WO2022267930A1 - Composé tricyclique, son procédé de préparation et son utilisation médicale - Google Patents

Composé tricyclique, son procédé de préparation et son utilisation médicale Download PDF

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WO2022267930A1
WO2022267930A1 PCT/CN2022/098560 CN2022098560W WO2022267930A1 WO 2022267930 A1 WO2022267930 A1 WO 2022267930A1 CN 2022098560 W CN2022098560 W CN 2022098560W WO 2022267930 A1 WO2022267930 A1 WO 2022267930A1
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alkyl
cycloalkyl
aryl
heteroaryl
amino
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PCT/CN2022/098560
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English (en)
Chinese (zh)
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闫旭
史建新
刘国标
陈士柱
刘原也
陈雷
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中国医药研究开发中心有限公司
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Priority to CN202280005551.XA priority Critical patent/CN115843293A/zh
Publication of WO2022267930A1 publication Critical patent/WO2022267930A1/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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles

Definitions

  • the present application relates to a tricyclic compound for preventing and/or treating diseases caused by biologically active carbonyl substances, a preparation method thereof, and a pharmaceutical composition containing the tricyclic compound.
  • Active carbonyl compounds represented by aldehyde compounds generally refer to all highly active electrophilic compounds containing one or more carbonyl groups, which have a wide range of sources and participate in many life behaviors and physiological activities.
  • Aldehydes are ubiquitous in the environment, from air, water, and soil to food, daily necessities, and indoor living places (Koren and Bisesi, CRC press, 2002). Natural sources of aldehydes include a range of pathways including plants, animals, microorganisms, and natural life processes (O'Brien et al., Critical reviews in toxicology, 2005, 35(7):609-662.).
  • plants are the most important source of aldehydes, such as vanillin, cinnamaldehyde, benzaldehyde, citral, crotonaldehyde, etc. are usually plant-derived aldehydes (Koren and Bisesi, CRC press, 2002; Feron et al., Mutation Research/Genetic Toxicology, 1991, 259(3-4):363-385.).
  • Man-made sources are mainly car exhaust, burning substances, cigarette smoking, overcooking of certain foods, industrial emissions, etc.
  • aldehydes produced from these sources include formaldehyde, acetaldehyde, benzaldehyde, propionaldehyde, acrolein, Glyoxal, glutaraldehyde, crotonaldehyde, m-tolualdehyde, 2,5-dimethylbenzaldehyde, 3-hydroxybenzaldehyde, etc.
  • formaldehyde acetaldehyde
  • benzaldehyde propionaldehyde
  • acrolein Glyoxal
  • glutaraldehyde crotonaldehyde
  • m-tolualdehyde 2,5-dimethylbenzaldehyde
  • 3-hydroxybenzaldehyde etc.
  • aldehydes are also produced in vivo through different physiological processes, such as lipid peroxidation, biotransformation of drugs and food, intermediates of biosynthetic and catabolic pathways, and endogenous generation of enzymatic reactions, etc.
  • active carbonyl compounds have high reactivity, and they can act as electrophiles and nucleophiles for addition reactions. This electrophile-nucleophile reaction and the resulting adducts are the physiological functions of aldehydes. and the main causes of toxicity. Its overexpression and clearance barriers involve but are not limited to mitochondrial damage, membrane damage, endoplasmic reticulum stress, activation of inflammatory mediators, immune dysfunction, etc. (Moghe et al., Toxicological Sciences, 2015, 143(2): 242-255 .).
  • 4-hydroxy-2-nonenal and nonenal produced in the process of lipid peroxidation are very easy to react with low molecular weight compounds or macromolecules (such as proteins and DNA) in physiological systems.
  • the diseases related to its adducts include cancer, neurodegenerative diseases, chronic inflammatory diseases and autoimmune diseases, etc. (Barrera et al., Antioxidants&redox signaling, 2015, 22(18):1681-1702.).
  • aldehydes Under normal physiological systems, aldehydes are in a state of equilibrium, but when this balance is disrupted, aldehydes, proteins, nucleic acids, and phospholipids conjugates, advanced lipid oxidation end products (ALE) and advanced glycation end products (AGE) will occur Generation and accumulation (Singh et al., The Korean Journal of Physiology & Pharmacology, 2014, 18(1): 1-14.).
  • ALE advanced lipid oxidation end products
  • AGE advanced glycation end products
  • methylglyoxal a by-product of glucose metabolism
  • arginine (Arg) and lysine (Lys) on proteins to form imidazolinone and carboxyethyl lysine; carbohydrates and ascorbate autoxidation products
  • Dialdehyde can form carboxymethyllysine with Lys.
  • the dicarbonyl group can directly and specifically act on the Arg residue, and the Arg residue has the highest probability of being located at the functional site of the protein. Therefore, the Arg modification leads to the loss of the side chain guanidino group and important functional Arg residues.
  • the protein carbonylation content is usually 1-5%, but when aging and disease occur, its content increases.
  • Methylglyoxal and glyoxal-modified proteins will be recognized by the body as misfolded proteins and directly degraded by the proteasome (Thornalley et al., Nucleic acids research, 2010, 38(16):5432-5442.).
