CN116120340B - Pyridooxazine compound, and preparation method, composition and application thereof - Google Patents
Pyridooxazine compound, and preparation method, composition and application thereof Download PDFInfo
- Publication number
- CN116120340B CN116120340B CN202111349592.4A CN202111349592A CN116120340B CN 116120340 B CN116120340 B CN 116120340B CN 202111349592 A CN202111349592 A CN 202111349592A CN 116120340 B CN116120340 B CN 116120340B
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- Prior art keywords
- oxazin
- pyrido
- dioxo
- acetic acid
- phenyl
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Health & Medical Sciences (AREA)
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Dermatology (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The present application relates to a novel compound of formula I: pyridoxal compounds and isomers thereof, or pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition and pharmaceutical application thereof in preventing and/or treating indications related to HIF-PHD (hypoxia inducible factor prolyl hydroxylase) inhibition. The pyridooxazine compounds and isomers thereof, or pharmaceutically acceptable salts thereof, of the present application are capable of reducing the enzymatic activity of HIF-PHD, preventing and/or treating indications associated with HIF-PHD inhibition, such as anemia, inflammatory bowel disease, antibacterial, wound healing, organ transplantation, bone repair and regeneration, radiation damage, arterial peripheral disease, neurodegenerative disease-related diseases.
Description
Technical Field
The present application relates to novel compounds capable of reducing the enzymatic activity of Hypoxia Inducible Factor (HIF) Prolyl Hydroxylase (PHD): pyridoxazine compounds and isomers thereof, or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions and their use in the prophylaxis and/or treatment of indications associated with HIF-PHD inhibition.
Background
Anemia is a clinical syndrome of lower peripheral red blood cell or hemoglobin capacity than normal caused by a variety of causes, including weakness, dizziness, fatigue, shortness of breath, and the like. The main function of erythrocytes is to bring oxygen to various tissues and organs throughout the body. The number of red blood cells or the concentration of hemoglobin is reduced when anemia occurs, and the effect of this oxygen-carrying action is affected, thereby causing a series of manifestations of hypoxia of tissues and organs.
Early responses to tissue Hypoxia induced Hypoxia Inducible Factor (HIF), which is a heterodimer consisting mainly of alpha and beta subunits with transcriptional activity, wherein the alpha subunit is strictly regulated by oxygen concentration and the beta subunit is continuously expressed, and thus HIF is studied mainly on the alpha subunit. A total of three HIF-alpha subunits (1, 2, 3) exist in mammals, of which HIF-1 alpha and HIF-2 alpha are relatively more and more studied. HIF cellular levels are regulated metabolically by hydroxylation of proline residues on their alpha subunits by prolyl hydroxylase (HIF-PHD). In cells with sufficient oxygen, HIF- α is hydroxylated by propyl-hydroxylase (PHD) at a conserved proline residue, resulting in its rapid degradation. Prolyl hydroxylase PHD exists in many isoforms and acts as an oxygen sensor and plays a role in regulating cellular metabolism in response to oxygen content in cells. The half-life of HIF is very short under aerobic conditions because the alpha subunit of HIF is oxidatively degraded by HIF-PHD with molecular oxygen as a substrate; hypoxia or inhibition of three isoforms of HIF-PHD (PHD-1, PHD-2, PHD-3) stabilizes HIF and stimulates erythrocyte production. PHD2 is an enzyme that is primarily involved in regulating the level of HIF-2. Alpha. Associated with erythropoietin, and PHD1 and PHD3 are relatively less important. This finding also led to the discovery that the production of erythrocytes can be promoted by inhibiting PHD2 expression and thereby increasing HIF-2α levels.
Since PHD plays a major role in oxygen sensing, HIF cell levels can be stabilized by inhibiting HIF-PHD, and thus disorders or diseases associated with HIF inhibition, such as anemia and the like, can be prevented and/or treated.
Prolyl-4-hydroxylase inhibitor substituted isoquinoline-3-carboxamides for the treatment of liver, kidney, lung and skin fibrotic diseases are disclosed in EP 0911340; WO2008067871 claims substituted dihydropyrazolone derivatives for the treatment and/or prophylaxis of diseases, in particular cardiovascular and hematological diseases and kidney diseases and for promoting wound healing; substituted bipyridyl dihydropyrazolone derivatives for the treatment and/or prophylaxis of renal diseases, cardiovascular and hematological diseases are described in US 20100093803; also disclosed in WO2020055164 are 7-hydroxy-4H-thiophene [3,2-b ] pyridine-5 derivatives for the treatment or prophylaxis of inflammatory bowel disease.
There is a need in the art to develop novel drugs that have potent inhibitory effects on HIF-PHD.
Disclosure of Invention
The application provides a novel and efficient pyridoxazine compound and an isomer or a pharmaceutically acceptable salt thereof.
The inventor discovers that the compound is a high-efficiency HIF-PHD inhibitor, has extremely strong HIF-PHD inhibition activity, and can be used for preparing drugs for preventing and/or treating the relevant indications of HIF-PHD inhibition, including anemia, inflammatory bowel disease, antibacterial, wound healing, organ transplantation, bone repair and bone regeneration, radiation injury, arterial peripheral diseases and neurodegenerative diseases. The present application has been completed based on the above findings.
Summary of The Invention
In order to solve the technical problems, the application adopts the following technical scheme:
the compound of the application has the following general formula,
and isomers thereof, or pharmaceutically acceptable salts thereof, wherein:
R 1 selected from hydrogen, substituted or unsubstituted C 1 -C 6 Alkyl group,A substituted or unsubstituted aromatic group;
R 2 、R 3 identical or different, independently of one another, hydrogen, halogen, C 1 -C 6 Alkoxy, or R 2 、R 3 Forming a polycyclic aromatic hydrocarbon, preferably naphthalene;
R 4 、R 5 、R 6 、R 7 identical or different, independently of one another, hydrogen, halogen, C 1 -C 3 An alkoxy group;
R 8 selected from hydrogen and benzyl;
x is selected from O or S.
