Patent Application
20230093476
The present invention provides methods of treating refractive ocular disorders such as presbyopia using compounds of Formula (I) and pharmaceutical compositions thereof either alone or in combination with other active agents. The present invention also provides compounds and pharmaceutical compositions.
As a person ages the minimum distance from the eye at which an object will come into focus increases, provided distance vision is corrected or is excellent unaided. This condition of increasing minimum focal length in individuals with excellent corrected or unaided distance vision is called presbyopia.
Presbyopia occurs because as a person ages the eye's accommodative ability which uses near reflex-pupil constriction, convergence of the eyes and particularly ciliary muscle contraction, decreases. This reduction in accommodation results in an inadequate change in the normal thickening and increased curvature of the anterior surface of the lens that is necessary for the shift in focus from distant objects to near objects. Important near focus tasks affected by presbyopia include viewing computer screens and reading print.
Presbyopia may be addressed by the use of eyeglasses, contact lenses or after undergoing invasive surgery. One such optical modification, the monovision procedure, can be executed with the use of glasses, contact lenses or even surgery. The monovision procedure corrects one eye for near focus and the other eye for distance focus. However, monovision correction is normally accompanied by loss of depth perception and distance vision particularly in dim light (e.g. night). Other surgical procedures that have been developed to relieve presbyopia include implantation of intraocular lenses and reshaping of the cornea. Presbyopia may also be addressed with general miotic agents, such as pilocarpine (a non-selective muscarinic acetylcholine receptor agonist), carbachol (a non-selective muscarinic acetylcholine receptor agonist), and phospholine iodide (an acetylcholinesterase inhibitor). These general miotic agents may cause substantial redness, severe nasal congestion and create ciliary muscle spasms.
Thus, there is a need in the art for new, improved, and/or complimentary ocular therapies for conditions such as presbyopia and other refractive related conditions.
PCT Publication No. WO 2011/103018 (“WO ‘018’”) describes substituted fused imidazole derivatives that upregulate expression of HMOX1 in vitro. PCT Publication No. WO 2012/094580 (“WO ‘580’”) describes various compounds that modulate cellular oxidative stress including fused imidazole derivatives having a structure similar to or the same as compounds disclosed in WO '018.
The present invention is directed to methods and compositions associated with treatment of one or more refractory ocular disorders including presbyopia.
In certain embodiments of the invention, a compound of the invention is administered alone. In other embodiments, a compound or composition of the invention is administered with one or more other drugs for the treatment of a refractory ocular condition.
The individual treated may be known to have an ocular condition, is suspected of or at risk for having an ocular condition. In embodiments of the invention, an individual is diagnosed with an ocular condition prior to receiving the inventive treatment.
The present invention is also directed to compounds of Formula (I) and pharmaceutically acceptable salts thereof and to pharmaceutical compositions comprising Formula (I) and pharmaceutically acceptable salts thereof, and methods of making thereof. In certain embodiments, the pharmaceutical compositions are suitable for ocular administration.
The following definitions are intended to clarify the terms defined. If a particular term used herein is not specifically defined, the term should not be considered to be indefinite. Rather, such undefined terms are to be construed in accordance with their plain and ordinary meaning to a person of ordinary skill in the field(s) of art to which the invention is directed.
As used herein the term “alkyl” refers to a straight or branched chain saturated hydrocarbon having one to ten carbon atoms, which may be optionally substituted, as herein further described, with multiple degrees of substitution being allowed. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, n-pentyl, neopentyl, n-hexyl, and 2-ethylhexyl.
The number carbon atoms in an alkyl group is represented by the phrase “Cx-y alkyl,” which refers to an alkyl group, as herein defined, containing from x to y, inclusive, carbon atoms. Thus, C1-6 alkyl represents an alkyl chain having from 1 to 6 carbon atoms and, for example, includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, n-pentyl, neopentyl, and n-hexyl.
As used herein, the term “alkylene” refers to a straight or branched chain divalent saturated hydrocarbon radical having from one to ten carbon atoms, which may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, n-propylene, 1-methylethylene, 2-methylethylene, dimethylmethylene, n-butylene, 1-methyl-n-propylene, and 2-methyl-n-propylene.
The number of carbon atoms in an alkylene group is represented by the phrase “Cx-y alkylene,” which refers to an alkylene group, as herein defined, containing from x to y, inclusive, carbon atoms. Similar terminology will apply for other terms and ranges as well. Thus, C1-4 alkylene represents an alkylene chain having from 1 to 4 carbons atoms, and, for example, includes, but is not limited to, methylene, ethylene, n-propylene, 1-methylethylene, 2-methylethylene, dimethylmethylene, n-butylene, 1-methyl-n-propylene, and 2-methyl-n-propylene.
As used herein, the term “cycloalkyl” refers to a saturated, three- to ten-membered, cyclic hydrocarbon ring, which may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. Such “cycloalkyl” groups are monocyclic, bicyclic, or tricyclic. Examples of “cycloalkyl” groups as used herein include, but are not limited to, cydopropyl, cydobutyl, cydopentyl, cydohexyl, cydoheptyl, norbornyl, and adamantyl.
The number of carbon atoms in a cydoalkyl group will be represented by the phrase “Cx-y cydoalkyl,” which refers to a cydoalkyl group, as herein defined, containing from x to y, inclusive, carbon atoms. Similar terminology will apply for other terms and ranges as well. Thus, C3-10 cycloalkyl represents a cycloalkyl group having from 3 to 10 carbons as described above, and for example, includes, but is not limited to, cydopropyl, cydobutyl, cydopentyl, cydohexyl, cydoheptyl, norbornyl, and adamantyl.
