WO2026008076A1 - Dérivé de flavonoïde contenant un donneur d'oxyde nitrique - Google Patents

Dérivé de flavonoïde contenant un donneur d'oxyde nitrique

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Publication number
WO2026008076A1
WO2026008076A1 PCT/CN2025/107263 CN2025107263W WO2026008076A1 WO 2026008076 A1 WO2026008076 A1 WO 2026008076A1 CN 2025107263 W CN2025107263 W CN 2025107263W WO 2026008076 A1 WO2026008076 A1 WO 2026008076A1
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Prior art keywords
alkylene
cycloalkyl
heterocyclic
alkyl
independently selected
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PCT/CN2025/107263
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English (en)
Chinese (zh)
Inventor
张飞
王森
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Suzhou Raymon Pharmaceuticals Company Ltd
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Suzhou Raymon Pharmaceuticals Company Ltd
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Publication of WO2026008076A1 publication Critical patent/WO2026008076A1/fr
Pending legal-status Critical Current
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to the field of pharmaceutical technology, and in particular to a class of flavonoid derivatives or pharmaceutically acceptable salts containing nitric oxide donors, their preparation methods, pharmaceutical compositions, and their use in the treatment of ophthalmic diseases related to ocular hypertension and optic nerve damage.
  • Glaucoma is a group of eye diseases characterized by retinal ganglion cell degeneration, specific optic nerve atrophy, and progressive visual field loss. It is primarily associated with pathological increases in intraocular pressure and is the most common cause of irreversible blindness.
  • the signaling pathways involved in the pathogenesis of glaucoma are highly complex, with downstream signaling factors often interfering with each other.
  • the main pathological mechanisms involve the upregulation of pro-apoptotic gene expression, the downregulation of neuroprotective and regenerative factors, and the production and action of factors that promote optic nerve damage. A series of changes at the molecular and cellular levels lead to impaired aqueous humor drainage and optic nerve damage, ultimately resulting in blindness.
  • Nitric oxide is an important intercellular signaling agent. In vivo, NO binds to soluble guanylate cyclase (sGC), which then converts guanosine triphosphate into cyclic guanosine monophosphate (cGMP). cGMP acts as a second messenger, regulating smooth muscle relaxation and vasodilation, as well as many other important biological processes, such as cell growth and differentiation, and platelet inhibition.
  • sGC soluble guanylate cyclase
  • cGMP cyclic guanosine monophosphate
  • NO plays an important physiological role in regulating optic nerve head blood flow and intraocular pressure (IOP).
  • NO donors reduce vascular resistance by relaxing smooth muscle, leading to local vasodilation and increased blood flow to the optic disc. Conversely, damage to the NO pathway reduces blood flow to the optic disc, resulting in ischemia.
  • cNOS Structural nitric oxide synthase
  • Schlemm's tubes trabecular meshwork
  • effusion ducts trabecular fibers of the ciliary muscle.
  • TM trabecular meshwork
  • NO donors can reduce IOP in animal models.
  • Mice overexpressing endothelial nitric oxide synthase (eNOS) have lower IOP; in contrast, eNOS knockout mice (mice lacking the functional eNOS gene, and therefore without endogenous eNOS) have elevated IOP.
  • sGC knockout mice show elevated IOP and optic nerve degeneration.
  • the mechanism by which NO reduces IOP appears to be through inhibition of actin-myosin interactions, thereby relaxing cells in the TM and Schlemm's tubes, leading to increased aqueous humor outflow and decreased IOP.
  • Glaucoma Treatment of glaucoma presents several challenges.
  • primary open-angle glaucoma is a chronic, progressive optic neuropathy characterized by optic nerve damage and obstruction of aqueous humor outflow from the trabecular meshwork.
  • R 5 is selected from hydrogen, -OH, -OC 1-10 alkyl groups, and... Each alkyl group is either unsubstituted or substituted with at least one substituent selected independently from RX5 ;
  • R1 and R2 or “ R1 and R4 ” or “ R2 and R3 ” or “ R6 and R7 ” or “ R7 and R8 ” or “ R8 and R9 ” or “ R9 and R10 ” together with the carbon atoms attached to them form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted by at least one substituent independently selected from RX ;
  • Each RA1 , RA2 , RA3, RA4 , RA6 , RA7, RA8 , RA9, RA10 , RB1 , RB2 , RB3 , RB4 , RB6 , RB7 , RB8 , RB9, and RB10 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl , C2-10 alkynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclic , -C1-4 alkylene- heterocyclic , aryl, -C1-4 alkylene -aryl, heteroaryl, -C1-4 alkylene-heteroaryl, and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is either unsubstituted or substituted by at least one
  • RA1 and RB1 or “ RA2 and RB2 ” or “ RA3 and RB3 ” or “RA4 and RB4” or “ RA6 and RB6 ” or “ RA7 and RB7 ” or “ RA8 and RB8 ” or “ RA9 and RB9 ” or “ RA10 and RB10 ” together with one or more atoms attached to them constitute a 4-12 membered heterocycle containing 0, 1 or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen and phosphorus, which is either unsubstituted or substituted with 1, 2 or 3 substituents selected from RX ;
  • R 11 is selected from hydrogen and C 1-10 alkyl groups, wherein the alkyl group is unsubstituted or substituted by at least one substituent independently selected from R X11 ;
  • Each Rc and Rd is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, M, -C1-4 alkylene-M, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclic group is unsubstituted or substituted by at least one substituent independently selected from R Y ;
  • Each M is independently selected from a NO donor
  • Each Ra1 and Rb1 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, -C1-4 alkylene-aryl, heteroaryl, -C1-4 alkylene-heteroaryl, and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is either unsubstituted or substituted by at least one substituent independently selected from R and Y ;
  • Ra1 and Rb1 together with one or more atoms attached to them form a 4-12 membered heterocycle containing 0, 1 or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen and phosphorus, which is either unsubstituted or substituted with 1, 2 or 3 substituents selected from R Y.
