percutaneous, sucking, parenteral, sublingual, intravaginal, it is intranasal, intraocularly, peritonaeum is interior, intramuscular, subcutaneous, intravenous administration.It is preferred that oral administration or drug administration by injection.
Pharmaceutical composition of the invention can be manufactured using method well known in the art, such as conventional mixing method, dissolution method, granulation, dragee method processed, levigate method, emulsion process, freeze-drying.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and it can be combined with each other between each technical characteristic specifically described in below (e.g. embodiment), to form a new or preferred technical solution.Due to space limitations, I will not repeat them here.
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 hydrogen in compound or group replaced deuterium；It is deuterated to can be a substitution, two replace, polysubstituted or full substitution.Term " one or more deuterated " is used interchangeably with " one or many deuterated ".
Herein, unless otherwise instructed, " non-deuterated compound " refers to that ratio containing D-atom is not higher than the compound of natural deuterium isotopic content (0.015%).
The invention also includes the compounds of isotope labelling, are equal to original chemical and are disclosed.It is same the compound of the present invention can be classified as The example of position element 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 or enantiomer in the present invention, diastereomer, isomers or pharmaceutically acceptable salt or solvate, wherein being within the scope of the present invention containing the isotope of above compound or other other isotope atoms.Certain compound isotopically labelleds in the present invention, such as3H and14The radioactive isotope of C is also useful in the experiment of the Tissue distribution of drug and substrate wherein.Tritium, i.e.,3H and carbon-14, i.e.,14C, their preparation and detection are easier, and are the first choices in isotope.The compound of isotope labelling can use general method that can be prepared by replacing with non isotopic reagent with the isotope labeling reagent being easy to get with the scheme in example.
Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the salt that the compounds of this invention and acid are formed.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；The organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, naphthalene sulfonic acids；And the amino acid such as proline, phenylalanine, aspartic acid, glutamic acid.Another kind of preferred salt is the salt that the compounds of this invention and alkali are formed, 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, diethyl amine salt, triethyl amine salt, tert-butylamine salt, ethylenediamine salt, oxyethylamine salt, dihydroxy ethylamine salt, three oxyethylamine salt, and the amine salt formed respectively by morpholine, piperazine, lysine.
Term " solvate " refers to that the compounds of this invention and solvent molecule are coordinated the complex to form special ratios." hydrate " refers to that the compounds of this invention and water carry out the complex of coordination formation.
The present invention provides the method for adjusting HIF and/or EPO, stablizes HIF by inhibiting HIF α hydroxylating and activates the expression of HIF controlling gene.The method can also be applied to prevention, in advance treatment or treatment HIF and/or EPO related conditions, including 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 ischaemic, kidney ischaemic and apoplexy；Peripheral vascular disorders, ulcer, burn and chronic wounds；Pulmonary embolism；And ischemia reperfusion injury, including ischemia reperfusion injury for example relevant to operation and 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 compound described herein.In one embodiment, when administering 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 significantly improve cardiac structure and performance.On the other hand, when administering after hepatogenotoxicity-ischemic injury, method of the invention improves liver function.Anoxic is an important component of liver diseases, especially in hepatotoxic compound, such as the related chronic liver disease of ethyl alcohol.Additionally, it is known that by HIF α The gene expression of induction increases in alcoholic liver disease, such as nitric oxide synthetase and glucose transporter-1.
Therefore, the present invention provides the method for the treatment of ischaemic or anoxic related conditions, and the method includes that the compound of therapeutically effective amount or its pharmaceutically acceptable salt is independent or administers subject with pharmaceutically acceptable excipient composition.In one embodiment, the compound, such as myocardial infarction, pulmonary embolism, intestinal obstruction, ishemic stroke and Renal Ischemia Reperfusion Injury are administered immediately after the patient's condition for generating ischaemic.In another embodiment, compound administering is diagnosed as to the patient of the relevant patient's condition of generation to Chronic ischemia, such as cardiac cirrhosis, macular degeneration, pulmonary embolism, acute respiratory failure, congenital alveolar dysplasia and congestive heart failure.
Another aspect of the present invention provides the method for having the patient that ischaemic or anoxic patient's condition danger occurs using compound described herein treatment, 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 provides the method for prevention ischemic tissue damage, and the method includes the patient for individually or with the administering of pharmaceutically acceptable excipient composition needing the compound of therapeutically effective amount or its pharmaceutically acceptable salt.In one embodiment, the compound, such as hypertension, diabetes, arterial occlusive disease, chronic venous insufficiency, Raynaud's disease, chronic ulcer of skin, hardening, congestive heart failure and systemic sclerosis can be administered based on the predisposed patient's condition.
In a particular embodiment, the method is used to increase vascularization in damaged tissues, wound and ulcer and/or granulation tissue is formed.For example, the compound of the present invention have been shown in wound healing can effective stimulus granulation tissue formed.Granulation tissue contains the leakage blood vessel newly formed and interim plasma protein matrix, such as fibrinogen and plasma fibronectin.Migration and proliferation of release the stimulation fibroblast and endothelial cell of growth factor from inflammatory cell, blood platelet and activation endothelium in granulation tissue.If vascularization or nerve stimulation weaken, ulcer can occur.Method of the invention effectively facilitates the formation of granulation tissue.Thus, the present invention is provided to treat with the tissue damage as caused by for example blocking, the method with the wound by such as wound or wound inducement or the patient with the chronic wounds or ulcer that are generated due to certain illness (such as diabetes).The method includes the patient for individually or with the administering of pharmaceutically acceptable excipient composition needing the compound of therapeutically effective amount or its pharmaceutically acceptable salt.
The another aspect of invention is provided treats subject using the compound to reduce or prevent the method that tissue damage relevant to ischaemic or anoxic occurs in advance.When administering immediately before being related to the patient's condition of ischaemic or anoxic, method of the invention generates treatment benefit.For example, showing that cardiac structure and performance are statistically had the improvement of significant meaning using method of the invention before induced myocardial infarction.On the other hand, when before ischemia reperfusion injury and between administer immediately when, method of the invention generates treatment benefit, substantially reduces Diagnostic parameters relevant to kidney failure.
Therefore, the present invention provides method of the treatment subject to reduce or prevent tissue damage relevant to ischaemic or anoxic in advance, the method include by the compound of therapeutically effective amount or its pharmaceutically acceptable salt individually or with pharmaceutically acceptable excipient composition Administer the patient with ischemic conditions medical history, such as myocardial infarction, or the patient with approaching ischemic conditions, such as angina pectoris.In another embodiment, can based on imply may the physical parameter of ischaemic administer the compound, such as the individual under general anesthesia or temporarily working under High aititude.In another embodiment, the compound can be used in organ transplant, to preparatory treating organs donor or before being implanted into receptor, to the organ for maintaining to remove from body.
