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US-12622893-B2 - Alpha2 adrenergic agonist codrugs conjugated with muscarinic agonist drugs

US12622893B2US 12622893 B2US12622893 B2US 12622893B2US-12622893-B2

Abstract

A co-drug or a pharmaceutical salt thereof includes a muscarinic agonist moiety and an alpha2 adrenergic agonist moiety. The muscarinic agonist moiety and the alpha2 adrenergic agonist moiety are connected covalently via a linker, and the link includes an ester bond, an amide bond, a carbamate bond, or a combination thereof.

Inventors

  • Wenkui Ken Fang
  • Jinsong Ni
  • Rong Yang
  • VAN DINH

Assignees

  • ADS THERAPEUTICS LLC

Dates

Publication Date
20260512
Application Date
20220331

Claims (9)

  1. 1 . A co-drug comprising a muscarinic agonist moiety and an alpha2 adrenergic agonist moiety, or a pharmaceutical salt thereof, wherein the muscarinic agonist moiety and the alpha2 adrenergic agonist moiety are connected covalently via a linker, and the link comprises an ester bond, an amide bond, a carbamate bond, or a combination thereof.
  2. 2 . The co-drug of claim 1 , wherein the co-drug is a compound of Formula I, an enantiomer, a diastereoisomer, a hydrate, a solvate, a crystal form, or a tautomer thereof, wherein: R is H, —CO—C 1-8 alkyl, —CO—C 1-8 alkyloxy; —CO-aryl, —CO-aryloxy, —CO—C 1-8 alkylaryl, or —CO—C 1-8 alkylaryloxy; Z is and R 1 is H or C 1-3 alkyl.
  3. 3 . The co-drug of claim 1 , wherein the co-drug is a compound of Formula II, an enantiomer, a diastereoisomer, a hydrate, a solvate, a crystal form, or a tautomer thereof, wherein: R 2 is H, C 1-3 alkyl; C 1-8 alkyloxy; aryl, aryloxy, C 1-8 alkylaryl, or C 1-8 alkylaryloxy; Z is and R 1 is H or C 1-3 alkyl.
  4. 4 . The co-drug of claim 1 , wherein the co-drug is a compound of Formula III, an enantiomer, a diastereoisomer, a hydrate, a solvate, a crystal form, or a tautomer thereof, wherein: R is H, —CO—C 1-18 alkyl, —CO—C 1-18 alkyloxy; —CO-aryl, —CO-aryloxy, —CO—C 1-18 alkylaryl, or —CO—C 1-18 alkylaryloxy; and Z is:
  5. 5 . The co-drug of claim 1 , wherein the co-drug is selected from the group consisting of 3-((S)-1-(1H-imidazol-4-yl)ethyl)-2-methylbenzyl (2S,3R)-2-ethyl-4-hydroxy-3-((1-methyl-1H-imidazol-5-yl)methyl) butanoate; 3-((S)-1-(1H-imidazol-4-yl)ethyl)-2-methylbenzyl (2S,3R)-4-acetoxy-2-ethyl-3-((1-methyl-1H-imidazol-5-yl)methyl) butanoate; (((2S,3R)-2-ethyl-4-hydroxy-3-((1-methyl-1H-imidazol-5-yl)methyl)butanoyl)oxy)methyl 2-((4-bromo-1H-benzo[d]imidazol-5-yl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate; (((2S,3R)-4-acetoxy-2-ethyl-3-((1-methyl-1H-imidazol-5-yl)methyl)butanoyl)oxy)methyl 2-((4-bromo-1H-benzo[d]imidazol-5-yl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate; (((2S,3R)-2-ethyl-4-hydroxy-3-((1-methyl-1H-imidazol-5-yl)methyl)butanoyl)oxy)methyl 2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate; (((2S,3R)-4-acetoxy-2-ethyl-3-((1-methyl-1H-imidazol-5-yl)methyl)butanoyl)oxy)methyl 2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate; 1-(((2S,3R)-2-ethyl-4-hydroxy-3-((1-methyl-1H-imidazol-5-yl)methyl)butanoyl)oxy)ethyl 2-((4-bromo-1H-benzo[d]imidazol-5-yl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate; 1-(((2S,3R)-4-acetoxy-2-ethyl-3-((1-methyl-1H-imidazol-5-yl)methyl)butanoyl)oxy)ethyl 2-((4-bromo-1H-benzo[d]imidazol-5-yl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate; 1-(((2S,3R)-2-ethyl-4-hydroxy-3-((1-methyl-1H-imidazol-5-yl)methyl)butanoyl)oxy)ethyl 2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate; 1-(((2S,3R)-4-acetoxy-2-ethyl-3-((1-methyl-1H-imidazol-5-yl)methyl)-butanoyl)oxy)ethyl 2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate; (2R,3S)-3-(2-((4-bromo-1H-benzo[d]imidazol-5-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl acetate; (2R,3S)-3-(2-((4-bromo-1H-benzo[d]imidazol-5-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl propionate; (2R,3S)-3-(2-((4-bromo-1H-benzo[d]imidazol-5-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl butyrate; (2R,3S)-3-(2-((4-bromo-1H-benzo[d]imidazol-5-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl cyclopropanecarboxylate; (2R,3S)-3-(2-((4-bromo-1H-benzo[d]imidazol-5-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl oleate; (2R,3S)-3-(2-((4-bromo-1H-benzo[d]imidazol-5-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl (9Z,12Z)-octadeca-9,12-dienoate; (2R,3S)-3-(2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl acetate; (2R,3S)-3-(2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl propionate; (2R,3S)-3-(2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl butyrate; (2R,3S)-3-(2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl cyclopropanecarboxylate; (2R,3S)-3-(2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl oleate; (2R,3S)-3-(2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl (9Z,12Z)-octadeca-9,12-dienoate; (2R,3S)-3-(2-((4-amino-2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl acetate; (2R,3S)-3-(2-((4-amino-2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl propionate; (2R,3S)-3-(2-((4-amino-2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl butyrate; (2R,3S)-3-(2-((4-amino-2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl cyclopropanecarboxylate; (2R,3S)-3-(2-((4-amino-2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl oleate; (2R,3S)-3-(2-((4-amino-2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl (9Z,12Z)-octadeca-9,12-dienoate; (2R,3S)-3-(2-((2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl acetate; (2R,3S)-3-(2-((2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl propionate; (2R,3S)-3-(2-((2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl butyrate; (2R,3S)-3-(2-((2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl cyclopropanecarboxylate; (2R,3S)-3-(2-((2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl oleate; and (2R,3S)-3-(2-((2,6-dichlorophenyl)amino)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-((1-methyl-1H-imidazol-5-yl)methyl)pentyl (9Z,12Z)-octadeca-9,12-dienoate.
  6. 6 . A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the co-drug according to claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.
  7. 7 . The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition is formulated for ocular administration, systemic administration, oral administration, intravenous administration, intradermal administration, or intracavernous administration.
  8. 8 . The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition is an eyedrop, a gel, or an implant.
  9. 9 . The pharmaceutical formulation of claim 8 , wherein the eyedrop is a solution, a suspension, or an emulsion.

