Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
• • 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
  • A61K31/12—Ketones
• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
• • 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
  • A61K31/66—Phosphorus compounds
  • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• • 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
  • A61K31/66—Phosphorus compounds
  • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• • 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
  • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
  • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
  • C07F9/09—Esters of phosphoric acids
  • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
  • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl

Definitions

• Cataracts are the leading cause of blindness (51 %) worldwide according to the World Health Organization (WHO), particularly in low- and middle-income countries. Data dating back to the beginning of this millennium showed that 30-60% of blindness in Africa and 60-80% in South East Asia is attributable to cataracts. In the United States, the current number of those with cataract is estimated to be more than 25.7 million. Projections from Prevent Blindness research estimate that the number will increase to 38.5 million by 2032, and to 45.6 million by the year 2050. Cataract is a clouding of the eye’s lens which blocks or changes the passage of light into the eye. Cataracts usually form in both eyes, but not at the same rate.
• WHO World Health Organization
• cataracts can develop slowly or quickly, or progress to a certain point, then not get any worse. Besides aging, other factors may cause cataracts to form. Eye infections, some medicines (such as steroids), smoking, injuries, trauma, or exposure to intense heat or radiation may cause cataracts. Too much exposure to non-visible sunlight (called UV or ultraviolet light) and various diseases, such as diabetes or metabolic disorders, may also contribute to cataracts formation.
• UV or ultraviolet light non-visible sunlight
• Presbyopia is the loss of accommodative ability of the eye resulting in the inability to focus on near objects. Presbyopia affects everyone over the age of 45 and has significant negative impacts on the quality of life.
• Current treatments for presbyopia include: (i) non-invasive approaches that utilize devices to help improve near and distance vision but do nothing to restore the natural process of accommodation and require constant use of the devices, and (ii) invasive surgical procedures which are associated with major complications including decrease in vision quality, regression effects, anisometropia, corneal ectasia, and haze. Most importantly, none of these methods can reverse presbyopia. Moreover, no treatment option exists that can either prevent or delay the onset of presbyopia.
• CM ciliary muscle
• proteins known as crystallins play a major role in the stiffening of the eye lens.
• the lens crystallins comprise three isoforms, a, b, and g and make up 90% of the eye lens protein content a crystalline (AC), an ATP-independent chaperone and member of the small heat shock protein (sHsp) family, constitutes 40% of the crystallin protein content. It exists as a hetero-oligomer of two subunits, aA-crystallin (AAC) and aB-crystallin (ABC) and its expression is primarily restricted to the eye lens. It recognizes exposed conformational features in partially unfolded lens proteins and sequesters them from one another, thereby reducing the population of aggregation-prone species that would otherwise lead to various age-related vision impairment.
• AAC aA-crystallin
• ABSC small heat shock protein
• presbyopia is the earliest observable symptom of age-related nuclear (ARN) cataract, a major cause of blindness in the world.
• SMDs small molecule disaggregases
• hAAC human ACC
• SMDs small molecule disaggregases
• Several SMDs were identified based on this approach. It is believed that these SMDs are useful for the treatment and management of presbyopia, and for the treatment and/or slowing down the progression of cataract.
• the cataract can be age-related (nuclear sclerotic, cortical, and posterior subcapsular), congenital, familial, secondary, traumatic, smoke-related and radiation cataracts.
• a compound for treating or managing presbyopia or slowing down the progression and/or treating cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (I) or a solvate or a pharmaceutically acceptable salt thereof, wherein,
• R 3a , Rs b , R 3C , and R 3d are each the same or different, and each independently are selected from the group consisting of: hydrogen, branched or linear (Ci-Ce)alkyl, halo(Ci-Ce)alkyl, (C 3 - C6)cycloalkyl, halo(C 3 -C 6 )cycloalkyl, and hydroxyl;
• R 4 is selected from the group consisting of: branched or linear (Ci-Ce)alkyl; halo(Ci-Ce)alkyl; (C 3 -C 6 )cycloalkyl; halo(C 3 -C 6 )cycloalkyl; aryl; haloaryl; and
• - Rsa and Rsb are each the same or different, and independently a branched or linear (Ci- C6)alkyl,
• - R6 is branched or linear (Ci-C6)alkyl, aryl, or a polyethylene glycol group or , wherein q is 1 to 10; - p is a number from 0 to 10,
• - n is a number from 0 to 10
• - X is a C or O.
