Dosing regimens for treating PKU with piperidine inhibitors of SLC6A19 function

Abstract

A method for treating phenylketonuria is disclosed, comprising administering to a patient in need of treatment for phenylketonuria an effective amount of the following compound: Compound (I) or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 406,446, filed September 14, 2022. [Background technology]

[0002] Phenyleketonuria (PKU) is an inborn error of metabolism caused by mutations in phenylalanine hydroxylase (PAH), an enzyme responsible for the metabolism of phenylalanine. PKU is an autosomal recessive metabolic disorder in which phenylalanine is not properly metabolized, resulting in abnormally high plasma levels of phenylalanine. Individuals with PKU have abnormally high blood levels of phenylalanine. If untreated, this can lead to irreversible neurological damage and various complications, including intellectual disability, seizures, and neurodevelopmental and behavioral disorders. PKU is difficult to treat because blood levels of phenylalanine are directly related to diet. Patients must adhere to a strict lifelong diet, which affects every aspect of their lives. The current standard of care is enzyme cofactor therapy and enzyme replacement therapy, but these therapies are not effective in all patients and carry potential risks of adverse events.

[0003] The enzyme responsible for metabolizing phenylalanine and thus maintaining phenylalanine homeostasis is phenylalanine hydroxylase (PAH). Loss-of-function (LOF) mutations in the PAH gene on chromosome 12q23.2 are known to cause most forms of PKU. These LOF mutations that cause PKU can be diagnosed as classic PKU (the most severe form) and less severe forms of "mild PKU" or "hyperphenylalaninemia." In addition to PAH, mutations in other enzymes that affect phenylalanine metabolism, such as dihydropteridine reductase (DHPR), an enzyme involved in the synthesis of cofactors required for PAH activity, can also increase phenylalanine concentrations. In addition to diet, blood amino acid concentrations, including phenylalanine concentrations, are regulated by SLC6A19, which is located in the proximal tubule of the kidney and is responsible for reabsorption of amino acids and returning them to the blood. Summary of the Invention

[0004] One aspect of the present invention provides methods and administration regimens useful for treating or preventing diseases or disorders associated with abnormal amino acid concentrations through modulation of SLC6A19 transport.

[0005] Another aspect of the present invention provides methods and administration regimens useful for treating or preventing diseases or disorders associated with genetic deficiencies in phenylalanine hydroxylase.

[0006] Accordingly, there is provided herein a method for treating or preventing a disease or disorder associated with a genetic deficiency in phenylalanine hydroxylase, said method comprising orally administering to a patient in need of such treatment or prevention an effective amount of the following compound, or a pharmaceutically acceptable salt thereof: [ka] Here, the compound is formulated as a tablet.

[0007] Also provided herein is a method for treating or preventing a disease or disorder associated with a genetic deficiency in phenylalanine hydroxylase, comprising orally administering to a patient in need of such treatment or prevention an effective amount of the following compound, or a pharmaceutically acceptable salt thereof: [ka] Here, the compound is formulated as a suspension.

[0008] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0009] Other features, objects, and advantages of the invention will become apparent from the detailed description and claims. [Brief explanation of the drawings]

[0010] [Figure 1] 1 is a graph of the pharmacodynamic effect of Compound 1 in healthy volunteers showing the change in total phenylalanine or total SLC6A19 amino acid substrate (Hartnup amino acid) secretion over 24 hours after a single dose of the compound (10-170 mg) in suspension form. [Figure 2] A 24-hour study of the pharmacokinetics of Compound 1 in healthy volunteers at three different doses (25 or 75 mg twice daily [BID], or 150 mg once daily [QD]) 14 days after administration of the compound in suspension. [Figure 3A]1 is a graph of the pharmacodynamic effect of Compound 1 over time in healthy volunteers by measuring the change in all SLC6A19 amino acid substrates (Hartnup amino acids) over 14 days following administration of the compound in suspension at three different doses (25 or 75 mg twice daily [BID], or 150 mg once daily [QD]). [Figure 3B] 1 is a graph of the pharmacodynamic effect of Compound 1 over time in healthy volunteers by measuring the change in total phenylalanine over 24 hours over 14 days following administration of the compound in suspension at three different doses (25 or 75 mg twice daily [BID], or 150 mg once daily [QD]). [Figure 4] 1 is a graph of the pharmacokinetics of Compound 1 over 72 hours in healthy volunteers in the fed or fasted state upon administration of 100 mg of the compound as a suspension or tablet. DETAILED DESCRIPTION OF THE INVENTION

[0011] definition For convenience, before further description of the present invention, certain terms employed in the specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and should be understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0012] In order to more readily understand the present invention, certain terms and phrases are defined below and throughout the specification.