  • Carbonyl stress induced by reactive carbonyl compounds can lead to non-specific modification of proteins and genetic material, resulting in cytotoxicity. Carbonyl stress can mediate mitochondrial protein dysfunction and increased reactive oxygen species formation (Yao and Brownlee, Diabetes, 2010,59(1):249-255.), crystallin and inflammatory protein expression (Yao and Brownlee, Diabetes, 2010, 59(1):249-255.; Ahmed et al., Diabetologia, 2005,48(8):1590-1603.), blood lipid-related lipoprotein abnormalities (Rabbani et al., Diabetologia.233 SPRING ST, NEW YORK, NY 10013 USA : SPRINGER,2009,52:S498-S499.), mitochondrial apoptosis pathway activation (Chan et al., Journal of cellular bi°Cchemistry, 2007,100(4):1056-1069.), cells detach from extracellular matrix and Apoptosis (Dobler et al., Diabetes, 2006, 55(7):19
  • the protein damage caused by reactive carbonyl substances is not only through carbonyl stress, but also may modify the amino acid side chain residues of specific proteins through the oxidative stress formed by strengthening the generation of reactive oxygen species, resulting in protein carbonylation, resulting in changes in protein activity and function. Protein carbonylation reversibly and irreversibly changes the spatial conformation of the polypeptide chain, partially or completely inhibits protein activity and causes cell dysfunction and tissue damage.
  • highly reactive carbon-based compounds can also lead to a decrease in enzyme activity through modification of the enzyme structure.
  • the reductase activity of liver mitochondrial cytochrome C is negatively correlated with protein carbonylation, indicating that protein oxidation can significantly reduce enzyme activity (Bruno et al., Journal of proteome research, 2009, 8(4):2070-2078.).
  • Active carbonyl species increase protein oxidation and carbonylation by inhibiting key cellular enzymes such as glutathione reductase and peroxidase (Shangari et al., Bi°Cchemical pharmacology, 2006,71(11):1610-1618.) .
  • adipocyte fatty acid-binding protein-4 and epidermal fatty acid-binding protein-5 are carbonylated, resulting in reduced ability to bind fatty acids, reduced lipolysis and obesity.
  • Fatty acid transporters containing two cysteine (Cys) residues are also susceptible to carbonylation (Febbraio et al., Cellular Lipid Binding Proteins. Springer, Boston, MA, 2002: 193-197.).
  • Fatty acid-binding proteins prevent lipotoxicity of long-chain fatty acids by binding or cross-linking with oxidized reactive long-chain fatty acids, and depletion of hepatic fatty acid-binding proteins will convert nonalcoholic fatty liver disease to nonalcoholic steatohepatitis (Charlton et al. Hepatology, 2009, 49(4):1375-1384.).
  • reactive carbonyl species derived from lipids and carbohydrates are more stable in nature, can integrate into or even escape cellular degradation, and can attack targets after formation. Therefore, these soluble active mediators and AGE precursors are not only cytotoxic, but also act as mediators and disseminators of oxidative stress and tissue damage, acting as "cytotoxic second messengers", and are risk factors for various diseases throughout the body.
  • cardiovascular diseases such as atherosclerosis, hypertension, cardiopulmonary dysfunction, etc.
  • respiratory diseases such as airway neuroinflammation, chronic obstructive pulmonary disease, respiratory allergy , asthma, etc.
  • neurodegenerative diseases such as Alzheimer's disease
  • diabetes and its complications eye diseases, such as dry eye, cataract, retinopathy, keratoconus, Fucker's endothelial dystrophy, retinal pigment Degeneration, glaucoma, allergic conjunctivitis, uveitis
  • skin diseases such as psoriasis, psoriasis, contact dermatitis, atopic dermatitis, acne, Sjogren's syndrome, etc.
  • autoimmune diseases such as lupus erythematosus, etc.
  • nervous system diseases such as autism, central nervous system toxicity, amyotrophic lateral sclerosis, etc.
  • digestive system diseases such as neurohepatitis, alcoholic liver disease, non-alcoholic fatty liver, ulcerative colitis, etc.
  • obesity cancer and aging-related diseases. Reduction or elimination of reactive carbonyl species can therefore ameliorate or alleviate the symptoms of these pathologies.
  • the inventors designed and synthesized a series of tricyclic compounds, which can be used to prevent and treat diseases related to active carbonyl compounds.
  • an object of the present invention is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • a 1 is selected from N or CR 1 ;
  • a 2 is selected from N or CR 2 ;
  • a 3 is selected from N or CR 3 ;
  • a 4 is selected from N or CR 4 ;
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more groups of Q replace;
  • R and R are each independently selected from hydrogen , halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycle radical, aryl, heteroaryl, -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a ;
  • R and R are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycle radical, aryl, heteroaryl, -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a ;
  • R and R are each independently selected from hydrogen, halogen, amino, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, One or more groups of carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl replace;
  • R 5 and R 6 form a cycloalkyl or heterocyclic group together with the carbon atoms they are connected to; the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, One or more of mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group substitution;
  • Q is selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a , wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, al
  • R a and R b are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more groups of radical, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
  • R a and R b form a nitrogen-containing heterocyclic group together with the nitrogen atom to which they are attached, and the nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto , carboxyl, ester group, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups;
  • n is an integer of 0 to 2.