As used herein, the term “heterocycle” or “heterocyclyl” refers to an optionally substituted mono- or polycyclic saturated ring system containing one or more heteroatoms. Such “hetercycle” or “heterocyclyl” groups may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. The term “heterocycle” or “heterocyclyl,” as used herein, does not include ring systems that contain one or more aromatic rings. Examples of heteroatoms include nitrogen, oxygen, or sulfur atoms, including N-oxides, sulfur oxides, and sulfur dioxides. Typically, the ring is three- to twelve-membered. Such rings may be optionally fused to one or more of another heterocyclic ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” groups, as used herein include, but are not limited to, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene, where attachment can occur at any point on said rings, as long as attachment is chemically feasible. Thus, for example, “morpholine” refers to morpholin-2-yl, morpholin-3-yl, and morpholin-4-yl.
As used herein, when “heterocycle” or “heterocyclyl” is recited as a possible substituent, the “heterocycle” or “heterocyclyl” group can attach through either a carbon atom or any heteroatom, to the extent that attachment at that point is chemically feasible. For example, “heterocyclyl” would include pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl. When “heterocycle” or “heterocyclyl” groups contain a nitrogen atom in the ring, attachment through the nitrogen atom can alternatively be indicated by using an “-ino” suffix with the ring name. For example, pyrrolidino refers to pyrrolidin-1-yl.
As used herein the term “halogen” refers to fluorine, chlorine, bromine, or iodine.
As used herein, the term “oxo” refers to a >C═0 substituent. When an oxo substituent occurs on an otherwise saturated group, such as with an oxo-substituted cycloalkyl group (e.g., 3-oxo-cyclobutyl), the substituted group is still intended to be a saturated group.
As used herein, the term “heteroaryl” refers to a five- to fourteen-membered optionally substituted mono- or polycyclic ring system, which contains at least one aromatic ring and also contains one or more heteroatoms. Such “heteroaryl” groups may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. In a polycyclic “heteroaryl” group that contains at least one aromatic ring and at least one non-aromatic ring, the aromatic ring(s) need not contain a heteroatom. Thus, for example, “heteroaryl,” as used herein, would include indolinyl. Further, the point of attachment may be to any ring within the ring system without regard to whether the ring containing the attachment point is aromatic or contains a heteroatom. Thus, for example, “heteroaryl,” as used herein, would include indolin-1-yl, indolin-3-yl, and indolin-5-yl. Examples of heteroatoms include nitrogen, oxygen, or sulfur atoms, including N-oxides, sulfur oxides, and sulfur dioxides, where feasible. Examples of “heteraryl” groups, as used herein include, but are not limited to, furyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,4-triazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, indolyl, isoindolyl, benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, pteridinyl, and phenazinyl, where attachment can occur at any point on said rings, as long as attachment is chemically feasible. Thus, for example, “thiazolyl” refers to thiazol-2-yl, thiazol-4-yl, and thiaz-5-yl.
As used herein, when “heteroaryl” is recited as a possible substituent, the “heteroaryl” group can attach through either a carbon atom or any heteroatom, to the extent that attachment at that point is chemically feasible.
As used herein, the term “heterocyclylene” refers to an optionally substituted bivalent heterocyclyl group (as defined above). The points of attachment may be to the same ring atom or to different ring atoms, as long as attachment is chemically feasible. The two points of attachment can each independently be to either a carbon atom or a heteroatom, as long as attachment is chemically feasible. Examples include, but are not limited to
where the asterisks indicate points of attachment.
As used herein, the term “heteroarylene” refers to an optionally substituted bivalent heteroaryl group (as defined above). The points of attachment may be to the same ring atom or to different ring atoms, as long as attachment is chemically feasible. The two points of attachment can each independently be to either a carbon atom or a heteroatom, as long as attachment is chemically feasible. Examples include, but are not limited to,
where the asterisks indicate points of attachment.
Various other chemical terms or abbreviations have their standard meaning to the skilled artisan. For example: “hydroxyl” refers to —OH; “methoxy” refers to —OCH3; “cyano” refers to —CN; “amino” refers to —NH2; “methylamino” refers to —NHCH3; “sulfonyl” refers to —SO2—; “carbonyl” refers to —C(O)—; “carboxy” or “carboxyl” refer to —CO2H, and the like. Further, when a name recited multiple moieties, e.g., “methylaminocarbonyl-methyl”, an earlier-recited moiety is further from the point of attachment than any later-recited moieties. Thus, a term such as “methylaminocarbonylmethyl” refers to —CH2—C(O)—NH—CH3.
As used herein, the term “substituted” refers to substitution of one or more hydrogens of the designated moiety with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated, provided that the substitution results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature from about −80° C. to about +40° C., in the absence of moisture or other chemically reactive conditions, for at least a week, or a compound which maintains its integrity long enough to be useful for therapeutic or prophylactic administration to a subject. As used herein, the phrases “substituted with one or more . . . ” or “substituted one or more times . . . ” refer to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met.
As used herein, the various functional groups represented will be understood to have a point of attachment at the functional group having the hyphen or dash (-) or an asterisk (*). In other words, in the case of —CH2CH2CH3, it will be understood that the point of attachment is the CH2 group at the far left. If a group is recited without an asterisk or a dash, then the attachment point is indicated by the plain and ordinary meaning of the recited group.
When any variable occurs more than one time in any one constituent (e.g., Rd), or multiple constituents, its definition on each occurrence is independent of its definition on every other occurrence.
As used herein, multi-atom bivalent species are to be read from left to right. For example, if the specification or claims recite A-D-E and D is defined as —OC(O)—, the resulting group with D replaced is: A-OC(O)-E and not A-C(O)O-E.
As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur.
As used herein, “administer” or “administering” means to introduce, such as to introduce to a subject a compound or composition. The term is not limited to any specific mode of delivery, and can include, for example, intravenous delivery, transdermal delivery, oral delivery, nasal delivery, ocular delivery and rectal delivery. Furthermore, depending on the mode of delivery, the administering can be carried out by various individuals, including, for example, a health-care professional (e.g., physician, nurse, etc.), a pharmacist, or the subject (i.e., self-administration).