[0013] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0014] The term "and / or," as used in the specification and claims, should be understood to refer to "either or both" of the elements so combined, i.e., elements that are conjunctive in some cases and disjunctive in other cases. Elements listed with "and / or" must be arranged in the same manner, i.e., "one or more" of the conjunctive elements. Other elements, whether related or unrelated to those elements specifically identified, may optionally be present in addition to the elements specifically identified in the "and / or" clause. Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising," a reference to "A and / or B" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); and so forth.

[0015] As used herein in the specification and claims, "or" shall be understood to have the same meaning as "and / or," as defined above. For example, when separating items in a list, "or" or "and / or" shall be construed as inclusive, i.e., including not only at least one, but also two or more of a number or list of elements, and optionally including additional items not listed. Only clearly indicated terms, such as "only one of," or "exactly one of," or, when used in the claims, "consisting of," shall mean the inclusion of exactly one element of a number or series of elements. Generally, as used herein, the term "or" shall only be construed as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." When used in the claims, "consisting essentially of" shall have its ordinary meaning as used in the field of patent law.

[0016] As used herein in the specification and claims, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one, optionally including two or more As, and no B (and optionally including elements other than B); in another embodiment to at least one, optionally including two or more Bs, and no A (and optionally including elements other than A); in yet another embodiment to at least one, optionally including two or more As, and at least one, optionally including two or more Bs (and optionally including other elements); and so forth.

[0017] It should also be understood that, unless expressly indicated otherwise, in any method claimed herein that includes more than one step or action, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited.

[0018] In the claims, as in the foregoing specification, transitional phrases such as "comprising / including," "carrying / having," "containing," "involving," "holding," "consisting of," and the like, shall be construed as open-ended, i.e., meaning inclusive but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of," respectively, shall be closed or semi-closed transitional phrases as defined in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0019] Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures, as being within the scope of the present invention.

[0020] Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group, and all such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0021] "Geometric isomer" refers to isomers that differ in the orientation of substituent atoms relative to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond can be in the E configuration (substituents on opposite sides of the carbon-carbon double bond) or the Z configuration (substituents on the same side). "R," "S," "S*," "R*," "E," "Z," "cis," and "trans" refer to structures relative to the core molecule. Certain disclosed compounds can exist in "atropisomeric" forms or as "atropisomers." Atropisomers are stereoisomers resulting from hindrance of rotation about a single bond, where the steric strain hindrance to rotation is sufficiently high to allow for separation of conformers. The compounds of the present invention can be prepared as individual isomers either by isomer-specific synthesis or by resolution from a mixture of isomers. Classical resolution techniques include using an optically active acid to form a salt of the free base of each isomer of the isomeric pair (followed by fractional crystallization and regeneration of the free base), using an optically active amine to form a salt of the acid form of each isomer of the isomeric pair (followed by fractional crystallization and regeneration of the free acid), using an optically pure acid, amine, or alcohol to form an ester or amide of each isomer of the isomer pair (followed by chromatographic separation and removal of the chiral auxiliary), or resolving the isomeric mixture of either the starting materials or the final product using a variety of well-known chromatographic methods.

[0022] For example, if a particular enantiomer of a compound of the present invention is desired, that enantiomer can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, separating the resulting mixture of diastereomers, and cleaving the auxiliary to obtain the desired pure enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by separation of the diastereomers so formed by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomers.

[0023] A mole fraction purity percentage is the mole ratio of an enantiomer (or diastereomer), or the ratio of moles of an enantiomer (or diastereomer) to moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction relative to other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction.