Previous research are it has been shown that the certain compounds used in the method for the invention are effective inhibitor of procollagen prolyl 4 hydroxylase.Although it is recognized that initially the recovery of infraction or wound needs connective tissue to deposit in necrotic zone, but present invention demonstrates that the treatment for cicatrization is without side-effects.Thus, oxygen-starved tissue's damage and provided benefit in fibrosis are being treated and prevented based on certain compounds of the invention, the present invention covers a kind of treat or prevent and is related to " double treatment " method of ischaemic or the anoxic patient's condition, including ischaemic relevant to concurrent reaction fibrosis or anoxic, such as myocardial infarction and the following congestive heart failure.A kind of compound can be used in the method, inhibits more than one 2-oxoglutaric acid dioxygenases with phase homospecificity or non-homospecificity, such as HIF prolyl hydroxylase and procollagen prolyl 4 hydroxylase.Alternatively, the combination of compound can be used in the method, wherein each compound specifically inhibits a kind of only 2-oxoglutaric acid dioxygenase, such as a kind of compound specifically inhibits HIF prolyl hydroxylase and second of compound specifically inhibits procollagen prolyl 4 hydroxylase.
In one aspect, the compound of the present invention inhibits one or more kinds of 2-oxoglutaric acid dioxygenases.In one embodiment, the compound inhibits at least two 2-oxoglutaric acid dioxygenase family members with phase homospecificity or non-homospecificity, such as HIF prolyl hydroxylase and HIF asparagine-hydroxylase (FIH-1).In another embodiment, the compound has specificity, such as HIF prolyl hydroxylase for a kind of 2-oxoglutaric acid dioxygenase, and shows seldom specificity for other family members or do not show specificity.
The compound can combine administering with a variety of other treatment methods.In one embodiment, the compound and another 2-oxoglutaric acid dioxygenase inhibitor administer together, and wherein both compounds have different specificity for a other 2-oxoglutaric acid dioxygenase family member.Described two compounds can be administered simultaneously with a ratio relative to another.For the measurement suitable for given therapeutic process or the ratio of particular subject within the technical level in the field.Alternatively, described two compounds can continuously administer in treatment time-histories, such as after myocardial infarction.In a particular embodiment, a kind of compound specifically inhibits the activity of HIF prolyl hydroxylase, and second of compound specifically inhibits the activity of procollagen prolyl 4 hydroxylase.In another particular embodiment, a kind of compound specifically inhibits the activity of HIF prolyl hydroxylase, and second of compound specifically inhibits the activity of HIF asparaginyl-hydroxylase enzyme.In another embodiment, the compound administers together with another therapeutic agent with different role mode, 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, such as in blood plasma, or apply in vitro, such as in the cell culture medium through adjusting.The present invention further provides the sides for increasing endogenous EPO content EPO related conditions, including the patient's condition for example relevant to anaemia and nerve problems are treated or treated in advance to method to prevent,.Anaemia related conditions include the illness such as acute or chronic kidney trouble, diabetes, cancer, ulcer, virus infection (such as HIV, bacterium or helminth), inflammation.The anaemia patient's condition can further comprise including such as radiotherapy, chemotherapy, dialysis and operation with program or the treatment-related patient's condition, described program or treatment.Anaemia associated disease also comprises abnormal hemoglobin and/or red blood cell, such as is found in such as microcytic anemia, hypochromic anemia, in alpastic anemia illness.
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 anaemia or the non-Anemic patients of the infected by HIV Anemic patients just treated with retrovir (Zidovudine) or other reverse transcriptase inhibitor, the anemic cancer patient or plan experience operation that receive neoplatin containing ring or the cyclic chemical therapy without neoplatin.The method for increasing endogenous EPO can also be used for prevention, in advance treatment or treatment EPO related conditions relevant to neuronal damage or nerve fiber degeneration, including but not limited to apoplexy, wound, epilepsy, spinal cord injury and neurodegenerative disorders.
In addition, anaemia or the endogenous EPO content in non-Anemic patients that the method can be used for increasing plan experience operation, to reduce to the needs of external source blood transfusion or with the storage in order to operation consent blood.A small amount of reduction not erythropoietic increase of stimulation of endogenous EPO or compensatory of the blood hematocrit occurred after usual blood supply self before surgery.However, the operation consent stimulation of endogenous EPO will effectively increase mass of red blood cells and self blood supply volume, while higher hematocrit levels are maintained, and the method specificity covers in this article.In some operation crowds, especially operation blood loss is more than 2 liters of individual, can be exposed to the open air using method of the invention to reduce heterologous blood.
Method of the invention can also be used for enhancing movenent performance, improve exercising ability and promotion or the aerobic adjusting of enhancing.For example, the method can be used to promote trained and soldier to can be used the method to improve such as endurance and endurance in sportsman.
The endogenous erythropoietin content in the culture medium that can increase external treatment culture cell and in the animal blood plasma of interior therapeutic has been displayed in method of the invention.Although kidney is the main source of internal hematopoietin, once appropriate stimulation, other organs, including brain, liver and marrow can and can really synthesize hematopoietin.The expression of endogenous erythropoietin in multiple organs, including brain, kidney and liver can be increased using method of the invention.In fact, method of the invention even increases the content of the endogenous erythropoietin in the double animals for surveying nephrectomy of experience.
Even if method of the invention is proved when kidney function damage, the content of hematopoietin can also be increased.Although the present invention is not limited by the mechanism that hematopoietin generates, usually the reduction of visible hematopoietin secretion is attributable to the hyperoxia caused by flowing in nephridial tissue/perfusion increases during kidney failure.
On the other hand, method of the invention increases hematocrit and haemoglobin blood level in the animal of interior therapeutic.The increase of the blood plasma EPO, hematocrit and the blood-hemoglobin that generate as compound uses in the method for the invention has dosage susceptibility, however can determine dosage to generate the level of response of constant, controllable the compounds of this invention.On the other hand, using chemical combination of the present invention The treatment of object can cure anaemia, such as by toxic chemical, such as the anaemia of chemotherapeutant neoplatin induction, or the anaemia due to caused by blood loss, such as wound, damage, helminth or operation.
It is the increase that immature erythrocyte (granulophilocyte) percentage is recycled in blood before hematocrit and blood-hemoglobin increase in animal with the compound of the present invention treatment.Thus, the present invention covers the purposes in method (if Pelham and Jackson is described in " european journal of biological chemistry " (Eur.J.Biochem.) 67:247-256 (1976)) of the content of the compounds of this invention granulophilocyte in increasing animal blood to generate cell-free reticulocyte lysate.By being used individually with the compound of the present invention or being treated in combination with another compound, such as acetylphenylhydrazine etc., the content increase of circulation granulophilocyte in animal (such as rabbit etc.).