Description

This application is the US National Stage Application of PCT/US2022/022835, filed on Mar. 31, 2022, which claims priority to U.S. Provisional Patent Application Nos. 63/176,149, filed on Apr. 16, 2021 and 63/272,134, filed on Oct. 26, 2021, both of which are incorporated by reference for all purposes as if fully set forth herein. FIELD OF THE INVENTION The present invention relates to a codrug of an alpha2 adrenergic agonist conjugated with a muscarinic agonist drug, a process for preparing the same, a pharmaceutical composition containing the same and the use as pharmaceuticals to treat various diseases. The present invention further describes single drug entities, formed by direct linkage of an alpha2 adrenergic agonist to a muscarinic agonist. Upon drug administration, the single drug entity undergoes selective cleavage at the linkage region to release the adrenergic agonist and the muscarinic agonist individual drugs. BACKGROUND OF THE INVENTION Alpha2 adrenergic agonists in the ocular application, for example, are well established drugs for lowering IOP and are used for treating glaucoma. This class of drugs can decrease the fluid production that supplies the liquid to maintain IOP. On the other hand, they can also increase the out-flow of liquid from vitreous humor. This double acting mechanism on both inflow and outflow makes them effective treatments for glaucoma. Presbyopia is another ocular indication that can be treated with alpha2 adrenergic agonists. They inhibit dilator muscle to reduce muscle activity. Since this muscle contributes to the opening of pupil, the alpha2 agonists will reduce the pupil size. This action causes an increase of the depth of field. Presbyopia is the reduced ability to see close objects and is associated with normal aging. The increased depth of field will make a person with presbyopia see close object more clearly. Muscarinic agonists are used for many diseases, including ocular indications. Their mechanisms of action in the eye are mostly mediated through the M3 receptor. Muscarinic agonists are used to treat glaucoma because they can contract the ciliary body muscle and opens the trabecular meshwork to increase the outflow of aqueous humor. This action help to reduce the IOP and can be used to treat glaucoma. This mechanism of action is different from the alpha2 mechanism discussed earlier, thus a muscarinic agonist, when combined with an alpha2 compound, may result in better efficacy. The muscarinic agonist can also be used to improve eyesight in persons with presbyopia. However, the mechanism of action is still not very clear and some agonists considered to be in the same class may work through different mechanisms. For example, pilocarpine is effective in treating presbyopia and the proposed mechanism is improving accommodation, possibly through ciliary tonic contraction reduction. But this hypothesis has not been proven. Another muscarinic drug, carbachol, may act on sphincter muscle to constrict pupil size. This action will increase the depth of field so that persons with presbyopia can see close objects more clearly. Since the pupil effect has a different mechanism than the alpha2 drugs, combining muscarinic agonist with an alpha agonist has synergistic effect on pupil constriction. A conjugate drug, also referred to as a co-drug, includes two or more different or same drugs within one single chemical entity wherein each drug contains an appropriate chemical functionality to enable them to be connected directly, which is cleavable and biologically labile. The alpha2 adrenergic agonist moiety and the muscarinic agonist moiety of the co-drug compounds disclosed herein are connected to each other via covalent bonds, such that said bond degrades in vivo to yield the respective muscarinic agonist and alpha2 adrenergic agonist. Each bond is, for example, an amide bond or an ester bond or others depending on the nature of the bonding site. By appropriate structural design, it may be possible to control the release of each drug. When the drugs are chemically combined, the resulting co-drug will usually have different physicochemical properties compared to the individual parent drugs, which may provide superior properties for delivery when compared to delivery of a physical mixture of the drugs. Enzymatic or hydrolytic degradation of these covalent bonds generally, yields the corresponding acid, or alcohol by hydrolysis or by a related reaction. A compound which degrades in vivo yields the active muscarinic agonist drug and the active alpha2 adrenergic agonist drug at some point in the metabolic process of the claimed compound. SUMMARY OF THE INVENTION In one embodiment, the present application discloses a co-drug that includes a muscarinic agonist moiety and an alpha2 adrenergic agonist moiety, or a pharmaceutical salt thereof. The muscarinic agonist moiety and the alpha2 adrenergic agonist moiety are connected covalently via a linker, and the link comprises an ester