WO2022095461A1 - 一种特异性增强TRPV4-KCa2.3复合体的空间耦联度的化合物及其用途 - Google Patents
一种特异性增强TRPV4-KCa2.3复合体的空间耦联度的化合物及其用途 Download PDFInfo
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- WO2022095461A1 WO2022095461A1 PCT/CN2021/101376 CN2021101376W WO2022095461A1 WO 2022095461 A1 WO2022095461 A1 WO 2022095461A1 CN 2021101376 W CN2021101376 W CN 2021101376W WO 2022095461 A1 WO2022095461 A1 WO 2022095461A1
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- compound
- trpv4
- pharmaceutically acceptable
- substituted
- acceptable salt
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Definitions
- the invention belongs to the field of chemical medicine, in particular to a compound that specifically enhances the spatial coupling degree of a TRPV4-KCa2.3 complex and uses thereof.
- TRP Transient receptor potential
- the TRPV4 (transient receptor potential vanilloid type 4) channel is a member of the TRP channel family vanilloid subfamily (TRPV), which is widely expressed on airway epithelial cells, macrophages, airway smooth muscle and other cells, and can be activated by a variety of stimuli. Such as pH, temperature, arachidonic acid, osmotic pressure, etc., play an important role in many physiological and pathological processes.
- TRPV4 transient receptor potential vanilloid type 4
- TRPV4 transient receptor potential vanilloid type 4
- TRPV transient receptor potential vanilloid type 4
- KCa2.3 is a small conductance calcium ion-activated potassium channel. Under physiological conditions, when cells are stimulated, the TRPV4 channel opens, and calcium ions flow in, which leads to the opening of the downstream KCa2.3 channel and the outflow of potassium ions, which makes the membrane potential tend to polarize and cause vasodilation. Studies have found that the dysfunction of TRPV4 is widely found in cardiovascular diseases such as hypertension and obesity. In the state of hypertension, the coupling between TRPV4 and KCa2.3 will be reduced, so that the vasodilation ability will also decrease.
- TRPV4 has been implicated in the pathogenesis of various diseases.
- Epithelial and endothelial barriers are characterized by intercellular tight junctions and adherent junctions that control the exchange of fluids and proteins from the vasculature to surrounding tissues.
- Injury eg, during pathological conditions or mechanical injury
- TRPV4 activation may be involved in disrupting the integrity of the epithelial and endothelial barriers, suggesting that edema formation may play a role in states of inflammation or tissue damage.
- TRPV4 is widely expressed throughout the gastrointestinal tract, including ileal and colonic tissues, DRG neurons, and fine nerve fibers associated with submucosa and subserosal vessels (Gastroenterology. 2008 Jun; 134(7): 2059-69.; Neurogastroenterol Motil. 2012 Nov;24(11):e557-60.). Indeed, colitis was associated with increased expression of TRPV4 in human and mouse colon tissues and in intestinal epithelial cells compared to healthy controls.
- TRPV4 channels are expressed in rat and mouse urothelial and detrusor cells (J. Mol. Neurosci. 2013;51:602-614.). TRPV4-mediated Ca influx may activate both BK and SK channels, resulting in reduced bladder contractions and promotion of storage life (Med Sci(Basel). 2019 May 22;7(5).pii:E67.). The TRPV4 channel in the bladder urothelium and detrusor muscle plays an important role in bladder function.
- TRPV4 TRPV4 expressed in neurons, astrocytes and glial cells.
- the TRPV4 channel senses pressure in the bladder and transmits signals to the brain, which regulate the function of the detrusor muscle.
- TRPV4 is also widely expressed in lung epithelial cells, and inhibitors targeting TRPV4 are considered to be a non-negligible part of the future treatment of pulmonary arterial hypertension.
- Administration of TRPV4 inhibitors prior to myocardial infarction prevented the development of edema. And stimulated edema to subside after myocardial infarction (Sci Transl Med.
- TRPV4 activation is a downstream stimulation of PAR2, histamine and serotonin receptors.
- functional loss of TRPV4 in mice Does not cause any noticeable sensory, muscular or inflammatory phenotype.
- multiple human TRPV4 mutations are associated with phenotypically distinct inflammatory, metabolic and musculoskeletal diseases.
- J Physiol.2019 Feb;597(4):997-1021. The fact that TRPV4 plays a fundamental and widespread role in normal physiology makes it a beautiful and complex potential pharmacological target
- TRPV4 was recently identified as a key regulator of endothelial barrier integrity and is a promising pharmacological target (Balakrishna, et al., 2014; Hamanaka, et al., 2010; Hamanaka, et al., 2007; Jian, et al., 2014; al., 2008; Jie, et al., 2015; Thorneloe, et al., 2012).
- TRPV4 channels are mainly expressed on endothelial cells, vascular smooth muscle cells, perivascular nerves, and cardiac fibroblasts to sense hemodynamic changes to maintain homeostasis.
- TRPV4 activity reduces blood flow-induced vascular responses. Activation of TRPV4 hyperpolarizes the membrane of vascular smooth muscle cells. In this case, Ca influx through TRPV4 channels stimulates Ca- sensitive K + channels in vascular smooth muscle cells, causing subsequent smooth muscle hyperpolarization.
- TRPV4 surface expression in mesenteric resistance arteries is concentrated in myoendothelial protrusions facing vascular smooth muscle (Sci Signal.
- TRPV4 inhibitor ruthenium red both of which showed a variety of other effects.
- Novel, more selective TRPV4 inhibitors include RN-1734, the widely used HC-067047 and the orally bioavailable GSK2193874.
- the latest generation of pharmacological inhibitors of TRPV4 have high affinity and specificity.
- TRPV4 inhibitors have been successfully used in vivo without significant side effects (Am J Physiol Lung Cell Mol Physiol. 2014 Jul 15; 307(2): L158-72.; Sci Transl Med.
- the present invention proposes a small molecule that can specifically restore the uncoupling of TRPV4 and KCa2.3 in the hypertensive state, and proposes a new therapeutic target for the treatment of hypertension.
- Medication for hypertensive patients provides more options.
- the combined drug in the treatment of hypertension also provides new options, which can effectively avoid possible side effects during use.
- the present invention prepares a specific compound that can act on the two action sites simultaneously by searching for the domain of the interaction site of the endothelial cell ion channel complex TRPV4-KCa2.3, and finds that the compound can enhance TRPV4-KCa2.3.
- the spatial coupling degree of the 3 complex is of great significance to the development of hypertension drugs.
- the first object of the present invention is to provide a compound having a structure represented by general formula (I) or a pharmaceutically acceptable salt thereof,
- X is selected from NH, O or CH2 ;
- Y is selected from NH or CH2 ;
- Z is selected from N or C
- R 1 is selected from H
- R 2 is selected from (i) substituted or unsubstituted phenyl with substituents optionally substituted with one or more substituents in halogen, C 1 -C 8 haloalkyl, cyano, (ii) N-aryl ylamino, wherein aryl is a substituted or unsubstituted phenyl group optionally substituted with one or more substituents in halogen, C 1 -C 8 haloalkyl, cyano, or (iii)
- n is represented as 0, 1, 2 or 3.
- R 2 when R 2 is a substituted or unsubstituted phenyl group, the substituent group is optionally selected from one or more substituents of halogen, CF 3 , CHF 2 , CH 2 F, CN replace.
- R 2 when R 2 is N-arylamino, the aryl group is a substituted or unsubstituted phenyl group, and the substituent group is optionally selected from halogen, CF 3 , CHF 2 , CH 2 One or more substituents of F, CN are substituted.
- the pharmaceutically acceptable salts are inorganic salts or organic salts, and inorganic salts include hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate , hydrogen sulfate, nitrate, phosphate, acid phosphate;
- the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, ethyl acetate Diate, Malonate, Succinate, Glutarate, Fumarate, Maleate, Lactate, Malate, Citrate, Tartrate, Mesylate, Ethyl Sulfonates, benzenesulfonates, salicylates, p-toluenesulfonates, ascorbates.
- the pharmaceutically acceptable salt is selected from hydrochloride, succinate or mesylate.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound having the structure represented by general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
- the compound of general formula (I) of the present invention or a pharmaceutically acceptable salt thereof when preparing a pharmaceutical composition, is usually mixed with a pharmaceutically acceptable carrier, excipient or diluent .
- a pharmaceutically acceptable carrier such as a tablet or capsule
- the content of the compound of general formula (I) or a pharmaceutically acceptable salt thereof may be 0.01-1000 mg, such as 0.05-800 mg, 0.1-500 mg, 0.01-300 mg, 0.01 mg -200mg, 0.05-150mg, 0.05-50mg, etc.