  • the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein, A 1 is selected from CR 1 ; A 2 is selected from N or CR 2 ; R 1 and R 2 are each independently selected from hydrogen, halogen, amino, cyano, hydroxyl , mercapto, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably, R 1 and R 2 are independently Earth is hydrogen.
  • the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Ring A is C 3 -C 8 cycloalkyl or 5 to 8 membered heterocyclic group, preferably C 5 -C 6 cycloalkyl or 5 to 7 membered heterocyclic group; the cycloalkyl or heterocyclic group is optionally further Substituted by one or more groups selected from Q;
  • Q is selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a , wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, al
  • R a and R b are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more groups of radical, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
  • R a and R b form a nitrogen-containing heterocyclic group together with the nitrogen atom to which they are attached, and the nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto , carboxyl, ester group, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups;
  • n is an integer of 0 to 2.
  • the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Ring A is C 6 -C 10 aryl or 5-6 membered heteroaryl, and the C 6 -C 10 aryl or 5-6 membered heteroaryl is optionally further selected from one or more groups of Q replace;
  • Q is selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) m R a , -S(O) m NR a R b , -NHS(O) m R a , wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl Optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, al
  • R a and R b are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more groups of radical, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted;
  • R a and R b form a nitrogen-containing heterocyclic group together with the nitrogen atom to which they are attached, and the nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto , carboxyl, ester group, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups;
  • n is an integer of 0 to 2.
  • the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein ring A is selected from The Q ring is defined as further defined in A through the optional formula (further I). Substituted by one or more groups from Q;
  • Q is selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, said C 1 -C 6 alkyl, C 3 - C 6 cycloalkyl, C 6 -C 10 aryl are optionally further selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C Substituted by one or more groups of 6 haloalkoxy.
  • the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (II) or a tautomer, mesoform, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • A is selected from N or CH ;
  • a 5 and A 6 are each independently selected from -O-, -S-, -NH-, -CH 2 -, -CH 2 -O-; preferably -O-;
  • Q is selected from halogen, oxo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, the C 1 -C 6 alkyl, C 3 -C 6 ring Alkyl, C 6 -C 10 aryl is optionally further selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy One or more groups of radicals are substituted;
  • n 0, 1, 2;
  • R 5 and R 6 are as defined in general formula (I).
  • the compound represented by the general formula (I) or (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (III) or tautomers, mesomers, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • A is selected from N or CH ;
  • a 5 and A 6 are each independently selected from -O-, -S-, -NH-, -CH 2 -, -CH 2 -O-; preferably -O-;
  • Q 1 is selected from halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl is optionally further selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy are substituted by one or more groups;
  • R 7 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • p 0, 1, 2;
  • R 5 and R 6 are as defined in general formula (I).
  • R 5 and R 6 are each independently selected from hydrogen, halogen, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl; the C 1 -C 6 alkyl, C 3 -C 6 cycloalkane The group is optionally further substituted by one or more groups selected from halogen;
  • the cycloalkyl or heterocyclic group is optionally further selected from halogen, amino , nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl or Multiple group substitutions.
  • R 5 and R 6 are each independently selected from C 1 -C 6 alkyl, preferably methyl.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention further provides a method for preparing the compound represented by the general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer Construct, or its mixture form, or the method for pharmaceutically acceptable salt thereof, it comprises the following steps:
  • Compound Ig is reacted with an alkyl Grignard reagent to obtain a compound of general formula (I), and the alkyl Grignard reagent is preferably methylmagnesium chloride or methylmagnesium bromide; the reaction is preferably carried out in a solvent, and the solvent is preferably anhydrous Tetrahydrofuran;
  • a 1 , A 2 , A 3 , A 4 , ring A, R 5 , and R 6 are as defined in general formula (I).
  • the present invention further provides a pharmaceutical composition, which contains the compound represented by the general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which contains the compound represented by the general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention further provides the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its mixture form, or its pharmaceutically acceptable salt, or the pharmaceutical composition containing it in the preparation of toxic aldehyde scavenger.
  • the present invention further provides the compound represented by general formula (I) according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a medicament for preventing and/or treating diseases related to active carbonyl compounds.
  • Another aspect of the present invention provides a compound represented by general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a toxic aldehyde scavenger.
  • Another aspect of the present invention provides a compound represented by general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer
  • the isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, is used as a medicament; preferably, the medicament is used for preventing and/or treating diseases related to active carbonyl compounds.
  • Another aspect of the present invention provides a compound represented by general formula (I) according to the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer
  • a method for preventing and/or treating diseases related to active carbonyl compounds comprising administering a preventive or therapeutically effective amount of the compound represented by general formula (I) or its compound according to the present invention to a patient in need Tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • Diseases related to active carbonyl compounds according to the present invention can be eye diseases, skin diseases, autoimmune diseases, digestive system diseases, cardiovascular diseases, respiratory diseases, neurodegenerative diseases, obesity, cancer and aging Associated diseases; preferably eye diseases, more preferably allergic conjunctivitis and dry eye.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used.
  • Soft gelatin capsules provide an oral formulation.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural
  • the resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorb
  • Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners.