  • Each Rc1 and Rd1 is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, -C1-4 alkylene -aryl, heteroaryl, -C1-4 alkylene-heteroaryl, and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is either unsubstituted or substituted by at least one substituent independently selected from R and Y ;
  • each Rc1 and Rd1 together with one or more carbon atoms attached to them can form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which is either unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R and Y.
  • Each R Y is independently selected from halogen, NO2 , -CN, C1-10 alkyl, -OH, -O ( C1-10 alkyl), -O ( C3-10 cycloalkyl), -O ( C1-4 alkylene- C3-10 cycloalkyl), -O (heterocyclic), -O ( C1-4 alkylene-heterocyclic), -SH, -S ( C1-10 alkyl), -S ( C3-10 cycloalkyl), -S ( C1-4 alkylene- C3-10 cycloalkyl), -S (heterocyclic), -S ( C1-4 alkylene-heterocyclic), -NH2 , -NH (C1-10 alkyl), -N ( C1-10 alkyl), -NH ( C3-10 cycloalkyl), -NH ( C1-4 alkylene- C3-10 cycloalkyl), -NH (heterocyclic), and -NH (
  • Each r is independently selected from 1 and 2;
  • Each t is independently selected from integers between 0 and 10;
  • Each u is independently selected from integers between 0 and 10;
  • Each k is independently selected from 1, 2, 3, and 4;
  • Each q is independently selected from 0, 1, 2, and 3;
  • the total number of M molecules is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the use of the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the preparation of medicaments for treating diseases, symptoms or conditions selected from intraocular pressure-related diseases and optic nerve damage-related diseases is provided.
  • Figures 1 to 5 show the protective effects of compounds 001, 004, 005, 006, and 007 against NMDA-induced retinal nerve cell damage, respectively.
  • Figure 6 shows the IOP response of normal-toning beagle dogs to solvent, timolol maleate, and compounds 004, 005, 006, and 007.
  • the vertical axis represents the change in intraocular pressure relative to baseline ( ⁇ IOP%).
  • ⁇ IOP% the change in intraocular pressure relative to baseline
  • Figure 7 shows the IOP response of a rat model of high intraocular pressure to solvent, timolol maleate, and compounds 001, 005, and 007.
  • Figure 8 shows the IOP response of a rat model of high intraocular pressure to solvent, timolol maleate, and compounds 001, 005, and 007.
  • the vertical axis represents the change in intraocular pressure relative to baseline ( ⁇ IOP%).
  • C1 - C10 or “ C1-10” covers the range of 1 to 10 carbon atoms and should be understood to also cover any subranges within it and each point value, such as C2-3 , C2-4 , C2-5 , C3-4 , C3-5 , C3-6 , C3-7 , C1-2 , C1-3 , C1-4 , C1-5 , C1-6 , C1-7 , C1-8 , C1-9 , etc. , as well as C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , etc.
  • C 3 -C 10 or “C 3-10” should also be understood in a similar way. For example, they can encompass C 3-4 , C 3-5 , C 3-6 , C 3-7 , C 3-8 , C 4-5 , C 4-6, C 4 -C 7 , C 5 - C 6 , and C 3 , C 4 , C 5 , C 6 , C 7, C 8 , C 9 , C 10 , etc.
  • the expression “3-14 yuan” should be understood as encompassing any subrange and each point value within it, such as 3-4, 3-5, 3-6 , 3-7, 3-8, 4-5, 4-6, 4-7, 5-6, 3, 4, 5, 6, or 7 yuan, etc.
  • the expressions "3-12 yuan,”"3-7yuan,” and “4-8 yuan” should also be understood in a similar way.
  • any variable e.g., RX
  • RX e.g., RX
  • each RX is independently selected means that if there are multiple RX , the options for each RX substituent are independent of each other in each case.
  • Other variables or statements should be understood in a similar manner.
  • substitution and “substituted” refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state.
  • connection point of a substituent may be any suitable location of the substituent.
  • the bond of a substituent is such that it is a bond that passes through the ring and connects two atoms, such a substituent may be bonded to either cyclic atom in the substituted ring.
  • halogen or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.
  • hydrocarbon group refers to a monovalent group derived from a hydrocarbon.
  • hydrocarbon groups include, but are not limited to, alkyl, alkenyl, alkynyl, cyclic hydrocarbon, and aryl groups.
  • alkyl refers to a saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, connected to the rest of the molecule by a single bond.
  • Alkyl groups include straight-chain alkyl groups and branched-chain alkyl groups.
  • Alkyl groups can contain 1-10 carbon atoms and are called C1-10 alkyl groups, such as C1-6 alkyl, C1-4 alkyl, C1-3 alkyl, C1-2 alkyl, C3 alkyl, C4 alkyl, and C3-6 alkyl.
  • Non-limiting examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc.
  • Non-limiting examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethyl
  • a divalent group is a group obtained by removing a hydrogen atom from an atom with free valence electrons in a corresponding monovalent group.
  • a divalent group has two connection sites that attach to the rest of the molecule, and these two connection sites can be located on the same atom or two different atoms of the divalent group.
  • alkylene or “alkylidene” refers to a saturated divalent hydrocarbon group.
  • Alkylenes include straight-chain or branched alkylenes. Examples of straight-chain alkylenes include, but are not limited to, methylene ( -CH2- ), -( CH2 ) 2- , -( CH2 ) 3- , -( CH2 ) 4- , -( CH2 ) 5- , -( CH2 ) 6- , etc.