Compared with prior art, the invention has the benefit that the compounds of this invention can be used for adjusting hypoxia inducible factor (HIF) and/or endogenous erythropoietin (EPO).Change metabolism of the compound in organism by this technology of deuterate, makes compound that there is better pharmacokinetic parameter characteristic.In such a case, it is possible to change dosage and form durative action preparation, improve applicability.The drug concentration of compound in animal body can be improved, to improve curative effect of medication due to its deuterium isotope effect with the hydrogen atom in deuterium substituted compound.The safety of compound may be improved since certain metabolites are suppressed with the hydrogen atom in deuterium substituted compound.
Specific embodiment
The preparation method of formula I structural compounds is described more particularly below, but these specific methods do not form any restrictions to the present invention.Various synthetic methods describing in the present specification or known in the art can also optionally be combined and are easily made by the compounds of this invention, and such combination can be easy to carry out by those skilled in the art in the invention.
In general, each reaction carries out under room temperature to reflux temperature (such as 0 DEG C~100 DEG C, preferably 0 DEG C~80 DEG C) usually in atent solvent in preparation flow.Reaction time is usually -60 hours 0.1 hour, preferably 0.5-24 hours.
Prepare intermediate 5- (3- chlorphenyl) -3- hydroxy-picolinic acid (compound 5):
The synthesis of the chloro- 5- of step 1:3- (3- chlorphenyl) cyanopyridine (compound 3).
By anhydrous N under nitrogen protection; dinethylformamide (DMF; 20mL) and water (2mL) is added to (3- chlorphenyl) boric acid (compound 1; 2.00g; 12.80mmol) and 3; 5- dichloro cyanopyridine (compound 2,2.40g, 14.10mmol), potassium carbonate (2.20 G, 15.94mmol) and PdCl2(dppf) in the mixture of (100mg), under nitrogen protection, 45 DEG C are stirred to react overnight for reaction.It is cooled to room temperature, add water (50mL) quenching reaction, it is extracted with ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure, concentrate carries out post separation, obtains 2.50g white solid, yield: 78.8%.LC-MS (APCI): m/z=249.1 (M+1).
The synthesis of step 2:5- (3- chlorphenyl) -3- methoxyl group cyanopyridine (compound 4).
At room temperature; sodium methoxide (3.45g, 6.39mmol) is added to the chloro- 5- of 3- (3- chlorphenyl) cyanopyridine (compound 3,2.50g under nitrogen protection; in the solution of anhydrous methanol (50mL) 10.00mmol), reaction return stirring is stayed overnight.It is cooled to room temperature, reaction solution is removed under reduced pressure, add water (50mL) quenching reaction, extracted with ethyl acetate (50mL x 3), merges organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, 1.05g white solid is obtained, yield: 43.0%.LC-MS (APCI): m/z=245.1 (M+1).
The synthesis of step 3:5- (3- chlorphenyl) -3- hydroxy-picolinic acid (compound 5).
At room temperature, 48% hydrobromic acid (10mL) is added in 5- (3- chlorphenyl) -3- methoxyl group cyanopyridine (compound 4,1.05g, 4.30mmol), under nitrogen protection, 100 DEG C are stirred to react overnight for reaction.It is cooled to room temperature.It is about 2 with 50% sodium hydroxide solution tune pH value under ice bath, continues stirring 1 hour, there are a large amount of white solids to be precipitated, filter cake is washed with water in filtering, and vacuum drying obtains 1.05g pale solid, yield: 99%.LC-MS (APCI): m/z=250.0 (M+1).
Embodiment 1 prepares (5- (3- chlorphenyl) -3- pyridone formoxyl) glycine -2,2-d2(compound 9)
Step 1: glycine methyl ester -2,2-d2The synthesis of hydrochloride (compound 7).
Under ice bath, thionyl chloride (0.58mL, 7.50mmol) is slowly dropped to glycine-d5In anhydrous methanol (6.5mL) solution of (500mg, 6.25mmol).After being added dropwise, reaction solution, which is warming up at 65 DEG C, to react 4 hours.It is concentrated under reduced pressure to give 750mg white solid, is directly used in next step.LC-MS (APCI): m/z=91.0 (M+1)；1H NMR(500MHz,DMSO-d6)δ3.71(s,3H)。
Step 2:(5- (3- chlorphenyl) -3- pyridone formoxyl) glycine methyl ester -2,2-d2The synthesis of (compound 8).
Under ice bath, by n,N-diisopropylethylamine (DIPEA, 777mg, 6.02mmol), I-hydroxybenzotriazole (HOBT, 407mg, 3.01mmol), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine (EDCI, 577mg, 3.01mmol) point It is not added in the solution of the anhydrous n,N-Dimethylformamide (20mL) of 5- (3- chlorphenyl) -3- hydroxy-picolinic acid (compound 5,500mg, 2.01mmol), after stirred under nitrogen reacts 15 minutes.Glycine methyl ester -2,2-d is added2Hydrochloride (390mg, 3.01mmol), is warming up to room temperature, and reaction 2 days is stirred at room temperature in reaction.Add water (50mL) quenching reaction, it is extracted with ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, 310mg white solid is obtained, yield: 45.8%.LC-MS (APCI): m/z=323.1 (M+1).
Step 3:(5- (3- chlorphenyl) -3- pyridone formoxyl) glycine -2,2-d2The synthesis of (compound 9).
At room temperature, by deuterium sodium oxide molybdena (2.89mL, 1M in D2O) it is added to (5- (3- chlorphenyl) -3- pyridone formoxyl) glycine methyl ester -2,2-d2In tetrahydrofuran (5mL) solution of (310mg, 0.96mmol), reaction is stirred to react 2 hours.Tetrahydrofuran is removed under reduced pressure, pH is adjusted to 2 or so with the dilute hydrochloric acid of 1N, ethyl acetate (30mL x 3) extraction.Merge organic layer, with saturated common salt water washing (30mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, obtains 245mg faint yellow solid, yield: 82.6%.LC-MS (APCI): m/z=309.0；1H NMR(500MHz,DMSO-d6) NMR (500MHz, DMSO-9.0 (M+1), obtaining bright compound can also optionally combine various synthetic methods describing in the present specification or known in the art and easily be made, and such combination can be by those skilled in the art in the invention easily.
Embodiment 2 prepares (5- (3- chlorphenyl) -3- pyridone formoxyl -6-d) glycine (compound 14)
The synthesis of step 1:2- carboxyl -5- (3- chlorphenyl) -3- pyridone -1- oxide (compound 10).