As used herein, “treat” or “treating” or “treatment” can refer to one or more of delaying the progress of a disease or condition, controlling a disease or condition, delaying the onset of a disease or condition, ameliorating one or more symptoms characteristic of a disease or condition, or delaying the recurrence of a disease or condition or characteristic symptoms thereof, depending on the nature of a disease or condition and its characteristic symptoms. “Treat” or “treating” or “treatment” may also refers to inhibiting the disease, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, and to inhibiting at least one physical parameter that may or may not be discernible to the subject. In certain embodiments, “treat” or “treating” or “treatment” refers to delaying the onset of the disease or at least one or more symptoms thereof in a subject which may be exposed to or predisposed to a disease even though that subject does not yet experience or display symptoms of the disease.
As used herein, “subject” may refer any mammal such as, but not limited to, humans. In one embodiment, the subject is a human. In another embodiment, the host is a human who exhibits one or more symptoms characteristic of a refractive ocular condition. The term “subject” does not require one to have any particular status with respect to any hospital, clinic, or research facility (e.g., as an admitted patient, a study participant, or the like). In an embodiment, the subject may be “a subject in need thereof.”
“Therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease, is sufficient to affect such treatment of the disease or symptom thereof. The “therapeutically effective amount” may vary depending, for example, on the compound, the disease and/or symptoms of the disease, severity of the disease and/or symptoms of the disease or disorder, the age, weight, and/or health of the subject to be treated, and the judgment of the prescribing physician. An appropriate amount in any given instance may be ascertained by those skilled in the art or capable of determination by routine experimentation. For example, a therapeutically effective amount may be determined by measuring clinical outcomes including, but not limited to, the elasticity, stiffness, viscosity, density, or opacity of a lens or by measuring a subject's visual acuity. In certain embodiments, a therapeutically effective amount of compound of Formula (I) or a pharmaceutically acceptable salt thereof used in the methods and compositions of the present invention may be an amount that is capable of reducing, reversing, and/or slowing the rate of oxidative damage of a lens.
As used herein, the term “compound of the invention” includes free acids, free bases, and any salts thereof of the compound of Formula (I). Thus, phrases such as “compound of embodiment 1” or “compound of claim 1” refer to any free acids, free bases, and any salts thereof that are encompassed by embodiment 1 or claim 1, respectively.
A. Treatment of an Ocular Condition and Related Disorders with Compounds of the Invention
In certain embodiments, the present invention is directed to methods for the treatment of a refractory ocular condition comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
In certain embodiments, the present invention is directed to compositions and methods for the treatment of a refractory ocular condition comprising administering a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical formulation is suitable for ocular administration. In further embodiments, the pharmaceutical formulation is administered ocularly and comprises a concentration from about 0.01% to about 5.0% w/v of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a concentration from about 0.10% to about 3.0% w/v of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
In certain other embodiments, the present invention is directed to a method of treating presbyopia comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention.
In certain other embodiments, the present invention is directed to a method of treating presbyopia comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention, wherein near vision acuity of the subject is improved by about 3 lines of resolution or more for at least 6 hours.
In certain other embodiments, the present invention is directed to a method of treating presbyopia comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention, wherein near vision acuity of the subject is improved to 20/40 near vision or wherein the subject has a gain of at least 10 letters in distance-corrected near visual acuity in the nondominant eye and/or as bilateral vision relative to vision prior to treatment.
In certain other embodiments, the present invention is directed to method of treating a refractive error of the eye in a subject in need thereof comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention wherein the refractive error of the eye is selected from presbyopia, myopia, hyperopia, astigmatism or a combination thereof.
In certain other embodiments, the present invention is further directed to a method for treating a refractive error of the eye comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention, wherein the size of the pupil is reduced to from about 1.5 to about 2.5 millimeters, or from about 1.7 to about 2.2 millimeters and wherein the refractive error is selected from the group consisting of a range of distance corrected vision for mild to moderate hyperopia of 3.0 diopters (D) or less; mild to moderate myopia of −5.0 D or less; regular astigmatism of 3.0 D or less; uncorrected distance vision for emmetropes of +0.50 to −0.50 spherical equivalent with regular astigmatism of 0.75 D or less; corneal irregular astigmatism, an ectasia induced corneal irregularity, a pellucid induced corneal irregularity, a higher order aberration and a refractive surgery induced higher order aberration.
The present invention is further directed to a method of increasing the visual depth of field (i.e. depth of focus) secondary to pupil miosis, comprising administering to a subject in need thereof a compound or pharmaceutical composition of the present invention.
The present invention is further directed to a method of treating a refractory ocular condition such as presbyopia comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention, wherein following treatment the subject is able to identify correctly at least 2, 5, or 10 additional letters in distance-corrected near visual acuity (DCNVA) in the nondominant eye or in bilateral vision relative to baseline (i.e., prior to treatment).
The present invention is further directed to a method of treating a refractory ocular condition such as presbyopia comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention, wherein following treatment the subject is able to achieve or correctly identify at least 60, 65, 70, 75, or 80 or more ETDRS letters in binocular DCNVA.
The present invention is further directed to a method of treating a refractory ocular condition such as presbyopia comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention, wherein a subject has at least a 5%, 10%, 15%, 20%, or 25% increase or improvement in binocular DCNVA relative to baseline (i.e., prior to treatment).
The present invention is further directed to a method of treating a refractory ocular condition such as presbyopia comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention, wherein following treatment the subject has a decrease (improvement) in Log MAR score of at least 0.050, 0.075, 0.100, 0.125, 0.150, 0.175, or 0.200 relative to baseline (i.e., prior to treatment). In another embodiment, the subject's Log MAR score is less than 0.300 Log MAR, or less than 0.250 Log MAR, or is less than 0.225 Log MAR, or less than 0.200 Log MAR following treatment.
The test for visual acuity may use the Snellen chart, the Early Treatment for Diabetic Retinopathy Study (ETDRS) chart, or another chart.
The present invention is further directed to a method of allowing binocular physiologic topical presbyopic correction.