Further, the present application also provides a compound represented by the following formula (ii):
wherein R is 1 、R 2 、R 3 、R 8 The definition is as above.
Preferably, the aromatic group is a substituted or unsubstituted phenyl or naphthyl group, when R 1 In the case of substituted or unsubstituted phenyl groups
Represented by R, wherein 1a 、R 1b 、R 1c 、R 1d 、R 1e Identical or different, independently of one another, represent hydrogen, halogen, hydroxy, amino, C substituted or unsubstituted by one or more halogens 1 -C 6 Alkyl, -C 1 -C 3 Alkoxy, nitro, -C 1 -C 3 Alkylamino, cyano;
preferably, wherein the halogen is F, cl, br, I, preferably F, cl; the C is 1 -C 6 Alkyl is straight chain alkyl, branched alkyl or cycloalkyl; the C is 1 -C 6 Alkoxy is straight chain alkyl oxygen, branched chain alkyl oxygen or cycloalkyl oxygen; by a means ofThe C is 1 -C 3 Alkoxy is straight chain alkyl oxygen radical, branched chain alkyl oxygen radical, the C 1 -C 3 Alkylamino is straight chain alkylamino, branched alkylamino.
Preferred compounds of the application are:
2- [2, 4-dioxo-7- (4-propoxyphenyl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- [2, 4-dioxo-7- (4-isobutoxyphenyl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- [2, 4-dioxo-7- (4-cyclohexyloxyphenyl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {7- [4- (4-fluorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (3-methoxyphenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (4-chlorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (4-cyanophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (naphthalen-1-yloxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- [2, 4-dioxo-7- (4-phenoxynaphthalen-1-yl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {7- [4- (4-bromophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (3, 5-difluorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (3, 5-dichlorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {2, 4-dioxo-7- [4- (m-tolyloxy) phenyl ] -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (4-chloro-3-methylphenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- [7- (3-methoxy-4-phenoxyphenyl) -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {7- [4- (3-chlorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {2, 4-dioxo-7- [4- (p-tolyloxy) phenyl ] -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (3-fluorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {2, 4-dioxo-7- [4- (3, 4, 5-trifluorophenoxy) phenyl ] -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- (2, 4-dioxo-7- {4- [4- (trifluoromethyl) phenoxy ] phenyl } -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl) acetic acid;
2- (2, 4-dioxo-7- {4- [3- (trifluoromethyl) phenoxy ] phenyl } -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl) acetic acid;
2- [7- (3-fluoro-4-phenoxyphenyl) -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {7- [4- (2-methoxyphenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (3-nitrophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (4-methoxyphenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- [2, 4-dioxo-7- (4-phenoxyphenyl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {7- [4- (3-aminophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (4-nitrophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- (7- {4- [4- (methylamino) phenoxy ] phenyl } -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl) acetic acid.
The compounds of the present application may be prepared according to the following synthetic route, however, the present application is not limited to these methods:
wherein R is 1 -R 8 X is defined as above, R 9 Representative ofSM and I-1 are subjected to coupling reaction to obtain I-1, hydrolysis is carried out to obtain I-2, demethylation is carried out to obtain I-3, and then acylation reaction, cyclization reaction and substitution reaction are carried out to obtain the compound shown in the formula I; optionally when R 8 In the case of benzyl, the compounds of formula I can also undergo hydrogenation debenzylation to remove benzyl.
The compounds of the application can also be prepared according to the following synthetic route:
wherein R is 1 -R 8 X is defined as above, R 9 Representative ofCoupling Ia and I-1-1 to obtain Ib, hydrolyzing Ib to obtain Ic, removing methyl from Ic to obtain Id, and performing acylation reaction and cyclization reaction to obtain a compound shown in the formula I; optionally R 8 In the case of benzyl, the compounds of formula I can also undergo hydrogenation debenzylation to remove benzyl.
The application also provides a pharmaceutical composition comprising a compound of formula (I) and isomers thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The application also provides the use of a compound of formula (I), or an isomer, or a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the prevention and/or treatment of an indication associated with HIF-PHD inhibition.
Preferably, the indication associated with HIF-PHD inhibition includes anemia, inflammatory bowel disease, antibacterial, wound healing, organ transplantation, bone repair and regeneration, radiation damage, arterial peripheral disease, neurodegenerative related disease, more preferably anemia.
Detailed Description
Various aspects and features of the application are described further below.
All documents cited herein are incorporated by reference in their entirety and are incorporated by reference herein to the extent they are not inconsistent with this application. Furthermore, various terms and phrases used herein have a common meaning known to those skilled in the art, and even though they are still intended to be described and explained in greater detail herein, the terms and phrases used herein should not be construed to be inconsistent with the ordinary meaning in the sense of the present application. The following are definitions of various terms used in the present application, which are applicable to terms used throughout the specification of the present application unless otherwise specified in the specific context.
The compounds according to the application may exist in tautomeric forms, the application then embraces all tautomeric forms.
The compounds of the present application have asymmetric centers and the compounds of the present application containing an asymmetrically substituted atom can be isolated in optically active or racemic forms, and one skilled in the art knows how to prepare optically active forms, such as by racemate resolution or synthesis from optically active starting materials. Unless a specific stereochemistry or isomeric form is specifically indicated, the present application includes all chiral, diastereomeric and racemates. Methods for preparing the compounds of the application and intermediates thereof are part of the present application. All tautomers of the compounds of the application are also part of the application.
