(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19)
`
`\
`W ld I t 11
`t
`1 P
`t
`\.
`"r 0,232,223,131, mp" y
`’/
`International Bureau
`(43) International Publication Date /
`26 October 2017 (26.10.2017) WI Po 1 P C T
`
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`(10) International Publication Number
`WO 2017/184871 A1
`
`21 3
`A
`h
`I
`.
`Pubhshildf
`.
`. U)
`_ 2V” "”emm’o’?“ 3.6”” War.” ”i
`— efore the expiration of the tzrne limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
`
`(51) International Patent Classification:
`A61K31/05 (2006.01)
`A61K31/661 (2006.01)
`A61K3I/10(2006.01)
`A61K3I/7012 (2006.01)
`A61K3I/4468 (2006.01)
`A61P25/I6 (2006.01)
`(21) International Application Number:
`
`PCT/US2017/028646
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`20 April 2017 (20.04.2017)
`
`English
`
`English
`
`(30) Priority Data:
`62/325,200
`
`20 April 2016 (20.04.2016)
`
`US
`
`1 North Waukegan
`(71) Applicant: ABBVIE INC. [US/US];
`Road, North Chicago, Illinois 60064 (US).
`
`(72) Inventors: KYM, Philip R.; 10002 Gracewood Avenue,
`Libertyville, Illinois 60048 (US). VOIGHT, Eric; 10615
`48th Avenune, Pleasant Prairie, Wisconsin 53148 (US).
`
`(74) Agent: MILLONIG, Robert C. et a1; Sterne, Kessler,
`Goldstein & Fox P.L.L.C, 1 100 New York Avenue, N.W.,
`Washington, DC 20005—3934 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR,
`KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
`SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind ofregional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`KM, ML, MR, NE, SN, TD, TG).
`
`(54) Title: CARBIDOPA AND L-DOPA PRODRUGS AND METHODS OF USE
`
`(57) Abstract: The present disclosure relates to (a) carbidopa prodrugs, (b) pharmaceutical combinations and compositions comprising
`a carbidopa prodrug and/or an L—dopa prodrug, and (0) methods of treating Parkinson's disease and associated conditions comprising
`administering a, carbidopa, prodrug and an L-dopa, prodrug to a, subject with Parkinson's disease.
`
`
`
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`PCT/US2017/028646
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`CARBIDOPA AND L-DOPA PRODRUGS AND METHODS OF USE
`
`FIELD OF THE INVENTION
`
`[1] The present disclosure relates to (a) carbidopa prodrugs, (b) L-dopa
`
`prodrugs, (c) pharmaceutical combinations and compositions comprising a
`
`carbidopa prodrug and/or an L-dopa prodrug, and (d) methods of treating
`
`Parkinson's disease and associated conditions comprising administering a
`
`carbidopa prodrug and an L-dopa prodrug to a subject with Parkinson’s disease.
`
`BACKGROUND OF THE INVENTION
`
`[2]
`
`Parkinson's disease is a chronic and progressive neurodegenerative
`
`condition characterized by reduced levels in the brain of the neurotransmitter
`
`dopamine (i.e., 3,4—dihydroxyphenethylamine). Administration of L—dopa (i.e., L—
`
`3,4-dihydroxyphenylalanine) currently is the most effective therapy for treating a
`
`patient with Parkinson’s disease. L-dopa, which unlike dopamine can cross the
`
`blood-brain barrier, is enzymatically converted in the brain to dopamine resulting
`
`in an increase in dopamine levels:
`0
`
`HO
`
`HO
`
`NH2
`
`L-Dopa
`
`OH
`
`Aromatic L-Amino ACId
`Decarboxylase
`
`HO
`
`NH2
`
`HO
`
`Dopamine
`
`[3] The conversion of L-dopa to dopamine is catalyzed by aromatic L-amino
`
`acid decarboxylase, a ubiquitous enzyme that promotes central as well as
`
`peripheral metabolism of L—dopa to dopamine. Due to the peripheral metabolism
`
`of L-dopa, a relatively large dose of L-dopa is required to achieve therapeutically
`
`effective dopamine levels in the brain. Administration of such large L-dopa doses
`
`results in elevated peripheral dopamine levels that can cause nausea in some
`
`patients. To overcome these problems, L—dopa generally is co—administered with
`
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`a peripheral aromatic L-amino acid decarboxylase inhibitor such as carbidopa
`
`(i.e., (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoic acid):
`
`
`
`Carbidopa
`
`Co-administration of carbidopa with L-dopa inhibits the peripheral metabolism of
`
`L—dopa to dopamine, which significantly reduces the L—dopa dose required for a
`
`therapeutically effective response and reduces the associated side effects.
`
`[4] Even when L-dopa and carbidopa are co-administered, however, it is
`
`difficult to consistently maintain the desired dopamine levels in the brain due to
`
`the relatively short half-life of L-dopa in plasma.
`
`In addition, the tolerance of many
`
`patients to variability in dopamine levels in the brain decreases as the disease
`
`progresses. One approach that has been effective in reducing variability of
`
`dopamine levels is the continuous intestinal delivery of an adjustable dose of an L-
`
`dopa/carbidopa gel known by its commercial name, DuoDopa® in Europe and
`
`Duopa® in the United States. DuoDopa®lDuopa® is a suspension of L-
`
`dopa/carbidopa monohydrate (4:1 ratio of L-dopa to carbidopa monohydrate) in an
`
`aqueous gel (carboxymethyl cellulose sodium) having a viscosity that permits
`
`homogeneous distribution of micronized substance particles. The gel is delivered
`
`to the proximal small intestine through a jejunal tube inserted through a