The present invention is further directed to a method of eliminating the need for monocular limitation due to distance blur, or reduced to treatment of mild hyperopes to counteract induced myopic blur, as typically associated with pilocarpine, or pilocarpine and alpha agonist combinations.
The present invention is further directed to a method of a refractory ocular condition by inhibiting or reversing the progression of age related degeneration of a crystalline lens in an eye, comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention.
The present invention is further directed at eliminating optical aberrations induced by corneal irregularity, opacities, or very high degrees of regular astigmatism that include regions adjacent or peripheral to the central 1.5 mm optical zone, and thereby inducing improved visual acuity and quality of vision by filtering out these aberrant optics in those suffering from irregular astigmatism or high degrees of more regular astigmatism, such as occurs in conditions such as keratoconus, photorefractive keratectomy induced corneal haze, diffuse lamellar keratitis (“DLK”) (post-lasik DLK), other iatrogenic corneal induced irregularity such as cataract incision, glaucoma filtering blebs, implanted glaucoma valves, corneal inlays with or without removal, ectasia post corneal surgery (lasik), and secondary to infection.
The present invention is also directed to methods of treating irregular astigmatism, keratoconic ectasia, and low myopia, or hyperopia, with or without astigmatism, comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the present invention.
The compounds and pharmaceutical composition described herein may also be used in a method for treating, reducing, or preventing oxidation damage or stress to cells, including ocular cells or the lens of an eye. Such a method includes the step of administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising Formula (I) or a pharmaceutically acceptable salt thereof to such a cell, either in vitro or in vivo. In one embodiment, a compound or pharmaceutical composition of the invention is delivered to a lens, either in vitro or in vivo.
Lens elasticity decreases with age and is a primary diagnostic and causative factor for presbyopia. Lens elasticity can be measured as accommodative amplitude in diopters (D). The lower the value of D, the less elastic the lens. In one embodiment, the agents described herein may decrease and/or maintain D at a value that is greater than the D value exhibited by an untreated lens of about the same age. In one embodiment, D is increased and/or maintained at a value about 2, 5, 7, 10, 15, 25, 50, 100, 150, or 200 percent above the line. In another embodiment, the agents described herein may cause a reduction in the rate of decline of elasticity (i.e., reduction in the rate of decrease in diopters) for an individual lens compared to the elasticity of the same lens before treatment. In another embodiment, the methods provide an objective increase in elasticity of at least about 0.1, 0.2, 0.5, 1, 1.2, 1.5, 1.8, 2, 2.5, 3, or 5 diopters.
Therapeutic efficacy can also be measured in terms of lens opacity. Lens opacity increases with age and may be used as an indirect diagnostic for lens elasticity. In one embodiment, the agents described herein may decrease and/or maintain lens opacity at a value that is less than the opacity value exhibited by an untreated lens of about the same age.
Treatment methods can be performed on subjects of any age, such as subjects that are 20, 25, 30, 35, 40, 45, 50, 52, 55, 57, 60, 70, 75, or 80 years of age or older, or between the ages of 20-40, or 30-50, or 40-60, or 50-70, or 60-80, or 70-90 years of age.
In certain embodiments, prior to treatment the subjects may have impaired near vision in each eye and/or when using both eyes, without any near correction. In other embodiments, prior to treatment, the subject may need a certain level of near correction. In other embodiments, prior to treatment, the subject has Distance Corrected Near Visual Acuity of 20/40 or worse than 20/40, 20/50, 20/70, or 20/100 and/or best Corrected Distance Visual Acuity of 20/40, or 20/20 or better than 20/20 in at least one eye or in both eyes. In other embodiments, the subject may not have or suffer from significant astigmatism, glaucoma, diabetes, diabetic retinopathy, or cataracts. In other embodiments, the subject may not have had eye surgery or ocular trauma.
Treatment methods include frequency of administration of every 6 hours, every 8 hours, 12 hours, 48 hours, 72 hours, 96 hours, 1 week, or 2 weeks. Treatment methods also include frequency of administration of four times a day (QID), three times a day (TID), two times a day (BID), or once a day (QD).
In another embodiment, the invention provides a method of treatment comprising administering a compound (or salt) of any one of embodiments 1 to 250 or of any one of Examples 1-474 (or salt) to a subject. In another embodiment, the invention provides a method of treatment comprising administering between 0.01 milligrams and 2 grams of a compound (or salt) of any one of embodiments 1 to 250 or of any one of Examples 1-474 (or salt) to a subject.
In each of the methods described above or below, a compound (or salt) of any of embodiments 1 to 250 or of any one of Examples 1-474 (or salt) may be administered to a subject as part of a pharmaceutically formulation, as described herein.
In each of the methods described herein, the method may further include the step of determining whether the subject has a refractive ocular condition.
B. Combination Treatments
Methods for treating refractive ocular conditions described herein may also include administering a compound of the invention in combination with or alternation with another active agent known to be useful in ocular disease, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent. For example, adjunctive agents might include one or more amino acids or choline to enhance the efficacy of the active agent.
The term “co-administer” means to administer more than one active agent, such that the duration of physiological effect of one active agent overlaps with the physiological effect of a second active agent. In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another.
In an embodiment, the additional active agent is selected from the group consisting of general miotic agents, such as a non-selective muscarinic acetylcholine receptor agonist (pilocarpine), a non-selective muscarinic acetylcholine receptor agonist (carbachol), an acetylcholinesterase inhibitor (phospholine iodide), or an alpha 2 selective vasoconstrictor (brimonidine). In other embodiments, the additional active agent is selected from the group consisting of lipoic acid, lipoic acid derivatives (such as lipoic acid choline ester), Nrf2 activators, antioxidants, detoxification agents, and anti-inflammatory agents. In one embodiment, the invention provides a pharmaceutical composition comprising a compound (or salt) of any one of embodiments 1 to 250 (or salt) or of any one of Examples 1-474 (or salt) and at least one other active ingredient selected from lipoic acid, lipoic acid derivatives (such as lipoic acid choline ester), Nrf2 activators, antioxidants, detoxification agents, and anti-inflammatory agents. In another embodiment, the invention provides for the use of a compound (or salt) of any one of embodiments 1 to 250 or of any one of Examples 1-474 (or salt) in combination with at least one other active ingredient selected from lipoic acid, lipoic acid derivatives (such as lipoic acid choline ester), Nrf2 activators, antioxidants, detoxification agents, and anti-inflammatory agents for simultaneous, subsequent, or sequential administration.