- compositions of the present invention can be formulated into conventional pharmaceutical formulations according to conventional manufacturing methods. For example, tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, tinctures, syrups, ointments, drops, suppositories, inhalants, propellants and the like.
- a compound of the present invention or a pharmaceutically acceptable salt thereof may be formulated as a solid preparation for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules Wait.
- the compound of formula (I) of the present invention is mixed as active ingredient with at least one conventional inert excipient (or carrier), for example with sodium citrate or dicalcium phosphate, or with a compound selected from the group consisting of: A mix of one or more:
- fillers or solubilizers such as starch, lactose, sucrose, glucose, mannitol and silicic acid, etc.;
- Binders for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, acacia, etc.;
- humectants such as glycerin, etc.
- disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, etc.;
- Absorption accelerators such as quaternary ammonium compounds, etc.
- Wetting agents such as cetyl alcohol and glycerol monostearate, etc.
- adsorbents for example, kaolin, etc.
- Lubricants such as talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc., or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.
- the solid dosage forms such as tablets, dragees, capsules, pills and granules may be coated with coatings and shell materials such as enteric coatings and other materials known in the art. or microencapsulated. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
- a compound of the present invention may be formulated in liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, Syrups, tinctures, etc.
- liquid dosage forms may contain inert diluents conventionally employed in the art, such as water and other solvents, solubilizers and emulsifiers, for example, ethanol, Isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, etc. or mixtures of these substances, etc.
- the liquid dosage forms of the present invention may also include conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents, and the like.
- the suspending agent includes, for example, ethoxylated stearyl alcohol, polyoxyethylene sorbitol, and sorbitan, microcrystalline cellulose, agar, etc., or mixtures of these substances .
- the compounds of the present invention and pharmaceutically acceptable salts thereof can be formulated in dosage forms for parenteral injection including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, Dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions.
- Suitable carriers, diluents, solvents, excipients include water, ethanol, polyols and suitable mixtures thereof.
- a compound of the present invention, or a pharmaceutically acceptable salt thereof may be formulated for topical administration in dosage forms including, for example, ointments, powders, suppositories, drops, sprays, inhalants, and the like .
- the compounds of the present invention or pharmaceutically acceptable salts thereof can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, especially in combination with other antihypertensive drugs.
- the therapeutic agents include but are not limited to: diuretic antihypertensive drugs, such as hydrochlorothiazide of thiazides, spironolactone of aldosterone, furosemide of loop diuretics, etc.; sympathetic nerve inhibitory drugs mainly It is propranolol, etc., which affect the renin-angiotensin system inhibitory drugs such as captopril and benazepril, which are angiotensin-converting enzyme (ACE) inhibitors; Valerian, which is an angiotensin II receptor blocker. Sartan; drugs that block calcium channel ions such as amlodipine.
- diuretic antihypertensive drugs such as hydrochlorothiazide of thiazides, spironolactone of aldosterone, furosemide of loop diuretics, etc.
- sympathetic nerve inhibitory drugs mainly It is propranolol, etc., which affect the renin-angiotensin system
- the ingredients to be combined may be administered simultaneously or sequentially, in a single formulation or in separate formulations.
- the combination includes not only a combination of one or other active agents of a compound of the present invention, but also a combination of two or more other active agents of a compound of the present invention.
- the object of the present invention also includes applying the compound having the structure represented by the general formula (I) or a pharmaceutically acceptable salt thereof to the preparation for the treatment of hypertension, hyperlipidemia, coronary heart disease, angina pectoris, myocardial infarction, sudden death, Arrhythmia, idiopathic pulmonary hypertension, cardiac channelopathies, coronary dilated disease, homozygous familial hypercholesterolemia, idiopathic cardiomyopathy, sitosterolemia drugs.
- the compound having the structure represented by the general formula (I) or a pharmaceutically acceptable salt thereof to the preparation for the treatment of hypertension, hyperlipidemia, coronary heart disease, angina pectoris, myocardial infarction, sudden death, Arrhythmia, idiopathic pulmonary hypertension, cardiac channelopathies, coronary dilated disease, homozygous familial hypercholesterolemia, idiopathic cardiomyopathy, sitosterolemia drugs.
- Fig. 1 is a change trend diagram of the corresponding [K + ] of the compound (437) of Example 4.
- Fig. 2 is a change trend diagram of the corresponding [K + ] of the compounds of Examples 5 and 6 (455, 469).
- FIG. 3 is a graph showing the results of measuring the efficiency of immunizing Fret with different compounds.
- Figure 4 shows the changes in blood pressure in hypertensive mice after using the compound (437) of Example 4.
- Figure 5 shows the changes in blood pressure in hypertensive mice after using the compound (455) of Example 5.
- Figure 6 is a graph showing the results of half-life determination of Example 4 (437) in four different species of liver microsomes.
- Figure 7 is a graph showing the results of half-life determination of Example 5 (455) in liver microsomes of two different species.
- Halogen in the present invention includes fluorine, chlorine, bromine and iodine.
- “Pharmaceutically acceptable salts” as used herein refers to those salts which retain the biological effectiveness and properties of the parent compound.
- the term “salt” refers to any salt of a compound according to the invention prepared from an inorganic or organic acid or base and an internally formed salt. Typically, such salts have a physiologically acceptable anion or cation.
- disease refers to any condition or disorder that impairs or interferes with the normal function of cells, organs or tissues.
- hypertensive drug refers to any agent useful in the treatment of hypertension.
- pharmaceutically acceptable means suitable for use in contact with human and other mammalian tissues without undue toxicity, irritation, allergic reaction, etc., within the scope of reasonable medicine, and with reasonable benefit/risk ratio of components.
- “Pharmaceutically acceptable salt” refers to any non-toxic salt which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or a prodrug of a compound.
- the term "effective amount” or “therapeutically effective amount” refers to an amount of a compound or pharmaceutical composition described herein that is sufficient for the intended application, including, but not limited to, treating a disease.
- the amount is the dose detected effective for enhancing the coupling between TRPV4 and KCa2.3; severity level, stage and progression of hypertension.
- the therapeutically effective amount may vary depending on the intended application, eg, in vitro or in vivo, the state and severity of the disease, the age, weight, or mode of administration of the subject, and the like. The term also applies to situations where a dose will induce electrophysiological activity in target cells, eg, cells.
- the specific dose will depend, for example, on the particular compound chosen, the subject species and their age/existing medical condition or risk of medical condition, the route of administration, the severity of the disease, administration in combination with other agents, The time of administration, the tissue to which it is administered, and the delivery device, etc.
- administering or “administering" a compound to an individual refers to providing a compound of the present invention to an individual in need of treatment.
- the compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention.
- the compounds of the present invention may also exhibit various tautomeric forms, in which case the present invention expressly includes all tautomeric forms of the compounds described herein. All such isomeric forms of such compounds are included in the present invention. All crystalline forms of the compounds described herein are expressly included in the present invention.
- an ethyl group “optionally” substituted with halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted (eg CH2CH2F ) , polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
- the synthesis method is as follows:
- Step a Preparation of 4-oxo-1,4-dihydroquinazoline-2-carboxylic acid ethyl ester
- 2-Aminobenzamide (10 g, 73.53 mmol) was suspended in diethyl oxalate (100 mL), slowly heated to 185° C., refluxed for 5 hours, cooled to room temperature, the solid was precipitated, filtered, and the filter cake petroleum ether Washed and dried to obtain 13 g of white solid with a yield of 86%.
- Step b Preparation of 4-oxo-1,4-dihydroquinazoline-2-carboxylic acid
- Step c Preparation of tert-butyl (3-(4-oxo-1,4-dihydroquinazoline-2-carboxamido)propyl)carbamate
- reaction solution was diluted with ethyl acetate, washed three times with water, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain 0.85 g of a white solid with a yield of 47%.
- Step d Preparation of N-(3-aminopropyl)-4-oxo-1,4-dihydroquinazoline-2-carboxamide hydrochloride
- Step e Preparation of 4-oxo-N-(3-(2-(pyridin-4-yl)acetamido)propyl)-1,4-dihydroquinazoline-2-carboxamide
- reaction solution was diluted with ethyl acetate, washed three times with water, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain 32 mg of white solid (4-oxo-N-(3-(2-( Pyridin-4-yl)acetamido)propyl)-1,4-dihydroquinazoline-2-carboxamide), 25% yield.