[0024] When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has at least one chiral center, the name or structure should be understood to encompass any enantiomer of the compound, free of the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has two or more chiral centers, the name or structure should be understood to encompass a diastereomer free of the other diastereomer, multiple diastereomers free of other diastereomeric pairs, a mixture of diastereomers, a mixture of diastereomeric pairs, a mixture of diastereomers enriched in one diastereomer relative to the other diastereomer(s), or a mixture of diastereomers enriched in one or more diastereomers relative to the other diastereomers. The present invention encompasses all of these forms.

[0025] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, hydrogen replaced with deuterium or tritium, or carbon replaced with 13 C or 14 Compounds produced by substituting C-enriched carbons are within the scope of the present invention.

[0026] For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, inside cover of Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0027] A "therapeutically effective amount" (or "effective amount") of a compound, in terms of therapeutic use, means the amount of compound(s) that, when administered as part of a desired dosing regimen (to a mammal, preferably a human), treats a disease or condition, e.g., in a preparation, alleviates symptoms, ameliorates pathology, or delays the onset of a disease condition, at a reasonable benefit / risk ratio applicable to any medical treatment, or according to clinically acceptable standards for cosmetic purposes.

[0028] The term "prophylactic or therapeutic" treatment is art-recognized and includes administration of one or more of the subject compositions to a host. If a therapeutic agent is administered prior to the onset of clinical signs of an undesired condition (e.g., a disease or other undesired condition in a host animal), the treatment is prophylactic (i.e., protects the host from the occurrence of the undesired condition). On the other hand, if administered after the appearance of the undesired condition, the treatment is therapeutic (i.e., is intended to reduce, ameliorate, or stabilize an existing undesired condition or its side effects).

[0029] The term "patient" or "subject" means a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is human.

[0030] The terms "reduce," "lower," "reduced," "reduce," "reduce," and "inhibit" are all generally used herein to refer to a statistically significant amount of reduction compared to a reference. However, for the avoidance of doubt, "reduce," "reduce," or "reduce," or "inhibit" typically refers to a reduction of at least 10% compared to a reference level, and can include, for example, a reduction of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, including any reduction between 10% and 99% compared to the complete absence of a given element or parameter compared to a reference level, or compared to the absence of a given treatment.

[0031] The terms "increased," "increase," or "improve," or "activate" are all used herein to generally mean an increase by a statistically significant amount, and for the avoidance of doubt, the terms "increased," "increase," or "improve," or "activate" mean an increase of at least 10% compared to a reference level, for example, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to and including a 100% increase compared to a reference level, or any increase between 10-100% compared to a reference level, or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold, or any increase between 2-fold and 10-fold or more compared to a reference level.

[0032] As used herein, a therapeutic agent that "prevents" or "reduces the risk of developing" a disease, disorder, or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disease or condition in a treated sample compared to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disease, disorder, or condition compared to an untreated control sample.

[0033] The term "treating" includes prophylactic and / or therapeutic treatment. The term "prophylactic or therapeutic" treatment is art-recognized and includes administration of one or more of the subject compositions to a host. If a therapeutic agent is administered prior to the onset of clinical signs of an undesired condition (e.g., a disease or other undesired condition in a host animal), the treatment is prophylactic (i.e., protects the host from the occurrence of the undesired condition). On the other hand, if administered after the appearance of an undesired condition, the treatment is therapeutic (i.e., is intended to reduce, ameliorate, or stabilize an existing undesired condition or its side effects).

[0034] As used herein, the term "modulate" includes upregulation and downregulation, eg, enhancing or inhibiting a response.

[0035] Compounds of the Invention In certain embodiments, the compound used in the methods of the invention has the structure: [ka] Compound 1, i.e., (R)-3-(1-cyclopropyl-3-(2-fluoro-4-(trifluoromethoxy)benzyl)ureido)piperidine-1-carboxamide, or a pharmaceutically acceptable salt thereof. The compound is an SLC6A19 inhibitor. For example, the compound reduces the whole body phenylalanine level in a subject.

[0036] Pharmaceutical Composition In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier for the treatment or prevention of a disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase.

[0037] In certain embodiments, the pharmaceutical composition is formulated as a tablet, hi other embodiments, the pharmaceutical composition is formulated as a suspension.