A. Compounds of the Invention (Compounds of Formula (I)))
A compound of Formula (I) has the structure shown below
where Y3 is cyclopropyl, —CF3, —OCF3, —OCH3, —OCH2CH3, —F, —Cl, —OH, —O(CH2)2—OH, —O(CH2)2—F, —SCH3, —S(O)2—CH3, —SCH2CH3, —S(O)2CH2CH3, —NH—CH3, —NH—CH2CH3, —N(CH3)2, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH3, —NH—C(O)—CH2CH3, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y4, where Y4 is —OH, —OCH3, —OCH2CH3, —OC(CH3)3, —NH2, —NH—CH3, —NH—CH2CH3, —N(CH3)2, —N(CH2CH3)2, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl;
where Y3 is -cyclopropyl, —CF3, —OCF3, —OCH3, —OCH2CH3, —F, —Cl, —OH, —O(CH2)2—OH, —O(CH2)2—F, —SCH3, —S(O)2—CH3, —SCH2CH3, —S(O)2CH2CH3, —NH—CH3, —NH—CH2CH3, —N(CH3)2, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH3, —NH—C(O)—CH2CH3, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y4, where Y4 is —OH, —OCH3, —OCH2CH3, —OC(CH3)3, —NH2, —NH—CH3, —NH—CH2CH3, —N(CH3)2, —N(CH2CH3)2, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl;
where Y3 is -cyclopropyl, —CF3, —OCF3, —OCH3, —OCH2CH3, —F, —Cl, —OH, —O(CH2)2—OH, —O(CH2)2—F, —SCH3, —S(O)2—CH3, —SCH2CH3, —S(O)2CH2CH3, —NH—CH3, —NH—CH2CH3, —N(CH3)2, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH3, —NH—C(O)—CH2CH3, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y4, where Y4 is —OH, —OCH3, —OCH2CH3, —OC(CH3)3, —NH2, —NH—CH3, —NH—CH2CH3, —N(CH3)2, —N(CH2CH3)2, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl;
where Y3 is cyclopropyl, —CF3, —OCF3, —OCH3, —OCH2CH3, —F, —Cl, —OH, —O(CH2)2—OH, —O(CH2)2—F, —SCH3, —S(O)2—CH3, —SCH2CH3, —S(O)2CH2CH3, —NH—CH3, —NH—CH2CH3, —N(CH3)2, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH3, —NH—C(O)—CH2CH3, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y4, where Y4 is —OH, —OCH3, —OCH2CH3, —OC(CH3)3, —NH2, —NH—CH3, —NH—CH2CH3, —N(CH3)2, —N(CH2CH3)2, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl;
Compounds 1-474 in Table A may be prepared as described in WO '018 or other methods apparent to one of skill in the art. For example, Compounds 473 and 474 in Table A may be prepared as described in the Examples section below.
The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids or bases. The phrase “pharmaceutically acceptable salt” means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, Vol 66(1), pp. 1-19 (1977).
The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, hyaluronic acid, malic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, malic acid, maleic acid, methanosulfonic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
In another aspect, the present invention provides a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in manufacture of a medicine or for use in treating a refractive ocular condition. In an embodiment, the present invention provides a pharmaceutical composition comprising a compound (or salt) of any one of embodiments 1 to 250 (recited above) and a pharmaceutical carrier. In another embodiment, the pharmaceutical composition comprises a compound (or salt) of any one of the examples 1-474 and a pharmaceutically acceptable carrier.
Thus, in another embodiment, the invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment, the invention provides a pharmaceutical composition comprising a compound (or salt) of any one of embodiments 1 to 250 or a compound (or salt) of any one of Examples 1-474 and a pharmaceutical acceptable carrier.
In another embodiment, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in medicine. In another embodiment, the invention provides a compound (or salt) of any one of embodiments 1 to 250 or a compound (or salt) of any one of Examples 1-474 for use in medicine.
B. Co-Administration
The present invention further provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in combination with one or more active compounds for simultaneous, subsequent, or sequential administration. The invention also provides for the use of a compound (or salt) of any one of embodiments 1 to 250 or a compound (or salt) of any one of Examples 1-474 in combination with one or more active compounds for simultaneous, subsequent, or sequential administration.
In one embodiment, the invention provides a pharmaceutical composition comprising a compound (or salt) of any one of embodiments 1 to 250 or a compound (or salt) of any one of Examples 1-474 and at least one other active ingredient selected from lipoic acid, lipoic acid derivatives (such as lipoic acid choline ester), Nrf2 activators, antioxidants, detoxification agents, and anti-inflammatory agents.
In another embodiment, the additional active agent is selected from the group consisting of general miotic agents, such as a non-selective muscarinic acetylcholine receptor agonist (pilocarpine), a non-selective muscarinic acetylcholine receptor agonist (carbachol), an acetylcholinesterase inhibitor (phospholine iodide), or an alpha 2 selective vasoconstrictor (brimonidine).
In another embodiment, the invention provides for the use of a compound (or salt) of any one of embodiments 1 to 250 or a compound (or salt) of any one of Examples 1-474 in combination with at least one other medically effective active ingredient selected from lipoic acid, lipoic acid derivatives (such as lipoic acid choline ester), Nrf2 activators, antioxidants, detoxification agents, and anti-inflammatory agents for simultaneous, subsequent, or sequential administration. In another embodiment, the additional active agent is selected from the group consisting of general miotic agents, such as a non-selective muscarinic acetylcholine receptor agonist (pilocarpine), a non-selective muscarinic acetylcholine receptor agonist (carbachol), an acetylcholinesterase inhibitor (phospholine iodide), or an alpha 2 selective vasoconstrictor (brimonidine).