- the synthesis method is as follows:
- Step g Preparation of 4-oxo-N-(3-(3-(pyridin-4-yl)ureido)propyl)-1,4-dihydroquinazoline-2-carboxamide
- the synthesis method is as follows:
- Step h Preparation of phenyl(4-((4-ethylpiperazin-1-yl)methyl)phenyl)carbamate
- Step i N-(3-(3-(4-(((4-ethylpiperazin-1-yl)methyl)phenyl)ureido)propyl)-4-oxo-1,4- Preparation of dihydroquinazoline-2-carboxamide
- the synthesis method is as follows:
- Step j Preparation of tert-butyl (5-oxo-5-(phenylamino)pentyl)carbamate
- Step k Preparation of 5-amino-N-phenylpentanamide hydrochloride
- Step 1 Preparation of 5-(3-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)ureido)-N-phenylpentanamide
- the synthesis method is as follows:
- p-Fluorobenzoic acid (560mg, 4mmol, 1.0eq) was dissolved in DMF (10mL), followed by adding tert-butyl N-(5-aminopentyl)carbamate (969.6mg, 4.8mmol, 1.2eq), EDCI ( 1150mg, 6mmol, 1.5eq), HOBT (810mg, 6mmol, 1.5eq), stirred at room temperature for 18h.
- the reaction solution was diluted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain 1.0 g with a yield of 77%.
- Step o Preparation of N-(5-(3-(4-(((4-ethylpiperazin-1-yl)methyl)phenyl)ureido)pentyl)-4-fluorobenzamide
- N-(5-aminopentyl)-4-fluorobenzamide hydrochloride (100 mg, 0.384 mmol, 1.0 eq) was dissolved in DMF (2 mL), followed by triethylamine (116.5 mg, 1.154 mmol, 3.0 eq) and phenyl (4-((4-ethylpiperazin-1-yl)methyl)phenyl)carbamate (156.2mg, 0.461mmol, 1.2eq), reacted at room temperature for 18h, the reaction solution was passed through Diluted with ethyl acetate, washed three times with water, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain 33 mg of white solid (N-(5-(3-(4-((((4-ethyl Piperazin-1-yl)methyl)phenyl)ureido)pentyl)-4-fluorobenzamide), 18.3% yield
- Endothelial cells were cultured for 3-5 days, using Example 1, 2, 3, 4, 5, and 6 at a concentration of 10 ⁇ Mol/L, after incubation for 24 hours, fixed with 4% paraformaldehyde for 30 minutes, and treated with 0.2% Triton X- Permeabilize with 100 PBS for 10 minutes and block with 5% BSA in PBS for 1 hour. Cells were then stained with TRPV4-550 and KCa2.3 as primary and conjugated secondary antibodies (Life Technologies) and with DAPI (Vector Laboratories, Burlingame, CA, USA). Images were taken with a laser confocal microscope, and Fret values were calculated. The specific results are shown in Table 1 and Figure 3.
- JNC-440 is used as the control group (Ctrl), and the structure of JNC-440 is as follows:
- FIG 3 shows the results of the efficiency measurement of the immunization of each compound with Fret.
- the results indicate the coupling degree of the two proteins. The higher the value, the higher the coupling degree of the two proteins.
- Example 365 The compound obtained in Example 1 involved in Figure 3 is abbreviated as Compound 365; the compound obtained in Example 2 is abbreviated as Compound 366; the compound obtained in Example 3 is abbreviated as Compound 491; the compound obtained in Example 4 is abbreviated as Compound 437;
- the compound obtained in Example 5 is abbreviated as Compound 455; the compound obtained in Example 6 is abbreviated as Compound 469;
- HS refers to high-salt diet-induced hypertensive mice, and WT refers to normal wild-type mice.
- Figure 1 shows the change of [K + ] corresponding to the compound of Example 4 (under a high-salt state (control group Ctrl) without drug incubation, the fluorescence intensity of potassium ions is low, that is, the ability of potassium efflux is weakened. In the incubation example After 4, its potassium efflux ability was enhanced.);
- Figure 2 shows the changes of [K + ] corresponding to the compounds of Examples 5 and 6 (in the high-salt state (control group) without drug incubation, the fluorescence intensity of potassium ions is higher than that of the compounds of Examples 5 and 6. Low, that is, the ability of potassium efflux is weakened. After incubation of Examples 5 and 6, the potassium efflux ability is enhanced, and the damaged function can be restored).
- mice The blood pressure of mice was measured by the IITC non-invasive sphygmomanometer and the tail-cuff method. Initially, mice were trained daily, for at least one week, for half an hour each time. Systolic blood pressure, diastolic blood pressure, mean arterial pressure and heart rate are obtained for each test. After the mice were adapted, the compound of Example 4 and the compound of Example 5 were given by gavage at a dose of 30 mg/kg, and then the blood pressure of the hypertensive mice was determined at a fixed point. And Example 5 can sustain the depressurization for 8h. The specific results are shown in Table 2 and Figures 4 and 5.
- Example 4 can continuously reduce blood pressure for 1.5 hours, while Example 5 can continuously reduce blood pressure for 8 hours.
- the horizontal axis of the line graph in FIG. 4 is time, the unit is hour; the vertical axis is systolic blood pressure (SBP), mean arterial pressure (MAP), diastolic blood pressure (DBP), and the unit is mmHg. Changes in blood pressure within 5 hours for hypertensive mice after using the compound (437) of Example 4.
- the vertical axis of the histogram is the change in mean arterial pressure, in mmHg. After using Example 4, the maximum value of mean arterial pressure change, that is, the maximum value of blood pressure drop is shown.
- HS hypertensive mice induced by high-salt diet (the model mice used in the in vivo experiments in this example); WT refers to normal wild-type mice; Ctrl control group refers to the model mice that were gavaged with normal saline, Compounds referred to in this application were not administered.
- the horizontal axis of the line graph in FIG. 5 is time, the unit is hour; the vertical axis is systolic blood pressure (SBP), mean arterial pressure (MAP), diastolic blood pressure (DBP), and the unit is mmHg. Changes in blood pressure within 9 hours for hypertensive mice after using the compound (455) of Example 5.
- the vertical axis of the histogram is the change in mean arterial pressure, in mmHg. After using Example 5, the maximum value of mean arterial pressure change, that is, the maximum value of blood pressure drop is shown.
- HS refers to high-salt diet-induced hypertensive mice (the model mice used in the in vivo experiments in this example), WT refers to normal wild-type mice; Ctrl control group refers to the model mice gavaged with normal saline , the compounds involved in this application are not administered.
- the total volume of the in vitro metabolic incubation system is 207 ⁇ L, and the organic solvent is less than 1%, including 188 ⁇ L of 0.1mol/L PBS buffer (pH 7.4), and 12 ⁇ L of NADPH generation system (10 ⁇ L of A solution and 2 ⁇ L of B solution). mixed).
- the abscissa in Figure 6 is time, in hours; the ordinate is the remaining drug percentage (%) and time (h).
- the figure shows the estimated half-life of Example 4 (437) in four different species of liver microsomes, mouse (mouse), rat (rat), human (human), dog (dog). Half-lives were 2.341 hours, 2.855 hours, 2.438 hours, 2.232 hours.
- the abscissa in Figure 7 is time, in hours; the ordinate is the percentage of remaining drug.
- the figure shows the estimated half-life of Example 5 (455) in liver microsomes of two different species, mouse (mouse) and human (human) half-lives of 4.23 hours and 3.35 hours, respectively.