`
`percutaneous endoscopic gastrostomy port. DuoDopa®/Duopa® is packaged in
`
`medication cassette reservoirs and continuously administered via a software-
`
`controlled ambulatory infusion pump. Although L—dopa and carbidopa have been
`
`co-administered to treat Parkinson’s disease for several decades, a
`
`pharmacokinetically-consistent delivery system that does not require intestinal
`
`insertion is not commercially available.
`
`[5] A major challenge to the development of less invasive or otherwise
`
`improved modes of administering L—dopa and carbidopa has been the solubility of
`
`those compounds. They each have low aqueous solubility at the pH range
`
`required for infusion. Stable, more highly concentrated, and/or less viscous
`
`formulations comprising L-dopa and/or carbidopa (or compounds capable of in
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`vivo bioconversion to L-dopa and/or carbidopa) are desirable. Such formulations
`
`can provide advantages over existing intestinal infusion therapy including: (a)
`
`decreasing the volume and improving the pumpability of the formulation to be
`
`delivered to the patient which also allows for a reduction of the size and weight of
`
`delivery device; (b) extending the shelf life of the formulation by reducing
`
`degradation and improving stability of the formulation; and/or (c) providing the
`
`patient with increased flexibility in managing their treatment by reducing or
`
`eliminating cold storage requirements for the formulation (e.g., longer times to
`
`handle the formulation outside of refrigerated storage). Such stable, more highly
`
`concentrated, and/or less viscous formulations also can be employed in less
`
`invasive modes of administration (e.g., subcutaneous infusion).
`
`[6] Accordingly, there is a continuing need for improved compositions and
`
`methods that can provide continuous and consistent dopamine levels in the brain
`
`to effectively treat movement disorders such as Parkinson's disease. The present
`
`disclosure provides such improved compositions and methods.
`
`10
`
`15
`
`SUMMARY OF THE INVENTION
`
`[7]
`
`In one aspect, the present disclosure relates to a compound
`
`20
`
`corresponding in structure to Formula (I):
`
`R20 (I)
`
`R30
`
`or a pharmaceutically acceptable salt thereof, wherein R1 is independently
`
`selected from the group consisting of hydrogen,
`
`0
`
`, and
`
`R2 and R3 are each independently selected from the group consisting of
`
`O
`
`O OH
`
`COZH
`
`(DH/Egg;
`OH
`
`F‘iAo
`
`25
`
`hydrogen,
`
`'F'>—O0H RW 04%
`NH3+CI-O
`
`,
`
`CHZOH
`
`Na
`
`,
`
`;
`
`,
`
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`O
`
`Nob+CI
`and O
`
`, wherein R5 is selected from the group consisting of
`
`hydrogen, methyl, and isopropyl; and R4 is independently selected from the group
`o
`
`consisting of hydrogen,
`
`0
`
`O
`
`, and
`
`O
`
`.
`
`gin/0VVoP_-OOHH WO\/\oPlogH
`
`[8]
`
`In another aspect, the present disclosure relates to a compound
`
`corresponding in structure Formula (II):
`
`0R5
`
`NHR9
`
`R50
`
`(H)
`
`or a pharmaceutically acceptable salt thereof, wherein R6 is independently
`
`selected from the group consisting of hydrogen,
`
`0
`
`, and
`
`0H ;
`
`R7 and R8 are each independently selected from the group consisting of
`
`COZH
`
`CHZOH
`
`hydrogen,
`
`,
`
`,
`
`(mm P'gOH RW Wm 0°39
`OH
`Fifi/\O
`NH3+CI
`Na .0
`“Ag/JOB?
`, and O
`
`, wherein R5 is selected from the group consisting of
`
`hydrogen, methyl, and isopropyl; and R9 is independently selected from the group
`
`{[(0VVoP_95H
`
`9?
`gin/owomchm
`
`consisting of hydrogen,
`
`0
`
`O
`
`, and
`
`O
`
`.
`
`[9]
`
`In another aspect,
`
`the present disclosure relates to a pharmaceutical
`
`combination comprising a first compound corresponding in structure to Formula (I),
`
`or a pharmaceutically acceptable salt
`
`thereof,
`
`and a second compound
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`corresponding in structure to Formula (II) or a pharmaceutically acceptable salt
`
`thereof.
`
`[10]
`
`In another aspect, the present disclosure relates to a pharmaceutical
`
`composition comprising a first compound corresponding in structure to Formula
`
`(I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically
`
`acceptable carrier.
`
`In certain aspects, the pharmaceutical composition may
`
`further comprise a second compound corresponding in structure to Formula (II) or
`
`a pharmaceutically acceptable salt thereof.
`
`[11]
`
`In another aspect, the present disclosure relates to a method of treating
`
`Parkinson’s disease or an associated condition in a patient comprising
`
`administering to the patient a therapeutically effective amount of a pharmaceutical
`
`combination comprising a first compound corresponding in structure to Formula
`
`(I), or a pharmaceutically acceptable salt thereof, and a second compound
`
`corresponding in structure to Formula (II), or a pharmaceutically acceptable salt
`
`thereof.
`
`In certain aspects, the method comprises administering the first
`
`compound corresponding in structure to Formula (I), or a pharmaceutically
`
`acceptable salt thereof, and the second compound corresponding in structure to
`
`Formula (II) in a single pharmaceutical composition or in separate pharmaceutical