In some embodiments, the compositions disclosed herein are co-administered in combination with one or more additional active agent for treatment of a refractive ocular condition.
C. Dosages and Dosage Regimes
The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment desired. Dosage amounts of 0.001 to 100 mg/kg of body weight daily may be administered to a subject.
An appropriate dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the present invention, may be determined according to any one of several well-established protocols. For example, animal studies such as studies using mice, rats, dogs, and/or monkeys may be used to determine an appropriate dose of a pharmaceutical compound. Results from animal studies may be extrapolated to determine doses for use in other species, such as for example, humans.
A compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered in a dosage of between 0.01 mg and 15 mg per kg. In an embodiment, dose may be between 0.01 mg and 1000 mg. In another embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered orally in an amount from 10 mg/day to 1000 mg/day, or from 25 mg/day to 800 mg/day, or from 37 mg/day to 750 mg/day, or from 75 mg/day to 700 mg/day, or from 100 mg/day to 600 mg/day, or from 150 mg/day to 500 mg/day, or from 200 mg/day to 400 mg/day. In another embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in ocularly in an amount from 0.010 mg/day to 5 mg/day, or from 0.025 mg/day to 1 mg/day, or from 0.050 mg/day to 1 mg/day, or from 0.100 mg/day to 1 mg/day, or from 0.250 mg/day to 1 mg/day, or from 0.50 mg/day to 1 mg/day. In other embodiments, the previous daily periods of administration of an amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be changed to a period of every 6 hours (or 4 times a day), 8 hours (or 3 times a day), 12 hours (or twice a day), 48 hours, 72 hours, 96 hours, 1 week, or 2 weeks. In some embodiments, the compound or composition is administered to the subject four times per day (QID), three times per day (TID), two times per day (BID), or once per day (QD).
In some embodiments, the composition is administered as part of a dosing regimen. For example, the patient can be administered a first dose of the composition for a first dosing period; and a second dose of the composition for a second dosing period, optionally followed by one or more additional doses for one or more additional dosing periods. The first dosing period can be less than one week, one week, or more than one week.
In some embodiments, the dosage regime is a dose escalating dosage regime.
D. Formulations
Pharmaceutical compositions comprising a compound of the invention are disclosed. The pharmaceutical compositions may be for administration by oral, parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), transdermal (either passively or using iontophoresis or electroporation), transmucosal (nasal, vaginal, rectal, or sublingual), or ocular routes of administration and can be formulated in unit dosage forms appropriate for each route of administration.
In some embodiments, a compound of the invention or a pharmaceutical composition is administered locally, to the site in need of therapy. For example, in some embodiments, a compound of the invention or a pharmaceutical composition is administered locally to the eye.
In an embodiment, the pharmaceutical compositions are formulated for oral delivery. Oral solid dosage forms are described generally in Remington's Pharmaceutical Sciences, 21th Ed. 2005 at Chapter 45. Solid dosage forms include tablets, capsules, pills, troches or lozenges, cachets, pellets, powders, or granules or incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc., or into liposomes. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the disclosed. The compositions may be prepared in liquid form, or may be in dried powder (e.g., lyophilized) form. Another embodiment provides liquid dosage forms for oral administration, including pharmaceutically acceptable emulsions, solutions, suspensions, and syrups, which may contain other components including inert diluents; adjuvants such as wetting agents, emulsifying and suspending agents; and sweetening, flavoring, and perfuming agents.
Controlled release oral formulations may be desirable. Compounds of the invention can be incorporated into an inert matrix which permits release by either diffusion or leaching mechanisms, e.g., gums. Slowly degenerating matrices may also be incorporated into the formulation.
The amount of the active agent (e.g., compound of Formula (I) or a pharmaceutically acceptable salt thereof) in an ocular pharmaceutical formulation can be selected based on the condition of the subject to be treated, including the subject's age, gender, as well as vision and lens status.
Ocular formulations include, but are not limited to, liquid formulations (e.g., solutions, suspensions) for topical administration as well as formulation for injection or ocular insert administration. The ocular formulation may be formulated for topical administration such as an eye drop, swab, ointment, gel, or mist (e.g, an aerosol or spray). In one embodiment, the formulation is an eye drop. For ocular formulations, the pharmaceutically acceptable excipients are selected to be compatible with, and suitable for, ocular use. Such excipients are well known in the art. In one embodiment, excipients may be selected to improve the solubility of the agent.
Exemplary amounts of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in an ocular formulation can be about 0.01% to about 20% w/v, about 0.1% to about 7.5% w/v, about 0.15% to about 5.0% w/v, about 0.5% to about 4.0% w/v, about 1.0% to about 4.0% w/v, about 3.0% w/v, or about 2% w/v. In another embodiment, the amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be about 0.01% to about 10% w/v, about 0.1% to about 7.5% w/v, about 0.15% to about 5.0% w/v, about 0.5% to about 4.0% w/v, about 1.0% to about 4.0% w/v, about 3.0% w/v, or about 2% w/v.
Excipients for an ocular formulation may include, but are not limited to, buffers, tonicity agents, viscosity agents, preservatives, preservatives, surfactants, emulsifiers, salts, lubricants, polymers, solvents, and other known excipients for ocular pharmaceutical formulations. Appropriate amounts can be determined by one of ordinary skill in the art, but non-limiting exemplary amounts (in % by weight) are also provided below.