  • preservatives such as ethyl or n-propylparaben
  • coloring agents such as ethyl or n-propylparaben
  • flavoring agents such as sucrose, saccharin, or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension can provide the active ingredient by the addition of water and for mixing a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing, wetting and suspending agents are as mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then treated in a mixture of water and glycerol to form a microemulsion.
  • the injectable solution or microemulsion can be injected into the patient's bloodstream by local bolus injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition of the present invention may be in the form of sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing agents, wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are prepared as injectables.
  • the pharmaceutical composition of the present invention may be in a form for topical administration, for example: cream, suspension, emulsion, ointment, gel, drop, oil, lotion, film, patch, tape, inhalant ,spray.
  • Intraocular administration may be in the form of subconjunctival, subfascial capsules; retrobulbar or intravitreal injections, depot injections, or implants.
  • Compounds administered by these routes can be in the form of solutions or suspensions.
  • Compounds administered by depot injection may contain a pharmaceutically acceptable carrier or excipient.
  • These pharmaceutically acceptable carriers or excipients may be natural or synthetic, and may be biodegradable or non-biodegradable, and facilitate the release of the drug in a controlled manner.
  • Implants for controlled release of compounds may be constructed of natural or synthetic, biodegradable or non-biodegradable materials.
  • the carrier is acceptable because it is compatible with the other components of the composition and is not deleterious to the patient.
  • Some examples of carriers include sugars such as lactose glucose and sucrose; starches such as corn starch and potato starch; cellulose; and cyclodextrins.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc.
  • the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • the present invention can contain the compound represented by the general formula (I), and its pharmaceutically acceptable salt, hydrate or solvate as the active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into clinically acceptable dosage forms.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like.
  • the compound of the present invention can be used as the sole active ingredient, or it can be used in combination with other therapeutic agents. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogens involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C, and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen ), tritium (T, also known as tritium), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
  • isotopes of carbon include 12 C, 13 C, and 14 C
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom of the alkyl group.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • alkylene refers to straight-chain and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10, preferably an integer from 1 to 6), and examples of the alkylene group include But not limited to methylene, ethylene, propylene and butylene, etc.; alkylene can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, The substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano radical, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkenylene refers to straight and branched divalent alkenyl groups, wherein alkenyl is as defined above.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg ethynyl, propynyl, butynyl and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynylene refers to straight and branched divalent alkynyl groups, wherein alkynyl is as defined above.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 10 carbon atoms, more preferably containing 3 to 7 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 5 to 12 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 12 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or a heteroatom of S(O) m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 5 to 12 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyls include:
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 5 to 12 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated ⁇ -electron system, preferably 6 to 14 10-membered, such as phenyl and naphthyl, more preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred examples are imidazolyl, furyl, thienyl, thiazolyl, pyryl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrimidyl Azolyl or thiazolyl.
  • the heteroaryl ring may be fused to an
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl or cycloalkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • haloalkyl refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • mercapto refers to -SH.
  • ester group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are independently substituted by a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Fig. 1 is a graph showing the time variation of the capture reaction of nonenal by the compounds of the examples of the present invention.
  • Fig. 2 is a graph showing the therapeutic scoring results of the compound of Example 12 of the present invention on C48/80-induced Wistar rat allergic conjunctivitis animal model.
  • the compounds of the present invention are prepared utilizing convenient starting materials and general preparative procedures.
  • the present invention gives typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimum conditions may vary with specific reactants or solvents used, but in general, reaction optimization steps and conditions can be identified.
  • protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions.
  • Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art.
  • Protecting Groups in Organic Preparations by T.W. Greene and G.M. Wuts (3rd Edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protecting groups.
  • the isolation and purification of compounds and intermediates takes appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods Mixed use.
  • specific usage method please refer to the examples described in the present invention.
  • other similar separation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • the lc6000 high performance liquid chromatograph (manufacturer: Innovation Tongheng) was used for the preparative liquid chromatography.
  • the thin-layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate, the specification of the silica gel plate used for thin-layer chromatography (TLC) is 0.20mm ⁇ 0.25mm, and the specification for the preparation of thin-layer chromatography (Prep-TLC) separation and purification products is used The specification is 0.5mm.
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide and other companies.
  • the reactions can all be carried out under a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Reaction solvents organic solvents or inert solvents are each expressed as the solvent used does not participate in the reaction under the described reaction conditions, including, such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc.
  • the solution refers to an aqueous solution.
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction temperature is between -78°C and 200°C.
  • the reaction time and conditions are, for example, between -78°C and 200°C under one atmospheric pressure, and the reaction is completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.
  • TLC thin layer chromatography
  • the eluent system of column chromatography and the developing agent system of thin layer chromatography that purify compound adopts include: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, the volume ratio of solvent according to The polarity of the compound can be adjusted, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.
  • 2,3-Dihydrobenzofuran-5-amine (10.0 g, 74.0 mmol) was dissolved in 1,4-dioxane (100 mL) at room temperature. Cool down to 0 °C, then add acetic anhydride (1.50 g, 148 mmol), pyridine (5.85 g, 74.0 mmol). Stir the reaction at 25°C for 16 hours, add 200 mL of water to the reaction solution, extract with 300 mL of ethyl acetate, and extract the aqueous phase twice with 100 mL of ethyl acetate.