Under ice bath, by trifluoro-acetic anhydride (2mL, 14.38mmol) it is added to the adduct (1.44g of urea-hydrogen peroxide, 15.31mmol) and in anhydrous acetonitrile (22mL) solution of 5- (3- chlorphenyl) -3- hydroxy-picolinic acid (1.80g, 7.23mmol).Reaction solution reacts 6 hours under ice bath.Acetonitrile is removed under reduced pressure, with the sodium thiosulfate quenching reaction of saturation, stirs 10 minutes, with dilute hydrochloric acid by system pH to being adjusted to 2 or so, filtering, water washing, vacuum drying obtains 750mg white solid.LC-MS (APCI): m/z=220 (M-COOH).
The synthesis of step 2:2- carboxyl -5- (3- chlorphenyl) -3- pyridone -1- oxide -6-d (compound 11).
At room temperature, by deuterium sodium oxide molybdena (8mL, 40%in D2O) it is added drop-wise to the D of 2- carboxyl -5- (3- chlorphenyl) -3- pyridone -1- oxide (1.80g, 6.77mmol)2In O (30mL) mixture, reaction is reacted overnight at 100 DEG C.It is cooled to room temperature, with the dilute hydrochloric acid tune pH value of 2M to 2 or so, there are a large amount of white solids to be precipitated, filter cake is washed with water in filtering, and vacuum drying obtains 1.8g white solid, yield: 100%.LC-MS (APCI): m/z=221.1 (M-COOH).
The synthesis of step 3:5- (3- chlorphenyl) -3- hydroxyl -2- ((2- methoxyl group -2- oxygen ethyl) carbamoyl) pyridine -1- oxide -6-d (compound 12).
Under ice bath, by DIPEA (655mg, 5.08mmol), HOBT (343mg, 2.54mmol), EDCI (487mg, 2.54mmol) it is added separately to 2- carboxyl -5- (3- chlorphenyl) -3- pyridone -1- oxide -6-d (450mg, in the solution of anhydrous n,N-Dimethylformamide (10mL) 1.69mmol), after stirred under nitrogen reacts 15min.It is added glycine methyl ester hydrochloride (319mg, 2.54mmol), is warming up to room temperature, reaction 2 days is stirred at room temperature in reaction.Add water (50mL) quenching reaction, it is extracted with ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, 360mg white solid is obtained, yield: 80.1%.LC-MS (APCI): m/z=338.1 (M+1).
Step 4:(5- (3- chlorphenyl) -3- pyridone formoxyl -6-d) glycine methyl ester (compound 13) synthesis.
At room temperature; by phosphorus trichloride (0.56mL; 1.12mmol; 2M in DCM) it is added to 5- (3- chlorphenyl) -3- hydroxyl -2- ((2- methoxyl group -2- oxygen ethyl) carbamoyl) pyridine -1- oxide -6-d (190mg; in the solution of anhydrous methylene chloride (10mL) 0.56mmol), refluxed under nitrogen is stirred to react 2 hours.It is cold to go to room temperature, add water quenching reaction, with the saturated solution of sodium bicarbonate tune pH of saturation to neutrality, is extracted with methylene chloride (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, 70mg white solid is obtained, yield: 38.9%.LC-MS (APCI): m/z=322.1 (M+1).
Step 5:(5- (3- chlorphenyl) -3- pyridone formoxyl -6-d) glycine (compound 14) synthesis.
At room temperature; by sodium hydroxide (0.65mL; it 1M) is added in tetrahydrofuran (5mL) solution of (5- (3- chlorphenyl) -3- pyridone formoxyl -6-d) glycine methyl ester (70mg, 0.22mmol), reaction is stirred to react 2 hours.Tetrahydrofuran is removed under reduced pressure, pH is adjusted to 2 or so with the dilute hydrochloric acid of 1N, ethyl acetate (30mL x 3) extraction.Merge organic layer, with saturated common salt water washing (30mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, obtains 65mg white solid, yield: 95.9%, LC-MS (APCI): m/z=308.0 (M+1)；1H NMR(500MHz,DMSO-d6) δ 12.81 (br, 1H), 12.36 (s, 1H), 9.35 (t, J=6.0Hz, 1H), 7.92 (s, 1H), 7.84-7.71 (m, 2H), 7.62-7.45 (m, 2H), 4.00 (d, J=6.1Hz, 2H).
Embodiment 3 prepares (5- (3- chlorphenyl) -3- pyridone formoxyl -6-d) glycine -2,2-d2(compound 17)
Step 1:5- (3- chlorphenyl) -3- hydroxyl -2- ((2- methoxyl group -2- oxygen ethyl -1,1-d2) carbamoyl) and pyridine -1- oxide -6-d (compound 15) synthesis.
Under ice bath, by DIPEA (191mg, 1.48mmol), HOBT (100mg, 0.74mmol), EDCI (142mg, 0.74mmol) it is added separately to 2- carboxyl -5- (3- chlorphenyl) -3- pyridone -1- oxide 6-d (450mg, in the solution of anhydrous n,N-Dimethylformamide (10mL) 1.69mmol), after stirred under nitrogen reacts 15 minutes.Glycine methyl ester -2,2-d is added2Hydrochloride (70mg, 0.54mmol), be warming up to room temperature, reaction 2 days is stirred at room temperature in reaction.Add water (50mL) quenching reaction, it is extracted with ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, 110mg white solid is obtained, yield: 66.2%.LC-MS (APCI): m/z=340.1 (M+1).
Step 2:(5- (3- chlorphenyl) -3- pyridone formoxyl -6-d) glycine methyl ester -2,2-d2The synthesis of (compound 16).
At room temperature, phosphorus trichloride (0.33mL, 0.65mmol, 2M/DCM) is added to 5- (3- chlorphenyl) -3- hydroxyl -2- ((2- methoxyl group -2- oxygen ethyl -1,1-d2) carbamoyl) and pyridine -1- oxide -6-d (110mg, 0.32mmol) anhydrous methylene chloride (10mL) solution in, refluxed under nitrogen is stirred to react 2 hours.It is cold to go to room temperature, add water quenching reaction, with the saturated solution of sodium bicarbonate tune pH of saturation to neutrality, is extracted with methylene chloride (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, 35mg white solid is obtained, yield: 33.8%.LC-MS (APCI): m/z=324.1 (M+1).
Step 5:(5- (3- chlorphenyl) -3- pyridone formoxyl -6-d) glycine -2,2-d2The synthesis of (compound 17).