  • branched alkylene groups include, but are not limited to, -CH( CH3 )-, -CH( C2H5 )-, -CH( CH3 ) -CH2- , -CH( C3H7 )-, -CH(C2H5 ) -CH2-, -C( CH3 ) 2 - CH2- , -(CH( CH3 )) 2- , -CH( CH3 )-( CH2 ) 2- , -CH2 -CH( CH3 ) -CH2- , -CH( C4H9 )-, -C (CH3 ) (C3H7 ) -, -C( C2H5 ) 2- , -CH( C3H7 ) -CH2- , -CH ( C2H5 )-CH( CH3 )-, and -CH ( C2H5 ) -( CH2 ) 2- .
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond.
  • Alkenyl groups can have 2-8 carbon atoms, i.e., "C 2-8 alkenyl,” such as C 2-4 alkenyl and C 3-4 alkenyl.
  • Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, etc.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond.
  • Alynyl groups can have 2-8 carbon atoms, i.e., "C 2-8 alkynyl,” such as C 2-4 alkynyl and C 3-4 alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl-1-alkynyl, propynyl-2-alkynyl, butynyl-1-alkynyl, butynyl-2-alkynyl, butynyl-3-alkynyl, etc.
  • Imyynyl refers to an unsaturated divalent hydrocarbon group having at least one triple bond. Imyynyl groups include straight-chain or branched-chain ynylyl groups. Examples of straight-chain ynylyl groups include, but are not limited to, -C ⁇ C-, -CH2 -C ⁇ C-, -( CH2 ) 2- C ⁇ C-, -( CH2 ) 3- C ⁇ C-, and -CH( CH3 )-C ⁇ C-.
  • cyclic hydrocarbon group refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group consisting of carbon and hydrogen atoms, preferably containing one or two rings.
  • the cyclic hydrocarbon group can be monocyclic, fused polycyclic, bridged, or spirocyclic.
  • the cyclic hydrocarbon group can have 3-10 carbon atoms, i.e., "C 3-10 cyclic hydrocarbon group,” such as C 3-8 , C 5 , C 6 , and C 7 cyclic hydrocarbon groups.
  • Non-limiting examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclic [2.2.1]heptyl, and spiro[3.3]heptyl.
  • the C atoms in the cyclic hydrocarbon group are optionally substituted with oxo groups.
  • the C atoms in the cyclic hydrocarbon group are optionally substituted with imino groups.
  • the imino group is substituted with -OR, where R is H or a C 1-10 alkyl group.
  • cycloalkyl and “cycloalkyl” have the same meaning herein and are used interchangeably.
  • a cycloalkyl group refers to a saturated cyclic hydrocarbon group.
  • a cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, or 10 cyclic carbon atoms (C 3-10 ).
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, and bicyclo[2.1.1]hexyl.
  • the cycloalkyl group is a C 3-7 monocyclic or bicyclic cycloalkyl group, preferably a C 3-6 monocyclic cycloalkyl group, particularly cyclopropyl.
  • heterocyclic group refers to a monocyclic or bicyclic cyclic system (3-14-membered, 7-14-membered, 3-8-membered, 3-7-membered, 4-6-membered, 5-6-membered) having, for example, 3-14 (e.g., 7-14, 3-8, 3-7, 4-6-membered, or 5-6-membered) ring atoms, wherein at least one ring atom (e.g., 1, 2, or 3) is a heteroatom selected from oxygen, sulfur, nitrogen, and phosphorus, and the remaining ring atoms are carbon atoms.
  • the cyclic system can be saturated (also understood as the corresponding "heterocyclic alkyl") or unsaturated (i.e., having one or more double and/or triple bonds within the ring).
  • the heterocyclic group can be benzofused.
  • the "heterocyclic group” or “heterocyclic hydrocarbon group” is not aromatic.
  • the C, N, S, and P atoms in the heterocycle are optionally substituted with oxygen.
  • the C, S, and P atoms in the heterocycle are optionally substituted with imino groups.
  • the imino group is substituted with -OR, where R is H or a C1-10 alkyl group.
  • the heterocyclic group can be, for example, a four-membered ring, such as azahexacyclic butyl or oxacyclic butyl; or a five-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyrrolinyl, oxopyrrolyl, 2-oxoimidazolidin-1-yl; or a six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, 1,1-dioxo-1,2-thiazin-2-yl or trithiaalkyl; or a seven-membered ring, such as diazacyclic butyl.
  • Base ring such as azahexacyclic butyl or oxacyclic butyl
  • Heterocyclic groups can be bicyclic, without limitation, such as five-membered fused five-membered rings, like octahydrocyclopentane[c]pyrrolithyl; or five-membered fused six-membered bicyclic rings, like octahydropyrrolo[1,2-b]pyrazinyl.
  • heterocycles can be unsaturated, meaning they can contain one or more double bonds without limitation.
  • unsaturated heterocycles containing nitrogen atoms can be 1,6-dihydropyrimidine, 1,2-dihydropyrimidine, 1,4-dihydropyrimidine, 1,6-dihydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-1H-pyrrole, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl rings.
  • Unsaturated heterocycles containing oxygen atoms can be 2H-pyran, 4H-pyran, or 2,3-dihydrofuran.
  • Unsaturated heterocycles containing sulfur atoms can be 2H-thiaran or 4H-thiaran.
  • Heterocycles can be benzofused without limitation, such as dihydroisoquinoline rings.
  • Exemplary bicyclic heterocyclic rings also include:
  • aryl refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic (e.g., bicyclic) ring with a conjugated ⁇ -electron system.
  • an aryl group can have 6-14 carbon atoms, suitably 6-10, and more preferably 6 or 10.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene.