[0038] The compositions and methods of the present invention can be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal, such as a human, or a non-human mammal. When administered to a subject, such as a human, the composition or compound is preferably administered as a pharmaceutical composition, for example, comprising a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline, or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for human administration, particularly for invasive administration routes (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical compositions may be in dosage unit form, such as tablets, suspensions, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilizates for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The compositions may also be present in transdermal delivery systems, e.g., skin patches. The compositions may also be present in solutions suitable for topical administration, such as eye drops.

[0039] Pharmaceutically acceptable carriers may contain physiologically acceptable agents that function, for example, to stabilize, increase the solubility, or enhance the absorption of compounds such as the compounds of the present invention. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low-molecular-weight proteins; or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix, into which, for example, the compounds of the present invention may be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to prepare and administer.

[0040] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0041] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting the subject chemical entity from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and These include soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances employed in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not cause a significant temperature increase when administered to a patient.

[0042] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of a compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfate. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19.)

[0043] In other cases, compounds useful in the methods of the present invention may contain one or more acidic functional groups, thereby enabling them to form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compound(s). These salts can also be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in their free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, e.g., Berge et al., supra).

[0044] The term "pharmaceutically acceptable cocrystal" refers to a solid coformer that does not form formal ionic interactions with the small molecule.

[0045] For any compound described herein, the therapeutically effective amount can be first determined from animal models.The therapeutically effective dose can also be determined from human data for compounds tested in humans and for compounds known to exhibit similar pharmacological activity, such as other related active agents.Higher doses may be required for parenteral administration.The applied dose can be adjusted according to the relative bioavailability and efficacy of the administered compound.Adjusting the dose to achieve maximum efficacy based on the methods described above and other methods well known in the art is well within the capabilities of those skilled in the art.

[0046] The formulations of the present invention may be administered in pharmaceutically acceptable solutions, which may conventionally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0047] When used in therapy, an effective amount of compound can be administered to a subject by any method that delivers the compound to the desired surface.The administration of pharmaceutical compositions can be carried out by any means known to those skilled in the art.Administration routes include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (e.g., into tumor or abscess), mucosal (e.g., topical to the eye), inhalation, and topical.

[0048] For intravenous and other parenteral administration routes, the compounds of the present invention can be formulated as lyophilized preparations, as lyophilized preparations of liposome intercalated or liposome-encapsulated active compounds, as lipid complexes in aqueous suspension, or as salt complexes. Lyophilized preparations are generally reconstituted with a suitable aqueous solution, such as sterile water or physiological saline, immediately prior to administration.

[0049] For oral administration, compounds can be easily formulated by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the treated subject. Pharmaceutical preparations for oral use can be obtained as solid excipients, optionally by grinding the resulting mixture, and optionally adding suitable excipients, followed by processing the granular mixture to obtain tablets or dragee cores. Suitable excipients are, in particular, sugars, including fillers such as lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, e.g., sodium alginate. Optionally, oral preparations may also be formulated with saline or buffers, e.g., EDTA, for neutralizing acidic conditions in the body, or may be administered without any carrier.

[0050] Oral dosage forms of one or more of the components described above are also specifically contemplated. One or more components may be chemically modified to facilitate oral delivery of the derivatives. Generally, contemplated chemical modifications involve attaching at least one moiety to the component molecule itself that (a) inhibits hydrolysis and (b) allows uptake from the stomach or intestine into the bloodstream. It may also be desirable to increase the overall stability of one or more components and extend their circulation time in the body. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts," In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., J. Appl. Biochem. 4:185-9 (1982). Other polymers that can be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane.For pharmaceutical applications, as indicated above, polyethylene glycol moieties are preferred.

[0051] The location of release of the component (or derivative) may be the stomach, the small intestine (duodenum, jejunum, or ileum), or the large intestine. One skilled in the art has available formulations that will not dissolve in the stomach but will release the substance in the duodenum or elsewhere in the intestine. Preferably, the release will avoid adverse effects in the stomach environment, either by protecting the compound (or derivative) of the invention or by releasing the biologically active substance in the intestine, etc., after passing through the stomach environment.