At room temperature, by deuterium sodium oxide molybdena (0.33mL, 1M in D2O) it is added to (5- (3- chlorphenyl) -3- pyridone formoxyl -6-d) glycine methyl ester -2,2-d2In tetrahydrofuran (2mL) solution of (35mg, 0.11mmol), reaction is stirred to react 2 hours.Tetrahydrofuran is removed under reduced pressure, pH is adjusted to 2 or so with the dilute hydrochloric acid of 1N, ethyl acetate (30mL x 3) extraction.Merge organic layer, with saturated common salt water washing (30mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, obtains 30mg white solid, yield: 95.9%.LC-MS (APCI): m/z=310.0 (M+1)；1H NMR(500MHz,DMSO-d6)δ12.75(br,1H),12.37(s,1H),9.34(s,1H),7.92(s,1H),7.83-7.72(m,2H),7.61-7.46(m,2H)。
Embodiment 4 prepares (5- (3- chlorphenyl -2,4,6-d3) -3- pyridone formoxyl) glycine (compound 25)
Step 1:3- chlorphenyl -2,4,6-d3The synthesis of ammonia (compound 19).
At room temperature, by DCl (235mg, 37%in D2O it) is added in heavy water (17mL) solution of 3- chloroaniline (800mg, 6.27mmol), 160 DEG C of microwave are reacted 1.5 hours.It is cooled to room temperature, with the sodium bicarbonate solution tune pH of saturation to alkalinity, ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (30mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, 800mg grease is obtained, yield: 100%.LC-MS (APCI): m/z=131.1 (M+1).
Step 2:2- (3- chlorphenyl -2,4,6-d3) -4,4,5,5- tetramethyl -1,3,2- two dislike borine (compound 20) synthesis.
At room temperature, dilute hydrochloric acid (12.5mL, 37.5mmol) and water (12mL) are added sequentially to 3- chlorphenyl -2,4,6-d3In methanol (25mL) solvent of ammonia (12.30mmol, 1.60g).By sodium nitrite (816mg in 6mL H at -10 DEG C2O, 12.40mmol) solution is added drop-wise in reaction solution, reaction reaction stirring 1 hour at -10 DEG C.Then connection boric acid pinacol ester (9.30g is dissolved in 25mL methanol, 37.00mmol) solution is added drop-wise in reaction solution, reaction is reacted 2 hours at 0 DEG C.It is extracted with ethyl acetate (60mL x 3).Merge organic layer, with saturated sodium bicarbonate solution and brine It (30mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, obtains 1.80g colorless oil.
The chloro- 5- of step 3:3- (3- chlorphenyl -2,4,6-d3) cyanopyridine (compound 21) synthesis.
Anhydrous N,N-dimethylformamide (20mL) and water (2mL) are added to 2- (3- chlorphenyl -2,4,6-d under nitrogen protection3) -4,4,5,5- tetramethyls -1,3,2- bis- dislike borine (1.80g, 7.47mmol) and 3,5- dichloro cyanopyridine (1.40g, 8.22mmol), potassium carbonate (1.30g, 9.34mmol) and PdCl2(dppf) in the mixture of (100mg), under nitrogen protection, 45 DEG C are stirred to react overnight for reaction.It is cooled to room temperature, add water (50mL) quenching reaction, it is extracted with ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure, concentrate carries out post separation, obtains 1.10g white solid, yield: 35.5%.LC-MS (APCI): m/z=293.0 (M+1).
Step 4:5- (3- chlorphenyl -2,4,6-d3) -3- methoxyl group cyanopyridine (compound 22) synthesis.
At room temperature, sodium methoxide (1.20g, 22.2mmol) is added to 3- chloro- 5- (3- chlorphenyl 2,4,6-d under nitrogen protection3) cyanopyridine (950mg, 3.77mmol) anhydrous methanol (20mL) solution in, reaction return stirring stay overnight.It is cooled to room temperature, is removed under reduced pressure anti- Answer liquid, add water (50mL) quenching reaction, it is extracted with ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure, concentrate carries out post separation, obtains 565mg white solid, yield: 60.7%.LC-MS (APCI): m/z=248.0 (M+1).
Step 5:5- (3- chlorphenyl -2,4,6-d3) -3- hydroxy-picolinic acid (compound 23) synthesis.
At room temperature, 48% hydrobromic acid (6mL) is added to 5- (3- chlorphenyl -2,4,6-d3) in -3- methoxyl group cyanopyridine (565mg, 2.28mmol), under nitrogen protection, 100 DEG C are stirred to react overnight for reaction.It is cooled to room temperature.It is about 2 with 50% sodium hydroxide solution tune pH value under ice bath, continues stirring 1 hour, there are a large amount of white solids to be precipitated, filter cake is washed with water in filtering, and vacuum drying obtains 525mg pale solid, yield: 91.4%.LC-MS (APCI): m/z=253.0 (M+1).
Step 6:(5- (3- chlorphenyl -2,4,6-d3) -3- pyridone formoxyl) and glycine methyl ester (compound 24) synthesis.
Under ice bath, by DIPEA (307mg, 2.38mmol), HOBT (161mg, 1.19mmol), EDCI (228mg, 1.19mmol) is added separately to 5- (3- chlorphenyl -2,4,6-d3) -3- hydroxy-picolinic acid (200mg, 0.79mmol) anhydrous n,N-Dimethylformamide (20mL) solution in, stirred under nitrogen react 15min after.It is added glycine methyl ester hydrochloride (150mg, 1.19mmol), is warming up to room temperature, reaction 2 days is stirred at room temperature in reaction.Add water (50mL) quenching reaction, it is extracted with ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, 120mg white solid is obtained, yield: 47.0%.LC-MS (APCI): m/z=324.0 (M+1).
Step 7:(5- (3- chlorobenzene -2,4,6-d3) -3- pyridone formoxyl) and glycine (compound 25) synthesis.
At room temperature, sodium hydroxide (1.11mL, 1M) is added to (5- (3- chlorphenyl -2,4,6-d3) -3- pyridone formoxyl) and glycine methyl ester (120mg, 0.37mmol) tetrahydrofuran (6mL) solution in, reaction be stirred to react 2 hours.Tetrahydrofuran is removed under reduced pressure, pH is adjusted to 2 or so with the dilute hydrochloric acid of 1N, ethyl acetate (30mL x 3) extraction.Merge organic layer, with saturated common salt water washing (30mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, obtains 40mg white solid, yield: 35.0%.LC-MS (APCI): m/z=310.0 (M+1)；1H NMR(400MHz,DMSO-d6) δ 12.81 (br, 1H), 12.37 (s, 1H), 9.37 (t, J=6.1Hz, 1H), 8.55 (d, J=1.9Hz, 1H), 7.79 (d, J=1.9Hz, 1H), 7.55 (s, 1H), 4.02 (d, J=6.1Hz, 2H).