  • heteroaryl should be understood to preferably refer to a monovalent monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 7, 8, 9, or 10 ring atoms ("5-10 heteroaryl"), particularly 5, 6, 9, or 10 ring atoms, and the ring atoms contain at least one (suitably 1-4, more preferably 1, 2, or 3) heteroatoms that may be the same or different, said heteroatoms being, for example, oxygen, nitrogen, or sulfur. Furthermore, in each case, the heteroaryl group may be benzofused.
  • the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, in
  • nitric oxide donor refers to a chemical structure that produces or releases NO in vivo.
  • the NO donor releases NO stably via a chemical process.
  • the NO donor may have a functional group capable of releasing NO, such as a nitroso or nitrosyl group; or, the NO donor may release NO under the catalysis of an enzyme; or, the NO donor may release NO through an oxidation or reduction reaction.
  • the NO donor contains a nitrate ester structure. In one embodiment, the nitrate ester is an alkyl nitrate ester. In one embodiment, the NO donor contains an azooxide structure. In one embodiment, the azooxide structure comprises... In one embodiment, the NO donor contains a furazan nitride structure. In another embodiment, the furazan nitride structure comprises... R can be, for example, CN or benzenesulfonyl.
  • Endogenous NO is primarily synthesized in vivo by nitric oxide synthase.
  • Three isoforms of this enzyme have been identified: endothelial NOS (eNOS) and neuronal NOS (nNOS), which are structurally expressed and whose NO production is highly regulated; and inducible NOS (iNOS), which is expressed in damaged tissues and whose NO production is largely uncontrolled, leading to higher local NO concentrations and thus cytotoxicity.
  • eNOS endothelial NOS
  • nNOS neuronal NOS
  • iNOS inducible NOS
  • iNOS expression is often associated with inflammatory responses.
  • Flavonoids are a class of compounds with a 2-phenylchromone skeleton. Some natural flavonoids have been reported in the literature to possess antioxidant, anti-inflammatory, vascular endothelial protective, and anti-angiogenic activities. Among these, antioxidant effects include scavenging reactive oxygen species (ROS) or inhibiting ROS production.
  • ROS reactive oxygen species
  • intraocular pressure-related diseases refers to ophthalmic diseases associated with or responding to intraocular pressure levels; it is a group of clinically heterogeneous diseases. Their sites of onset are not limited to the eye.
  • Normal intraocular pressure refers to intraocular pressure under normal physiological conditions.
  • high intraocular pressure refers to intraocular pressure that is higher than normal.
  • high intraocular pressure refers to intraocular pressure of approximately 8 mmHg or higher, approximately 9 mmHg or higher, approximately 10 mmHg or higher, approximately 11 mmHg or higher, approximately 12 mmHg or higher, approximately 13 mmHg or higher, approximately 14 mmHg or higher, approximately 15 mmHg or higher, approximately 16 mmHg or higher, approximately 17 mmHg or higher, approximately 18 mmHg or higher, approximately 19 mmHg or higher, approximately 20 mmHg or higher, approximately 21 mmHg or higher, approximately 22 mmHg or higher, approximately 23 mmHg or higher, approximately 24 mmHg or higher, approximately 25 mmHg or higher, approximately 26 mmHg or higher, approximately 27 mmHg or higher, approximately 28 mmHg or higher, approximately 29 mmH
  • the individual is a person, and "high intraocular pressure” refers to an intraocular pressure, for example, above approximately 20 mmHg. Intraocular pressure can be measured using a tonometer. High intraocular pressure can cause compression and ischemia of the retina and optic nerve, leading to retinal and optic nerve damage.
  • diseases associated with high intraocular pressure include, but are not limited to, glaucoma and optic nerve damage.
  • optical nerve injury-related diseases refers to diseases that present with or are caused by optic nerve injury.
  • optic nerve injury-related diseases include, but are not limited to, neurodegenerative eye diseases, injuries caused by trauma or surgery, and eye diseases caused by diabetes, inflammation, or tumors.
  • small organic molecule or “low molecular weight compound” refer to molecules whose size is comparable to that of organic molecules commonly used in pharmaceuticals.
  • the small organic molecule has a size of about 100 to about 2000 Da, preferably about 200 to about 1000 Da, for example about 200 to about 900 Da, about 200 to about 800 Da, about 200 to about 700 Da, about 200 to about 600 Da, or about 200 to about 500 Da.
  • Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.
  • the compounds of this invention encompass pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites, or prodrugs.
  • the compounds of this invention can exist in specific geometric or stereoisomeric forms. All such compounds are contemplated.
  • the compounds of this invention may contain E or Z configurations of carbon-carbon or carbon-nitrogen double bonds, where “E” indicates that, according to the Cahn-Ingold-Prelog preference rule, the preferred substituent is on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and “Z” indicates that the preferred substituent is on the same side of the carbon-carbon or carbon-nitrogen double bond.
  • the compounds of this invention may also exist as mixtures of “E” and “Z” isomers.
  • Isomeric forms also include cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Purification and separation of such substances can be achieved using standard techniques known in the art.
  • Optically pure enantiomers can be obtained by resolving racemic mixtures using conventional methods, such as by forming diastereomer salts using optically active acids or bases, or by forming covalent diastereomers. Mixtures of diastereomers can be separated into individual diastereomers based on their physical and/or chemical differences using methods known in the art (e.g., by chromatography or fractional crystallization). An optically active enantiomer base or acid is then released from the separated diastereomer salt.
  • Another method for separating racemic enantiomers uses chiral chromatography (e.g., chiral HPLC columns), where the separated chiral isomers may be conventionally derivatized or not derivatized prior to separation, depending on which method allows for more efficient separation of the chiral isomers. Enzymatic methods can also be used to separate derivatized or underivatized chiral isomers. Similarly, optically pure compounds of the present invention can be obtained via chiral synthesis using optically active starting materials.