In one embodiment, the ocular pharmaceutical composition may include one or more buffers to adjust or maintain the pH of the formulation. In one embodiment, the pH is near physiological pH of about 7. Thus, the pH of the formulation can be between about 4 to about 8, or about 5 to about 8, or about 6 to about 7, or about 6.8 to about 7.2, or about 7.1 to about 7.5. In another embodiment, the pH is about 5.5, or about 5 to about 7, or about 4.5 to about 6, or about 4.5 to about 5.5, or about 5.5 to about 6.5, or about 5 to about 6, or about 5.25 to about 5.75, or about 5.5. Exemplary buffers include, but are not limited to, phosphate buffers (e.g., sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous), borate buffers, and HBSS (Hank's Balanced Salt Solution). In one embodiment, the buffer is a phosphate buffer. In another embodiment, the buffer is sodium phosphate monobasic monohydrate and/or sodium phosphate dibasic anhydrous. The buffer amount (amount of either total buffer or a single buffer excipient) can be 0.1% to about 3.0% w/v, about 0.2% to about 2.0% w/v, about 0.5% to about 2.5% w/v, about 0.75% to about 2.25% w/v, about 1.5% to about 2.5% w/v, or about 1.0% to about 2.0% w/v.
In one embodiment, the ocular pharmaceutical composition may include one or more tonicity agents. Although the formulation may be hypertonic or hypotonic, isotonic formulations are preferred (260-320 mOsm). Exemplary tonicity agents include, but are not limited to, sodium chloride. The tonicity agent amount can be about 0.1% to about 5% w/v, about 0.1% to about 2% w/v, about 0.1% to about 1% w/v, about 0.25% to about 0.75% w/v, about 0.2% to about 0.6% w/v, or about 0.5% w/v.
In one embodiment the ocular pharmaceutical composition may include one or more viscosity agents to increase the viscosity of the formulation. Exemplary viscosity agents include, but are not limited to, cellulosic agents (e.g., hydroxypropyl methylcellulose), polycarbophil, polyvinyl alcohol. In one embodiment, the viscosity agent is a cellulosic agent, e.g., hydroxypropyl methylcellulose. The viscosity agent amount can be about 0.1% to about 5% w/v, about 0.1% to about 2% w/v, about 0.1% to about 1% w/v, about 0.1% to about 0.4% w/v, or about 0.2% w/v.
In one embodiment, the ocular pharmaceutical composition may include one or more preservatives to minimize microbial contamination or enhance shelf life. Exemplary preservatives include, but are not limited to, benzalkonium chloride (BAK), cetrimonium, chlorobutanol, edetate disodium (EDTA), polyquaternium-1 (Polyquad™), polyhexamethylene biguanide (PHMB), stabilized oxychloro complex (PURITE™), sodium perborate, and Soflia™. The preservative amount may be, e.g., less than about 0.02% w/v, about 0.004% w/v or less, or about 0.005% to about 0.01% w/v.
In one embodiment, the ocular pharmaceutical composition may include one or more stabilizers. Exemplary stabilizers include, but are not limited to, amino acids such as alanine. The stabilizer amount can be about 0.1% to about 5% w/v, about 0.1% to about 2% w/v, about 0.1% to about 1% w/v, about 0.25% to about 0.75% w/v, about 0.2% to about 0.6% w/v, or about 0.5% w/v.
In one embodiment, the ocular pharmaceutical composition may include one or more surfactants. Exemplary surfactants include, but are not limited to, cyclodextrins, polyoxyl alkyls, poloxamers or combinations thereof, and may include in addition combinations with other surfactants such as polysorbates. Embodiments include polyoxyl 40 stearate and optionally Poloxamer 108, Poloxamer 188, Poloxamer 407, Polysorbate 20, Polysorbate 80, ionically charged (e.g. anionic) beta-cyclodextrins with or without a butyrated salt (Captisol™) 2-hydroxypropyl beta cyclodextrin (“HPBCD”), alpha cyclodextrins, gamma cyclodextrins, Polyoxyl 35 castor oil, and Polyoxyl 40 hydrogenated castor oil or combinations thereof. In certain embodiments, the addition of an anionic surfactant such as sodium lauryl sulfate and or sodium ester lauryl sulfate may be preferred. In other embodiments, the addition of polysorbate 80 may be preferred. The amount surfactant (either total surfactant or a single surfactant) can be 0.1% to about 3.0% w/v, about 0.2% to about 2.0% w/v, about 0.5% to about 2.5% w/v, about 0.75% to about 2.25% w/v, about 1.5% to about 2.5% w/v, or about 1.0% to about 2.0% w/v.
To a DMF or THF solution of a 6-chloro-5-nitro-nicotinic acid methyl ester is added 2 M methylamine in THF and the reaction mixture stirred at room temperature for 16 h. The resulting mixture is poured into water to precipitate the product. The precipitate may be filtered and dried to give the product, which may not be purified further before use in the next step.
10% Pd/C is added to a solution of the nitro compound in methanol. The resulting mixture is stirred at room temperature under a 112 atmosphere for 16 h. The contents may then be filtered through a pad of Celite or silica gel and the solid washed with portions of methanol. The filtrate and washings are combined and evaporated to afford the corresponding diamine, which may not be purified further before use in the next step.
1,1′-Thiocarbonylimidazole is added to a solution of an amine with triethylamine (1 eq.) in acetonitrile (10 mL). The reaction mixture is stirred at room temperature (1-24 h). The solvent is then evaporated, and the product suspended in acetonitrile. The solvent is then evaporated to produce the product as a precipitate. The precipitate is filtered and washed with acetonitrile and dried. The product may be used directly in the next step without further purification.
To the product obtained immediately above is added EDAC at room temperature followed by a substituted diaminopyridine, and the reaction mixture is stirred at 90° C. for 16 h. The reaction mixture is then cooled to room temperature, poured into cold water, and the solid collected by filtration. The crude product thus obtained may be purified by trituration with methanol.
A solution of NaOH in water is added to a solution of an ester in 1:1 THF/MeOH, and the resulting mixture is stirred at 60° C. for 16 h. After completion of the reaction, the mixture is concentrated under vacuum. The pH of the resulting suspension may be adjusted by the dropwise addition of 6 N HCl to pH ˜3, and the precipitate collected by filtration, washed with water and dried under vacuum. The desired carboxylic acid may be used without purification.