• Ri and R2 are the same. In some aspects, at least one of Ri and R2 is hydrogen. In some aspects, at least one of R3a, R3b, R3c, and R3d is hydrogen. In some aspects, each of R3a, R3b, R3c, and R3d is hydrogen.
• R6 is a branched (C3-C6)alkyl, such as isopropyl
• each of R3a, R3b,R3c, and R3d is hydrogen.
• R6 is a branched (C3-C6)alkyl, such as isopropyl
• each of R3a, R3b,R3c, and R3d is hydrogen.
• R6 is isopropyl
• each of R2, R3a, R3b,R3c, and R3d is hydrogen.
• the compounds of formula (I) are produced by the following general reaction: [0028] General scheme for making prodrugs:
• a method of treating, preventing, reducing the occurrence of, or reducing, ameliorating, or alleviating the symptoms associated with presbyopia, cataract, transthyretin (TTR)-associated amyloidosis, or other conditions or disorders associated with the eye comprising administering to a subject in need thereof, an effective amount of the compound of formula (I), including each of the disclosed compounds and the compounds of formula (la), (lb), (lc), (Id), (le), and (If).
• TTR transthyretin
• a pharmaceutical composition comprising a compound of formula (I), including each of the disclosed compounds and the compounds of formula (la), (lb), (lc), (Id), (le), and (If), and one or more pharmaceutically excipients.
• the compound of formula (I), including each of the disclosed compounds and the compounds of formula (la), (lb), (lc), (Id), (le), and (If), may be administered to a subject in need thereof, in an amount effective to reduce or inhibit the formation of, or dissolve high molecular weight aggregates of human a-A-crystallin, or to treat, prevent, or reduce the occurrence of or to reduce, ameliorate, or alleviated symptoms associated with conditions relating to human a-A-crystallin.
• the conditions include but are not limited to: transthyretin (TTR)-associated amyloidosis, Prion, Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease and Ankyloblepharon-ectodermal dysplasia- cleft lip/palate syndrome.
• TTR transthyretin
• the compounds of formula (I), including each of the disclosed compounds and the compounds of formula (la), (lb), (lc), (Id), (le), and (If) may be administered through any route of administration, including but not limited to oral, nasal, intranasal, intramuscular, intravenous, subcutaneous, rectal, sublingual, intrathecal, transdermal, intraocularly, inhalation or other topical.
• the compounds of formula (I), including each of the disclosed compounds and the compounds of formula (la), (lb), (lc), (Id), (le), and (If) are administrated through intraocularly or topically to the eye.
• the pharmaceutically composition is an ophthalmic solution or suspension comprising the compound of formula (I) and one or more pharmaceutically acceptable excipients suitable for administration to the eye.
• any structure disclosed herein also includes any tautomer which may be formed.
• reference to a compound should be construed broadly to include pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms, non-covalent complexes, and combinations thereof, of a chemical entity of the depicted structure or chemical name.
• a pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human.
• a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
• a salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
• a prodrug is a compound which is converted to a therapeutically active compound after administration. For example, conversion may occur by the removal of a biologically labile group.
• Prodrug preparation is well known in the art. For example, “Prodrugs and Drug Delivery Systems,” which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.
• Tautomers are isomers that are in rapid equilibrium with one another. For example, tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion.
• Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein.
• alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.
• Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.
• alkyl refers to a functional group comprising a straight-chain or branched-chain hydrocarbon containing from 1 to 20 carbon atoms linked exclusively by single bonds and not having any cyclic structure.
• An alkyl group may be optionally substituted as defined herein.
• alkyl groups includes, without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, and the like.
• alkenyl refers to a functional group comprising a straight-chain or branched-chain hydrocarbon containing from 2 to 20 carbon atoms and having one or more carbon-carbon double bonds and not having any cyclic structure.
• An alkenyl group may be optionally substituted as defined herein.
• alkenyl groups include, without limitation, ethenyl, propenyl, 2- methylpropenyl, butenyl, 1 ,4-butadienyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, and the like.
• the point of attachment can be on the double bond carbon or on any single bond carbon.
• alkynyl refers to a functional group comprising a straight-chain or branched-chain hydrocarbon containing from 2 to 20 carbon atoms and having one or more carbon-carbon triple bonds and not having any cyclic structure.
• An alkynyl group may be optionally substituted as defined herein.