`
`compositions.
`
`[12]
`
`Further benefits of the present disclosure will be apparent to one skilled
`
`in the art from reading this patent application. The embodiments of the disclosure
`
`described in the following paragraphs are intended to illustrate the invention and
`
`should not be deemed to narrow the scope of the invention.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[13] This written description uses examples to disclose the invention,
`
`including the best mode, and also to enable any person skilled in the art to
`
`practice the invention, including making and using any of the disclosed carbidopa
`
`prodrugs or pharmaceutical compositions, and performing any of the disclosed
`
`methods or processes. The patentable scope of the invention is defined by the
`
`claims, and may include other examples that occurto those skilled in the art.
`
`Such other examples are intended to be within the scope of the claims if they
`
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`have elements that do not differ from the literal language of the claims, or if they
`
`include equivalent elements.
`
`|.
`
`Definitions
`
`[14]
`
`Section headings as used in this section and the entire disclosure are
`
`not intended to be limiting.
`
`[15] Where a numeric range is recited, each intervening number within the
`
`range is explicitly contemplated with the same degree of precision. For example,
`
`for the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9,
`
`and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,
`
`6.9 and 7.0 are explicitly contemplated.
`
`In the same manner, all recited ratios
`
`also include all sub-ratios falling within the broader ratio.
`1) u
`
`[16] The singular forms “a,
`
`an” and “the” include plural referents unless the
`
`context clearly dictates otherwise.
`
`[17] The term “and/or” as used in a phrase such as “A and/or B” herein is
`
`intended to include “A and B”, “A or B”, A” and “B”.
`
`[18] The term “about” generally refers to a range of numbers that one of skill
`
`in the art would consider equivalent to the recited value (i.e., having the same
`
`function or result).
`
`In many instances, the term "about" may include numbers that
`
`are rounded to the nearest significant figure.
`
`[19] Unless the context requires otherwise, the terms "comprise,"
`
`"comprises," and “comprising" are used on the basis and clear understanding that
`
`they are to be interpreted inclusively, rather than exclusively, and that Applicant
`
`intends each of those words to be so interpreted in construing this patent,
`
`including the claims below.
`
`[20] The terms "improve" and “improving” have their plain and ordinary
`
`meaning to one skilled in the art of pharmaceutical or medical sciences and
`
`specifically include ameliorating the effects of Parkinson’s disease, or decreasing
`
`or lessening a side effect of Parkinson’s disease.
`
`[21] The term "patient" includes mammals and humans, particularly humans.
`
`[22] The term "pharmaceutically acceptable carrier" or "pharmaceutically
`
`acceptable excipient" refers to any and all solvents, dispersion media,
`
`preservatives, antioxidants, coatings, isotonic and absorption delaying agents,
`
`and the like, that are compatible with pharmaceutical administration.
`
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`[23] The term "pharmaceutically acceptable salt" refers to a salt of a
`
`compound that is pharmaceutically acceptable and that possesses the desired
`
`pharmacological activity of the parent compound. Such salts include: (1) acid
`
`addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic
`
`acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic
`
`acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic
`
`acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid,
`
`maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-
`
`10
`
`15
`
`hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
`
`ethanesulfonic acid, 1,2—ethane—disulfonic acid, 2—hydroxyethanesulfonic acid,
`
`benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2—naphthalenesulfonic acid,
`
`4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]-oct-2-ene-1-
`
`carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,
`
`tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
`
`hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; and
`
`(2) salts formed when an acidic proton present in the parent compound either is
`
`replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an
`
`aluminum ion; or coordinates with an organic base such as ethanolamine,
`
`diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and the
`
`20
`
`like.
`
`[24] The terms "reduce" and "reducing" have their plain and ordinary
`
`meanings to one skilled in the art of pharmaceutical or medical sciences and
`
`specifically include diminishing or decreasing the number of occurrences, the
`
`duration, orthe intensity, of a Parkinson’s disease side effect, such as dyskinesias
`
`25
`
`or hallucinations.
`
`[25] The term "therapeutically effective amount" means an amount of a
`
`compound that, when administered to a patient suffering from or susceptible to
`