  • N-(6-nitro-2,3-dihydrobenzofuran-5-yl)acetamide 8.00g, 36.2mmol
  • ethanol 300mL
  • hydrochloric acid 50mL, 33 %
  • ammonia water was added dropwise to make it weakly alkaline, filtered, and the obtained filter cake was dried to obtain 6.00 g of the title product as an orange-red solid, yield: 92.1%.
  • 6-Nitro-2,3-dihydrobenzofuran-5-amine (7.00 g, 38.9 mmol) was dissolved in hydrochloric acid (20 mL) at room temperature. The temperature was raised to 100° C., stirred for 10 minutes, cooled to 0° C., and saturated sodium nitrite solution (3.22 g, 46.7 mmol) was added dropwise. The reaction was stirred at 0°C for 30 minutes, and potassium iodide solution (9.68 g, 58.3 mmol) was added dropwise. The temperature was raised to 70°C, and the reaction was stirred for 2 hours.
  • reaction solution was poured into saturated NaHSO 3 solution, extracted with 300 mL ethyl acetate, and the organic phase was washed successively with hydrochloric acid (50 mL, 10%), NaOH solution (50 mL), Na 2 SO 3 solution (50 mL), and saturated brine, Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Step 10 Preparation of 1-(7-(ethoxycarbonyl)-2,3-dihydrofuro[3,2-g]quinolin-6-yl)pyridin-1-ium bromide (1j)
  • reaction solution in the previous step was cooled to 18-22°C, and 6-amino-2,3-dihydrobenzofuran-5-carbaldehyde (270mg, 1.65mmol) and pyridine (700mg, 8.47mmol) were added. Stir overnight at 80°C under a nitrogen atmosphere, and the reaction solution is directly used in the next step.
  • the reaction solution in the previous step was cooled to 70°C, morpholine (800 mg, 9.20 mmol) was added, and stirred at 80°C for 18 hours under a nitrogen atmosphere.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 12 Preparation of 2-(6-amino-2,3-dihydrofuro[3,2-g]quinolin-7-yl)propan-2-ol (1)
  • Step 7 Preparation of 1-(3-ethoxy-2,3-dioxopropyl)pyridine-1-ammonium bromide (1i)
  • Step 8 Preparation of 1-(6-(ethoxycarbonyl)-2,3-dihydrofuro[2,3-g]quinolin-7-yl)pyridin-1-ium bromide (2g)
  • reaction solution in the previous step was cooled to 18-22°C, and 5-amino-2,3-dihydrobenzofuran-6-carbaldehyde (2f) (50.0 mg, 0.600 mmol) and pyridine (743 mg, 9.40 mmol) were added. Stir overnight at 80°C under a nitrogen atmosphere, and the reaction solution is directly used in the next step.
  • Step 9 Preparation of ethyl 7-amino-2,3-dihydrofuro[2,3-g]quinoline-6-carboxylate (2h)
  • the reaction solution in the previous step was cooled to 70°C, morpholine (887mg, 10.2mmol) was added, and stirred at 80°C for 18 hours under a nitrogen atmosphere.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 10 Preparation of 2-(7-amino-2,3-dihydrofuro[2,3-g]quinolin-6-yl)propan-2-ol (2)
  • Step 6 Preparation of 1-(2-(ethoxycarbonyl)-7,8-dihydro-6H-cyclopenta[g]quinolin-3-yl)pyridin-1-ium bromide (3f)
  • reaction solution in the previous step was cooled to 18-22°C, and 6-amino-2,3-dihydro-1H-indene-5-carbaldehyde (140mg, 0.62mmol) and pyridine (251mg, 3.17mmol) were added. Under a nitrogen atmosphere, it was stirred at 80° C. overnight, and the reaction solution was directly used in the next step.
  • Step 7 Preparation of ethyl 3-amino-7,8-dihydro-6H-cyclopenta[g]quinoline-2-carboxylate (3 g)
  • Step 8 Preparation of 2-(3-amino-7,8-dihydro-6H-cyclopenta[g]quinolin-2-yl)propan-2-ol (3)
  • methylmagnesium chloride (3N, 0.78mL, 2.34mmol) was added to THF (10mL) at 0°C, followed by 3-amino-7,8-dihydro-6H dissolved in THF (10mL) -Ethyl cyclopenta[g]quinoline-2-carboxylate (100 mg, 0.390 mmol), stirred at room temperature for 4 hours.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • 6-amino-1,3-dihydroisobenzofuran-5-carboxylic acid methyl ester (1.80g, 9.30mmol) was dissolved in tetrahydrofuran (20mL), then cooled to 0°C, and four Lithium aluminum hydride (354 mg, 9.30 mmol).
  • the reaction was stirred at room temperature for 0.5 hour, 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • reaction solution in the previous step was cooled to 18-22°C, 6-amino-1,3-dihydroisobenzofuran-5-aminoformaldehyde (300mg, 1.84mmol) and pyridine (743mg, 9.40mmol) were added, and the Stirring at 80°C overnight, the reaction solution was directly used in the next step.
