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WO2025124462A1 - Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique, ainsi que sa préparation et son utilisation - Google Patents

Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique, ainsi que sa préparation et son utilisation Download PDF

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Publication number
WO2025124462A1
WO2025124462A1 PCT/CN2024/138691 CN2024138691W WO2025124462A1 WO 2025124462 A1 WO2025124462 A1 WO 2025124462A1 CN 2024138691 W CN2024138691 W CN 2024138691W WO 2025124462 A1 WO2025124462 A1 WO 2025124462A1
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Prior art keywords
pharmaceutically acceptable
alkoxy
cycloalkyl
compound
alkyl
Prior art date
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English (en)
Chinese (zh)
Inventor
贾振华
王宏涛
侯云龙
齐慧
秘尧
郝媛媛
童亚男
张朋飞
李发光
郝梦安
王晓航
许铎
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Shijiazhuang Yiling Pharmaceutical Co Ltd
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Shijiazhuang Yiling Pharmaceutical Co Ltd
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Publication of WO2025124462A1 publication Critical patent/WO2025124462A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a tricyclic fused heterocyclic compound and a preparation method and application thereof, and in particular, to a tricyclic fused heterocyclic compound and a preparation method thereof and application thereof as a phosphodiesterase PDE3/4 dual inhibitor.
  • Phosphodiesterase belongs to a superfamily enzyme system, including at least 11 families and 22 subtypes, and is involved in intracellular and extracellular information transmission and functional regulation. PDE can catalyze the hydrolysis of intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to generate AMP and GMP, respectively.
  • cAMP cyclic adenosine monophosphate
  • cGMP cyclic guanosine monophosphate
  • the PDE3 family consists of two genes, namely PDE3A and PDE3B.
  • the activity of PDE3 in the respiratory system is mainly concentrated in alveolar macrophages, endothelial cells, and platelets.
  • PDE3 is involved in the regulation of various physiological activities in the body, such as vasodilation of vascular smooth muscle, anti-platelet aggregation, anti-thrombosis, cardiotonic and anti-cell proliferation. Excessive use of PDE3 inhibitors can cause adverse reactions such as hypotension and tachycardia, which greatly limits its clinical application.
  • PDE4 is an enzyme that specifically hydrolyzes cAMP. Its family consists of four subtypes: PDE4A, PDE4B, PDE4C, and PDE4D. Each subtype has a corresponding gene encoding and has different cell distribution and functions. PDE4 is mainly distributed in airway smooth muscle cells, inflammatory cells, and immune cells, regulating intracellular cAMP levels. Currently, most clinical PDE4 inhibitors have a certain degree of side effects, such as gastrointestinal reactions such as nausea and vomiting, and even depression.
  • inhaled PDE3/4 appears to be a more attractive approach to target the key pathological features of COPD and asthma.
  • evidence has shown that inhaled dual-target PDE3/4 inhibitors have synergistic inhibitory effects, including synergistic anti-inflammatory and bronchodilatory effects.
  • CN100415743C discloses a pyrimido[6,1a]isoquinolin-4-one derivative:
  • the compound of the general formula is used as a PDE inhibitor for the treatment of respiratory diseases such as asthma, has a longer duration of action than troquinein, and does not have the very bitter taste of troquinein.
  • An object of the present invention is to provide a novel compound as a PDE inhibitor.
  • Another object of the present invention is to provide a method for preparing the compound.
  • Another object of the present invention is to provide the use of the compound.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the compound and use thereof.
  • Another object of the present invention is to provide an intermediate for preparing the compound.
  • Another object of the present invention is to provide a method for preparing the intermediate.
  • the present invention provides a compound having structural formula I or a pharmaceutically acceptable form thereof,
  • X is selected from C, N, O and S;
  • R 5 is selected from H, halogen, CN, C 1-6 alkoxy, C 1-6 straight chain alkyl, C 3-6 branched chain alkyl and C 3-6 cycloalkyl;
  • n 0, 1 or 2;
  • k 0, 1, or 2;
  • H of the compound of formula I is optionally further substituted with 0 to 6 Ds.
  • R 1 and R 2 are each independently selected from H, CH 3 , CHF 2 , and CD 3 .
  • R 1 and R 2 correspond to the groups or values shown in any one of Compounds 1 to 34, respectively.
  • R 3 , R 4 , and R 5 are each independently selected from H, CH 3 , i-Pr, OMe, CN, CD 3 or halogen.