  • the compounds of the present invention can exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound.
  • a solvent particularly, for example, water, methanol, or ethanol
  • the amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric proportions.
  • This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • the compounds of this invention can exist in isotopically labeled or enriched forms, containing one or more atoms with masses and mass numbers different from the most common atomic masses and mass numbers found in nature.
  • the isotopes can be radioactive or non-radioactive.
  • Isotopes of atoms such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2H , 3H , 13C , 14C , 15N , 18O , 32P , 35S , 18F , 36Cl , and 125I .
  • the scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered.
  • metabolites of the compounds of this invention i.e., substances formed in the body when the compounds of this invention are administered.
  • Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compounds.
  • the present invention further includes, within its scope, prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may have little or no pharmacological activity themselves, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the present invention having the desired activity.
  • prodrugs of the compounds of the present invention which are certain derivatives of the compounds of the present invention that may have little or no pharmacological activity themselves, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the present invention having the desired activity.
  • polymorph or “polymorphic material” refers to a single polymorph or a mixture of more than one polymorph in any proportion.
  • crystal form or “crystal” refers to any solid substance that exhibits a three-dimensional arrangement, as opposed to amorphous solid substances, and produces characteristic X-ray powder diffraction patterns with clearly defined peaks.
  • amorphous refers to any solid substance that is not ordered in three dimensions.
  • pharmaceutically acceptable means that, within the normal range of medical judgment, contact with a patient's tissues will not cause inappropriate toxicity, irritation, allergic reactions, etc.
  • pharmaceutically acceptable carrier refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carriers” include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.
  • active ingredient refers to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom.
  • the terms "effective amount,” “therapeutic effective amount,” or “preventive effective amount” refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect.
  • the determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance.
  • the appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.
  • the term "individual” includes humans or non-human animals. Exemplary human individuals include individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals.
  • non-human animals includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (I): D1 a ⁇ F1 (I)
  • Each D1 is an independent portion containing a nitric oxide donor
  • F1 is the portion containing flavonoid structures
  • a is any integer from 0 to 10.
  • the compound of formula (I) does not include the following structures:
  • R is a substituted or unsubstituted C1-12 alkyl or a substituted or unsubstituted benzyl group; the substituent is a C1-4 alkyl or a C1-4 alkoxy group; and n is an integer from 2 to 8.
  • a is 1, 2, or 3, preferably 1 or 2, particularly 1.
  • F1 is 5,6,7-trihydroxy-4-oxo-2-phenyl-4H-chromene.
  • equation (I) has the structure of equation (I-1):
  • R 5 is selected from hydrogen, -OH, -OC 1-10 alkyl groups, and... Each alkyl group is either unsubstituted or substituted with at least one substituent selected independently from RX5 ;
  • R1 and R2 or “ R1 and R4 ” or “ R2 and R3 ” or “ R6 and R7 ” or “ R7 and R8 ” or “ R8 and R9 ” or “ R9 and R10 ” together with the carbon atoms attached to them form a saturated or unsaturated 3-7 membered ring containing 0, 1, 2 or 3 heteroatoms, wherein the heteroatoms are independently selected from oxygen, sulfur, nitrogen and phosphorus, and the ring is unsubstituted or substituted by at least one substituent independently selected from RX ;
  • Each RA1 , RA2 , RA3, RA4 , RA6 , RA7, RA8 , RA9, RA10 , RB1 , RB2 , RB3 , RB4 , RB6 , RB7 , RB8 , RB9, and RB10 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl , C2-10 alkynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclic , -C1-4 alkylene- heterocyclic , aryl, -C1-4 alkylene -aryl, heteroaryl, -C1-4 alkylene-heteroaryl, and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is either unsubstituted or substituted by at least one
  • RA1 and RB1 or “ RA2 and RB2 ” or “ RA3 and RB3 ” or “RA4 and RB4” or “ RA6 and RB6 ” or “ RA7 and RB7 ” or “ RA8 and RB8 ” or “ RA9 and RB9 ” or “ RA10 and RB10 ” together with one or more atoms attached to them constitute a 4-12 membered heterocycle containing 0, 1 or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen and phosphorus, which is either unsubstituted or substituted with 1, 2 or 3 substituents selected from RX ;
  • R 11 is selected from hydrogen and C 1-10 alkyl groups, wherein the alkyl group is unsubstituted or substituted by at least one substituent independently selected from R X11 ;
  • Each Rc and Rd is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, M, -C1-4 alkylene-M, wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocyclic group is unsubstituted or substituted by at least one substituent independently selected from R Y ;
  • Each M is independently selected from the NO donor; NO represents nitric oxide.
  • Each Ra1 and Rb1 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, -C1-4 alkylene-aryl, heteroaryl, -C1-4 alkylene-heteroaryl, and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is either unsubstituted or substituted by at least one substituent independently selected from R and Y ;
  • Ra1 and Rb1 together with one or more atoms attached to them form a 4-12 membered heterocycle containing 0, 1 or 2 additional independent heteroatoms selected from oxygen, sulfur, nitrogen and phosphorus, which is either unsubstituted or substituted by 1, 2 or 3 substituents selected from R Y.
  • Each Rc1 and Rd1 is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 ynyl, C3-10 cycloalkyl, -C1-4 alkylene- C3-10 cycloalkyl, heterocyclic, -C1-4 alkylene-heterocyclic, aryl, -C1-4 alkylene -aryl, heteroaryl, -C1-4 alkylene-heteroaryl, and Each of the alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is either unsubstituted or substituted by at least one substituent independently selected from R and Y ;
  • each Rc1 and Rd1 together with one or more carbon atoms attached to them can form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which is either unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R and Y.