  • the reaction solution in the previous step was cooled to 70°C, morpholine (887mg, 10.2mmol) was added, and the reaction was stirred at 80°C for 18 hours under a nitrogen atmosphere.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 8 Preparation of 2-(3-amino-6,8-dihydrofuro[3,4-g]quinolin-2-yl)propan-2-ol (4)
  • Step 6 1-(6-(Ethoxycarbonyl)-2,2-difluoro-[1,3]dioxolano[4,5-g]quinolin-7-yl)pyridine-1- Preparation of onium bromide (5e)
  • reaction solution in the previous step was cooled to 18-22°C, and 6-amino-2,2-difluorobenzo[d][1,3]dioxolane-5-carbaldehyde (200mg, 1.00mmol) and Pyridine (183 mg, 2.32 mmol) was stirred at 80° C. for 9 hours under a nitrogen atmosphere, and the reaction solution was directly used in the next step.
  • Step 7 Preparation of ethyl 7-amino-2,2-difluoro-[1,3]dioxolano[4,5-g]quinoline-6-carboxylate (5f)
  • the reaction solution in the previous step was cooled to 70°C, morpholine (487mg, 5.60mmol) was added, and then heated to 80°C, and stirred at 80°C for 4 hours under a nitrogen atmosphere.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 8 2-(7-Amino-2,2-difluoro-[1,3]dioxolano[4,5-g]quinolin-6-yl)propan-2-ol (5) preparation
  • methylmagnesium chloride (3N, 0.97mL, 2.92mmol) was added dropwise to THF (10mL) at 0°C, and then 7-amino-2,2-difluoro-[ 1,3] Ethyl dioxopenta[4,5-g]quinoline-6-carboxylate (100 mg, 0.338 mmol), stirred at room temperature for 2 hours.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 4 Preparation of ethyl 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carboxylate (6d)
  • ethyl 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carboxylate (1.70g, 5.67mmol) was dissolved in Tetrahydrofuran (5 mL) and methanol (5 mL), then water (5 mL) and NaOH (2.27 g, 56.7 mmol) were added. Stir at room temperature for 16 hours.
  • Step 7 Preparation of 6-amino-2-methyl-2-phenylbenzo[d][1,3]dioxolane-5-carbaldehyde (6 g)
  • Step 8 Preparation of ethyl 7-amino-2-methyl-2-phenyl-[1,3]dioxolano[4,5-g]quinoline-6-carboxylate (6h)
  • 2-methyl-5-nitrobenzoic acid methyl ester (5.00g, 25.6mmol) was added to a dry 250mL one-necked flask, carbon tetrachloride (100mL), N-bromosuccinyl Amine (NBS) (9.10 g, 51.2 mmol), azobisisobutyronitrile (AIBN) (420 mg), heated to 80°C and stirred for 16 hours.
  • Step 7 Preparation of 6-amino-5-(hydroxymethyl)-2-methylisoindolin-1-one (7 g)
  • Step 8 Preparation of 6-amino-2-methyl-1-oxoisoindoline-5-carbaldehyde (7h)
  • Step 9 Preparation of ethyl 3-amino-7-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (7i)
  • 1-(3-Ethoxy-2,3-dioxopropyl)pyridin-1-ammonium bromide 147 mg, 0.760 mmol was dissolved in ethanol (5 mL) at room temperature. Add pyridine (70.0 mg, 0.890 mmol), heat to 65° C., and stir for 1 hour. Cool down to room temperature, add 6-amino-2-methyl-1-oxoisoindoline-5-carbaldehyde (120mg, 0.630mmol) and pyridine (130mg, 1.65mmol), heat to 85°C, and stir for 5 hours .
  • 6-amino-2-benzyl-1-oxoisoindoline-5-carboxylic acid ethyl ester (3.35 g, 10.8 mmol) was dissolved in tetrahydrofuran (70 mL) middle. Under a nitrogen atmosphere, lithium aluminum hydride (821mg21.6mmol) was slowly added at 0°C, and reacted for 1 hour at 0°C.
  • Step 7 Preparation of ethyl 3-amino-7-benzyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (8g)
  • Step 8 Preparation of ethyl 3-amino-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-2-carboxylate (8h)
  • Step 9 Preparation of 3-amino-2-(2-hydroxypropan-2-yl)-6,7-dihydro-8H-pyrrolo[3,4-g]quinolin-8-one (8)
  • Step 8 Preparation of 6-amino-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde (9h)
  • Step 10 1-(7-(Ethoxycarbonyl)-3-oxo-3,4-dihydro-2H-[1,4]oxazino[2,3-g]quinolin-8-yl) Preparation of pyridin-1-ium bromide (9i).
  • Step 11 Preparation of ethyl 8-amino-3-oxo-3,4-dihydro-2H-[1,4]oxazino[2,3-g]quinoline-7-carboxylate (9j)
  • the reaction solution in the previous step was cooled to 70°C, morpholine (487mg, 5.60mmol) was added, and then heated to 80°C, and stirred at 80°C for 4 hours under a nitrogen atmosphere.
  • 50 mL of water was added to the reaction solution, extracted with 50 mL of dichloromethane, and the aqueous phase was extracted twice with 50 mL of dichloromethane.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 12 Preparation of 8-amino-7-(2-hydroxypropan-2-yl)-2H-[1,4]oxazino[2,3-g]quinolin-3(4H)-one (9)
  • methylmagnesium chloride (3N, 0.97mL, 2.92mmol) was added dropwise to THF (10mL) at 0°C, and then 8-amino-3-oxo-3,4 dissolved in THF (10mL) -Ethyl dihydro-2H-[1,4]oxazino[2,3-g]quinoline-7-carboxylate (70.0 mg, 0.244 mmol), stirred at room temperature for 2 hours.