`Parkinson’s disease or an associated condition is sufficient, either alone or in
`
`combination with additional therapies, to effect treatment for Parkinson’s disease
`
`30
`
`or the associated condition. The "therapeutically effective amount" will vary
`
`depending, for example, on the compound, the condition treated and its severity,
`
`and the age and weight of the patient to be treated.
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`[26] The terms "treat" and "treating" have their plain and ordinary meaning
`
`to one skilled in the art of pharmaceutical or medical sciences and specifically
`
`include improving the quality of life or reducing the symptoms or side effects of
`
`Parkinson’s disease.
`
`ll.
`
`Carbidopa and L—Dopa Prodrugs
`
`[27] As previously noted, the inherently low aqueous solubility of L-dopa and
`
`carbidopa at physiologically acceptable pH for infusion presents a significant
`
`technical challenge to the development of improved pharmaceutical compositions
`
`and methods of treatment. Such challenges include, for example, difficulties in
`
`achieving appropriate closing volume and formulation stability within the required
`
`pH limitations. These challenges are further complicated by the requirement that
`
`the pharmaceutical compositions and methods of treatment provide
`
`pharmacokinetically-appropriate and pharmacokinetically-consistent control of
`
`dopamine levels in the patient’s brain.
`
`[28]
`
`Prior prodrug approaches have failed for a number of reasons due to
`
`these technical challenges (including insufficient chemical stability, insufficient
`
`solubility, in vivo bioconversion issues, and the like) and no L-dopa prodrugs or
`
`carbidopa prodrugs for infusion have been successfully commercialized. The
`
`prodrugs, pharmaceutical combinations and compositions, and methods of
`
`treatment of the present disclosure, however, have overcome these challenges.
`
`They can be used to treat patients suffering from Parkinson’s disease and
`
`associated conditions and do not always require invasive surgery.
`
`In various
`
`embodiments of the present disclosure, the compositions comprise L-dopa and
`
`carbidopa prodrugs that convert to L-dopa and carbidopa in vivo which allows for
`
`delivery by continuous administration methods including intragastric,
`
`intramuscular, intravenous, and subcutaneous administration. These novel
`
`prodrugs, combinations, compositions, and methods of the present disclosure
`
`represent an advancement in the treatment of Parkinson’s disease and other
`
`related conditions.
`
`A. Carbidopa Prodrugs
`
`[29]
`
`In one embodiment, therefore, the present disclosure relates to a
`
`compound corresponding in structure to Formula (I):
`
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` (l)
`
`or a pharmaceutically acceptable salt thereof, wherein R1 is independently
`
`selected from the group consisting of hydrogen,
`
`0PK/
`
`P—OOHH
`
`0
`
`VO’R—OH
`
`0H ;
`
`, and
`
`R2 and R3 are each independently selected from the group consisting of
`
`COZH
`
`(DH/EA;
`OH
`
`V0
`
`hydrogen,
`
`'F'>—O0H RW 014% O“s"
`NH3+CI
`Na .08
`
`,
`
`,
`
`CHZOH
`
`NO)?
`, and OH
`
`, wherein R5 is selected from the group consisting of
`
`hydrogen, methyl, and isopropyl; and R4 is independently selected from the group
`
`OH
`{[(ovV0P_OH
`
`"_
`ein/OwO/ROCHH
`
`consisting of hydrogen,
`
`0
`
`O
`
`, and
`
`O
`
`.
`
`In one
`
`aspect, the compound corresponds in structure to Formula (I).
`
`In another aspect,
`
`the compound is a pharmaceutically acceptable salt of a compound corresponding
`
`in structure to Formula (I).
`
`[30]
`
`In one embodiment, R2 and R3 are both the same (e.g., both hydrogen,
`
`COZH
`o
`
`OH
`OH
`
`both
`
`0“
`
`, etc.).
`
`In another embodiment R2 and R3 are different (e.g.,
`
`_
`.
`R2 IS hydrogen and R3 IS
`
`cogH
`0
`
`OH
`
`OH
`
`0“
`
`, etc).
`
`[31] Additionally or alternatively, R2 is hydrogen and R3 is selected from the
`
`10
`
`15
`
`group consisting of hydrogen,
`
`COZH
`
`(mm ('5 OH RW
`OH OH
`iii/\O’ \
`,
`NH3+CI',
`
`,
`
`OH
`
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`WO 2017/184871
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`
`.
`
`,
`
`, wherein R5 is selected from
`
`the group consisting of hydrogen, methyl, and isopropyl.
`
`[32] Additionally or alternatively, R2 is hydrogen and R3 is selected from the
`
`COZH
`
`(DH/m4,
`OH
`
`P\-OH Rik mm
`V0 \OH
`NH3+cr
`
`CHZOH
`
`group consisting of
`
`0\,,0
`3:6
`Na ‘0
`
`,and
`
`5
`
`,
`NH Cl
`
`_
`_
`, whereIn R5 Is selected from the group
`
`consisting of hydrogen, methyl, and isopropyl.
`
`[33] Additionally or alternatively, R2 is hydrogen and R3 is
`
`[34] Additionally or alternatively, R2 is hydrogen and R3 is
`
`[35] Additionally or alternatively, R2 is hydrogen and R3 is
`
`COZH
`
`OH OH
`
`.
`
`S?
`P—OH
`’ \
`
`0
`RW
`NH3+C'_, wherein
`
`10
`
`R5 is selected from the group consisting of hydrogen, methyl, and isopropyl.
`HO
`
`[36] Additionally or alternatively, R2 is hydrogen and R3 is
`
`CHZOH
`
`m,
`OH OH
`
`.
`
`OO90
`s
`[37] Additionally or alternatively, R2 is hydrogen and R3 isNa '0 9i.
`
`NO)?
`[38] Additionally or alternatively, R2 is hydrogen and R3 is O
`
`H+'C|
`
`[39] Additionally or alternatively, R2 is hydrogen and R3 is hydrogen.
`
`-10-
`
`