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Abstract
一种特异性增强TRPV4-KCa2.3复合体的空间耦联度的化合物及其用途,属于化学医药领域。其具有通式(I)结构的化合物主要针对在高血压患者中TRPV4与KCa2.3解偶联情况,可以使得解偶联的两个蛋白重新耦联,使其恢复正常状态。TRPV4与KCa2.3在正常情况下,由TRPV4接受钙离子的信号,由于钙离子内流,刺激下游的KCa2.3通道的钾离子外流,去极化使得血管舒张,从而使得高血压患者的血压恢复正常水平。
Description
本发明属于化学医药领域,具体涉及一种特异性增强TRPV4-KCa2.3复合体的空间耦联度的化合物及其用途。
瞬时受体电位(transient receptor rotential,TRP)离子通道,是一类非选择性阳离子通道蛋白,首次发现于黑腹果蝇的视觉传导系统中。目前在哺乳动物中发现了近30种TRP通道,并将其划分为7个亚族:TRPV(vanniloid),TRPM(melastatin),TRPA(ankryin),TRPML(mucolipin),TRPP(polycistin),TRPC(caninocal)和TRPN(drosophila NOMPC)。([J]Arch.2011May;461(5):493-498).TRP通道根据环境中温度、化学物质、pH值、渗透压等变化调节细胞外阳离子的通透性(.Int.J.Biochem.Cell Biol.2016;78:217–228.),从而调节细胞功能。TRPV4(transient receptor potential vanilloid type 4)通道是TRP通道家族香草素亚家族(TRPV)成员,广泛表达在呼吸道的上皮细胞、巨噬细胞、气道平滑肌等细胞上,可以被多种刺激物激活,如PH、温度、花生四烯酸、渗透压等,在许多生理和病理过程中发挥重要作用。其在内皮细胞的功能受到广泛关注,参与了多种血管功能,包括应答血流剪切力,调节血管张力,机械信号传导,血管新生等。
KCa2.3为小电导钙离子激活的钾通道。在生理情况下,当细胞受到刺激时,TRPV4通道打开,钙离子内流,从而引起下游的KCa2.3通道的打开,钾离子外流,使得膜电位趋于极化,同时引起血管舒张。研究发现TRPV4的功能失调广泛存在于高血压,肥胖等心血管疾病当中,在高血压状态下,TRPV4与KCa2.3之间的耦联会降低,从而使得血管舒张能力也随之下降。而在血管活性物质中筛选出一种可以增强TRPV4和KCa2.3耦联的小分子,对于高血压之后的新药开发提供了一种新的思路。由于TRPV4的广泛表达,其与多种疾病的发病机制相关。上皮和内皮屏障的特征是细胞间紧密连接和粘附连接,这些连接和连接控制着流体和蛋白质从脉管系统到周围组织的交换。损伤(例如在病理状态或机械损伤期间)会破坏屏障的完整性,并导致流体和血浆蛋白通过细胞间间隙不受控制地运动,从而导致水肿形成。而TRPV4激活可能参与破坏上皮和内皮屏障的完整性,表明在炎症或组织损伤状态下水肿形成可能发挥作用。TRPV4在整个胃肠道中广泛表达,包括回肠和结肠组织,DRG神经元以及与粘膜下层和浆膜下血管相关的细神经纤维(Gastroenterology.2008Jun;134(7):2059-69.; Neurogastroenterol Motil.2012Nov;24(11):e557-60.)。实际上,与健康对照组相比,结肠炎与人和小鼠结肠组织以及肠上皮细胞中的TRPV4的表达增加有关。与未发炎结肠的患者相比,结肠炎患者的浆膜和浆膜血管更受TRPV4阳性感觉神经支配。TRPV4通道在大鼠和小鼠的尿路上皮和逼尿肌细胞中表达(J.Mol.Neurosci.2013;51:602–614.)。TRPV4介导的Ca
2+内流可能同时激活了BK和SK通道,从而导致膀胱收缩减少并促进储存期(Med Sci(Basel).2019 May 22;7(5).pii:E67.)。膀胱尿路上皮和逼尿肌中的TRPV4通道在膀胱功能中起着重要的作用。其上游可以追溯到在神经元,星形胶质细胞和神经胶质细胞中表达的TRPV4。TRPV4通道感受膀胱中的压力,将信号传导至大脑,从而调节逼尿肌的功能。TRPV4在肺上皮细胞中也有广泛表达,针对TRPV4的抑制剂,被认为是肺动脉高压未来治疗中不可忽略的一部分。在心肌梗死之前给予TRPV4抑制剂均可以防止水肿的发展。并在心肌梗死后刺激水肿消退(Sci Transl Med.2012 Nov 7;4(159):159ra148.)TRPV4激活是对PAR2,组胺和5-羟色胺受体的下游刺激。(Am J Physiol Renal Physiol.2010 Mar;298(3):F692–F701.Biochem Biophys Res Commun.2001 Aug 3;285(5):1250-2.)有趣的是,小鼠中TRPV4的功能性缺失不会导致任何明显的感觉,肌肉或炎症表型。(J Biol Chem.2010 Aug 27;285(35):27176-81.)然而,多种人类TRPV4突变与表型上不同的炎症,代谢和肌肉骨骼疾病有关。(J Physiol.2019 Feb;597(4):997-1021.)TRPV4在正常生理中起着基本且广泛的作用,这一事实使其成为令人着迷而又复杂的潜在药理学靶标
TRPV4最近被确定为内皮屏障完整性的关键调节剂,并且是有希望的药理靶点(Balakrishna,et al.,2014;Hamanaka,et al.,2010;Hamanaka,et al.,2007;Jian,et al.,2008;Jie,et al.,2015;Thorneloe,et al.,2012)。在心血管系统中,TRPV4通道主要在内皮细胞、血管平滑肌细胞、血管周围神经和心脏成纤维细胞上表达,以感知血液动力学变化,从而维持体内的平衡。(J Cardiovasc Pharmacol.2013 Feb;61(2):113-9.)TRPV4活性的降低会降低血流诱导的血管反应。TRPV4的激活会使血管平滑肌细胞的膜超极化。在这种情况下,通过TRPV4通道流入的Ca
2+会刺激血管平滑肌细胞中的Ca
2+敏感K
+通道,从而引起随后的平滑肌超极化。(Biochim Biophys Acta.2007 Aug;1772(8):907-14.)在肠系膜阻力动脉中TRPV4表面表达集中在面对血管平滑肌的肌内皮突起中(Sci Signal.2014 Jul 8;7(333):ra66.),这可能有助于通过小(SKCa)和(IKCa)钙激活的钾通道(Sonkusare,et al。,2012;EMBO Mol Med.2017 Nov;9(11):1491-1503.)中等传导性在平滑肌和内皮之间发出信号。
早期研究使用了非选择性TRPV4抑制剂钌红,它们都表现出多种其他作用。新型的,更具选择性的TRPV4抑制剂包括RN-1734,广泛使用的HC-067047和可口服生物利用的 GSK2193874。TRPV4的最新一代药理抑制剂具有高亲和力和特异性。实际上,TRPV4抑制剂已经成功地在体内使用,没有明显的副作用(Am J Physiol Lung Cell Mol Physiol.2014 Jul15;307(2):L158-72.;Sci Transl Med.2012 Nov 7;4(159):159ra148.),并且新型TRPV4拮抗剂最近已进入I和II期临床试验并公布了初步的结果(GSK2798745;NCT02119260),这是葛兰素史克抑制剂GSK2798745(clinicaltrials.gov NCT02119260)的人体试验中的第一项。GSK2193874化合物报道了阳性结果且没有副作用,因此我们迫切期待该试验的结果(Sci Transl Med.2012 Nov 7;4(159):159ra147.)。还进行了两项进一步的临床研究,一项I期研究旨在验证评估肺水肿的方法,最终目的是在这种情况下测试TRPV4抑制剂(NCT02135861);以及一项II期研究,以评估TRPV4抑制对充血性心力衰竭患者肺气体转移和呼吸的影响(NCT02497937)。GSK2193874可有效预防小鼠急性和慢性心力衰竭引起的肺水肿。
此外,近期有国际申请专利EP20170784400及EP20170784691阐述了吡咯烷磺酰胺类似物,含有它们的药物组合物及其作为TRPV4拮抗剂的用途。US201816217948阐述了提供了治疗和/或预防皮肤病的方法;提供了减少皮肤发炎,减轻疼痛和/或减少有需要的受试者的瘙痒的方法。JP20150014057阐述了提供TRPV4(瞬时受体电位阳离子通道亚家族V成员4)活化剂,降血压预防或改善剂以及自主神经调节剂,其利用TRPV4活化剂的功效并用作其施用手段。近年来,对于疗效更佳、副作用更小、代谢稳定性高、生物利用度好的降压药存在更高、更迫切的需求。如何克服现降压药所存在的非专一性靶点,副作用较多的问题是目前亟需解决的。