  • naphthalene-2,3-diol (3.00g, 18.7mmol) was added to acetic acid (30mL), bromine (5.77g, 36.1mmol) was added thereto, and the reaction solution was heated to 120°C and stirred for 45 minutes . Cool to room temperature, pour into ice water, add ethyl acetate for extraction, concentrate under reduced pressure, and recrystallize the residue with acetic acid to obtain 6.00 g of the title compound as a yellow solid, yield: 67.0%.
  • 1,4,6,7-tetrabromonaphthalene-2,3-diol (5.00 g, 11.0 mmol) was added to acetic acid (100 mL), and stannous chloride (20.0 g, 88.0 mmol) was added, The reaction liquid was warmed up to 120°C and stirred for 45 minutes. Cool to room temperature, concentrate under reduced pressure, and recrystallize the residue from toluene. The crude title compound, 3.00 g, was obtained as a white solid.
  • Step 3 Preparation of 8,9-dibromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepane (11c).
  • Step 5 Preparation of 9-bromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepan-8-amine (11e)
  • N-(9-bromo-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepan-8-yl)-1,1- Diphenylformimine (900mg, 1.97mmol) was added to tetrahydrofuran (50mL), 3M hydrochloric acid (10mL), then the system was stirred at room temperature for 16 hours, concentrated under reduced pressure, the residue was extracted with ethyl acetate, saturated sodium carbonate The solution was washed, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developer: EA) to obtain 450 mg of the title compound as light yellow oil, yield: 78.0 %.
  • Step 6 Preparation of methyl 9-amino-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepane-8-carboxylate (11f)
  • Step 7 2-(9-Amino-3,4-dihydro-2H-naphtho[2,3-b][1,4]dioxepan-8-yl)propan-2-ol ( 11) Preparation.
  • methylmagnesium chloride (3mol/L, 2.00mL) was added into anhydrous tetrahydrofuran (10mL), and slowly added dropwise to 9-amino-3,4-dihydro-2H- Methyl naphtho[2,3-b][1,4]dioxepane-8-carboxylate (100 mg, 0.366 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred for 1 hour.
  • reaction solution was quenched with saturated aqueous ammonium chloride (10mL), extracted with ethyl acetate (40mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was prepared by preparative liquid chromatography Separation (column model: Gemini-C18 150 x 21.2mm, 5um, mobile phase: acetonitrile/water, gradient: 10%-90%) gave 20.0 mg of the title compound as a white solid, yield: 30.0%.
  • Step 1 Preparation of 6,7-dibromo-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolane (12a)
  • reaction solution was cooled and concentrated under reduced pressure.
  • Step 3 Preparation of 7-bromo-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolan-6-amine (12c)
  • Step 4 Preparation of methyl 7-amino-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolane-6-carboxylate (12d)
  • methyl 7-amino-2-methyl-2-phenylnaphtho[2,3-d][1,3]dioxolane-6-carboxylate 300mg , 0.895mmol was added to a solution of methylmagnesium bromide (2.09mL, 3mol/L) in anhydrous tetrahydrofuran (10mL). Stir at 0°C for 3 hours under nitrogen atmosphere.
  • reaction solution was quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (40 mL ⁇ 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was prepared by preparative liquid chromatography Separation (column model: Gemini-C18 150*21.2mm, 5um, mobile phase: acetonitrile/water 0.05% formic acid, gradient: 2min-30% ⁇ 22min-70%), 20.0mg of the title compound was obtained as a white solid, yield: 6.67%.
  • Examples 12A and 12B (S)-2-(7-Amino-2-methyl-2-phenyl-naphtho[2,3-d][1,3]dioxolane-6- base) propan-2-ol and (R)-2-(7-amino-2-methyl-2-phenyl-naphtho[2,3-d][1,3]dioxolane-6 -yl)propan-2-ol (12A and 12B) Preparation
  • Compound 13 was prepared according to the synthesis method of Example 12, except that 4-methylacetophenone was used instead of acetophenone to obtain 15.0 mg of the title compound as an off-white solid, yield: 5.00%.
  • Compound 14 was prepared according to the synthesis method of Example 12, except that 4-chloroacetophenone was used instead of acetophenone to obtain 70.0 mg of the title compound as an off-white solid, yield: 58.0%.
  • Compound 15 was prepared according to the synthesis method of Example 12, except that 4-chloro-2-fluoroacetophenone was used instead of acetophenone to obtain 15.0 mg of the title compound as an off-white solid, yield: 15.0%.
  • Compound 16 was prepared according to the synthesis method of Example 12, except that 3-chloro-acetophenone was used instead of acetophenone to obtain 33.0 mg of the title compound as an off-white solid, yield: 16.5%.
  • Compound 17 was prepared according to the synthesis method of Example 12, except that 2-chloro-acetophenone was used instead of acetophenone to obtain 29.6 mg of the title compound as an off-white solid, yield: 11.8%.
  • Compound 18 was prepared according to the synthesis method of Example 12, except that 3-fluoroacetophenone was used instead of acetophenone to obtain 40.0 mg of the title compound as an off-white solid, yield: 20.0%.