`

`WO 2017/184871
`
`PCT/US2017/028646
`
`[40] Additionally or alternatively, R2 is selected from the group consisting of
`
`COZH
`
`Wm 'POOH RW OHZer
`OH
`V0
`NHH3+Cl
`
`CHZOH
`
`Na -0:08x
`
`hydrogen,
`
`, and O
`
`H+Cl
`
`, wherein R5 is selected from the group consisting of
`
`hydrogen, methyl, and isopropyl and R3 is hydrogen.
`
`5
`
`[41] Additionally or alternatively,OR2 selected from the group consisting of
`(mm P—OH RW 014% 0‘Sp
`OH
`V0 \OH ’
`NH3+CI
`’ Na+ -O83 and
`
`CHZOH
`
`COZH
`
`O
`
`0*
`
`H Cl
`
`, wherein R5 is selected from the group consisting of hydrogen,
`
`methyl, and isopropyl and R3 is hydrogen.
`
`.
`.
`.
`.
`[42] Additionally or alternatively, R2 is
`
`10
`
`[43] Additionally or alternatively, R2 is
`
`[44] Additionally or alternatively, R2 ls
`
`COZH
`O
`
`OH
`
`0H
`
`OH
`
`.
`and R3 is hydrogen.
`
`0
`V0, |F'>\—0H
`OH and R3 is hydrogen.
`
`0
`RW
`NHJC", wherein R5 ls selected from
`
`the group consisting of hydrogen, methyl, and isopropyl and R3 is hydrogen.
`
`HO CHZOH
`O
`
`OH
`
`[45] Additionally or alternatively, R2 is
`
`OH
`
`and R3 is hydrogen.
`
`()0\\/I
`s
`[46] Additionally or alternatively, R2 is Na '0 .33 and R3 is hydrogen.
`
`-11-
`
`