发明内容
要解决的技术问题:本发明提出一种作为可特异性恢复在高血压状态下解偶联的TRPV4和KCa2.3的小分子,为高血压的治疗提出一个新的治疗靶点,为临床上高血压患者用药提供更多的选择。此外,在高血压治疗过程中的联合用药同样提供新的选择,可有效避免使用时可能带来的副作用。本发明通过寻找内皮细胞离子通道复合体TRPV4-KCa2.3的相互作用位点的结构域,制备了能同时作用于这两个作用位点的特异性化合物,发现该化合物能增强TRPV4-KCa2.3复合体的空间耦联度,并对高血压药物的研发具有重大的意义。
本发明的第一个目的是提供一种具有通式(I)所示结构的化合物或其药学上可接受的盐,
其中:
X选自NH、O或CH
2;
Y选自NH或CH
2;
Z选自N或C;
R
2选自(i)取代基取代或未取代的苯基,取代基任选自卤素、C
1-C
8卤代烷基、氰基中的一个或多个取代基取代,(ii)N-芳基基氨基,其中,芳基为取代基取代或未取代的苯基,取代基任选自卤素、C
1-C
8卤代烷基、氰基中的一个或多个取代基取代,或(iii)
n表示为0、1、2或3。
在本发明的一中实施方式中,当R
2为取代基取代或未取代的苯基时,取代基任选自卤素、CF
3、CHF
2、CH
2F、CN的一个或多个取代基取代。
在本发明的一种实施方式中,当R
2为N-芳基基氨基时,芳基为取代基取代或未取代的苯基,取代基任选自卤素、CF
3、CHF
2、CH
2F、CN的一个或多个取代基取代。
在本发明的一种实施方式中,所述的药学上可接受的盐为无机盐或有机盐,无机盐包括盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐;所述有机盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、丁二酸盐、戊二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、对甲苯磺酸盐、抗坏血酸盐。更进一步地,所述药学上可接受的盐选自盐酸盐、琥珀酸盐或甲磺酸盐。
进一步地,通式(I)的化合物或它们的盐可以溶剂合物的形式分离,且因此任何这种溶剂合物都属于本发明的范围。
本发明还提供一种药物组合物,包括具有通式(I)所示结构的化合物或其药学上可接受的盐,以及药学上可接受载体、赋形剂或稀释剂。
在本发明的一种实施方式中,在制备药物组合物时,通常是将本发明通式(I)化合物或其药学上可接受的盐与药学上可接受载体、赋形剂或稀释剂混合。其中,在单位剂型(例如一 个药片或胶囊)中,通式(I)化合物或其药学上可接受的盐的含量可以为0.01-1000mg,例如0.05-800mg、0.1-500mg、0.01-300mg、0.01-200mg、0.05-150mg、0.05-50mg等。
可以按常规制备方法将所述本发明组合物配置为常规药物制剂。例如片剂、丸剂、胶囊剂、散剂、颗粒剂、乳液剂、混悬剂、分散液、溶液剂、酊剂、糖浆剂、软膏剂、滴剂、栓剂、吸入剂、喷射剂等。
在本发明的一种实施方式中,本发明化合物或其药学上可接受的盐可以配制为用于口服给药的固体制剂,包括,但不限于胶囊剂、片剂、丸剂、散剂、颗粒剂等。在这些固体剂型中,本发明式(I)化合物作为活性成分与至少一种常规惰性赋形剂(或载体)混合,例如与柠檬酸钠或磷酸二钙,或与选自下述成分中的一种或多种混合:
(1)填料或增溶剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸等;
(2)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等;
(3)保湿剂,例如,甘油等;
(4)崩解剂、例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些符合硅酸盐和碳酸钠等;
(5)缓溶剂,例如石蜡等;
(6)吸收加速剂,例如季铵化合物等;
(7)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯等;
(8)吸附剂,例如,高岭土等;
(9)润滑剂,例如,滑石、硬脂酸钙、固体聚乙二醇、十二烷基硫酸钠等,或其混合物。胶囊剂、片剂、丸剂中也可包含缓冲剂。
在本发明的一种实施方式中,所述固体剂型例如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材料如肠溶衣和其他本领域公知的材料晶型包衣或微囊化。它们可包含不透明剂,并且,这种组合物中活性成分的释放可以延迟的方式在消化道的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性成分也可与上述赋形剂中的一种或者多种形成微胶囊形式。
在本发明的一种实施方式中,本发明化合物或其药学上可接受的盐可以配制为用于口服给药的液体剂型,包括,但不限于药学上可接受的乳液、溶液、悬浮液、糖浆、酊剂等。除了作为活性成分的式(I)化合物或其药学上可接受的盐外,液体剂型可包含本领域中常规采用的惰性稀释剂,例如水和其他溶剂、增溶剂和乳化剂,例如,乙醇、异丙醇、碳酸乙酯、乙 酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油类,特别是棉籽油、花生油、玉米油、橄榄油、蓖麻油、芝麻油等或这些物质的混合物等。除了这些惰性稀释剂外,本发明液体剂型也可包括常规助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料等。
在本发明的一种实施方式中,所述悬浮剂包括,例如,乙氧基化十八烷醇、聚氧乙烯山梨醇、和脱水山梨醇、微晶纤维素、琼脂等或这些物质的混合物。
在本发明的一种实施方式中,本发明化合物和其药学上可接受的盐可以配置为用于胃肠外注射的剂型,包括,但不限于生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,以及用于重新溶解成无菌的可注射溶液和分散液的无菌粉末。适宜的载体、稀释剂、溶剂、赋形剂包括水、乙醇、多元醇及其适宜的混合物。
在本发明的一种实施方式中,本发明化合物或其药学上可接受的盐可以配置为用于局部给药的剂型,包括如软膏剂、散剂、栓剂、滴剂、喷射剂和吸入剂等。作为活性成分的本发明通式(I)化合物或其药学上可接受的盐在无菌条件下和生理上可接受的载体及任选的防腐剂、缓冲剂,和必要时可能需要的推进剂一起混合。
本发明所述的化合物或其药学上可接受的盐可以单独给药,或者与其他药学上可接受的治疗剂联合给药,特别是与其他抗高血压药物组合。
在本发明的一种实施方式中,所述治疗剂包括但不限于:利尿降压药物,如噻嗪类的氢氯噻嗪,醛固酮类的螺内酯以及袢利尿剂的呋塞米等;交感神经抑制药物主要是普萘洛尔等,影响肾素-血管紧张素系统抑制药物如血管紧张素转换酶(ACE)抑制药的卡托普利、贝那普利;血管紧张素II受体阻断药的缬沙坦;阻滞钙通道离子的药物如氨氯地平等。待组合的各成分可同时或顺序的给予,以单一制剂形式或者以不同制剂的形式给予。所述组合不仅包括本发明化合物的一种或其他活性剂的组合,而且也包括本发明化合物的两种或更多的其他活性剂的组合。
本发明目的还包括将具有通式(I)所示结构的化合物或其药学上可接受的盐应用于制备用于治疗哺乳动物的高血压、高血脂、冠心病、心绞痛、心肌梗死、猝死、心律失常、特发性肺动脉高压、心脏离子通道病、冠状动脉扩张病、纯合子家族性高胆固醇血症、特发性心肌病、谷固醇血症的药物中。
本发明有益效果:
得到一系列的低毒性、高活性的小分子,并且在动物水平上也得到了较好的实验结果,与经典的相似药物相比,其药效无明显差异,已经得到一个比较理想的结果。
图1为实施例4化合物(437)相应的[K
+]的变化趋势图。
图2为实施例5、6化合物(455、469)相应的[K
+]的变化趋势图。
图3为不同化合物的免疫Fret的效率测定结果图。
图4为使用实施例4化合物(437)之后对于高血压小鼠的血压变化情况。
图5为使用实施例5化合物(455)之后对于高血压小鼠的血压变化情况。
图6为实施例4(437)在四种不同种属的肝微粒体中的半衰期测定结果图。
图7为实施例5(455)在两种不同种属的肝微粒体中的半衰期测定结果图。
在本发明中卤素包括氟、氯、溴和碘。
在本发明中“药学上可接受的盐”是指表示保留母体化合物的生物有效性和性质的那些盐。术语“盐”是指由无机或有机酸或碱和内部形成的盐制备的根据本发明的化合物的任何盐。通常,这种盐具有生理上可接受的阴离子或阳离子。