  • Each R Y is independently selected from halogen, NO2 , -CN, C1-10 alkyl, -OH, -O ( C1-10 alkyl), -O ( C3-10 cycloalkyl), -O ( C1-4 alkylene- C3-10 cycloalkyl), -O (heterocyclic), -O ( C1-4 alkylene-heterocyclic), -SH, -S ( C1-10 alkyl), -S ( C3-10 cycloalkyl), -S ( C1-4 alkylene- C3-10 cycloalkyl), -S (heterocyclic), -S ( C1-4 alkylene-heterocyclic), -NH2 , -NH (C1-10 alkyl), -N ( C1-10 alkyl), -NH ( C3-10 cycloalkyl), -NH ( C1-4 alkylene- C3-10 cycloalkyl), -NH (heterocyclic), and -NH (
  • Each r is independently selected from 1 and 2;
  • Each t is independently selected from integers between 0 and 10;
  • Each u is independently selected from integers between 0 and 10;
  • Each k is independently selected from 1, 2, 3, and 4;
  • Each q is independently selected from 0, 1, 2, and 3;
  • the total number of M molecules is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • each RA1 , RA2, RA3 , RA4 , RA6 , RA7, RA8 , RA9 , RA10 , RB1 , RB2 , RB3 , RB4 , RB6 , RB7 , RB8 , RB9 , and RB10 is independently selected from hydrogen, C1-10 alkyl groups , and ...
  • Each alkyl group is either unsubstituted or substituted with at least one substituent independently selected from R X.
  • each R A1 , R A2 , R A3 , R A4 , R A6 , R A7 , R A8 , R A9 , R A10 , R B1 , R B2 , R B3 , R B4 , R B6 , R B7 , R B8 , R B9 and R B10 is independently selected from hydrogen, methyl and
  • each R Y is independently selected from halogen, NO 2 , -CN, C1-10 alkyl, -OH, -O ( C1-10 alkyl), -SH, -S ( C1-10 alkyl), -NH 2 and -NH ( C1-10 alkyl), preferably selected from halogen, NO 2 , -CN and C1-10 alkyl.
  • u is 0. In another implementation, t is 0.
  • each RA1 is a methyl group.
  • R2 is selected from hydrogen, -OR A2 , and Preferred selections are from -OR A2 and Specifically, -OR A2 .
  • each R A2 is hydrogen. In another embodiment, each R A2 is methyl.
  • R 3 is selected from hydrogen, -OR A3 , and Preferred selections are from -OR A3 and Specifically, -OR A3 .
  • each RA3 is hydrogen. In another embodiment, each RA3 is methyl.
  • R1 is R2 and R3 are -OH, or (2) R2 is R1 and R3 are -OH, or (3) R1 and R2 are independently -OH. R3 is -OH, or (4) R1 , R2 and R3 are each independently -OH.
  • R5 is hydrogen
  • At least two of R6 , R7 , R8 , R9 and R10 are hydrogen.
  • R6 , R7 , R8 , R9 , and R10 are hydrogen.
  • k is 1, 2, or 3.
  • each Rc and Rd is independently selected from hydrogen, halogen, and C1-10 alkyl, wherein the alkyl is unsubstituted or substituted by at least one substituent independently selected from Ry .
  • the value of q is calculated by including the number of M values when Rc or Rd is M or -C1-4 alkylene-M. In one embodiment, q is 0.
  • the structure can be represented as -(L) k ⁇ M.
  • the structure of -(L) k ⁇ is selected from -( CH2 ) j- , -O-, -O- CH2- , Where j is an integer between 0 and 10.
  • the structure of -(L) k ⁇ is selected from -( CH2 ) j- , Where j is an integer between 0 and 10.
  • each NO donor is independently selected from nitrates, furazolidone oxides, azooxides, thionitrites, and sydnone imines.
  • the azooxide is an azomonium glycol salt.
  • M is in
  • R 12 is -NR A12 RB12 ;
  • RB12 and RB12 are independently selected from hydrogen, C 1-10 alkyl and C 2-10 alkenyl, wherein each alkyl and alkenyl is unsubstituted or substituted by at least one substituent independently selected from RX ;
  • RA12 and RB12 together with the N atom attached to them form a 4-12 membered heterocycle containing 0, 1 or 2 additional heteroatoms selected from oxygen, sulfur, nitrogen and phosphorus, which is either unsubstituted or substituted with 1, 2 or 3 substituents selected from RX .
  • M is R13 is selected from hydrogen, halogen, C1-10 alkyl, -OH and -O ( C1-10 alkyl).
  • each M is independently selected from -ONO 2 , Preferred selection from -ONO 2 , Where R is CN or benzenesulfonyl, wherein the benzene ring of the benzenesulfonyl group is unsubstituted or substituted by 1, 2 or 3 independent substituents selected from R and Y.
  • each M when there are multiple M's, each M is identical. In another implementation, when there are multiple M's, each M may be identical or different.
  • the structure is selected from -( CH2 ) j - ONO2 , Preferably selected from -( CH2 ) j - ONO2 ,
  • formula (I-1) has the structure of formula (I-2-1), formula (I-2-2), or formula (I-2-3):
  • L1 , L2 , and L3 are independently selected from L;
  • M1 , M2 , and M3 are independently selected from M;
  • R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8 , R9 , R10 , L, M are defined as in equation (I-1).
  • equation (I-1) has the structure of equation (I-3):
  • L1 and L2 are independently selected from L;
  • M1 and M2 are independently selected from M;
  • R3 , R4 , R5 , R6 , R7 , R8 , R9 , R10 , L, and M are defined as in equation (I-1).
  • equation (I-1) has the structure of equation (I-4):
  • L1 , L2 , and L3 are independently selected from L;
  • M1 , M2 , and M3 are independently selected from M;
  • R4 , R5 , R6 , R7 , R8 , R9 , R10 , L, and M are defined as in equation (I-1).