Embodiment 5 prepares (5- (3- chlorphenyl -2,4,6-d3) -3- pyridone formoxyl) glycine -2,2-d2(compound 27)
Step 1:(5- (3- chlorphenyl -2,4,6-d3) -3- pyridone formoxyl) glycine methyl ester -2,2-d2The synthesis of (compound 26).
Under ice bath, by DIPEA (500mg, 3.87mmol), HOBT (260mg, 1.93mmol), EDCI (370mg, 1.93mmol) is added separately to 5- (3- chlorphenyl -2,4,6-d3) -3- hydroxy-picolinic acid (324mg, 1.29mmol) anhydrous n,N-Dimethylformamide (20mL) solution in, stirred under nitrogen react 15 minutes after.Glycine methyl ester -2,2-d is added2Hydrochloride (250mg, 1.93mmol), is warming up to room temperature, and reaction 2 days is stirred at room temperature in reaction.Add water (50mL) quenching reaction, it is extracted with ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, 160mg white solid is obtained, yield: 38.3%.LC-MS (APCI): m/z=326.0 (M+1).
Step 2:(5- (3- chlorobenzene -2,4,6-d3) -3- pyridone formoxyl) glycine -2,2-d2The synthesis of (compound 27).
At room temperature, by deuterium sodium oxide molybdena (1.48mL, 1M in D2O) it is added to (5- (3- chlorphenyl -2,4,6-d3) -3- pyridone formoxyl) glycine methyl ester -2,2-d2In tetrahydrofuran (6mL) solution of (160mg, 0.49mmol), reaction is stirred to react 2 hours.Tetrahydrofuran is removed under reduced pressure, pH is adjusted to 2 or so with the dilute hydrochloric acid of 1N, ethyl acetate (30mL x 3) extraction.Merge organic layer, with saturated common salt water washing (30mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, obtains 75mg white solid, yield: 49.2%.LC-MS (APCI): m/z=312.0 (M+1)；1H NMR(400MHz,DMSO-d6) δ 12.81 (s, 1H), 12.38 (s, 1H), 9.36 (s, 1H), 8.55 (d, J=1.9Hz, 1H), 7.78 (d, J=1.9Hz, 1H), 7.55 (s, 1H).
Embodiment 6 prepares (5- (3- chlorphenyl -6-d) -3- pyridone formoxyl) glycine (compound 35)
The synthesis of step 1:3- chlorphenyl -6-d- ammonia (compound 29).
At room temperature, by Pd/C (500mg, 55%in D2O) it is added to the CH of the chloro- 6- bromaniline (3.00g, 14.56mmol) of 3-3In OD (20mL) solution, two drop NaOD (40%in D are added dropwise2O) solution, reaction solution is in D2Lower room temperature reaction is overnight.Diatomite filtering, is concentrated under reduced pressure filtrate, obtains 2.8g yellow solid, yield: 92.5%.LC-MS (APCI): m/z=131.1 (M+1).
Step 2:2- (3- chlorphenyl -6-d) -4,4,5,5- tetramethyl -1,3,2- two dislikes the synthesis of borine (compound 30).
At room temperature, dilute hydrochloric acid (13.6mL, 40.9mmol) and water (13mL) are added sequentially in methanol (27mL) solvent of 3- chlorobenzene -6-d- ammonia (13.40mmol, 2.80g).By sodium nitrite, (890mg is dissolved in 6.5mL H at -10 DEG C2O, 13.50mmol) solution is added drop-wise in reaction solution, reaction reaction stirring 1 hour at -10 DEG C.Then connection boric acid pinacol ester (10.14g is dissolved in 27mL methanol, 40.30mmol) solution is added drop-wise in reaction solution, reaction is reacted 2 hours at 0 DEG C.It is extracted with ethyl acetate (60mL x 3).Merge organic layer, with saturated sodium bicarbonate solution and brine It (30mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, obtains 3.00g colorless oil.
The synthesis of the chloro- 5- of step 3:3- (3- chlorphenyl -6-d) cyanopyridine (compound 31).
By anhydrous N under nitrogen protection; dinethylformamide (20mL) and water (2mL) are added to 2- (3- chlorphenyl -6-d) -4; 4,5,5- tetramethyls -1; 3; 2- bis- dislikes borine (3.00g, 12.6mmol) and 3,5- dichloro cyanopyridine (2.40g; 13.8mmol), potassium carbonate (2.17g, 15.70mmol) and PdCl2(dppf) in the mixture of (100mg), under nitrogen protection, 45 DEG C are stirred to react overnight for reaction.It is cooled to room temperature, add water (50mL) quenching reaction, it is extracted with ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure, concentrate carries out post separation, obtains 2.00g white solid, yield: 59.7%.LC-MS (APCI): m/z=290.0 (M+CH3CN)。
The synthesis of step 4:5- (3- chlorphenyl -6-d) -3- methoxyl group cyanopyridine (compound 32).
At room temperature; by sodium methoxide (2.60g under nitrogen protection; it 48.00mmol) is added in the solution of anhydrous methanol (40mL) of the chloro- 5- of 3- (3- chlorphenyl 6-d) cyanopyridine (2.00g, 8.00mmol), reaction return stirring is stirred overnight.It is cooled to room temperature, reaction solution is removed under reduced pressure, add water (50mL) quenching reaction, extracted with ethyl acetate (50mL x 3), merges organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, 1.30g white solid is obtained, yield: 66.0%.LC-MS (APCI): m/z=245.9 (M+1).
The synthesis of step 5:5- (3- chlorphenyl -6-d) -3- hydroxy-picolinic acid (compound 33).
At room temperature, 48% hydrobromic acid (15mL) is added in 5- (3- chlorphenyl -6-d) -3- methoxyl group cyanopyridine (1.30g, 5.29mmol), under nitrogen protection, 100 DEG C are stirred to react overnight for reaction.It is cooled to room temperature.It is about 2 with 50% sodium hydroxide solution tune pH value under ice bath, continues stirring 1 hour, there are a large amount of white solids to be precipitated, filter cake is washed with water in filtering, and vacuum drying obtains 1.30g white solid, yield: 97.9%.LC-MS (APCI): m/z=251.0 (M+1).
Step 6:(5- (3- chlorphenyl -6-d) -3- pyridone formoxyl) glycine methyl ester (compound 34) synthesis.
Under ice bath, by DIPEA (307mg, 2.40mmol), HOBT (161mg, 1.20mmol), EDCI (228mg, 1.20mmol) it is added separately to 5- (3- chlorphenyl -6-d) -3- hydroxy-picolinic acid (200mg, in the solution of anhydrous n,N-Dimethylformamide (20mL) 0.80mmol), after stirred under nitrogen reacts 15min.It is added glycine methyl ester hydrochloride (150mg, 1.19mmol), is warming up to room temperature, reaction 2 days is stirred at room temperature in reaction.Add water (50mL) quenching reaction, it is extracted with ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, 95mg white solid is obtained, yield: 36.9%.LC-MS (APCI): m/z=321.9 (M+1).