如本文使用的术语“疾病”是指损害或干扰细胞、器官或组织的正常功能的任何病症或紊乱。
如本文使用的术语“降压药”是指在高血压治疗中有用的任何试剂。
如本文使用的术语“药学可接受的”是指在合理的医学范围内,适用于与人和其他哺乳动物的组织接触而没有过度毒性、剌激、过敏反应等,并且有合理的利益/风险比的组分。“药学上可接受的盐”是指任何无毒性的盐,其在施用于受者后,能够直接或间接地提供本发明的化合物或化合物的前药。
如本文所使用的术语“有效量”或“有效治疗量”是指本文所述的化合物或药物组合物的量是足以达到预期的应用,包括,但不限于治疗疾病。在一些实施方案中,所述量是检测到的有效用于增强TRPV4与KCa2.3之间耦联的剂量;高血压的严重性水平,阶段和进展。有效治疗量可以根据预定应用发生变化,例如体外或者体内,疾病的状况和严重程度,受试者年龄,重量,或给药方式等。该术语也适用于剂量将诱导靶细胞,例如,细胞的电生理活动情况。具体剂量将取决于,例如,特定的化合物中选取,受试者物种和他们的年龄/现有的健康状况或健康状况的风险,给药途径,疾病的严重程度,与其他药剂组合给药,给药时间,给其施用的组织,和给药装置等。
在本发明中“给药”或“给予”个体化合物是指向需要治疗的个体提供本发明的化合物。
本发明的化合物可以含有一个或多个不对称中心,并且因此作为外消旋物和外消旋混合物、单一对映体、单独的非对映体和非对映体混合物出现。这些化合物的所有此类异构体形式均明确地包括在本发明中。本发明的化合物还可以表现为多种互变异构形式,在此情况下,本发明明确地包括本文所述的化合物的所有互变异构形式。此类化合物的所有此类异构体形式包括在本发明中。本文所述的化合物的所有结晶形式明确地包括在本发明中。
在本发明中“任选自”或“任选地”是指随后描述的事件或情况可能发生或可能不发生,该描述包括发生所述事件或情况和不发生所述事件或情况。例如,乙基“任选”被卤素取代,指乙基可以是未被取代的(CH
2CH
3)、单取代的(如CH
2CH
2F)、多取代的(如CHFCH
2F、CH
2CHF
2等)或完全被取代的(CF
2CF
3)。本领域技术人员可理解,对于包含一个或多个取代基的任何基团,不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
在整个本说明书中提到的“实施方式”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”或“在本申请的部分实施方式中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此,在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”或“在本申请的部分实施方式中”不必全部指同一实施方案。此外,具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
除非本申请中另外要求,在整个说明书和其后的权利要求书中,词语“包括(comprise)”及其英文变体例如“包括(comprises)”和“包括(comprising)”应解释为开放式的、含括式的意义,即“包括但不限于”。
应当理解,在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象,除非文中另外明确地规定。
实施例1:4-氧代-N-(3-(2-(吡啶-4-基)乙酰氨基)丙基)-1,4-二氢喹唑啉-2-羧酰胺
合成方法如下:
步骤a:4-氧代-1,4-二氢喹唑啉-2-羧酸乙酯的制备
将2-氨基苯甲酰胺(10g,73.53mmol)混悬于草酸二乙酯(100mL)中,慢慢加热至185℃,回流5小时,冷却至室温后,固体析出,过滤,滤饼石油醚洗涤,干燥得白色固体13g,收率86%。
步骤b:4-氧代-1,4-二氢喹唑啉-2-羧酸的制备
将4-氧代-1,4-二氢喹唑啉-2-羧酸乙酯(2g,9.2mmol,1.0eq)混悬于四氢呋喃(20mL)和水(10mL)中,加入氢氧化钾(1.5g,27.5mmol,3.0eq),室温搅拌2小时。旋蒸除去乙醇,反应液冷却至0℃,稀盐酸调Ph=2-3,固体析出,过滤,干燥得白色固体1.2g,收率69%。
步骤c:(3-(4-氧代-1,4-二氢喹唑啉-2-甲酰胺基)丙基)氨基甲酸叔丁酯的制备
将4-氧代-1,4-二氢喹唑啉-2-羧酸(1g,5.26mmol,1.0eq)溶于DMF(10mL)中,依次加入N-叔丁氧羰基-1,3-丙二胺(1.1g,6.31mmol,1.2eq)、EDCI(1.51g,7.89mmol,1.5eq)、HOBt(1.06g,7.89mmol,1.5eq)和三乙胺(0.8g,7.89mmol,1.5eq),室温搅拌18小时。将反应液经乙酸乙酯稀释,水洗3次,饱和氯化钠洗涤1次,无水硫酸钠干燥,浓缩得白色固体0.85g,收率47%。
步骤d:N-(3-氨基丙基)-4-氧代-1,4-二氢喹唑啉-2-羧酰胺盐酸盐的制备
将(3-(4-氧代-1,4-二氢喹唑啉-2-甲酰胺基)丙基)氨基甲酸叔丁酯(500mg,1.44mmol)溶于盐酸甲醇(5mL)中,室温搅拌3小时,浓缩得白色固体380mg,收率93%。
步骤e:4-氧代-N-(3-(2-(吡啶-4-基)乙酰氨基)丙基)-1,4-二氢喹唑啉-2-羧酰胺的制备
将N-(3-氨基丙基)-4-氧代-1,4-二氢喹唑啉-2-羧酰胺盐酸盐(100mg,1.77mmol,1.0eq)溶于DMF(2mL)中,依次加入4-吡啶乙酸盐酸盐(367.4mg,2.12mmol,1.2eq)、EDCI(510mg,2.65mmol,1.5eq)、HOBt(357.7mg,2.65mmol,1.5eq)和三乙胺(536. 3mg,5.31mmol,3.0eq),室温搅拌18小时。将反应液经乙酸乙酯稀释,水洗3次,饱和氯化钠洗涤1次,无水硫酸钠干燥,浓缩,柱纯化得白色固体32mg(4-氧代-N-(3-(2-(吡啶-4-基)乙酰氨基)丙基)-1,4-二氢喹唑啉-2-羧酰胺),收率25%。
ESI-MS m/z:366.1[M+H]
+,
1H NMR(400MHz,DMSO-d
6)δ12.13(s,1H),9.04(s,1H),8.47(d,J=8.0Hz,2H),8.18(t,J=8.0Hz,2H),7.89(t,J=8.0Hz,1H),7.78(d,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7.27(d,J=8.0Hz,2H),3.47(s,2H),3.32-3.25(m,2H),3.15-3.10(m,2H),1.72-1.66(m,2H).
实施例2:4-氧代-N-(3-(3-(吡啶-4-基)脲基)丙基)-1,4-二氢喹唑啉-2-羧酰胺
合成方法如下:
步骤f:苯基吡啶-4-基氨基甲酸酯的制备
将4-氨基吡啶(200mg,2.13mmol,1.0eq)溶于DMF(2mL)中,加入三乙胺(257.9mg,2.55mmol,1.2eq),降温至0℃,慢慢加入氯甲酸苯酯(399mg,2.55mmol,1.2eq),0℃反应3小时。将反应液经乙酸乙酯稀释,水洗3次,饱和氯化钠洗涤1次,无水硫酸钠干燥,浓缩得365mg,收率82%
步骤g:4-氧代-N-(3-(3-(吡啶-4-基)脲基)丙基)-1,4-二氢喹唑啉-2-羧酰胺的制备
将N-(3-氨基丙基)-4-氧代-1,4-二氢喹唑啉-2-羧酰胺盐酸盐(100mg,0.353mmol,1.0eq)溶于DMF(2mL)中,依次加入三乙胺(107.2mg,1.06mmol,3.0eq)和苯基吡啶-4-基氨基甲酸酯(90.6mg,0.424mmol,1.2eq),室温反应18h,将反应液经乙酸乙酯稀释,水洗3次,饱和氯化钠洗涤1次,无水硫酸钠干燥,浓缩,柱纯化得白色固体20mg(4-氧代-N-(3-(3-(吡啶-4-基)脲基)丙基)-1,4-二氢喹唑啉-2-羧酰胺),收率15.4%。
ESI-MS m/z:367.1[M+H]
+,
1H NMR(400MHz,DMSO-d
6)δ12.15(s,1H),9.09(s,1H),9.01(s,1H),8.27(d,J=8.0Hz,2H),8.17(d,J=8.0Hz,1H),7.88(d,J=8.0Hz,1H),7.78(d, J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7.36(d,J=4.0Hz,2H),6.45(t,J=4.0Hz,1H),3.38-3.32(m,2H),3.20-3.13(m,2H),1.74-1.70(m,2H).