  • formula (I-2-1) has the structure of formula (I-5-1):
  • L1 and M1 are defined as in equation (I-2-1).
  • formula (I-2-2) has the structure of formula (I-5-2):
  • formula (I-2-3) has the structure of formula (I-5-3):
  • L3 and M3 are defined as in equation (I-2-3).
  • equation (I-3) has the structure of equation (I-6):
  • L1 , L2 , M1 and M2 are defined as in equation (I-3).
  • equation (I-4) has the structure of equation (I-7):
  • L1 , L2 , L3 , M1 , M2 and M3 are defined as in equation (I-4).
  • the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  • compositions and pharmaceutical preparations are provided.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, isotopic compound, metabolite or prodrug, and at least one pharmaceutically acceptable carrier.
  • compositions of the present invention can be administered in any manner, provided they achieve the effect of preventing, alleviating, preventing, or treating symptoms in humans or animals.
  • various suitable dosage forms can be prepared depending on the route of administration.
  • they can be administered to patients orally or parenterally in conventional formulations.
  • These conventional formulations include, for example, capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.
  • the routes of administration are particularly ocular, such as ocular surface administration, intraocular administration, or periocular administration.
  • the formulations are particularly eye drops and eye ointments.
  • the dosage of the compound administered to the subject can be adjusted to a considerable extent.
  • the dosage can be varied depending on the specific route of administration and the subject's needs, and can be determined by a healthcare professional.
  • the present invention or its pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, tautomers, isotopic compounds, metabolites or prodrugs, or pharmaceutical compositions thereof, can be used to treat or prevent ocular hypertension-related diseases and optic nerve damage-related diseases.
  • the present invention also provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the preparation of medicaments for the treatment or prevention of diseases, symptoms or conditions selected from intraocular pressure-related diseases and optic nerve damage-related diseases, wherein the compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof are optionally used in combination with a second therapeutic agent.
  • the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof, optionally in combination with a second therapeutic agent, for the treatment of diseases related to high intraocular pressure or optic nerve damage.
  • the present invention provides a method for treating ocular hypertension-related diseases or optic nerve injury-related diseases, the method comprising administering to an individual in need an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof is optionally used in combination with a second therapeutic agent.
  • the disease, condition, or symptom is selected from: glaucoma, neurodegenerative eye disease, and optic nerve injury.
  • the disease, symptom, or condition is selected from: glaucoma, age-related macular degeneration, diabetic retinopathy, cataracts, uveitis, keratitis, high intraocular pressure caused by retinal vascular occlusion, and optic nerve damage.
  • the compounds of the present invention or their pharmaceutically acceptable salts, or the pharmaceutical compositions of the present invention may be used alone or in combination with other therapeutic agents.
  • the use of adjuvants can enhance the therapeutic effect of the compounds of this invention (e.g., the therapeutic benefit of using an adjuvant alone is minimal, but when used in combination with another drug, it can enhance the individual's therapeutic benefit), or, for example, the combination of the compounds of this invention with another equally effective therapeutic agent can enhance the individual's therapeutic benefit.
  • the compounds of this invention in combination with another drug for treating glaucoma may enhance clinical benefit.
  • Combined therapies include, but are not limited to, physical therapy, psychotherapy, small molecule targeted therapeutic agents (e.g., kinase inhibitors), etc. Regardless of the disease, symptom, or condition, the two therapies should have an additive or synergistic effect on the individual's therapeutic benefit.
  • novel small molecule compound containing a nitric oxide (NO) donor provided by this invention exhibits outstanding intraocular pressure-lowering activity and protective effect on optic nerve cells.
  • the compounds of the present invention can treat or prevent diseases related to high intraocular pressure and optic nerve damage, such as glaucoma, age-related macular degeneration, diabetic retinopathy, cataracts, uveitis, keratitis, high intraocular pressure caused by retinal vascular occlusion, and optic nerve damage, and have good prospects for development into drugs.
  • diseases related to high intraocular pressure and optic nerve damage such as glaucoma, age-related macular degeneration, diabetic retinopathy, cataracts, uveitis, keratitis, high intraocular pressure caused by retinal vascular occlusion, and optic nerve damage, and have good prospects for development into drugs.
  • Excellent pharmacokinetic properties e.g., good corneal absorption and/or other pathways of absorption, good stability in plasma, cornea and/or aqueous humor, suitable half-life and duration of action.
  • Intraocular pressure was measured using an Icare TONOVET Plus tonometer.
  • the compound of formula (I-1) can be prepared and synthesized by various methods from compound Z1 containing active group 1 and compound Z2 containing active group 2, which are known in the literature or are well known to those skilled in the art.
  • active groups e.g., leaving groups attached to O, C, N, or S atoms
  • one of active group 1 and active group 2 is a carboxyl group, a sulfonic acid group, a phosphoryl group with a free -OH terminus, an active ester, an acyl chloride, or an isocyanate, and the other is an amino group, an amine group, a hydroxyl group, or a halogen group; or, one of active group 1 and active group 2 is an amino group, a hydroxyl group, or a thiol group, and the other is a halogen group, a hydroxyl group, or an aldehyde group.
  • one of active group 1 and active group 2 is a carboxyl group, and the other is a hydroxyl group or a halogen group, and active group 1 and active group 2 react to form an ester bond.
  • Intermediate L1-2 (123 g, 643.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran and water, and LiOH (5.0 eq) was added and reacted for 12 h to obtain intermediate L1-3 (1.3 g, 7.34 mmol).
  • Intermediate L2-2 (123 g, 643.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran and water, and LiOH (5.0 eq) was added and reacted for 12 h to obtain intermediate L2-3 (200 mg, 1.13 mmol).