  • R 3 , R 4 , and R 5 correspond to the groups or values shown in any one of Compounds 1 to 34, respectively.
  • X is selected from C and O; and R 5 is selected from H and C 1-6 alkyl.
  • R 7 is H.
  • n is 0 or 1
  • k is 1 or 2.
  • R 6 corresponds to the group or value shown in any one of Compounds 1 to 34.
  • the compound of formula I of the present invention in the compound of formula I of the present invention or a pharmaceutically acceptable form thereof, the compound has a structure shown in formula Ia:
  • R 8 is selected from amino
  • k 1 or 2.
  • R 8 is selected from amino
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, n, and k correspond to the groups or values shown in any one of Compounds 1 to 34, respectively.
  • the compound of formula I of the present invention in the compound of formula I of the present invention or a pharmaceutically acceptable form thereof, is selected from one or more of the compounds shown in Table 1:
  • the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt or cocrystal, a stereoisomer, a tautomer, a deuterated substance, a solvate, a chelate, a non-covalent complex or a prodrug.
  • the present invention also provides an intermediate compound having a structure shown in Formula II:
  • R1 , R2 , R3 , R4 , R5 , R7 , X, n, k are as defined in any of the embodiments of the compound of formula I or its pharmaceutically acceptable form according to the ⁇ first aspect> of the present invention.
  • R9 and R10 are each independently H, Boc, Cbz, SEM, Fmoc, Alloc, Pht, OTs, PMB, Bn, Trt.
  • the present invention also provides a method for preparing the compound described in the first aspect of the present invention or a pharmaceutically acceptable form thereof.
  • a synthetic route can be designed based on the chemical structure of the compound of formula I or a pharmaceutically acceptable form thereof and with reference to known methods in the art to prepare the compound of formula I or a pharmaceutically acceptable form thereof.
  • the method of preparing the compound of the first aspect of the present invention or a pharmaceutically acceptable form thereof comprises:
  • the intermediate compound of formula II described in the ⁇ second aspect> of the present invention is subjected to modification reaction at the R 9 and R 10 ends to prepare a compound of structural formula I.
  • the method of preparing the compound described in the ⁇ first aspect> of the present invention or a pharmaceutically acceptable form thereof also includes a process for preparing the intermediate compound described in the ⁇ second aspect> of the present invention.
  • the method of preparing the compound described in the ⁇ first aspect> of the present invention or a pharmaceutically acceptable form thereof comprises the steps shown in any reaction scheme in the examples.
  • the present invention also provides a pharmaceutical composition, comprising: the compound described in the ⁇ First Aspect> of the present invention or a pharmaceutically acceptable form thereof (preferably a pharmaceutically acceptable salt), and a pharmaceutically acceptable carrier, excipient and/or one or more other therapeutic agents.
  • the present invention also provides the use of the compound or a pharmaceutically acceptable form thereof (preferably a pharmaceutically acceptable salt) described in the ⁇ first aspect> of the present invention or the pharmaceutical composition described in the ⁇ fourth aspect> of the present invention in the preparation of a preparation for inhibiting phosphodiesterase.
  • the phosphodiesterase includes PDE3 and/or PDE4.
  • the present invention also provides the use of the compound described in the ⁇ first aspect> of the present invention or a pharmaceutically acceptable form thereof (preferably a pharmaceutically acceptable salt) or the pharmaceutical composition described in the ⁇ fourth aspect> of the present invention in the preparation of a drug for treating phosphodiesterase-related diseases.
  • the present invention also provides a method for treating phosphodiesterase-related diseases, which comprises administering to a subject an effective amount of the compound described in the ⁇ First Aspect> of the present invention or a pharmaceutically acceptable form thereof (preferably a pharmaceutically acceptable salt) or the pharmaceutical composition described in the ⁇ Fourth Aspect> of the present invention.
  • the phosphodiesterase comprises PDE3 and/or PDE4.
  • the phosphodiesterase-related disease includes a respiratory disease such as asthma.
  • the subject is a mammal or a human, preferably, the subject is a human.
  • the compound of the present invention having structural formula I or a pharmaceutically acceptable form thereof can be used as a phosphodiesterase inhibitor, has a highly effective inhibitory activity on phosphodiesterase, especially PDE3 and/or PDE4, and has practical value.
  • the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention, prepared from a compound having a specific substituent discovered by the invention and a relatively nontoxic acid or base.
  • a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, phosphate-hydrogen, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and the like; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid.
  • Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • utectic refers to a crystalline material comprising two or more distinct solids at room temperature, each solid having different physical properties, such as structure, melting point, and heat of fusion.
  • stereoisomer refers to a stable isomer that has a vertical asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane polarized light. Since there are asymmetric centers and other chemical structures that may cause stereoisomerism in the compounds of the present invention, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention and their salts may include asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, enantiomers and mixtures of diastereomers. Generally, these compounds can be prepared in the form of racemic mixtures.
  • such compounds can be prepared or separated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or single stereoisomer-enriched (purity ⁇ 98%, purity ⁇ 95%, ⁇ 93%, ⁇ 90%, ⁇ 88%, ⁇ 85% or ⁇ 80%) mixtures.
  • a single stereoisomer of a compound is synthesized from an optically active starting material containing the desired chiral center, or prepared by preparing a mixture of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatography, use of a chiral resolution agent, or direct separation of enantiomers on a chiral chromatographic column.
  • Starting compounds with specific stereochemistry are either commercially available or prepared as described herein and resolved by methods well known in the art. Unless otherwise indicated, all stereoisomeric forms of the compounds of the invention are within the scope of the compounds of the invention.
  • tautomer refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers include (but are not limited to) interconversions through proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imino alcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the compounds of the present invention.
  • the compounds represented by the structural formulas of the present invention may be in the form of a purified single stereoisomer or tautomer, or in the form of a mixture containing a plurality of stereoisomers or tautomers.
  • solvate refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates, ethanolates, acetoneates, and the like.
  • chelate refers to a complex having a ring structure, which is obtained by chelation of two or more ligands with the same metal ion to form a chelate ring.
  • non-covalent complex is formed by the interaction of a compound with another molecule, wherein no covalent bond is formed between the compound and the molecule.
  • complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also known as ionic bonding).
  • prodrug refers to a derivative compound that can directly or indirectly provide a compound of the present invention after being applied to a patient.
  • Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compound of the present invention when administered to a patient (e.g., more easily absorbed into the blood), or compounds that promote the delivery of the parent compound to the site of action (e.g., the lymphatic system).
  • all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.
  • substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl.
  • substituent Y may be hydrogen, halogen, hydroxyl, cyano, alkyl or aryl; similarly, when substituent Y is hydrogen, substituent X may be hydrogen, halogen, hydroxyl, cyano, alkyl or aryl.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis of chemical achievable.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • variable in a structural formula When a variable in a structural formula is selected from missing, it means that it does not exist. For example, when R in C-R is selected from missing, it means that the structure is actually C.
  • variable connecting two groups in a structural formula When a variable connecting two groups in a structural formula is selected from a bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in A-L-Z represents a bond or does not exist, it means that the structure is actually A-Z.
  • substituent When the substituent is listed without indicating through which atom it is connected to the substituted group, such substituent can be bonded through any atom thereof.
  • a phenyl substituent can be bonded to the substituted group through any carbon atom on the benzene ring.
  • alkyl is used to refer to a straight or branched saturated hydrocarbon group, which may be monosubstituted (e.g., -CH 2 F) or polysubstituted (e.g., -CF 3 ), and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine).
  • alkyl groups examples include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • alkylene refers to a divalent straight or branched alkane group consisting only of carbon atoms and hydrogen atoms, containing no saturation, and connected to other fragments by two single bonds, including (but not limited to) methylene, 1,1-ethylene and 1,2-ethylene, etc.
  • C 1-3 alkylene refers to a saturated divalent straight or branched alkyl group containing from 1 to 3 carbon atoms.
  • cycloalkyl includes any stable cyclic or polycyclic hydrocarbon radical, any carbon atom is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or polyvalent.
  • cycloalkyl radicals include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like.
  • alkoxy means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein.
  • C1-5 alkoxy includes C1, C2, C3, C4 and C5 alkoxy.
  • Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy.
  • the alkoxy group may be optionally substituted with one or more substituents described herein.
  • 3-6 membered ring means a saturated or unsaturated monocyclic ring with or without heteroatoms, which contains 3, 4, 5 or 6 C, O, S, N atoms in the ring; the "3-6 membered ring” can be connected to the rest of the structural formula through any carbon atom or, if present, a nitrogen atom.
  • amino refers to -NH2 , -NH(alkyl), or -N(alkyl)(alkyl).