实施例3:N-(3-(3-(4-(((4-乙基哌嗪-1-基)甲基)苯基)脲基)丙基)-4-氧代-1,4-二氢喹唑啉-2-羧酰胺
合成方法如下:
步骤h:苯基(4-((4-乙基哌嗪-1-基)甲基)苯基)氨基甲酸酯的制备
将4-(4-乙基哌嗪-1-甲基)-苯胺(500mg,2.28mmol,1.0eq)溶于DMF(5mL)中,加入三乙胺(345.9mg,3.42mmol,1.5eq),降温至0℃,滴加氯甲酸苯酯(391.2mg,2.51mmol,1.1eq),加完后室温反应2h,反应液经乙酸乙酯稀释,水洗,饱和氯化钠洗,无水硫酸钠干燥,浓缩,柱层析得到油状物480mg,产率62%。
步骤i:N-(3-(3-(4-(((4-乙基哌嗪-1-基)甲基)苯基)脲基)丙基)-4-氧代-1,4-二氢喹唑啉-2-羧酰胺的制备
将N-(3-氨基丙基)-4-氧代-1,4-二氢喹唑啉-2-羧酰胺盐酸盐(100mg,0.353mmol,1.0eq)溶于DMF(2mL)中,依次加入三乙胺(107.2mg,1.06mmol,3.0eq)和苯基(4-((4-乙基哌嗪-1-基)甲基)苯基)氨基甲酸酯(143.7mg,0.424mmol,1.2eq),室温反应18h,将反应液经乙酸乙酯稀释,水洗3次,饱和氯化钠洗涤1次,无水硫酸钠干燥,浓缩,柱纯化得白色固体32mg(N-(3-(3-(4-(((4-乙基哌嗪-1-基)甲基)苯基)脲基)丙基)-4-氧代-1,4-二氢喹唑啉-2-羧酰胺),收率18.4%。
ESI-MS m/z:492.3[M+H]
+,
1H NMR(400MHz,DMSO-d
6)δ9.09(s,1H),8.47(s,1H),8.17(d,J=8.0Hz,1H),7.87(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7.32(d,J=8.0Hz,2H),7.13-7.09(m,3H),6.17(t,J=4.0Hz,1H),3.40-3.32(m,2H),3.20-3.10(m,2H),2.91(s,2H),2.70-2.67(m,2H),2.33-2.28(m,10H),0.97(t,J=8.0Hz,3 H).
实施例4:5-(3-(4-((4-乙基哌嗪-1-基)甲基)苯基)脲基)-N-苯基戊酰胺
合成方法如下:
步骤j:(5-氧代-5-(苯基氨基)戊基)氨基甲酸叔丁酯的制备
将苯胺(689mg,7.41mmol,1.0eq)溶于DMF(20mL)中,依次加入Boc-5-氨基戊酸(1930mg,8.89mmol,1.2eq),EDCI(2122mg,11mmol,1.5eq),HOBT(1490mg,11mmol,1.5eq),室温搅拌18h。反应液经乙酸乙酯稀释,水洗,饱和氯化钠洗,无水硫酸钠干燥,浓缩得到1.8g,收率83%。
步骤k:5-氨基-N-苯基戊酰胺盐酸盐的制备
将(5-氧代-5-(苯基氨基)戊基)氨基甲酸叔丁酯(1g,3.42mmol)溶于盐酸-甲醇(10mL)溶液中,室温下搅拌3小时,浓缩,得到650mg,收率83%。
步骤l:5-(3-(4-((4-乙基哌嗪-1-基)甲基)苯基)脲基)-N-苯基戊酰胺的制备
将5-氨基-N-苯基戊酰胺盐酸盐的制备(100mg,0.438mmol,1.0eq)溶于DMF(2mL)中,依次加入三乙胺(132.9mg,1.316mmol,3.0eq)和苯基(4-((4-乙基哌嗪-1-基)甲基)苯基)氨基甲酸酯(178.2mg,0.525mmol,1.2eq),室温反应18h,将反应液经乙酸乙酯稀释,水洗3次,饱和氯化钠洗涤1次,无水硫酸钠干燥,浓缩,柱纯化得白色固体23mg(5-(3-(4-((4-乙基哌嗪-1-基)甲基)苯基)脲基)-N-苯基戊酰胺),收率12%。
ESI-MS m/z:438.3[M+H]
+,
1H NMR(400MHz,Chloroform-d)δ8.20(s,1H),7.53(d,J=8.0Hz,2H),7.27-7.25(m,3H),7.18(t,J=8.0Hz,3H),7.07(q,J=8.0Hz,2H),5.42(s,1H),3.45(s,2H),3.24(d,J=4.0Hz,2H),2.50-2.36(m,12H),1.71(t,J=8.0Hz,2H),1.52(t,J=8.0Hz,2H),1.09(t,J=8.0Hz,3H).
实施例5:5-(3-(4-((4-乙基哌嗪-1-基)甲基)苯基)脲基)-N-(4-氟苯基)戊酰胺
合成方法参见实施例4的制备,区别在于,把苯胺替换成对氟苯胺。
ESI-MS m/z:456.3[M+H]
+,
1H NMR(400MHz,DMSO-d
6)δ9.92(s,1H),8.34(s,1H),7.61-7.58(m,2H),7.30(d,J=8.0Hz,2H),7.13–7.09(m,4H),6.11(t,J=4.0Hz,1H),3.34(s,2H),3.10(q,J=6.0Hz,2H),2.51-2.21(m,12H),1.61(t,J=8.0Hz,2H),1.45(t,J=8.0Hz,2H),0.97(t,J=8.0Hz,3H).
实施例6:N-(5-(3-(4-(((4-乙基哌嗪-1-基)甲基)苯基)脲基)戊基)-4-氟苯甲酰胺
合成方法如下:
步骤m:(5-(4-氟苯甲酰胺基)戊基)氨基甲酸叔丁酯的制备
将对氟苯甲酸(560mg,4mmol,1.0eq)溶于DMF(10mL)中,依次加入N-(5-氨基戊基)氨基甲酸叔丁酯(969.6mg,4.8mmol,1.2eq),EDCI(1150mg,6mmol,1.5eq),HOBT(810mg,6mmol,1.5eq),室温搅拌18h。反应液经乙酸乙酯稀释,水洗,饱和氯化钠洗,无水硫酸钠干燥,浓缩得到1.0g,收率77%。
步骤n:N-(5-氨基戊基)-4-氟苯甲酰胺盐酸盐的制备
将(5-(4-氟苯甲酰胺基)戊基)氨基甲酸叔丁酯(1g,3.84mmol)溶于盐酸-甲醇(10mL)溶液中,室温下搅拌3小时,浓缩得到680mg,收率84.8%。
步骤o:N-(5-(3-(4-(((4-乙基哌嗪-1-基)甲基)苯基)脲基)戊基)-4-氟苯甲酰胺的制备
将N-(5-氨基戊基)-4-氟苯甲酰胺盐酸盐(100mg,0.384mmol,1.0eq)溶于DMF(2mL)中,依次加入三乙胺(116.5mg,1.154mmol,3.0eq)和苯基(4-((4-乙基哌嗪-1-基)甲基)苯基)氨基甲酸酯(156.2mg,0.461mmol,1.2eq),室温反应18h,将反应液经乙酸乙酯稀释,水洗3次,饱和氯化钠洗涤1次,无水硫酸钠干燥,浓缩,柱纯化得白色固体33mg(N-(5-(3-(4-(((4-乙基哌嗪-1-基)甲基)苯基)脲基)戊基)-4-氟苯甲酰胺),收率18.3%。
ESI-MS m/z:470.3[M+H]
+,
1H NMR(400MHz,DMSO-d
6)δ8.46(t,J=8.0Hz,1H),8.32(s,1H),7.92-7.88(m,2H),7.27(d,J=10.0Hz,4H),7.10(d,J=8.0Hz,2H),6.07(t,J=8.0Hz,1H),3.25(q,J=6.0Hz,2H),3.07(q,J=6.0Hz,2H),2.40-2.25(m,12H),1.54(t,J=8.0Hz,2 H),1.45(t,J=8.0Hz,2H),1.32(t,J=8.0Hz,2H),0.96(t,J=8.0Hz,3H).