[0052] To ensure full gastric resistance, a coating that is impermeable to at least pH 5.0 is essential. Examples of more common inactive ingredients used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings can also be used as mixed films.

[0053] A coating or mixture of coatings can also be used on tablets not intended for gastric protection. This can include sugar coatings or coatings that make the tablet easier to swallow. Capsules can consist of a hard shell (such as gelatin) for delivery of dry therapeutics (e.g., powder), or a soft gelatin shell can be used for liquid forms. The shell material for cachets can be thick starch or other edible paper. For pills, lozenges, molded tablets, or powder tablets, wet massing techniques can be used.

[0054] The therapeutic agent may also be included in the formulation as fine multiparticulates in the form of granules or pellets about 1 mm in size. The formulation of material for capsule administration may also be as a powder, lightly compressed plugs, or tablets. The therapeutic agent may be prepared by compression.

[0055] Both colorants and flavoring agents may be included. For example, the compounds (or derivatives) of the present invention may be formulated (such as encapsulated in liposomes or microspheres) and then further included in an edible product, such as a refrigerated beverage, containing colorants and flavoring agents.

[0056] The volume of the therapeutic agent can be diluted or increased with an inert material. These diluents can include carbohydrates, especially mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, and starch. Certain inorganic salts can be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents include Fast-Flo, Emdex, STA-Rx 1500, Emcompress, and Avicell.

[0057] Disintegrants may be included in the formulation of therapeutic agents to form solid dosage forms. Materials used as disintegrants include, but are not limited to, starch, including the commercially available starch-based disintegrant Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethylcellulose, sponge, and bentonite may also be used. Another form of disintegrant is an insoluble cationic exchange resin. Powdered gums can be used as binders, including powdered gums such as agar, Karaya, or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0058] Binders can be used to hold the therapeutic agent and form a hard tablet and include materials derived from natural products such as gum arabic, tragacanth, starch, and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) can both be used in alcoholic solution to granulate the therapeutic agent.

[0059] Antifriction agents may be included in the formulation of the therapeutic agent to prevent sticking during the formulation process. Lubricants can be used as a layer between the therapeutic agent and the die wall, and include, but are not limited to, stearic acid with magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils, and waxes. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols of various molecular weights, and Carbowax 4000 and 6000 can also be used.

[0060] Glidants may be added which may improve the flowability of the drug during formulation and aid in rearrangement during compression. Glidants may include starch, talc, pyrogenic silica, and hydrated silicoaluminate.

[0061] Surfactants may be added as wetting agents to aid in the dissolution of therapeutic agents in aqueous environments. Surfactants may include anionic surfactants such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic surfactants may also be used, including benzalkonium chloride and benzethonium chloride. Potential nonionic surfactants that can be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glycerol monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants may be present alone or in a mixture of different ratios in the formulation of the compound or derivative of the present invention.

[0062] Orally available pharmaceutical preparations include push-fit capsules made of gelatin as well as sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optional stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres are well defined in the art. All oral formulations must be in a dosage suitable for such administration.

[0063] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0064] For topical administration, the compounds may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, and those designed for transdermal, transmucosal, oral or pulmonary administration.

[0065] For administration by inhalation, the compound for use according to the present invention can be conveniently delivered in the form of aerosol spray presentation from a pressurized pack or nebulizer by using suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.For pressurized aerosol, dosage unit can be determined by providing a valve that delivers a metered amount.For example, gelatin capsules and cartridges for use in inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0066] Also contemplated herein is pulmonary delivery of the compounds disclosed herein (or salts thereof). The compounds are delivered to the lungs of a mammal during inhalation, cross the epithelial lining of the lungs, and reach the bloodstream. Other reports on inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprorelin acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (α1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (α1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins," Proceedings of Symposium on Respiratory Drug Delivery. II, Keystone, Colorado, March (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor-alpha) and U.S. Patent No. 5,284,656 to Platz et al. (granulocyte colony-stimulating factor; incorporated by reference). Methods and compositions for pulmonary delivery of systemically acting drugs are described in U.S. Patent No. 5,451,569, issued September 19, 1995 to Wong et al. (incorporated by reference).