The application furthermore comprises the carboxyl-substituted esterification products of the compounds according to the application.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the resulting compound after substitution is stable.
The terms "alkoxy" and "alkylamino" are used in conventional sense to refer to an alkyl group attached to the remainder of the molecule through an oxygen atom or amino group, respectively, wherein alkyl is as described herein.
As used herein, the term "halogen", "halo", and the like, means fluorine, chlorine, bromine, or iodine, particularly fluorine, chlorine, bromine, and particularly preferably fluorine, chlorine.
As used herein, the term "alkyl" refers to an alkyl group having the indicated number of carbon atoms, which is a straight or branched chain alkyl group, and which may include its sub-groups, e.g., reference to "C 1 -C 6 Alkyl "when it may also include C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 2 -C 6 Alkyl, C 2 -C 4 Alkyl groups, etc., and specific groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
As used herein, the term "pharmaceutically acceptable salt" means a salt which is not only physiologically acceptable to the subject, but also refers to a synthetic substance of pharmaceutical use, such as a salt formed as an intermediate in the preparation of chiral resolution, which salt may play a role in obtaining the end product of the present application, although it is not directly administered to the subject.
As used herein, the term "disease" refers to a physical state of the subject that is associated with the disease of the present application. For example, the arterial peripheral disease and the neurodegenerative related disease according to the present application.
In a further aspect the application relates to pharmaceutical compositions comprising the compounds of the application as active ingredient. The pharmaceutical compositions may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use may be made by combining the compounds of the application with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
The compound of the present application or a pharmaceutical composition containing the same may be administered in unit dosage form by the enteral or parenteral route such as oral, intravenous, intramuscular, intravenous, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory tract, skin, vaginal, rectal, etc.
The dosage form may be a liquid, solid or semi-solid dosage form. The liquid preparation can be solution (including true solution and colloid solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including injection solution, powder injection and transfusion), eye drop, nasal drop, lotion, liniment, etc.; the solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and sprays; the semisolid dosage form may be an ointment, gel, paste, or the like.
The compound of the application can be prepared into common quick-release preparations, slow-release preparations, controlled-release preparations, targeted preparations and various microparticle administration systems.
For the preparation of the compounds of the present application into tablets, various excipients known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, cosolvents. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, etc.; the lubricant and cosolvent may be talc, magnesium stearate, etc.
The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets.
In order to prepare the administration unit into a capsule, the compound of the present application as an active ingredient may be mixed with a diluent and a cosolvent, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient of the compound can be prepared into particles or pellets by mixing with a diluent, an adhesive and a disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants and co-solvents used to prepare tablets of the compounds of the application may also be used to prepare capsules of the compounds of the application.
For the purpose of administration, the drug or the pharmaceutical composition of the present application can be administered by any known administration method to enhance the therapeutic effect.
The compounds or compositions of the present application may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present application has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual circumstances.
Beneficial technical effects
The inventor discovers that the compound has good HIF-PHD inhibition activity, and the IC50 is smaller than that of a positive control drug roflumistat (Roxadustat). The application provides a pyridooxazine compound with novel structure and strong activity, which can be used for preventing and/or treating indications related to HIF-PHD inhibition, has good inhibition activity on PHD receptors, and can be used for preventing and treating anemia, inflammatory bowel disease, antibiosis, wound healing, organ transplantation, bone repair and bone regeneration, radiation injury, arterial peripheral diseases and diseases related to neurodegenerative diseases, in particular anemia.
Detailed Description
The examples set forth below are presented to aid one skilled in the art in better understanding the technical solution of the present application and are not intended to limit the application in any way.