• alkynyl groups include, without limitation, ethynyl, propynyl, hydroxypropynyl, butynyl, butyn-1-yl, butyn-2-yl, 3-methylbutyn-1-yl, pentynyl, pentyn-1- yl, hexynyl, hexyn-2-yl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, octadecynyl, nonadecynyl, eicosynyl, and the like.
• the point of attachment can be on the triple bond carbon or on any single bond carbon.
• alkoxy refers to -O- alkyl, -O-alkenyl, or -O-alknyl, wherein alkyl, alkenyl, and alkynyl are as defined above.
• alkoxyalkyl means an alkyl as defined above substituted with an alkoxy group as defined above (in one aspect one or two alkoxy groups).
• C2-6 alkoxyalkyl means the total number of carbon atoms. Examples include but not limited to 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2- ethoxyethyl, and the like.
• aryl refers to monocyclic, bicyclic (fused), and tricyclic (fused or spiro) hydrocarbon ring system having a total of five to fourteen ring atoms.
• aryl is monocyclic, the monocyclic is aromatic and contains no heteroatom.
• aryl is bicyclic or tricyclic, at least one of the ring in the bicyclic or tricyclic is aromatic and contains no heteroatom, and when the other ring(s) is aromatic, the other ring(s) does not contain a heteroatom, but when the other ring(s) is not aromatic, the other ring(s) may or may not contain a heteroatom.
• aryl examples include, without limitation, benzene, naphthalene, indane, 1 ,2,3,4-tetrahydronaphthalene, chromane, isochromane, 1 ,2,3,4-tetrahydroquinoline, thiochromane 1 ,1 -dioxide, 6,7,8,9-tetrahydro-5H- benzo[7]annulene, and 2,3-dihydrobenzofuran.
• aralkyl refers to a 5 to 12 membered heteroaryl or 6 to 12 membered aryl, as defined herein, substituted for a hydrogen of an Ci-6 alkyl.
• cycloalkyl refers to a monocyclic, bicyclic (fused, bridged, or spiro), or tricyclic (fused or spiro) hydrocarbon ring system having a total of three to fourteen ring atoms, which is completely saturated or contains one or more units of unsaturation, but none of the individual ring in the monocyclic, bicyclic, or tricyclic hydrocarbon is aromatic, and none of the ring atoms is a heteroatom. The point of attachment can be on the saturated or unsaturated carbon.
• a bridged bicyclic cycloalkyl refers to two hydrocarbon rings share three or more carbon atoms, separating the two bridgehead carbon atoms by a bridge containing at least one atom.
• Examples of cycloalkyl include, but not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane, spiro[2.5]octane, spiro[3.5]nonane, spiro[4.5]decane, and spiro[5.5]undecane.
• haloalkyl refers to alkyl as defined above, wherein one or one to five hydrogens are replaced with halogen atom(s), including those substituted with different halogen atoms.
• haloalkyl includes, but not limited to, -CF3, -CH2CI, -CHF2, and -CF2CF3.
• haloalkoxy refers to alkoxy as defined above, wherein one or one to five hydrogens are replaced with halogen atom(s), including those substituted with different halogen atoms.
• haloalkoxy includes, but not limited to, -OCF3 and -OCFIF2.
• halo or halogen means fluoro, chloro, bromo, or iodo; in one aspect, fluoro or chloro.
• spiro refers to a moiety comprising two rings sharing one common atom.
• Fig. 1A shows various concentrations of CAP1160 exposed to UV.
• Fig. 1 B shows absorbance at 600 nm for various concentrations of CAP1160 exposed to UV.
• Example 1 Prevention of UVC/l-teC -induced aggregation of bovine lens extracts by CAP 1160
• Bovine lens lysates (2 mg/ml, 50 mI) were incubated with various concentrations of CAP1160 (structure shown below) or a vehicle (0.5% DMSO), and then left unexposed (no exposure) or exposed to UV (UV-irradiated). See Fig. 1A. At various time points, wells-containing bovine lens lysates were pictured and the corresponding absorbance at 600 nm (A600) was measured. See Figs. 1A and 1 B. Representative brightfield images of wells taken 7 min after initial UV exposure (Fig. 1 A) and corresponding A600 (Fig. 1 B). [0054] The results show that CAP1160 delays, in a dose-dependent manner, the opacification of bovine lens protein lysates induced by UV irradiation.
• Example 2 General scheme for making prodrugs
• starting compound 1 and the reagent used for reacting with the OH group are mere examples, and each may be selected as appropriate based on the desired end product.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Ophthalmology & Optometry (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Emergency Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (6)

Applications Claiming Priority (2)

Publications (1)

Family

ID=84692077

Family Applications (1)

Country Status (7)

Cited By (2)

Citations (1)

Family Cites Families (7)

• 2021
  • 2021-11-15 CN CN202180090238.6A patent/CN116963727A/zh active Pending
• 2022
  • 2022-06-28 CA CA3225704A patent/CA3225704A1/en active Pending
  • 2022-06-28 MX MX2024000116A patent/MX2024000116A/es unknown
  • 2022-06-28 CN CN202280058201.XA patent/CN117915900A/zh active Pending
  • 2022-06-28 US US18/575,218 patent/US20240327439A1/en active Pending
  • 2022-06-28 JP JP2023580804A patent/JP2024524433A/ja active Pending
  • 2022-06-28 WO PCT/US2022/035336 patent/WO2023278464A1/en not_active Ceased
  • 2022-06-28 EP EP22834075.8A patent/EP4362923A4/en not_active Withdrawn

Patent Citations (1)

Non-Patent Citations (5)

Also Published As

Similar Documents

Legal Events