To a solution of a carboxylic acid in dry DMF is added DIEA followed by HBTU, and the reaction mixture is stirred at room temperature for 30 min. An appropriate amine is then added, and the reaction stirred at room temperature for 16 h. The contents may be diluted with ice-water, and the product precipitated. The product may be isolated after filtration either with subsequent washings with water and DCM/methanol or through silica gel chromatography using hexanes/ethyl acetate (from 80:20 to 60:40) as an eluent system.
Compound 473
6-Methylamino-5-nitro-nicotinic acid methyl ester (5.0 g) was prepared by following General Procedure A starting from 6-chloro-5-nitro-nicotinic acid methyl ester (5.0 g) and methylamine (33% in EtOH, 24 mL) in THE (150 mL). The crude product was used in the next step without further purification.
5-Amino-6-methylamino-nicotinic acid methyl ester (4.8 g) was prepared by following General Procedure B starting from 6-methylamino-5-nitro-nicotinic acid methyl ester (5.0 g) and Pd/C (20% by weight, 1.0 g) in methanol:THF (1:1, 50 mL). The crude product was used in the next step without further purification.
Methyl 3-methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxylate (5.0 g) was prepared by following General Procedure C starting from 6-(trifluoromethyl)-1,3-benzothiazol-2-amine (5.0 g), 5-amino-6-methylamino-nicotinic acid methyl ester (5.0 g), 1,1′-thiocarbonyl-diimidazole (5.0 g), and EDAC (4.5 g). The crude product was used in next step without further purification.
3-Methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxylic acid (4.2 g) was prepared by following General Procedure D starting from methyl 3-methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxylate (5.0 g) and NaOH (2N, 25 mL) in methanol:THF (2:1, 50 mL). The crude product was used in next step without further purification.
N-[2-(2-Hydroxyethoxy)ethyl]-3-methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxamide (40 mg) was prepared by following General Procedure E starting from 3-methyl-2-[[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxylic acid (100 mg), 2-(2-aminoethoxy)ethanol (100 mg), HBTU (200 mg) and DIEA (0.2 mL) in DMF (2.0 mL). LC/MS: m/z 481.7. 1H NMR (DMSO-ds, 400 MHz): δ 8.67-8.59 (m, 211), 8.29-8.23 (d, 211), 7.71-7.69 (d, 1H), 4.61 (s, 1H), 3.68 (br s, 3H), 3.57-3.44 (m, 811), 3.32 (br s, 2H).
Compound 474
1-Ethyl-N-[2-(2-hydroxyethoxy)ethyl]-2-[[5-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino]benzimidazole-5-carboxamide (40 mg) was prepared by following General Procedure E starting from 3-ethyl-2-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino]imidazo[4,5-b]pyridine-6-carboxylic acid (100 mg) (See WO 018), 2-(2-aminoethoxy)ethanol (100 mg), HBTU (200 mg) and DIEA (0.2 mL) in DMF (2.0 mL). LC/MS: m/z 510.7.
Purpose
Evaluate effect of test compounds (Examples 46 and 134) on the changes in lens elasticity in vitro in the lens from aged mice.
Methods
Test compounds (Examples 46 and 134) at 50 μM and 500 μM, Positive Control of Lipoic Acid at 50 μM and 500 μM, and control treatment were administered to lenses (12 per group) according to methods described in Invest Ophthalmol Vis Sci. 2016; 57:2851-2863. Briefly, seven month old C57BL/6J mice (male) were euthanized by CO2 overdose. Lenses were removed and placed in culture medium. Lenses were incubated for about 2 hours at 37° C. The medium was replaced with fresh medium supplemented with test compounds or with fresh medium. After about 14 hours incubation at 37° C., lenses were removed from culture medium.
Measurement of lens elasticity was performed according to the methods described in Invest Ophthalmol Vis Sci. 2016; 57:2851-2863. Briefly, lenses were placed on slides and photographed. A second photograph was taken after a coverslip was placed on the lens. Equatorial diameters changed by the coverslips placed on the lens were analyzed.
Results
Treatment of lenses with Examples 46 and 134 at both concentrations of 50 μM and 500 μM significantly increased lens elasticity relative to control. Further, there was dose dependent increase in elasticity with Examples 46 and 134 from the lower dose (50 μM) to the higher dose (500 μM). Further, the efficacy of Examples 46 and 134 were almost the same as that of the positive control groups using lipoic acid. A summary of the results is provided in Table 1 and in
Purpose
Evaluate effect of topically applied test compounds (Examples 46 and 134) on the changes of lens elasticity in aged mice.
Methods
Test compounds (Examples 46 and 134), positive control of Lipoic Acid Choline Ester (LACE), and control treatment were topically administered to right eyes according to methods described in Invest Ophthalmol Vis Sci. 2016; 57:2851-2863. Briefly, eight month old C57BL/6J mice (male) were treated with 2.5 μL of each test sample three times per day (TID) at about 4-hour intervals in the right eyes for 2 weeks. The left eyes were used as untreated controls. Each treatment group included 10 mice, and the vehicle group included 5 mice.
Measurement of lens elasticity was performed according to the methods described in Invest Ophthalmol Vis Sci. 2016; 57:2851-2863. Briefly, after 2-week treatment, mice were euthanized by CO2 overdose. Lenses were removed and analyzed for changes in elasticity. Lenses were placed on slides and photographed. A second photograph was taken after a coverslip was placed on the lens. Equatorial diameters changed by the coverslips placed on the lens were analyzed.
Results
Repeated installation of 0.15%, 0.5%, 1.5% solutions comprising the compound of Example 46 or Example 134 TID significantly increased elasticity of the mouse lenses. The efficacy of 0.5% and 1.5% solutions comprising the compound of Example 46 or Example 134 were better than or equivalent to that of 1.5% solutions comprising LACE.
A summary of the results for the compound of Example 134 is provided in Table 2 and in
A summary of the results for the compound of Example 134 is provided in Table 3 and in
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US21/16018 | 2/1/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62970515 | Feb 2020 | US |