For all of the following examples, standard procedures and methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structure of the compounds is determined by nuclear magnetic resonance spectroscopy (NMR) and/or Mass Spectrometry (MS). The m.p. is the melting point given in degrees Celsius, the temperature being uncorrected.
Example 1:2- [2, 4-dioxo-7- (4-propoxyphenyl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid (Compound 1)
The synthetic route is as follows:
step 1 preparation of Compounds 1-2
To a mixed solution of 1, 4-dioxane (75.0 ml) and water (37.5 ml) of compound 4-propoxyphenylboronic acid (2700.0 mg,15.0mmol,1.2 eq.) was added compound 1-1 (2662.9 mg,12.5mmol,1.0 eq.) tris (dibenzylideneacetone) dipalladium (228.9 mg,0.25mmol,0.02 eq.) tricyclohexylphosphine (168.3 mg,0.6mmol,0.048 eq.) and potassium phosphate (4511.4 mg,21.25mmol,1.7 eq.) were introduced and stirred under reflux at 100℃for 16 hours. After completion of the reaction, water was added for dilution, and extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a crude product (4960.0 mg). 1 H NMR(400MHz,Chloroform-d)δ8.47(d,J＝1.7Hz,1H),7.56–7.51(m,2H),7.42(d,J＝1.7Hz,1H),7.06–7.00(m,2H),4.03(s,3H),3.99(t,J＝6.6Hz,2H),1.91–1.80(m,2H),1.07(t,J＝7.4Hz,3H)，LC-MS(ESI)m/z[M+H] + :269.13。
Step 2 preparation of Compounds 1-3
To a mixed solution of intermediate 1-2 (2500.0 mg,9.3mmol,1.0 eq.) in ethanol (20.0 ml) and water (10.0 ml) was added sodium hydroxide (1860.0 mg,46.5mmol,5.0 eq.) and stirred under reflux at 90℃for 16 hours. After the completion of the reaction, ethanol was distilled off under reduced pressure, the pH was adjusted to 3 to 4 with 6mol/l hydrochloric acid, and a brown solid was obtained by suction filtration, which was dried under vacuum at 50℃to obtain intermediate compound 1-3 (2564.0 mg). 1 H NMR(400MHz,Chloroform-d)δ8.39(s,1H),7.56(d,J＝8.2Hz,3H),7.03(d,J＝8.0Hz,2H),4.06(s,3H),4.03–3.94(m,2H),1.91–1.80(m,2H),1.07(t,J＝6.8Hz,3H)，LC-MS(ESI)m/z[M+H] + :288.12。
Step 3 preparation of Compounds 1-4
A mixed solution of intermediate 1-3 (2550.0 mg,8.9 mmol) in glacial acetic acid (15.0 ml, 99.5%) and hydrochloric acid (15.0 ml, 36-38%) was heated to 120℃under reflux. After 14 hours the reaction was complete and, after reversion to room temperature, the pH was adjusted to 2-3 with 4mol/l sodium hydroxide solution. Suction filtration gave a brown solid which was dried under vacuum at 50℃to give intermediate compounds 1-4 (1817.1 mg). 1 H NMR(400MHz,DMSO-d6)δ8.42(d,J＝1.8Hz,1H),7.93(d,J＝1.8Hz,1H),7.80(d,J＝8.8Hz,2H),7.07(d,J＝8.8Hz,2H),4.01(t,J＝6.5Hz,2H),3.95(s,1H),1.76(p,J＝7.0Hz,3H),1.02–0.97(m,3H)，LC-MS(ESI)m/z[M+H] + :274.11。
Step 4 preparation of Compounds 1-5
To a mixed solvent of methylene chloride (50.0 ml) and N, N-dimethylformamide (25.0 ml) of intermediate 1-4 (1570.9 mg,5.8mmol,1.0 eq.) was added benzyl glycinate hydrochloride (1389.4 mg,6.9mmol,1.2 eq.) 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (3585.5 mg,6.9mmol,1.2 eq.) and room temperature (26.4 ℃) stirred for 5 minutes, N-isopropylethylamine (2225.6 mg,17.2mmol,3.0 eq.) was added, after 16 hours, the reaction was completed, diluted with water, and washed with saturated sodium chloride, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, 10g of silica gel was added, and column chromatography was separated to give white powder intermediate 1-5 (1848.8 mg) LC-MS (ESI) M/z [ M+H ]] + :421.18。
Step 5 preparation of Compounds 1-6
To a solution of intermediate 1-5 (1848.8 mg,4.4mmol,1.0 eq.) in methylene chloride (40.0 ml) under inert gas, triethylamine (2226.2 mg,22.0mmol,5.0 eq.) was added, and after stirring at-5℃for 20min, a solution of bis (trichloromethyl) carbonate (783.5 mg,2.6mmol,0.6 eq.) in methylene chloride (40.0 ml) was added dropwise thereto, and the reaction was continued at-5℃for 3 hours. Quenching with water, extracting with ethyl acetate, washing with saturated sodium chloride, mixing the organic phases, drying over anhydrous sodium sulfate, distilling off the solvent under reduced pressure, and adding methyl acetateAlcohol (40.0 ml) was stirred for 30min and suction filtered to give intermediate compounds 1-6 (1144.1 mg) as light brown powders. 1H NMR (400 MHz, DMSO-d 6) δ9.09 (d, J=1.9 Hz, 1H), 8.29 (d, J=1.9 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.40 (d, J=4.4 Hz, 4H), 7.38-7.33 (M, 1H), 7.12 (d, J=8.8 Hz, 2H), 5.24 (s, 2H), 4.79 (s, 2H), 4.03 (t, J=6.5 Hz, 2H), 1.77 (H, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H), LC-MS (ESI) M/z [ M+H ]] + :447.16。
Step 6 preparation of Compound 1
Intermediate 1-6 (200.0 mg) was charged into a pressure-resistant reactor, followed by addition of mixed solvents methylene chloride (20.0 ml) and methanol (20.0 ml), palladium on carbon (10%, water 55%), continued to be fed with hydrogen, and stirred at room temperature (25.9 ℃ C.) for 5 hours. Insoluble solids were removed by suction filtration, the solvent was distilled off under reduced pressure, methanol (5.0 ml) was added thereto and stirred for 30 minutes, and dried under vacuum at 50℃to give the target molecular compound 1 (145.0 mg) as a white powder. 1H NMR (400 MHz, DMSO-d 6) delta 13.35 (s, 1H), 9.08 (d, J=1.9 Hz, 1H), 8.29 (d, J=1.9 Hz, 1H), 7.91 (d, J=8.9 Hz, 2H), 7.12 (d, J=8.9 Hz, 2H), 4.61 (s, 2H), 4.03 (t, J=6.5 Hz, 2H), 1.77 (H, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). LC-MS (ESI) M/z [ M+H ] +:357.11.
Example 2:
2- [2, 4-dioxo-7- (4-isobutoxyphenyl) -2H-pyrido [2,3-e ]][1,3]Oxazin-3 (4H) -yl]Acetic acid (Compound 2, LC-MS (ESI) M/z [ M+H)] + 371.12) is obtained by the method described in example 1.