Step 7:(5- (3- chlorphenyl -6-d) -3- pyridone formoxyl) glycine (compound 35) synthesis.
At room temperature; by sodium hydroxide (0.90mL; it 1M) is added in tetrahydrofuran (5mL) solution of (5- (3- chlorphenyl -6-d) -3- pyridone formoxyl) glycine methyl ester (95mg, 0.30mmol), reaction is stirred to react 1hrs.Tetrahydrofuran is removed under reduced pressure, pH is adjusted to 2 or so with the dilute hydrochloric acid of 1N, ethyl acetate (30mL x 3) extraction.Merge organic layer, with saturated common salt water washing (30mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, obtains 87mg white solid, yield: 100%.LC-MS (APCI): m/z=307.9 (M+1).
Embodiment 7 prepares (5- (3- chlorphenyl -6-d) -3- pyridone formoxyl) glycine -2,2-d2(compound 37)
Step 1:(5- (3- chlorphenyl -6-d) -3- pyridone formoxyl) glycine methyl ester -2,2-d2The synthesis of (compound 36).
Under ice bath, by DIPEA (307mg, 2.40mmol), HOBT (161mg, 1.20mmol), EDCI (228mg, 1.20mmol) it is added separately to 5- (3- chlorphenyl -6-d) -3- hydroxy-picolinic acid (200mg, in the solution of anhydrous n,N-Dimethylformamide (20mL) 0.80mmol), after stirred under nitrogen reacts 15 minutes.Glycine methyl ester hydrochloride -2,2-d is added2(150mg, 1.19mmol), is warming up to room temperature, and reaction 2 days is stirred at room temperature in reaction.Add water (50mL) quenching reaction, it is extracted with ethyl acetate (50mL x 3), merge organic layer, with saturated common salt water washing (50mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, and concentrate carries out post separation, 86mg white solid is obtained, yield: 33.2%.LC-MS (APCI): m/z=324.0 (M+1).
Step 2:(5- (3- chlorphenyl -6-d) -3- pyridone formoxyl) glycine -2,2-d2The synthesis of (compound 37).
At room temperature, deuterium sodium oxide molybdena (0.80mL, 1M in D2O) is added to (5- (3- chlorphenyl -2,4,6-d3) -3- pyridone formoxyl) glycine methyl ester -2,2-d2In tetrahydrofuran (5mL) solution of (86mg, 0.27mmol), reaction is stirred to react 2 hours.Decompression Tetrahydrofuran is removed, pH is adjusted to 2 or so with the dilute hydrochloric acid of 1N, ethyl acetate (30mL x 3) extraction.Merge organic layer, with saturated common salt water washing (30mL x 2), organic layer is dry with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure, obtains 80mg white solid, yield: 49.2%.LC-MS (APCI): m/z=310.0 (M+1).
Biological activity test.
Mouse tissue HIF western blot analysis.
The mortar and pestle being stored under -80 DEG C of mouse tissue liquid nitrogen frozen are ground into a powder.Nucleus extraction object is prepared using NE-PER kit (Pierce Biotechnology).To carry out immune precipitation, by nucleus extraction object to organize to be added to than ratio of the antibody for 200:1 in the anti-monoclonal antibody in the shallow lake HIF-1.The suspension is cultivated 4 hours in conical micro centrifugal pipe at 4 DEG C.Then albumin A/G coupling sepharose 4B (suspension of 40 lipolysaccharide pearl egg %) is added in the pipe.After rotating through night at 4 DEG C, the pearl is washed 3 times with ice-cold phosphate buffer.Then the ice-cold phosphate sample buffer solution preparation of the pearl is used for SDS-PAGE with after 40 by the pearl.On the Protein transfer separated from SDS-PAGE to the nitrocellulose plate with XCell-II Blot Module system.5% BSA of trace is closed, is then cultivated with HIF-1 dimension rabbit antibody with the diluted ratio of 1:100.Then trace is washed with Tris buffered saline/Tween-20 buffer and cultivated with the goat-anti rabbit secondary antibody that horseradish peroxidase is conjugated.Trace is imaged with ECL reagent.Print image is captured with 1600 scanner of Epson Expression.
To the compounds of this invention and its not deuterated compound AKB-6548 test and comparison simultaneously, the ability that they promote mouse tissue secretion HIF protein is evaluated, in experimental result such as the following table 1.By analysis of experimental results, the compounds of this invention promotes the ability of mouse tissue secretion HIF protein to be significantly stronger than not deuterated compound AKB-6548.
Table 1: the mouse tissue HIF Western blot experiment result of embodiment compound
Compound number HIF-α(pg/mL)
AKB-6548 360.36
Compound 9 393.67
Compound 14 432.70
Compound 17 693.63
Compound 25 383.94
Compound 27 427.92
Compound 35 395.54
Compound 37 410.74
Mice serum EPO test.
Mice serum EPO is detected according to operation instructions using the mouse Quantikine hematopoietin ELISA kit of R&DSystems.
To the compounds of this invention and its not deuterated compound AKB-6548 test and comparison simultaneously, the ability that they promote mouse secretion EPO is evaluated, in experimental result such as the following table 2.By analysis of experimental results, the compounds of this invention promotes the ability of mouse secretion EPO to be significantly stronger than not deuterated compound AKB-6548, illustrates that the compounds of this invention can be used for preparing the drug of regulation human body anaemia.
Table 2: the mice serum EPO experimental result of embodiment compound
Compound number EPO(mlU/mL)
AKB-6548 67.86
Compound 9 60.77
Compound 14 88.24
Compound 17 94.71
Compound 25 83.36
Compound 27 78.75
Compound 35 124.13
Compound 37 117.59
Metabolic stability evaluation.
Microsomal assay: people's hepatomicrosome: 0.5mg/mL, Xenotech；Rat liver microsomes: 0.5mg/mL, Xenotech；Coenzyme (NADPH/NADH): 1mM, Sigma Life Science；Magnesium chloride: 5mM, 100mM phosphate buffer (pH 7.4).
The preparation of stock solution: precision weighs a certain amount of COMPOUNDS EXAMPLE 1-7 powder, and is dissolved to 5mM respectively with DMSO.