[0067] Contemplated for use in the practice of the present invention are a variety of mechanical devices designed for pulmonary delivery of therapeutic products, including, but not limited to, nebulizers, metered dose inhalers, and dry powder inhalers, all of which are well known to those skilled in the art.

[0068] Some specific examples of commercially available devices suitable for practicing the present invention are the Ultravent nebulizer manufactured by Mallinckrodt, Inc., St. Louis, Mo., the Acorn II nebulizer manufactured by Marquest Medical Products, Englewood, Colo., the Ventolin metered-dose inhaler manufactured by Glaxo Inc., Research Triangle Park, North Carolina, and the Spinhaler powder inhaler manufactured by Fisons Corp., Bedford, Mass.

[0069] All such devices require the use of formulations suitable for dispensing and administering the compounds of the present invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material in addition to the usual diluents, adjuvants, and / or carriers useful in therapeutics. The use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is also contemplated. The chemically modified compounds of the present invention can be prepared into various formulations depending on the type of chemical modification or the type of device employed.

[0070] Formulations suitable for use in either jet or ultrasonic nebulizers typically contain a compound (or derivative) of the invention dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution. The formulation may also contain a buffer and a simple sugar (e.g., for inhibitor stabilization and to control osmolality). Nebulizer formulations may also contain a surfactant to reduce or prevent surface-induced aggregation of the compound of the invention caused by atomization of the solution to form the aerosol.

[0071] Formulations for use with metered dose inhalers generally comprise a fine powder containing the compound (or derivative) of the present invention suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, hydrochlorofluorocarbon, hydrofluorocarbon, or hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or a combination thereof. Suitable surfactants include sorbitan trioleate and soybean lecithin. Oleic acid may also be useful as a surfactant.

[0072] Formulations for dispensing from powder inhalation devices comprise a finely divided dry powder containing a compound (or derivative) of the invention, and may contain a bulking agent such as lactose, sorbitol, sucrose, or mannitol in an amount sufficient to facilitate dispersion of the powder from the device, e.g., 50-90% by weight of the formulation. The compound (or derivative) of the invention should advantageously be prepared in particulate form having an average particle size of less than 10 micrometers (μm), most preferably 0.5-5 μm, for most effective delivery to the deep lung.

[0073] Nasal delivery of the pharmaceutical compositions of the present invention is also contemplated. Nasal delivery allows the pharmaceutical compositions of the present invention to enter the bloodstream directly after administration of the therapeutic product to the nose, without the product being deposited in the lungs. Nasal delivery formulations include those based on dextran or cyclodextran.

[0074] For nasal administration, a useful device is a small, hard bottle equipped with a metered-dose sprayer. In one embodiment, the metered dose is delivered by drawing a solution of the pharmaceutical composition of the present invention into a chamber of a fixed volume, which has an opening dimensioned to aerosolize the aerosol formulation by forming a spray when the liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[0075] Alternatively, it is a plastic squeeze bottle with an opening or aperture sized to aerosolize the aerosol formulation by forming a spray when squeezed. The opening is usually in the top of the bottle, which is generally tapered to partially fit into the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler provides a metered amount of the aerosol formulation to administer a measured amount of drug.

[0076] When systemic delivery is desired, the compound can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. Injectable preparations can be provided in unit dosage form, for example, in ampoules or multi-dose containers, with preservatives added. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain formulatory agents such as suspending agents, stabilizers, and / or dispersing agents.

[0077] Pharmaceutical preparations for parenteral administration include aqueous solutions of active compounds in water-soluble form.In addition, suspensions of active compounds can be prepared as suitable oily injection suspensions.Suitable lipophilic solutions or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions can contain substances that increase the viscosity of suspensions, such as sodium carboxymethylcellulose, sorbitol, or dextran.Optionally, suspensions can also contain suitable stabilizers or agents that increase the solubility of compounds, allowing the preparation of highly concentrated solutions.