Example 3:2- {7- [4- (4-fluorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid (Compound 4)
Step 1: synthesis of Compound 4-2
1, 4-Dioxahexa-to Compound 4-1 (1920.0 mg,6.2mmol,1.1 eq.)To a mixed solution of ring (50.0 ml) and water (25.0 ml), 3-methoxy-5-bromopyridine carbonitrile (1184.0 mg,5.6mmol,1.0 eq.) of tris (dibenzylideneacetone) dipalladium (101.8 mg,0.11mmol,0.02 eq.) of the compound, tricyclohexylphosphine (75.7 mg,0.27mmol,0.048 eq.) of the compound, potassium phosphate (2010.0 mg,9.45mmol,1.7 eq.) of the compound were added, the gas was replaced with nitrogen for 5 minutes, and the mixture was stirred at reflux at 100℃for 16 hours. After completion of the reaction, water was added for dilution, and extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give a crude product (1936.8 mg). 1 H NMR(400MHz,Chloroform-d)δ8.47(d,J＝1.7Hz,1H),7.56(d,J＝8.7Hz,2H),7.43(d,J＝1.6Hz,1H),7.11–7.03(m,6H),4.04(s,3H)。LC-MS(ESI)m/z[M+H] + :321.10。
Step 2: synthesis of Compound 4-3
To a mixed solution of intermediate 4-2 (1930.0 mg,6.0mmol,1.0 eq.) in ethanol (20.0 ml) and water (10.0 ml) was added sodium hydroxide (1208.0 mg,30.2mmol,5.0 eq.) and stirred under reflux at 90℃for 16 hours. After the completion of the reaction, ethanol was distilled off under reduced pressure, the pH was adjusted to 3 to 4 with 6mol/l hydrochloric acid, and a brown solid was obtained by suction filtration, which was dried under vacuum at 50℃to obtain intermediate compound 4-3 (1859.1 mg). 1 H NMR(400MHz,DMSO-d6)δ8.44(d,J＝1.5Hz,1H),7.84(d,J＝8.7Hz,2H),7.78(d,J＝1.5Hz,1H),7.27(t,J＝8.8Hz,2H),7.17–7.10(m,4H),3.94(s,3H)。LC-MS(ESI)m/z[M+H] + :340.10。
Step 3: synthesis of Compound 4-4
A mixed solution of intermediate compound 4-3 (1859.1 mg,5.5 mmol) in glacial acetic acid (15 ml, 99.5%) and hydrochloric acid (15 ml, 36-38%) was heated to 120℃under reflux. After 16h the reaction is complete, and after reversion to room temperature, the pH is adjusted to 2-3 with 4mol/l sodium hydroxide solution. Suction filtration gave a light brown solid which was dried under vacuum at 50℃to give Compound 4-4 (1608.8 mg). 1 H NMR(400MHz,DMSO-d6)δ8.44(d,J＝1.8Hz,1H),7.92(d,J＝1.8Hz,1H),7.87(d,J＝8.7Hz,2H),7.28(t,J＝8.8Hz,2H),7.16(dd,J＝9.1,4.5Hz,2H),7.10(d,J＝8.8Hz,2H)。LC-MS(ESI)m/z[M+H] + :326.08。
Step 4: synthesis of Compound 4-5
To a mixed solvent of intermediate compound 4-4 (1600.0 mg,4.9mmol,1.0 eq.) and N, N-dimethylformamide (10.0 ml), benzyl glycinate hydrochloride (1487.0 mg,7.4mmol,1.5 eq.) 1-hydroxybenzotriazole (731.0 mg,5.4mmol,1.1 eq.) 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1415.0 mg,7.4mmol,1.5 eq.) was added, and after 16 hours, N-diisopropylethylamine (3178.0 mg,24.6mmol,5.0 eq.) was added, and diluted with water (10.0 ml) 5 times, dried over anhydrous sodium sulfate, filtered, and separated by column chromatography to give pale yellow powder 4-5 (1190.0 mg). LC-MS (ESI) M/z [ M+H] + :473.15。
Step 5: synthesis of Compounds 4-6
To a solution of intermediate compound 4-5 (1190.0 mg,2.5mmol,1.0 eq.) in methylene chloride (30.0 ml) under inert gas, triethylamine (1275.0 mg,12.6mmol,5.0 eq.) was added, and after 30 minutes a solution of bis (trichloromethyl) carbonate (448.6 mg,1.5mmol,0.6 eq.) in methylene chloride (30.0 ml) was added dropwise with stirring at-5℃and the reaction was carried out at-5℃for 1 hour. Quench with water, extract with ethyl acetate, wash with saturated sodium chloride, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent by distillation under reduced pressure, add methanol (20.0 ml) and stir for 30min, suction filter to give intermediate 4-6 (924.3 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ9.09(d,J＝1.8Hz,1H),8.33(d,J＝1.9Hz,1H),7.97(d,J＝8.8Hz,2H),7.40(d,J＝4.4Hz,4H),7.37(dd,J＝7.7,4.1Hz,1H),7.29(t,J＝8.8Hz,2H),7.21–7.16(m,2H),7.14(d,J＝8.8Hz,2H),5.24(s,2H),4.79(s,2H)。LC-MS(ESI)m/z[M+H] + :499.13。
Step 6: synthesis of Compound 4
Intermediate 4-6 (200.0 mg) was added to the pressure-resistant reactor, followed by addition of mixed solvents dichloromethane (20.0 ml) and methanol (20.0 ml), palladium on carbon (40.0 mg, content 10%, water 55%), and stirring at room temperature (26.1 ℃) for 5 hours. Removing insoluble solid by suction filtration, removing solvent by distillation under reduced pressure, adding methanol (5 ml), stirring for 30min, 50Vacuum drying at C gave title compound 4 (60.0 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.32(d,J＝1.9Hz,1H),7.98(d,J＝2.0Hz,2H),7.29(dd,J＝9.8,7.7Hz,2H),7.22–7.10(m,4H),4.61(s,2H)。LC-MS(ESI)m/z[M+H]+:409.08。
Example 4:
2- {2, 4-Dioxy-7- [4- (m-tolyloxy) phenyl ]]-2H-pyrido [2,3-e][1,3]Oxazin-3 (4H) -yl } acetic acid, (Compound 13, LC-MS (ESI) M/z [ M+H)] + 405.11) is obtained by the method described in example 3.