  • aromatic ring means a polyunsaturated aromatic alkane monocyclic ring which may be mono- or polysubstituted.
  • 4-6 membered heterocycloalkyl means a saturated monovalent monocyclic hydrocarbon ring containing 3, 4 or 5 carbon atoms and one or more heteroatom groups selected from O, NR a , wherein Ra represents a hydrogen atom or a C 1-6 alkyl group; the "4-6 membered heterocycloalkyl” can be connected to the rest of the molecule through any carbon atom or, if present, a nitrogen atom.
  • heteromatic ring refers to an aromatic ring containing one to four heteroatoms selected from one or more of N, O and S.
  • the term "3-8 membered heterocyclyl" used in the present invention refers to a heterocyclyl having 3 to 8 ring atoms.
  • the heterocyclyl group can be oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, or trithianyl.
  • aryl refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated ⁇ electron system.
  • C 6-10 aryl used in the present invention refers to an aryl group having 6 to 10 carbon atoms.
  • the aryl group can be phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthenyl, azulenyl, fluorenyl, indenyl, pyrenyl, etc.
  • heteroaryl refers to a monocyclic or fused polycyclic aromatic group having a conjugated ⁇ electron system, whose ring atoms are composed of carbon atoms and at least one heteroatom selected from N, O and S. If the valence bond requirements are met, the heteroaryl can be connected to the rest of the molecule through any one of the ring atoms.
  • heteroaryl used in the present invention refers to a heteroaryl having 5 to 10 ring atoms.
  • the heteroaryl can be thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and benzo derivatives thereof, pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, purinyl, etc.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • hydroxy refers to -OH.
  • cyano refers to -CN.
  • amino refers to -NH 2 .
  • the term “pharmaceutical composition” refers to a mixture of one or more compounds of the present invention or a pharmaceutically acceptable form and other chemical components, wherein “other chemical components” refers to a pharmaceutically acceptable carrier, excipient and/or one or more other therapeutic agents.
  • Carrier refers to a material that does not significantly irritate the organism and does not eliminate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate the administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders and disintegrants.
  • the compound of the present invention has good PDE inhibitory activity and has potential application value in treating diseases related to PDE, especially diseases related to PDE3/PDE4.
  • the structures of the compounds were determined by nuclear magnetic resonance or mass spectrometry.
  • Nuclear magnetic resonance was measured using a BRUKER 400M nuclear magnetic spectrometer, the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ) or deuterated chloroform (CDCl 3 ), the internal standard was tetramethylsilane (TMS), and the chemical shift ( ⁇ ) was given in units of 10 -6 (ppm).
  • Mass spectra were measured using a Waters ACQUITY Arc/ACQUITY QDa or Thermo U3000-ISQ EC LC/MS instrument.
  • Thermo U3000 high pressure liquid chromatograph was used for HPLC analysis.
  • Hanbang DAC-50 or Shimadzu LC-20AP preparative chromatograph was used for HPLC preparation.
  • Reaction monitoring uses thin layer chromatography or liquid chromatography-mass spectrometry.
  • the developing solvent systems used in thin layer chromatography are: dichloromethane and methanol system, petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, or a small amount of triethylamine is added to adjust it.
  • Liquid chromatography-mass spectrometry uses Waters ACQUITY Arc/ACQUITY QDa or Thermo U3000-ISQ EC liquid chromatography-mass spectrometer.
  • the eluent system includes: dichloromethane and methanol system, petroleum ether and ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound, or a small amount of triethylamine is added for adjustment.
  • reaction temperature was room temperature (20° C. to 30° C.), and the solvents were dried and purified according to standard methods.
  • triethylamine (26.4 g, 260.2 mmol, 20.0 eq.), 1,3-bis(diphenylphosphino)propane (1.1 g, 2.6 mmol, 0.2 eq.) and palladium acetate (0.6 g, 2.6 mmol, 0.2 eq.) were added in batches to a solution of 2-chloro-6,8-dimethylquinoline (2.5 g, 13.1 mmol, 1.0 eq.) and methyl acrylate (11.2 g, 130.1 mmol, 10.0 eq.) in N,N-dimethylformamide (20 ml) at room temperature. The residue was stirred and reacted overnight at 100 degrees Celsius under nitrogen protection.
  • the reaction mixture was cooled to room temperature.
  • the reaction mixture was extracted with ethyl acetate (3x 50 ml).
  • the organic phases were combined, backwashed with saturated sodium chloride solution (2x 30 ml), and dried over sodium sulfate.