[0078] Alternatively, the active compound may be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0079] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0080] In addition to the formulations described above, the compounds can also be formulated as depot preparations. Such long-acting preparations can be formulated using suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0081] The pharmaceutical compositions may also comprise suitable solid- or gel-phase carriers or excipients, examples of which include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0082] Suitable liquid or solid pharmaceutical preparation forms include, for example, aqueous or saline solutions for inhalation, microencapsulation, cochleation, coating on fine gold particles, encapsulation in liposomes, nebulization, aerosolization, pellets for skin implantation, or dried on sharp objects for rubbing on the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or sustained-release preparations of active compounds, which may be prepared using conventional excipients and additives and / or auxiliaries, such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers, as described above. Pharmaceutical compositions are suitable for use in various drug delivery systems. For a brief review of drug delivery methods, see Langer R, Science 249:1527-33 (1990).

[0083] The compounds of the present invention, and optional other therapeutic agents, may be administered as is (neat) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in medicine, the salt or cocrystal must be pharmaceutically acceptable; however, pharmaceutically unacceptable salts or cocrystals may conveniently be used to prepare the pharmaceutically acceptable salt or cocrystal. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Additionally, such salts may be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0084] Suitable buffering agents include acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v), chlorobutanol (0.3-0.9% w / v), parabens (0.01-0.25% w / v), and thimerosal (0.004-0.02% w / v).

[0085] The pharmaceutical compositions of the present invention contain an effective amount of a compound described herein and an optional therapeutic agent contained in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers, diluents, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic, organic or inorganic component that is combined with an active ingredient to facilitate application. The components of the pharmaceutical compositions also can be mixed with the compounds of the present invention, and with each other, in a manner such that there is no interaction that would substantially impair the desired pharmaceutical effect.

[0086] The therapeutic agent(s), including but not limited to, the compounds of the present invention, may be provided in particles. As used herein, particle refers to nanoparticles or microparticles (or larger particles in some cases) that may comprise all or part of the compounds of the present invention or other therapeutic agent(s) described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including but not limited to, an enteric coating. The therapeutic agent(s) may also be dispersed throughout the particle. The therapeutic agent(s) may also be adsorbed onto the particle. The particles may have any order of release rate, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to the therapeutic agent(s), the particles may contain any material commonly used in the pharmaceutical and medical arts, including but not limited to, disintegrating, non-disintegrating, biodegradable, or non-biodegradable materials, or combinations thereof. The particles may be microcapsules containing the compounds of the present invention in solution or in a semi-solid state. The particles may be of virtually any shape.

[0087] Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for delivering therapeutic agent(s). Such polymers can be natural or synthetic. The polymer is selected based on the desired period of release. Bioadhesive polymers of particular interest include the biodegradable hydrogels described in Sawhney HS et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein by reference. These include polyhyaluronic acid, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[0088] The therapeutic agent(s) may be contained in a controlled-release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation is controlled. This refers to immediate-release and non-immediate-release formulations, where non-immediate-release formulations include, but are not limited to, sustained-release and delayed-release formulations. The term "sustained-release" (also called "extended-release") is used in its conventional sense to refer to a drug formulation that provides a sustained release of drug over an extended period of time, preferably, but not necessarily, providing a substantially constant blood concentration of drug over an extended period of time. The term "delayed-release" is used in its conventional sense to refer to a drug formulation in which there is a time lag between administration of the formulation and the release of drug from the formulation. "Delayed-release" may or may not involve a sustained release of drug over an extended period of time, and therefore may or may not be "sustained-release."

[0089] For the treatment of chronic conditions, the use of long-term sustained-release implants may be particularly suitable. "Long-term" release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30 to 60 days. Long-term sustained-release implants are well known to those skilled in the art and include some of the release systems described above.

[0090] It will be understood by those skilled in the relevant art that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the invention contained herein, in view of the information known to those skilled in the art, and can be made without departing from the scope of the invention or any embodiment thereof. Having now described the invention in detail, the present invention will be more clearly understood by reference to the following examples. The examples are included herein for illustrative purposes only and are not intended to limit the invention.

[0091] Treatment methods One aspect of the present invention provides methods and administration regimens useful for treating or preventing diseases or disorders associated with abnormal amino acid concentrations through modulation of SLC6A19 transport.

[0092] Another aspect of the present invention provides methods and administration regimens useful for treating or preventing diseases or disorders associated with genetic deficiencies in phenylalanine hydroxylase.