EXAMPLE 5 2- [2, 4-dioxo-7- (4-cyclohexyloxyphenyl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid (Compound 3)
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Step 1: synthesis of Compound 3-1
4-hydroxyphenyl boric acid (2.00 g,14.49mmol,1 eq), tricyclohexylphosphorus (630 mg,2.92mmol,0.2 eq), 3-methoxy-5-bromopyridine carbonitrile (3.07 g,14.49mmol,1 eq), tris (dibenzylideneacetone) dipalladium (1.33 g,1.45mmol,0.1 eq), potassium phosphate (9.21 g,43.47mmol,3 eq), dioxane (50 mL) and water (50 mL) were added to a 250mL single-necked flask and reacted at 100℃for 3 hours. Ethyl acetate (200 mL) and water (100 mL) were added to dilute the system, the solution was extracted, the organic phase was dried over anhydrous sodium sulfate, and the mixture was dried and stirred. The product was isolated by normal phase column, ethyl acetate and petroleum ether (1:1) system and dried by spin to give compound 3-1 (1.80 g, 54.9%) as a yellow solid. [ MS ]]+：227.07。 1 H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.60(d,J＝1.8Hz,1H),7.89(d,J＝1.8Hz,1H),7.79-7.70(m,2H),6.99-6.90(m,2H),4.07(s,3H)。LC-MS(ESI)m/z[M+H] + :227.08。
Step 2: synthesis of Compound 3-2
Compound 3-1 (1.80 g, 7.9)6mmol,1 eq), sodium hydroxide (1.60 g,39.70mmol,5 eq), ethanol (30 mL) and water (15 mL) were added to a 100mL single-necked flask, and the reaction was refluxed for 3 hours, and the excess ethanol was removed by rotary evaporation. The pH was adjusted to 3 with hydrochloric acid (2M) to precipitate a yellow solid. Filtering and drying to obtain the compound 3-2 (1.26 g, 64.57%). [ MS ]]+：302.13。 1 HNMR(400MHz,DMSO-d6)δ8.49(d,J＝1.7Hz,1H),8.03(d,J＝1.8Hz,1H),7.75(dd,J＝9.1,2.6Hz,2H),6.99-6.93(m,2H),4.05(s,3H)。LC-MS(ESI)m/z[M+H] + :246.08。
Step 3: synthesis of Compound 3-3
Compound 3-2 (1.20 g,4.98mmol,1 eq), concentrated hydrochloric acid (8 mL) and anhydrous acetic acid (8 mL) were added to a 100mL single-necked flask and reacted overnight at 85 ℃. The pH was adjusted to 4 with aqueous NaOH to precipitate a yellow solid. Filtering and vacuum drying to obtain crude product of the compound 3-3 (1.10 g). [ MS ]]+：232.05。 1 H NMR(400MHz,DMSO-d6)δ8.40(d,J＝1.9Hz,1H),7.94(d,J＝1.9Hz,1H),7.74-7.70(m,2H),6.96-6.91(m,2H)。LC-MS(ESI)m/z[M+H] + :232.06。
Step 4: synthesis of Compounds 3-4
To a 100mL one-necked flask, compound 3-3 (1.00 g,4.32mmol,1 eq), benzyl glycinate hydrochloride (1.31 g,6.48mmol,1.5 eq), propylphosphoric anhydride (1.65 g,5.18mmol,1.2 eq), triethylamine (1.31 g,12.96mmol,3 eq) and N, N-dimethylformamide (10 mL) were sequentially added and reacted overnight at room temperature. Water (50 mL) and ethyl acetate (100 mL) were added to extract the fractions, and the organic phase was dried over anhydrous sodium sulfate and the solvent was spun-dried. Reverse phase column separation: water (1%formic acid) and acetonitrile system, polarity is 40% -50%, time is 10 minutes, monitor under 254 nm. Spin-drying afforded compound 3-4 (710 mg, 43.38%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ12.21(s,1H),9.83(s,1H),9.44(t,J＝6.2Hz,1H),8.46(d,J＝2.0Hz,1H),7.71-7.64(m,2H),7.61(d,J＝1.9Hz,1H),7.42-7.30(m,5H),6.93-6.86(m,2H),5.18(s,2H),4.15(d,J＝6.2Hz,2H)。LC-MS(ESI)m/z[M+H] + :379.13。
Step 5: synthesis of Compound 3-5
Dichloromethane (2 mL) dissolved compound 3-4 (700 mg, 1.85)mmol,1 eq) and triethylamine (936 mg,8.25mmol,5 eq) were added to a 50mL single-necked flask and bis (trichloromethyl) carbonate (549 mg,1.85mmol,1 eq) was added dropwise to the above system at-5℃and reacted at constant temperature for 1.5 hours. Excess dichloromethane was removed by rotary evaporation followed by addition of anhydrous methanol (3 mL), sonication, filtration, and vacuum drying to give the product compound 3-5 (420 mg, 56.14%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.15(d,J＝1.9Hz,1H),8.42(d,J＝1.9Hz,1H),8.12-8.00(m,2H),7.70-7.60(m,2H),7.43-7.34(m,5H),5.24(s,2H),4.81(s,2H)。LC-MS(ESI)m/z[M+H] + :405.11。
Step 6: synthesis of Compounds 3-6
Compound 3-5 (400 mg,0.98mmol,1 eq), bromocyclohexane (240 mg,1.48mmol,1.5 eq) and cesium carbonate (964 mg,2.96mmol,3 eq) were added to N, N-diisopropylethylamine (5 mL) and reacted at 80℃for 3 hours. Filtration followed by separation on a reverse phase column, water (1% formic acid) and acetonitrile system, polarity 45% -60%, time 15 min, monitoring at 254 nm. Spin-drying afforded compound 3-6 (110 mg, 22.81%). LC-MS (ESI) M/z [ M+H] + :487.19。
Step 7: synthesis of Compound 3
Compounds 3-6 (100 mg,0.78mmol,1 eq) and Pd/C (15 mg) were added to a mixed solution of absolute ethanol (20 mL) and dichloromethane (20 mL) and reacted overnight at room temperature under hydrogen atmosphere. Pd/C was removed by filtration and dried by spin-drying. Methanol (2 mL) was added and the mixture was sonicated to give compound 3 (70 mg, 85.91%) as a white solid after filtration. LC-MS (ESI) M/z [ M+H] + :397.14。
EXAMPLE 6 2- {2, 4-dioxo-7- [4- (p-tolyloxy) phenyl ] -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid (Compound 17)
Step 1: synthesis of Compound 17-1