  • 1,4-Butanediol (10 g, 111 mmol) was reacted with ethyl bromide (1.0 eq) and NaH (1.0 eq) in tetrahydrofuran (ice-water bath) and purified to give intermediate L4-2 (3.1 g, 17.6 mmol).
  • the intermediate L6-3 obtained in step 6.2 was hydrolyzed with LiOH.
  • the final purified intermediate L6-4 (13.7 g, 72.5 mmol) was obtained.
  • Example 1 Protective effect of compound against NMDA-induced retinal nerve cell damage
  • retinal ganglion cells were used for the following assays.
  • N-methyl-D-aspartate can activate NMDA receptors on the RGC cell membrane, triggering intracellular calcium ion accumulation, further activating the intracellular calcium ion cascade, and inducing cellular glutamate excitotoxicity. Glutamate excitotoxicity is the final pathway in the neuronal death process of many neurodegenerative diseases.
  • NMDA is commonly used to induce cellular glutamate excitotoxicity and oxidative stress responses, causing apoptosis in cultured retinal neurons. This apoptosis model is used to study the neuroprotective effects of drugs.
  • RGC-5 cells (Guangzhou Genio Biotechnology Co., Ltd.) were placed in DMEM medium containing 10% fetal bovine serum and cultured in an incubator at 37°C with 5% CO2. The cells were passaged every 2-3 days by digestion with 0.25% trypsin.
  • RGC-5 cells (1 ⁇ 105 cells/mL) were seeded into 96-well culture plates. After adhesion, the cells were divided into 8 groups: NMDA damage group (negative control group), blank control group, positive control group, and treatment groups of compounds 001, 004, 005, 006, and 007. Each group had 6 replicates.
  • each group was divided into three subgroups, which were treated with the following concentrations of the compounds: 0.1 ⁇ M, 1 ⁇ M, and 10 ⁇ M, respectively.
  • the positive control group was treated with dizoxipine (Sigma-Aldrich) to reach the test concentration of 10 ⁇ M.
  • the negative control group and the blank control group were treated with an equal volume of DMEM (Adamas Life) complete medium.
  • the MTT colorimetric assay results showed that, compared with the negative control group, the cell viability of each subgroup in the positive control group and the treatment groups of compounds 001, 004, 005, 006, and 007 was significantly increased (* indicates P ⁇ 0.05, ** indicates P ⁇ 0.01), as shown in Figures 1 to 5.
  • Example 2 Effect of compound on intraocular pressure in a comparative dog
  • Dissolve compounds 004, 005, 006, and 007 in a solvent (10 mM disodium hydrogen phosphate buffer solution of 0.5% Tween 80 and 0.02% benzalkonium chloride (pH 7.0)) to prepare a 0.25% solution.
  • the following groups were formed: negative control group (solvent group), positive control group (administered timolol maleate eye drops (Bausch & Lomb, specification: 0.5%) (Shandong Bausch & Lomb Freda Pharmaceutical Co., Ltd.), and treatment groups for compounds 004, 005, 006, and 007 (administered 0.25% compound solution).
  • the administration route was intraconjunctival instillation, with a volume of 50 ⁇ L/eye/time, administered twice daily at approximately 10:00 AM and 5:00 PM for 15 consecutive days. The first day of administration was recorded as Day 1.
  • the eyelids were gently pulled open to avoid contact with the ocular surface. 50 ⁇ L of solvent or test sample was pipetted into the conjunctival sac, and the eyelids were gently closed several times.
  • Intraocular pressure measurement Once before the first dose on Day 1, once at 2 hours and once at 4 hours after the first dose on Day 1, and once before the first dose on Day 2, Day 4, Day 7, Day 13, Day 15, and Day 16; detailed test data are shown in Table 2 and Figure 6.
  • IOP intraocular pressure
  • mice During the experimental drug administration phase, 50 successfully modeled rats were randomly divided into three groups according to the following scheme: negative control group (high intraocular pressure solvent group), positive control group (administered with timolol maleate eye drops (Bausch & Lomb, specification: 0.5%), and compound 001, 005, and 007 treatment groups (administered with 0.25% compound solution). Additionally, 10 rats were randomly selected from the solvent group described in section 4 above as a non-model blank control group for the efficacy test phase. The administration route was intraconjunctival instillation of 20 ⁇ L/eye/time, twice daily at 10:00 AM and 5:00 PM for 15 consecutive days. The first day of administration was recorded as Day 1.
  • dexamethasone sodium phosphate eye drops will continue to be administered twice daily at the same time as during modeling to maintain intraocular pressure in the right eye of rats in the negative control group (high intraocular pressure solvent group), positive control group (administered timolol maleate eye drops (Bausch & Lomb, specification: 0.5%)), and compound 001, 005, and 007 treatment groups (administered 0.25% compound solution).
  • Intraocular pressure measurement Intraocular pressure was measured once on Day 1 before the first dose, once on Day 2 before the first dose, once on Day 4 before the first dose, once on Day 6 before the first dose, once on Day 8 before the first dose, once on Day 10 before the first dose, once on Day 13 before the first dose, once on Day 15 before the first dose, and once on Day 16.

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Abstract

La présente invention relève du domaine technique de la médecine, et concerne en particulier une classe de composés contenant un donneur d'oxyde nitrique (NO) ou un sel pharmaceutiquement acceptable, son procédé de préparation, une composition pharmaceutique de celui-ci, et leur utilisation dans le traitement ou la prévention de maladies associées à l'hypertension oculaire et de maladies associées à une lésion nerveuse optique.
PCT/CN2025/107263 2024-07-05 2025-07-07 Dérivé de flavonoïde contenant un donneur d'oxyde nitrique Pending WO2026008076A1 (fr)

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