Phosphate buffer (100mM, pH7.4 preparation): the 0.5M dipotassium hydrogen phosphate solution of the 0.5M potassium dihydrogen phosphate 150mL and 700mL that prepare in advance is taken to mix, mixed liquor pH value is adjusted to 7.4 with 0.5M dipotassium hydrogen phosphate solution again, 5 times are diluted with ultrapure water using preceding, magnesium chloride is added, phosphate buffer (100mM) is obtained, wherein potassium phosphate containing 100mM, 3.3mM magnesium chloride, pH 7.4.
Prepare NADPH regenerative system solution (containing 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: the acetonitrile solution containing 50ng/mL Propranolol Hydrochloride and 200ng/mL orinase (internal standard).It takes 25057.5 μ L phosphate buffers (pH7.4) into 50mL centrifuge tube, is separately added into 812.5 μ L people's hepatomicrosomes, mix, obtain the hepatomicrosome dilution that protein concentration is 0.625mg/mL.Take 25057.5 μ L phosphate buffers (pH7.4) to 50mL centrifuge tube In, 812.5 μ L SD rat liver microsomes are separately added into, are mixed, the hepatomicrosome dilution that protein concentration is 0.625mg/mL is obtained.
The incubation of sample: being diluted to 0.25mM for the stock solution of respective compound with the aqueous solution containing 70% acetonitrile respectively, spare as working solution.It takes people's hepatomicrosome of 398 μ L or rat liver microsomes dilution that 96 holes are added respectively to be incubated in plate (N=2), is separately added into the working solution of 2 μ L 0.25mM, mixes.
The measurement of metabolic stability: the terminate liquid of 300 μ L pre-cooling is added in every hole of 96 hole deep-well plates, is placed on ice, as termination plate.It is in water bath that 96 holes incubation plate and NADPH regenerative system, which are placed in 37, and 5min is incubated in 100 revs/min of concussions in advance.80 μ L Incubating Solutions addition termination plate is taken out from the every hole of plate is incubated for, mixes, 20 μ L NADPH regenerative system solution is supplemented, as 0min sample.Again to be incubated for the every hole of plate be added 80 again to NADPH regenerative system solution, starting reaction starts timing.The reaction density of respective compound is 1 μM, protein concentration 0.5mg/mL.When reacting 10,30,90min, 100 μ L reaction solutions are respectively taken, are added in termination plate, vortex 3min terminates reaction.Termination plate is centrifuged 10min under the conditions of 5000 × g, 40.It takes 100in supernatant to being previously added in 96 orifice plates of 100 μ L distilled water, mixes, sample analysis is carried out using LC-MS/MS.
Data analysis: by LC-MS/MS system detection respective compound and interior target peak area, compound and internal standard peak area ratio are calculated.Slope is measured by the natural logrithm of the percentage of compound surplus and time mapping, and calculates t according to the following formula1/2And CLint, wherein V/M is equal to 1/ protein concentration.
Experimental result is as shown in table 2 below, and compared with AKB-6548, the compounds of this invention all shows excellent metabolic stability in people's hepatomicrosome and rat liver microsomes experiment.
The liver particle metabolic evaluation of 1 embodiment 1-10 compound of table
Pharmacokinetic Evaluation in rat.
6 male Sprague-Dawley rats, 7-8 week old, weight about 210g are divided into 2 groups, and every group 3, the compound (through vein 3mg/kg, taking orally 10mg/kg) through vein or oral single dosage compares its pharmacokinetic difference.
Rat is raised using standard feed, gives water.Test is fasted for first 16 hours.Drug is dissolved with PEG400 and dimethyl sulfoxide.Eye socket blood sampling, the time point of blood sampling are 0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration.
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% heparin salting liquids in test tube.Before use, test tube is in 60 liquid.Drying is overnight.After being completed with the latter time point blood specimen collection, put to death after rat etherization.
After blood specimen collection, test tube is leniently overturned immediately to 5 times, is placed on ice after guaranteeing mixing sufficiently.Blood sample is placed in centrifugation 5 minutes after guaranteeing mixing sufficiently 4, and blood plasma is separated with red blood cell.100 μ L blood plasma are sucked out into clean plastic centrifuge tube with pipettor, show title and the time point of compound.Blood plasma is stored in -80 DEG C before being analyzed.With the concentration of the compounds of this invention in LC-MS/MS measurement blood plasma.Pharmacokinetic parameter is based on every animal blood concentration in different time points into calculating.
The experimental results showed that the compounds of this invention has better pharmacokinetics in animal body, thus has better pharmacodynamics and therapeutic effect relative to control compound AKB-6548.
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, test method without specific conditions in embodiment, usually according to normal condition, or according to the normal condition proposed by manufacturer.Unless otherwise stated, 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 specific implementation of the invention is only limited to these instructions.For those of ordinary skill in the art to which the present invention belongs, without departing from the inventive concept of the premise, a number of simple deductions or replacements can also be made, all shall be regarded as belonging to protection scope of the present invention.

Claims (7)

  1. A kind of substituted heteroaryl amide compounds, it is characterised in that: the heteroaryl amide compounds as shown in formula (I) or its crystal form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate or solvated compounds,
    Wherein, R1、R2、R3、R4、R5、R6、R7、R8It is each independently hydrogen, deuterium, halogen；
    Additional conditions are R1、R2、R3、R4、R5、R6、R7And R8In at least one be deuterated or deuterium.
  2. Compound according to claim 1, it is characterised in that: R1And R2It is each independently deuterium or hydrogen.
  3. Compound according to claim 1, it is characterised in that: R3And R4It is each independently deuterium or hydrogen.
  4. Compound according to claim 1, it is characterised in that: R5、R6、R7、R8It is each independently deuterium or hydrogen.
  5. Compound according to claim 1, it is characterised in that: the compound is selected from the group compound or its pharmaceutically acceptable salt:
  6. A kind of pharmaceutical composition, it is characterized by: its pharmaceutical composition for containing pharmaceutically acceptable carrier and the heteroaryl amide compounds replaced as claimed in any one of claims 1 to 5, wherein or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, stereoisomer, prodrug or isotopic variations.
  7. A kind of compound as described in claim 1, or the purposes of its crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, it is characterized by: the purposes in preparation prevention and treatment study on anemia of chronic disease, poor glucose tolerance and/or nephrosis anemia associated and anemia of cancer or haemocyte associated disease drug.
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CN105451739A (en) * 2013-06-13 2016-03-30 阿克比治疗有限公司 Compositions and methods for treating anemia
WO2016153996A1 (en) * 2015-03-20 2016-09-29 Akebia Therapeutics, Inc. Deuterium-enriched hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors

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CN105451739A (en) * 2013-06-13 2016-03-30 阿克比治疗有限公司 Compositions and methods for treating anemia
WO2016153996A1 (en) * 2015-03-20 2016-09-29 Akebia Therapeutics, Inc. Deuterium-enriched hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors

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