The compound 3-5 (400 mg,0.98mmol,1 eq) produced in reference example 3, 1-iodo-4-toluene (235 mg,1.08mmol,1.1 eq),4-imidazole carboxylic acid (21 mg,0.19mmol,0.2 eq), cuprous iodide (19 mg,0.10mmol,0.1 eq) and potassium phosphate (311 mg,1.47mmol,1.5 eq) were added to anhydrous acetonitrile (4 mL) and reacted at 80℃for 3 hours. Filtration followed by separation on a reverse phase column, water (1% formic acid) and acetonitrile system, polarity 55% -65%, time 15 min, monitoring at 254 nm. Spin-drying afforded compound 17-1 (95 mg, 19.42%). LC-MS (ESI) M/z [ M+H] + :495.16。
Step 2: synthesis of Compound 17
Compound 17-1 (90 mg,0.18mmol,1 eq) and Pd/C (10 mg) were added to a mixed solution of absolute ethanol (10 mL) and dichloromethane (10 mL), and the mixture was reacted overnight at room temperature under a hydrogen atmosphere. Pd/C was removed by filtration and dried by spin-drying. Methanol (2 mL) was added and the mixture was filtered to give compound 17 (41 mg, 55.70%) as a white solid. LC-MS (ESI) M/z [ M+H] + :405.11。
The following compounds were obtained by reference to the procedure of example 6:
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example 30: PHD2 enzyme inhibition Activity test of Compounds of the application and isomers thereof, or pharmaceutically acceptable salts thereof
Compound configuration: the compound was dissolved in DMSO (dimethyl sulfoxide) to 10mM stock solution;
1& 10. Mu.M inhibition test: taking mother solution, diluting to 10 mu M and 1 mu M with buffer solution and testing PHD2 inhibition rate
IC 50 And (3) testing: mu.L of mother liquor was pipetted into 97. Mu.L of FP buffer as a first concentration gradient, followed by three-fold gradient dilution, a total of 12 concentrations were set for testingFitting to obtain IC 50 。
PHD enzyme expression and purification: the PHD2 (181-426) sequence recombinant plasmid marked with His-tag is transferred into a strain for preservation and use. The plate-labeled monoclonal was picked up and incubated overnight at 37℃at 250rpm in 100mL LB medium containing kana antibiotics. 20mL of seed solution was taken the next day and added to 2L of LB containing antibiotics (1% inoculation), and cultured at 37℃at 200rpm until OD 600 After 0.6, 1mM IPTG (isopropyl-. Beta. -D-thiogalactoside) was added for induction overnight. Collecting bacteria, centrifuging at 7500rpm×10min, discarding supernatant, weighing bacterial mud, re-suspending with lysate (LysiSBuf) (10 mL buf/g pellet), placing on ice, and performing ultrasonic crushing; centrifuging 12000rpm multiplied by 30min, reserving supernatant, and carrying out SDS-PAGE protein electrophoresis identification. Recombinant PHD2 protein contains His-tag label, and is purified by nickel ion metal chelate affinity chromatography column using AKTA TM The purifier performs automatic separation and purification, and the separated PDH2 enzyme is used for determining the protein concentration by BCA method.
Buffer solution preparation: 10mM Hepes,150mM NaCl,0.05% Tween-20, pH 7.4.
Test scheme: buffer for experiment (10mM Hepes,150mM NaCl,0.05% Tween-20, 10. Mu.M MnCl) 2 20. Mu.M of 2-OG, pH 7.4). FITC-labeled small molecule fluorescent probes are tool molecules, and the reaction is carried out in 384 black hole plates, and the total volume of the reaction is 60 mu L. The probe concentration is determined, 1 mu M small molecule fluorescent probe is diluted to 12 different concentrations by using buffer solution, 60 mu L of probe dilution is added into 384 Kong Heiban, the mixture is incubated for 0.5h at room temperature, spectraMax GeminiXS is used for measuring the fluorescence polarization value, when the fluorescence polarization value of the mixture is stable, the probe concentration is determined, and finally the probe concentration is determined to be 5nM. The protein-probe curve was searched, PHD2 protein concentration was similarly searched, the final concentration of probe molecules was immobilized, and the appropriate protein concentration was determined, and finally the protein concentration was determined to be 20nM. Finally selecting proper protein-probe concentration, firstly adding 20 mu L of compound to be tested (the compound concentration is 100 mu M, the compound concentration is three times diluted, and the total concentration is 12) into a 384-hole blackboard, then adding 60nM 20 mu L of PHD2 protein into the 384-hole blackboard, finally adding 15nM probe molecule into the 384-hole blackboard, and after shaking the test system at room temperature for 60min, exciting light wavelength and excitation light wavelength at 485nM535nm emitted light wave is used for detection, and the detection instrument is a Molecular Device SPARK enzyme-labeled instrument. Data processing is carried out by adopting GraphPad Prism 8.0 to obtain the IC 50 。
Test results:
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the results show that the compound of the application has very strong inhibition effect on PHD2 and IC 50 The values all reached the order of μm, which is less than the positive control drug roflumilast (Roxadustat). This strong inhibition is of great therapeutic interest for the treatment of conditions or diseases associated with HIF-PHD inhibition.