  • Compound 19 was prepared according to the synthesis method of Example 12, except that 2-fluoroacetophenone was used instead of acetophenone to obtain 17.0 mg of the title compound as an off-white solid, yield: 6.0%.
  • Compound 20 was prepared according to the synthesis method of Example 12, except that 4-fluoropropiophenone was used instead of acetophenone to obtain 20.0 mg of the title compound as an off-white solid, yield: 7.1%.
  • Compound 21 was prepared according to the synthesis method of Example 12, except that 1-(4-methoxyphenyl)ethan-1-one was used instead of acetophenone to obtain 40.0 mg of the title compound as an off-white solid, yield: 30.0%.
  • Compound 22 was prepared according to the synthesis method of Example 12, except that 4-fluoroacetophenone was used instead of acetophenone to obtain 20.0 mg of the title compound as an off-white solid, yield: 6.6%.
  • Compound 23 was prepared according to the synthesis method of Example 12, except that cyclopropylbenzophenone was used instead of acetophenone to obtain 10.0 mg of the title compound as an off-white solid, yield: 10.0%.
  • the aldehyde capture test disclosed in the present invention adopts nonenal, a lipid metabolite with stable properties, as a model aldehyde to react with the example compound, and the specific scheme is as follows.
  • Liquid chromatograph Waters I Class
  • Liquid phase conditions mobile phase A: acetonitrile solution containing 0.1% formic acid; B: aqueous solution containing 0.1% formic acid;
  • the injection volume is 0.5mL.
  • the retention time of the model aldehyde nonenal was 2.42 minutes.
  • the aldehyde capture rate is represented by the slope of the capture curve per unit time. The larger the absolute value of the slope, the faster the capture rate.
  • the compounds of the examples of the present invention have the ability to capture aldehydes.
  • Test example 2 Therapeutic effect of the compound of the present invention on allergic conjunctivitis animal model
  • C48/80 is a polymer formed by the condensation of N-methyl-p-methoxyphenethylamine and formaldehyde, which can directly act on G protein and induce mast cell degranulation. After degranulation, mast cells release histamine, Active substances such as kinins can cause acute type I allergic reactions such as telangiectasia and increased permeability. It can cause allergic conjunctivitis if applied topically to the ocular surface.
  • the Wistar rats (Victoria Lihua) were randomly divided into groups, with 6 animals in each group.
  • the groups are as follows: normal control group, model control group, positive drug group, embodiment administration group.
  • the normal control group did not carry out verification model building, and the rest of the groups were all carried out model establishment, and the positive drug was emedastine fumarate eye drops ( Alcon, H20181192).
  • the process of model establishment, drug administration and evaluation is as follows:

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Abstract

L'invention concerne un composé tricyclique et son procédé de préparation, et son utilisation médicale. En particulier, la présente invention concerne un composé chimique représenté par la formule générale (I), une composition pharmaceutique le contenant, son procédé de préparation, et son application dans la prévention et/ou le traitement de diverses maladies provoquées par des aldéhydes toxiques. Les définitions de chaque groupe dans la formule générale (I) sont telles que présentées dans la description.
PCT/CN2022/098560 2021-06-25 2022-06-14 Composé tricyclique, son procédé de préparation et son utilisation médicale WO2022267930A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105120866A (zh) * 2013-01-23 2015-12-02 奥尔德拉医疗公司 与毒性醛相关的疾病和治疗
WO2017035077A1 (fr) * 2015-08-21 2017-03-02 Aldeyra Therapeutics, Inc. Composés deutérés et leurs utilisations
WO2018039192A1 (fr) * 2016-08-22 2018-03-01 Aldeyra Therapeutics, Inc. Composés de piégeage d'aldéhydes et leurs utilisations
WO2018039197A1 (fr) * 2016-08-22 2018-03-01 Aldeyra Therapeutics, Inc. Composés de piégeage d'aldéhydes et leurs procédés d'utilisation
CN108135867A (zh) * 2015-08-21 2018-06-08 奥尔德拉医疗公司 醛结合物和其用途
WO2021136244A1 (fr) * 2019-12-30 2021-07-08 中国医药研究开发中心有限公司 Composé tricyclique et son procédé de préparation et son utilisation médicale

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105120866A (zh) * 2013-01-23 2015-12-02 奥尔德拉医疗公司 与毒性醛相关的疾病和治疗
WO2017035077A1 (fr) * 2015-08-21 2017-03-02 Aldeyra Therapeutics, Inc. Composés deutérés et leurs utilisations
CN108135867A (zh) * 2015-08-21 2018-06-08 奥尔德拉医疗公司 醛结合物和其用途
WO2018039192A1 (fr) * 2016-08-22 2018-03-01 Aldeyra Therapeutics, Inc. Composés de piégeage d'aldéhydes et leurs utilisations
WO2018039197A1 (fr) * 2016-08-22 2018-03-01 Aldeyra Therapeutics, Inc. Composés de piégeage d'aldéhydes et leurs procédés d'utilisation
WO2021136244A1 (fr) * 2019-12-30 2021-07-08 中国医药研究开发中心有限公司 Composé tricyclique et son procédé de préparation et son utilisation médicale

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