`

`WO 2017/184871
`
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`
`[47] Additionally or alternatively, R2 is
`
`o
`
`0*N
`O H+cr
`
`and R3 is hydrogen.
`
`[48]
`
`In another embodiment, the present disclosure relates to a compound
`
`corresponding in structure to Formula (I) or a pharmaceutically acceptable salt
`
`thereof, wherein R1 is independently selected from the group consisting of
`
`FK/O‘PCOOHH
`n
`
`0
`
`an
`
`,
`
`hydrogen,
`
`(l?
`d V0” P\_OH
`
`OH ; R2 and R3 are each hydrogen, and
`
`R4 is independently selected from the group consisting of hydrogen,
`
`9
`army—00m wow/Pg?
`
`0
`
`0
`
`, and
`
`O
`
`.
`
`In one aspect, the compound
`
`corresponds in structure to Formula (I).
`
`In another aspect, the compound is a
`
`pharmaceutically acceptable salt of a compound corresponding in structure to
`
`10
`
`Formula (I).
`
`[49]
`
`In another embodiment, the present disclosure relates to a compound
`
`corresponding in structure to Formula (I) or a pharmaceutically acceptable salt
`
`thereof, wherein R1 is hydrogen; R2 and R3 are each independently selected from
`
`the group consisting of hydrogen,
`
`OH OH
`
`V0" ,
`
`OH
`
`,
`
`NHJCI’,
`
`COZH
`
`HO CHZOH
`% O\\’/O
`
`OH
`
`15
`
`OH
`
`,
`
`O
`
`0%
`OHJrCl—
`
`, wherein R5 is selected from
`
`+
`
`Na
`
`,S
`'0 3i and
`,
`
`the group consisting of hydrogen, methyl, and isopropyl; and R4 is independently
`OH
`
`slow-OH
`
`selected from the group consisting of hydrogen,
`
`0
`
`0
`
`, and
`
`S?
`slow/w
`
`O
`
`.
`
`In one aspect, the compound corresponds in structure to
`
`-12-
`
`

`

`WO 2017/184871
`
`PCT/US2017/028646
`
`Formula (I).
`
`In another aspect, the compound is a pharmaceutically acceptable
`
`salt of a compound corresponding in structure to Formula (I).
`
`[50]
`
`In another embodiment, the present disclosure relates to a compound
`
`corresponding in structure to Formula (I) or a pharmaceutically acceptable salt
`
`thereof, wherein R1 is hydrogen; R2 and R3 are hydrogen; and R4 is independently
`
`selected from the group consisting of hydrogen,
`
`OH
`
`Fin/0V0}P’—OH
`0
`0
`
`, and
`
`S?
`hrOWO’PgS“
`
`O
`
`. In one aspect, the compound corresponds in structure to
`
`Formula (I).
`
`In another aspect, the compound is a pharmaceutically acceptable
`
`salt of a compound corresponding in structure to Formula (I).
`
`[51]
`
`In another embodiment, the present disclosure relates to a compound
`
`corresponding in structure to Formula (I-a):
`HO
`
`HO
`
`
`
`p/_
`
`o
`
`(I-a),
`
`or a pharmaceutically acceptable salt thereof.
`
`In one aspect, the compound
`
`corresponds in structure to Formula (I—a).
`
`In another aspect, the compound is a
`
`pharmaceutically acceptable salt of a compound corresponding in structure to
`
`Formula (I-a).
`
`[52]
`
`In another embodiment, the present disclosure relates to a compound
`
`corresponding in structure to Formula (I-b):
`HO
`(:02H
`
`HO
`
`
`
`0
`Ll—OH
`O
`HN\NH
`T \/\O/ \OH
`
`o
`
`(I-b),
`
`10
`
`15
`
`20
`
`or a pharmaceutically acceptable salt thereof.
`
`In one aspect, the compound
`
`corresponds in structure to Formula (I—b).
`
`In another aspect, the compound is a
`
`-13-
`
`

`

`WO 2017/184871
`
`PCT/US2017/028646
`
`pharmaceutically acceptable salt of a compound corresponding in structure to
`
`Formula (I-b).
`
`[53]
`
`In another embodiment, the present disclosure relates to a compound
`
`corresponding in structure to Formula (I) or a pharmaceutically acceptable salt
`
`thereof, wherein R1 is independently selected from the group consisting of
`
`NOP-OHOH
`
`0
`
`,
`
`hydrogen,
`
`rug/\OPCOH
`
`OH ;R2 and R3 are each independently
`
`selected from the group consnsting of hydrogen,
`
`_
`
`_
`
`OH
`
`COZH
`0
`
`o
`ll
`
`0mg, VO,P\—OH
`
`OH
`
`,
`
`OH ,
`
`CHZOH
`0,553),
`
`[(0)]?
`0*
`HCI
`P O
`Na —0’S?‘ and
`
`5
`NHH3+Cl
`
`, wherein R5 is
`
`selected from the group consisting of hydrogen, methyl, and isopropyl; and R4 is
`
`hydrogen.
`
`In one aspect, the compound corresponds in structure to Formula (I).
`
`In another aspect, the compound is a pharmaceutically acceptable salt of a
`
`compound corresponding in structure to Formula (I).
`
`[54]
`
`In another embodiment, the present disclosure relates to a compound
`
`corresponding in structure to Formula (I) or a pharmaceutically acceptable salt
`
`thereof, wherein R1 is hydrogen; R2 and R3 are each independently selected from
`
`10
`
`15
`
`the group consisting of hydrogen,
`
`COZH
`
`(mm,
`OH
`
`xii/\O
`
`5
`
`P—O0H RA
`KJHJCI-
`
`HO CHZOH
`m Odo
`
`:S
`
`0%
`Owe.-
`
`, wherein R5 is selected from
`
`the group consisting of hydrogen, methyl, and isopropyl; and R4 is hydrogen.
`
`In
`
`one aspect, the compound corresponds in structure to Formula (I).
`
`In another
`
`20
`
`aspect, the compound is a pharmaceutically acceptable salt of a compound
`
`corresponding in structure to Formula (I).
`
`-14-
`
`