The above embodiments are merely representative. As can be seen from the above examples, the compounds of the present application are ideal high-potency HIF-PHD inhibitors, and can be expected to be useful for the treatment or prevention of conditions or diseases associated with HIF-PHD inhibition, such as anemia, inflammatory bowel disease, antibacterial, wound healing, organ transplantation, bone repair and regeneration, radiation damage, peripheral arterial disease, neurodegenerative disease-related diseases, and can be formulated into oral preparations (tablets or capsules, etc.). Tablets or capsules made with the compounds of the present application may be taken one or more times a day. The compound of the application can also be combined with other medicaments to prepare compound preparations.
The foregoing is only a preferred embodiment of the present application, but the scope of the present application is not limited thereto, and any person skilled in the art should be able to apply equivalents and modifications according to the technical scheme and the inventive concept thereof within the scope of the present application.
Claims (10)
1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, characterized in that,
R 1 selected from hydrogen, C 1 -C 6 Alkyl, naphthyl orWherein R is 1a 、R 1b 、R 1c 、R 1d 、R 1e Identical or different, independently of one another, represent hydrogen, halogen, hydroxy, amino, C substituted or unsubstituted by one or more halogens 1 -C 6 Alkyl, -C 1 -C 3 Alkoxy, nitro, -C 1 -C 3 Alkylamino, cyano;
R 2 、R 3 identical or different, independently of one another, hydrogen, halogen, C 1 -C 6 Alkoxy, or R 2 、R 3 Forming naphthalene therebetween;
R 4 、R 5 、R 6 、R 7 identical or different, independently of one another, hydrogen, halogen, C 1 -C 3 An alkoxy group;
R 8 selected from hydrogen and benzyl;
x is selected from O or S.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, represented by the formula:
wherein R is 1 、R 2 、R 3 、R 8 Has the same definition as the above claim 1.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the halogen is F, cl, br, I.
4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the halogen is F, cl.
5. A compound selected from the following group of compounds, or a pharmaceutically acceptable salt thereof:
2- [2, 4-dioxo-7- (4-propoxyphenyl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- [2, 4-dioxo-7- (4-isobutoxyphenyl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- [2, 4-dioxo-7- (4-cyclohexyloxyphenyl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {7- [4- (4-fluorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (3-methoxyphenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (4-chlorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (4-cyanophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (naphthalen-1-yloxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- [2, 4-dioxo-7- (4-phenoxynaphthalen-1-yl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {7- [4- (4-bromophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (3, 5-difluorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (3, 5-dichlorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {2, 4-dioxo-7- [4- (m-tolyloxy) phenyl ] -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (4-chloro-3-methylphenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- [7- (3-methoxy-4-phenoxyphenyl) -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {7- [4- (3-chlorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {2, 4-dioxo-7- [4- (p-tolyloxy) phenyl ] -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (3-fluorophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {2, 4-dioxo-7- [4- (3, 4, 5-trifluorophenoxy) phenyl ] -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- (2, 4-dioxo-7- {4- [4- (trifluoromethyl) phenoxy ] phenyl } -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl) acetic acid;
2- (2, 4-dioxo-7- {4- [3- (trifluoromethyl) phenoxy ] phenyl } -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl) acetic acid;
2- [7- (3-fluoro-4-phenoxyphenyl) -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {7- [4- (2-methoxyphenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (3-nitrophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (4-methoxyphenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- [2, 4-dioxo-7- (4-phenoxyphenyl) -2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl ] acetic acid;
2- {7- [4- (3-aminophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- {7- [4- (4-nitrophenoxy) phenyl ] -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl } acetic acid;
2- (7- {4- [4- (methylamino) phenoxy ] phenyl } -2, 4-dioxo-2H-pyrido [2,3-e ] [1,3] oxazin-3 (4H) -yl) acetic acid.
6. A process for the preparation of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that the process comprises the steps of:
wherein R is 1 -R 8 X is as defined in claim 1, R 9 Representative ofCoupling Ia and I-1-1 to obtain Ib, hydrolyzing Ib to obtain Ic, removing methyl from Ic to obtain Id, and performing acylation reaction and cyclization reaction to obtain a compound shown in the formula I; optionally R 8 In the case of benzyl, the compounds of formula I can also undergo hydrogenation debenzylation to remove benzyl.
7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
8. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a composition according to claim 7, for the manufacture of a medicament for the prevention and/or treatment of an indication associated with HIF-PHD inhibition.
9. The use according to claim 8, wherein the indication associated with HIF-PHD inhibition is anemia, inflammatory bowel disease, antibacterial, wound healing, organ transplantation, bone repair and regeneration, radiation damage, arterial peripheral disease, neurodegenerative related disease.
10. The use according to claim 9, wherein the indication associated with HIF-PHD inhibition is anemia.
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| KR20200030466A (en) * | 2018-09-12 | 2020-03-20 | 크리스탈지노믹스(주) | 7-hydroxy-4h-thieno[3,2-b]pyridin-5-one derivatives and methods of use of thereof |
| CN109293673A (en) * | 2018-10-10 | 2019-02-01 | 中国药科大学 | A kind of prolyl hydroxylase small-molecule fluorescent probe and preparation method thereof |
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