  • the resulting mixture was filtered and the filtrate was concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography to give methyl (2E)-3-(6,8-dimethylquinolin-2-yl)prop-2-enoate (1.5 g, yield 43%) as a solid.
  • the obtained residue was purified by reverse phase column chromatography under the following conditions: column specifications, mobile phase, water and acetonitrile, 10% to 90% gradient in 30 minutes, UV254 nanometer detector to obtain 3-(1-(9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrimidin[6,1-a]isoquinolin-2-yl)6,8-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)ethylurea (200 mg, yield 70%).
  • the FP method was used to test the PDE enzyme activity inhibition experiment of the compounds in each example, and comparative example compound 1 (Compound RPL-554 in Example 1 of CN100415743C) and comparative example compound 2 were used as positive controls.
  • PDE enzyme and substrate FAM-cyclic AMP/cyclic AMP solution in reaction buffer (1 ⁇ IMAP Reaction Buffer containing 0.1% BSA supplemented with 1mM DTT).
  • the starting concentration of the positive control in PDE is 1/10 ⁇ M, 3-fold dilution, 10+0 dose.
  • 0.05 ⁇ L of compound in 100% DMSO was delivered to a 384-well plate (Corning 4514) by acoustic liquid delivery technology (Echo 655), centrifuged at 1000 rpm for 1 minute; 2.5 ⁇ L of PDE enzyme solution was transferred to a 384 reaction plate and centrifuged at 1000 rpm for 1 minute, incubated at 25°C for 10 minutes; 2.5 ⁇ L of Sub solution was transferred to a 384 reaction plate, centrifuged at 1000 rpm for 1 minute, incubated at 25°C for 60 minutes; 15 ⁇ L of binder mixture was transferred to a 384 reaction plate and centrifuged at 1000 rpm for 1 minute, incubated at 25°C for 60 minutes; finally, FP signals were read using BMG (PHERAstar FSX). IC50 values and nonlinear regression curve fitting were obtained using GraphPad Prism software.

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  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé inhibiteur de phosphodiestérase, son procédé de préparation et son utilisation. En particulier, l'invention concerne un composé de formule structurale (I) ou une forme pharmaceutiquement acceptable de celui-ci, chaque substituant étant tel que défini dans la description, respectivement. Le composé selon l'invention ou sa forme pharmaceutiquement acceptable peut être utilisé comme inhibiteur de phosphodiestérase et présente une activité élevée.
PCT/CN2024/138691 2023-12-13 2024-12-12 Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique, ainsi que sa préparation et son utilisation Pending WO2025124462A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1348453A (zh) * 1999-03-31 2002-05-08 韦尔纳利斯有限公司 嘧啶并[6,1－a] 异喹啉－4－酮衍生物
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
CN103183675A (zh) * 2011-12-27 2013-07-03 山东轩竹医药科技有限公司 磷酸二酯酶-4抑制剂
US20180132516A1 (en) * 2016-11-16 2018-05-17 Sensorygen, Inc. Positive allosteric modulators of sweet taste
WO2020011254A1 (fr) * 2018-07-13 2020-01-16 正大天晴药业集团股份有限公司 Composé tri-cyclique condensé en tant que double inhibiteur de pde3/pde4
WO2023109802A1 (fr) * 2021-12-14 2023-06-22 海思科医药集团股份有限公司 Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique et son utilisation
WO2023138676A1 (fr) * 2022-01-21 2023-07-27 四川海思科制药有限公司 Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique et son utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1348453A (zh) * 1999-03-31 2002-05-08 韦尔纳利斯有限公司 嘧啶并[6,1－a] 异喹啉－4－酮衍生物
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
CN103183675A (zh) * 2011-12-27 2013-07-03 山东轩竹医药科技有限公司 磷酸二酯酶-4抑制剂
US20180132516A1 (en) * 2016-11-16 2018-05-17 Sensorygen, Inc. Positive allosteric modulators of sweet taste
WO2020011254A1 (fr) * 2018-07-13 2020-01-16 正大天晴药业集团股份有限公司 Composé tri-cyclique condensé en tant que double inhibiteur de pde3/pde4
WO2023109802A1 (fr) * 2021-12-14 2023-06-22 海思科医药集团股份有限公司 Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique et son utilisation
WO2023138676A1 (fr) * 2022-01-21 2023-07-27 四川海思科制药有限公司 Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique et son utilisation

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