实施例7体外耦联活性测试
内皮细胞培养3-5d,用实施例1、2、3、4、5、6以10μMol/L的浓度,孵育24小时之后,用4%多聚甲醛固定30分钟,用含0.2%Triton X-100的PBS通透10分钟,并用含5%BSA的PBS封闭1小时。然后将细胞用TRPV4-550和KCa2.3作为一抗和偶联的二抗(Life Technologies)进行染色,并用DAPI(Vector Laboratories,Burlingame,CA,USA)进行染色。用激光共聚焦显微镜进行拍摄,并计算Fret值。具体结果见表1和图3。
表1体外耦联活性检测结果
化合物 | Fret效率值(平均值) |
JNC-440 | 5.02 |
实施例1 | 6.06 |
实施例2 | 5.98 |
实施例3 | 5.62 |
实施例4 | 8.15 |
实施例5 | 7.68 |
实施例6 | 7.98 |
其中,JNC-440作为对照组(Ctrl),JNC-440的结构如下所示:
图3为各化合物免疫Fret的效率测定结果,该结果表明两个蛋白的耦联成度,该值越高,两蛋白耦联成都越高。
图3中涉及到的实施例1所得化合物简记为化合物365;实施例2所得化合物简记为化合物366;实施例3所得化合物简记为化合物491;实施例4所得化合物简记为化合物437;实施例5所得化合物简记为化合物455;实施例6所得化合物简记为化合物469;HS是指高盐饮食诱导的高血压小鼠,WT是指正常的野生型小鼠。
在高盐状态下,TRPV4与KCa2.3的耦联下降,但在使用了实施例1(化合物365)、实施例2(化合物366)、实施例3(化合物491)、实施例4(化合物437)、实施例5(化合物455)、实施例6(化合物469)之后可以增强二者耦联。FRET实验证明:将实施例1、2、3、4、5、6孵育24小时后,TRPV4和KCa2.3的偶联增强了,且都优于已有化合物JNC-440。
实施例8细胞内K
+测定
将肠系膜原代内皮细胞培养3-5天后,与实施例4、5、6以10μmol/L的浓度孵育24小时之后,将培养基弃去,含有PBFI的NPSS以1:200的比例在37℃的培养箱中以黑暗环境中孵育。使用Olympus荧光成像系统在340和380nm处双重激发测量荧光。计算[K
+]的变化作为PBFI比的变化。图1为实施例4化合物相应的[K
+]的变化(在无药物孵育的高盐状态下(对照组Ctrl),钾离子的荧光强度较低,即钾外流的能力减弱。而孵育实施例4之后,其钾外流能力增强。);图2为实施例5、6化合物相应的[K
+]的变化(在无药物孵育的高盐状态下(对照组Ctrl),钾离子的荧光强度较低,即钾外流的能力减弱。而孵育实施例5、6之后,其钾外流能力增强,可恢复受损的功能)。
结果显示,孵育24h后,可显著提高细胞钾外流能力。即改善在高盐状态下由于TRPV4和KCa2.3解偶联导致的钾外流减弱,有效增强TRPV4与KCa2.3之间的耦联。
实施例9体内对高血压小鼠血压的影响探究
使用IITC无创血压计,尾套法对小鼠血压进行测定。最初,将小鼠进行每天训练,至少一周,每次半个小时。每次测试可得到收缩压,舒张压,平均动脉压以及心率。在小鼠适应后,灌胃给予实施例4化合物和实施例5化合物,剂量为30mg/kg,之后定点测定高血压小鼠血压情况,由结果得出,实施例4降压仅持续1.5h,而实施例5可持续降压8h。具体结果见表2和图4和5。
表2化合物在体内对高血压小鼠血压的影响结果
化合物 | 平均动脉压变化值(mmHg) |
JNC-440 | 10 |
实施例4 | 16 |
实施例5 | 38 |
根据测定结果,可以发现:在以30mg/kg的剂量灌胃之后,测量血压发现,实施例4可持续降压1.5h,而实施例5则可以持续降压8h。
图4中的折线图的横坐标为时间,单位小时;纵坐标分别为收缩压(SBP),平均动脉压(MAP),舒张压(DBP),单位为毫米汞柱。使用了实施例4化合物(437)之后,对于高血压小鼠在5小时以内的血压变化情况。柱状图的纵坐标为平均动脉压的变化值,单位为毫米汞柱。表明在使用了实施例4之后,对平均动脉压变化的最大值,即血压下降的最大值。HS是指高盐饮食诱导的高血压小鼠(本实施例体内实验中使用的模型鼠);WT是指正常的野生型小鼠;Ctrl对照组是指利用生理盐水对模型鼠进行灌胃,不给予本申请涉及的化合物。
图5中的折线图的横坐标为时间,单位小时;纵坐标分别为收缩压(SBP),平均动脉压(MAP),舒张压(DBP),单位为毫米汞柱。使用了实施例5化合物(455)之后,对于高血压小 鼠在9小时以内的血压变化情况。柱状图的纵坐标为平均动脉压的变化值,单位为毫米汞柱。表明在使用了实施例5之后,对平均动脉压变化的最大值,即血压下降的最大值。HS是指高盐饮食诱导的高血压小鼠(本实施例体内实验中使用的的模型鼠),WT是指正常的野生型小鼠;Ctrl对照组是指利用生理盐水对模型鼠进行灌胃,不给予本申请涉及的化合物。
实施例10体外代谢测定
体外代谢孵育体系总体积为207μL,有机溶剂少于1%,包括0.1mol/L的PBS缓冲液(pH 7.4)188μL,NADPH发生系统12μL(10μL的A液和2μL的B液临用时冰浴上混合制得)。冰浴上将2μL 20μm/L的实施例4和5加入孵育体系中,37℃水浴中预孵5min;然后冰浴上分别加入5μL不同种属的肝微粒体酶,混匀,37℃水浴中孵育,在0,10,30,60,90,120,180,360,480min时间点加入400μl的冰乙腈(含50ng/ml内标(咖啡因))终止反应,平行实验3次。13000rpm/15min,取上清,送超高效液相色谱串联四级杆飞行时间质谱联用仪检测。结果显示,实施例4的半衰期在2.5h左右,且无种属差异。实施例5的半衰期则在4±0.5h,无种属差异。具体结果见表3。
表3化合物体外代谢的测定结果
化合物 | 在人肝微粒孵育所得半衰期(h) |
JNC-440 | 0.813 |
实施例4 | 2.438 |
实施例5 | 3.350 |
不同种属的代谢结果见表4和表5。
表4化合物(实施例4)在不同种属的肝微粒体中的的测定结果
表5化合物(实施例5)在不同种属的肝微粒体中的代谢的测定结果
图6中横坐标为时间,单位小时;纵坐标为剩余药物百分比(%)时间(h)。该图表明了实施例4(437)在四种不同种属的肝微粒体中的半衰期的推测,分别为mouse(小鼠)、rat(大鼠)、human(人)、dog(狗)的半衰期为2.341小时、2.855小时、2.438小时、2.232小时。
图7中横坐标为时间,单位小时;纵坐标为剩余药物百分比。该图表明了实施例5(455)在两种不同种属的肝微粒体中的半衰期的推测,分别为mouse(小鼠)、human(人)的半衰期为4.23小时、3.35小时。
结合表4、5和图6、7,可发现:实施例4化合物的体外半衰期为2.5h左右,且无种属代谢差异性。而实施例5化合物的体外半衰期为4h左右,同样也无种属代谢差异性。
Claims (10)
- 根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,当R 2为取代基取代或未取代的苯基时,取代基任选自卤素、CF 3、CHF 2、CH 2F、CN的一个或多个取代基取代。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,当R 2为N-芳基氨基时,芳基为取代基取代或未取代的苯基,取代基任选自卤素、CF 3、CHF 2、CH 2F、CN的一个或多个取代基取代。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述的药学上可接受的盐为无机盐或有机盐;所述无机盐包括盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐;所述有机盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、丁二酸盐、戊二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、对甲苯磺酸盐、抗坏血酸盐。
- 权利要求1-4任一项所述的化合物或其药学上可接受的盐在制备用于治疗哺乳动物的高血压、高血脂、冠心病、心绞痛、心肌梗死、猝死、心律失常的药物中的用途。
- 一种药物组合物,其特征在于,包括权利要求1-4任一项所述的化合物或其药学上可接受的盐,以及药学上可接受载体。
- 根据权利要求6所述的药物组合物,其特征在于,所述药物组合药物的剂型包括片剂、丸剂、胶囊剂、散剂、颗粒剂、乳液剂、混悬剂、分散液、溶液剂、酊剂、糖浆剂、软膏剂、滴剂、栓剂、吸入剂、喷射剂。
- 根据权利要求6所述的药物组合物,其特征在于,所述药物组合药物还包括如下任意一种或多种成分:赋形剂、稀释剂、增溶剂、粘合剂、保湿剂、崩解剂、缓溶剂、润湿剂、吸附剂、润滑剂。
- 根据权利要求6所述的药物组合物,其特征在于,所述组合物还包括抗高血压剂。
- 根据权利要求9所述的药物组合物,其特征在于,所述抗高血压剂选自以下:(i)钙通道阻滞剂;(ii)血管紧张素转化酶抑制剂;(iii)利尿剂;(iv)交感神经抑制药;(v)血管扩张药。
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