`

`WO 2017/184871
`
`PCT/US2017/028646
`
`[55]
`
`In another embodiment, the present disclosure relates to a compound
`
`corresponding in structure to Formula (I) or a pharmaceutically acceptable salt
`
`thereof, wherein R1 is independently selected from the group consisting of
`O
`
`gi/
`
`0‘ ,OH
`
`Iii—OH
`0
`
`Vo/Igi—OH
`OH ; R2 and R3 are hydrogen; and R4 is
`
`, and
`
`OH
`
`independently selected from the group consisting of hydrogen,
`
`0
`
`O
`
`,
`
`9
`wow/Pg?
`
`and
`
`O
`
`.
`
`In one aspect, the compound corresponds in structure
`
`to Formula (I).
`
`In another aspect, the compound is a pharmaceutically acceptable
`
`salt of a compound corresponding in structure to Formula (I).
`
`[56]
`
`In another embodiment, the present disclosure relates to a compound
`
`10
`
`corresponding in structure to Formula (I) or a pharmaceutically acceptable salt
`
`thereof, wherein R1 is independently selected from the group consisting of
`o
`
`0\ [OHN P—OH
`
`O
`
`Egg/\O, 'F'>\—0H
`OH ; R2 and R3 are each independently selected
`
`, and
`
`from the group consisting of hydrogen,
`
`COZH
`0
`
`OH
`9 RW
`0%, V0 \OH ,
`NH3+C|'
`,P_OH
`:
`
`HO CHZOH
`m 0“”0
`
`+
`Na —0
`
`/S
`3g and
`,
`
`,
`
`OH OH
`
`,
`
`O
`
`0%
`©H+cr
`
`, wherein R5 is selected from
`
`15
`
`20
`
`the group consisting of hydrogen, methyl, and isopropyl; and R4 hydrogen.
`
`In one
`
`aspect, the compound corresponds in structure to Formula (I).
`
`In another aspect,
`
`the compound is a pharmaceutically acceptable salt of a compound corresponding
`
`in structure to Formula (I).
`
`[57]
`
`In another embodiment, the present disclosure relates to a compound
`
`corresponding in structure to Formula (I) or a pharmaceutically acceptable salt
`
`thereof, wherein R1 is independently selected from the group consisting of
`
`-15-
`
`

`

`WO 2017/184871
`
`PCT/US2017/028646
`
`PK/O OH
`PI-OH
`0
`
`, and
`
`9
`VO/PCOH
`0H ; R2 and R3 are each independently selected
`
`from the group consisting of hydrogen,
`
`HO CHZOH
`O
`OH OH
`
`1
`
`O ,0 O\ /
`:s
`Na '0 9i ,and
`
`1
`
`COZH
`
`O
`
`5
`
`O
`
`OH OH
`
`O
`
`,P—OH
`Iii/\o \
`
`E
`NH3+CI'
`
`0%
`
`_
`
`+
`H CI
`
`, wherein R5 is selected from
`
`the group consisting of hydrogen, methyl, and isopropyl; and R4 hydrogen.
`
`In one
`
`aspect, the compound corresponds in structure to Formula (I).
`
`In another aspect,
`
`the compound is a pharmaceutically acceptable salt of a compound corresponding
`
`in structure to Formula (I).
`
`[58]
`
`In another embodiment, the present disclosure relates to a compound
`
`corresponding in structure to Formula (I) or a pharmaceutically acceptable salt
`
`thereof, wherein R1 is independently selected from the group consisting of
`
`NOP-OOHH
`
`voila—OH
`
`0
`
`, and
`
`0H ; R2 and R3 are hydrogen; and R4 hydrogen.
`
`In
`
`one aspect, the compound corresponds in structure to Formula (I).
`
`In another
`
`aspect, the compound is a pharmaceutically acceptable salt of a compound
`
`corresponding in structure to Formula (I).
`
`[59] Various other compounds corresponding in structure to Formula (I) or
`
`pharmaceutically acceptable salts thereof are contemplated herein. Examples of
`
`suitable compounds corresponding in structure to Formula (I) are provided below
`
`in Table 1, which provides R1, R2, R3, R4 and/or R5 substituents for compounds
`
`corresponding in structure to Formula (I).
`
`Table 1
`
`_ompound
`
`“—n-ir
`
`hydrogen - (l-d)
`
`(l-c)
`
`fifeV0\fiLOOH
`“‘fi
`Erin/OWO/PVOH
`
`hydrogen
`hydrogen
`
`hydrogen
`hydrogen
`
`hydrogen
`
`-16-
`
`

`

`WO 2017/184871
`
`PCT/US2017/028646
`
`
`
`hydrogen
`COzH
`hydrogen
`hydrogen
`(I-e)
`
`
`(I-f)
`
`hydrogen
`
`hydrogen
`
`HO
`
`hydrogen
`
`(I-g)
`(I-h)
`
`hydrogen
`hydrogen
`
`hydrogen
`
`hydrogen
`hydrogen
`
`hydrogen
`
`hydrogen -\
`hydrogen -8
`
`hydrogen
`
`
`
`hydrogen
`
`hydrogen
`
`hydrogen
`
`hydrogen
`
`
`
`hydrogen
`
`hydrogen
`
`hydrogen
`
`
`
`hydrogen
`
`hydrogen
`
`(I-m)
`
`hydrogen
`
`OH
`
`C02H
`O
`
`hydrogen
`
`Isopropyl
`
`hydrogen
`
`hydrogen
`
`0
`
`E: hydrogen
`OH OH
`h dro en
`V P
`y
`g
`hydrogen
`
`hydrogen
`h dro en
`y
`g
`hydrogen
`
`I-o
`
`(I-n)
`(
`)
`(I-p)
`
`(I-q)
`
`hydrogen
`h dro en
`y
`g
`hydrogen
`
`hydrogen
`
`hydrogen
`
`
`
`
`
`
`
`
`
`hydrogen
`
`hydrogen
`
`hydrogen
`
`hydrogen
`
`hydrogen
`
`hydrogen
`
`hydrogen
`
`Methyl
`
`hydrogen
`
`-17-
`
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`

`WO 2017/184871
`
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`
`
`
`OH
`O
`(I-u)
`hydrogen
`OH
`0‘32”
`C02H
`hydrogen
`0% 0%;
`
`
`(I-v)
`
`hydrogen
`
`H0
`
`H0
`
`hydrogen
`
`hydrogen
`
`(I—y)
`
`hydrogen
`
`hydrogen
`
`
`
`
`
`
`hydrogen
`
`hydrogen
`
`hydrogen
`
`Methyl
`
`
`
`hydrogen
`
`hydrogen
`
`Isopropyl
`
`[60]
`
`In various embodiments, the present disclosure relates to a compound
`
`corresponding in structure to any one of Formula (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-
`
`i), (H), (l-k), (l-l), (l-m), (l-n). (l-O), (l-p), (I-Q), (l-r), (l-S), (l-t), (l-U), (l-V), (l-W), (l-X),
`
`(I-y), (I-z), (I-aa), (I-ab), or (I-ac) or a pharmaceutically acceptable salt thereof.
`
`In
`
`one aspect, the compound corresponds in structure to any one of Formula (I—c),
`
`(l—
`
`d), (l-e), (l-f), (l-g), (l-h), (H), (H), (l-k), (l-l), (l-m), (l-n), (l-O),
`
`(l-IO), (I-Q), (l-r), (l-S),
`
`(I-t), (I-u), (I-v), (I-w), (I-x), (I-y), (I-z), (I-aa), (I-ab), or (I-ac).
`
`In another aspect, the
`
`compound is a pharmaceutically acceptable salt of a compound corresponding in
`
`10
`
`structure to any one of Formula (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (H), (H), (I-k), (I-I),
`
`(l-m), (l-n), (l-O), (l-p), (l-Q), (l-r), 0-8) (H), (I-U), (l-V), (l-W), (l-X), (l-y), (l-Z), (l-aa),
`
`(I—ab), or (I—ac).
`
`B. L-Dopa Prodrugs
`
`[61]
`
`In another embodiment, the present disclosure relates to a compound
`
`corresponding in structure Formula (II):
`
`-18—
`
`

`

`WO 2017/184871
`
`PCT/US2017/028646
`
`0R5
`
`NHRg
`
`R80
`
`(H)
`
`or a pharmaceutically acceptable salt thereof, wherein R6 is independently
`
`selected from the group consisting of hydrogen,
`
`0PK/
`
`P—OOHH
`
`0
`
`, and
`
`O
`
`Fifi [Pi—OH
`O OH ;
`
`R7 and R8 are each independently selected from the group consisting of
`
`COZH
`
`(DH/EA;
`OH
`
`3%OH RW 014% 0“s”
`NH3+CI
`Na .0”8
`
`CHZOH
`
`V0
`
`hydrogen,
`
`, and O
`
`H+Cl
`
`, wherein R5 is selected from the group consisting of
`
`hydrogen, methyl, and isopropyl; and R9 is independently selected from the group
`
`consisting