[0093] One aspect of the present invention provides a method for treating or preventing a disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase, comprising orally administering to a patient in need of such treatment or prevention an effective amount of the following compound, or a pharmaceutically acceptable salt thereof: [ka] Here, the compound is formulated as a tablet.

[0094] In certain embodiments, the amount of the compound is from about 5 mg / day to about 1025 mg / day.

[0095] In certain embodiments, the amount of the compound is from about 75 mg / day to about 1025 mg / day.

[0096] In certain embodiments, the amount of the compound is about 100 mg / day to about 500 mg / day. In other embodiments, the amount of the compound is about 500 mg / day to about 1000 mg / day. In other embodiments, the amount of the compound is about 100 mg / day to about 200 mg / day. In other embodiments, the amount of the compound is about 200 mg / day to about 300 mg / day. In other embodiments, the amount of the compound is about 300 mg / day to about 400 mg / day. In other embodiments, the amount of the compound is about 400 mg / day to about 500 mg / day. In other embodiments, the amount of the compound is about 500 mg / day to about 600 mg / day. In other embodiments, the amount of the compound is about 600 mg / day to about 700 mg / day. In other embodiments, the amount of the compound is about 700 mg / day to about 800 mg / day. In other embodiments, the amount of the compound is about 800 mg / day to about 900 mg / day. In other embodiments, the amount of compound is from about 900 mg / day to about 1000 mg / day.

[0097] In certain embodiments, the amount of the compound is about 100 mg / day, about 125 mg / day, about 150 mg / day, or about 175 mg / day. In other embodiments, the amount of the compound is about 200 mg / day, about 225 mg / day, about 250 mg / day, or about 275 mg / day. In other embodiments, the amount of the compound is about 300 mg / day, about 325 mg / day, about 350 mg / day, or about 375 mg / day. In other embodiments, the amount of the compound is about 400 mg / day, about 425 mg / day, about 450 mg / day, about 475 mg / day, or about 500 mg / day. In other embodiments, the amount of the compound is about 500 mg / day, about 525 mg / day, about 550 mg / day, or about 575 mg / day. In other embodiments, the amount of the compound is about 600 mg / day, about 625 mg / day, about 650 mg / day, or about 675 mg / day. In other embodiments, the amount of the compound is about 700 mg / day, about 725 mg / day, about 750 mg / day, or about 775 mg / day. In other embodiments, the amount of the compound is about 800 mg / day, about 825 mg / day, about 850 mg / day, or about 875 mg / day. In other embodiments, the amount of the compound is about 900 mg / day, about 925 mg / day, about 950 mg / day, about 975 mg / day, or about 1000 mg / day.

[0098] In certain embodiments, the amount of the compound is from about 5 mg / day to about 100 mg / day.

[0099] In certain embodiments, the amount of the compound is about 5 mg / day to about 25 mg / day. In other embodiments, the amount of the compound is about 25 mg / day to about 50 mg / day. In other embodiments, the amount of the compound is about 50 mg / day to about 75 mg / day.

[0100] In certain embodiments, the amount of compound is about 5 mg / day, about 10 mg / day, about 25 mg / day, about 50 mg / day, or about 75 mg / day. In certain embodiments, the % w / w of compound in the tablet is about 5% to about 30% w / w.

[0101] In certain embodiments, the % w / w of the compound in the tablet is about 5% to about 10% w / w, while in other embodiments, the % w / w of the compound in the tablet is about 20% to about 30% w / w.

[0102] In certain embodiments, each component of the tablet is intragranular.

[0103] In certain embodiments, at least one component of the tablet, other than the compound, is extragranular.

[0104] In certain embodiments, the tablet is a coated tablet.

[0105] In certain embodiments, the amount of compound is administered in a single daily dose, hi other embodiments, the amount of compound is administered in two equal divided doses per day.

[0106] In certain embodiments, the compound is administered once daily (QD). In other embodiments, the amount of compound is administered twice daily (BID).

[0107] In one particular embodiment, 25 mg of the compound is administered twice daily (BID).

[0108] In one particular embodiment, 75 mg of the compound is administered twice daily (BID).

[0109] In certain embodiments, 150 mg of the compound is administered once daily (QD).

[0110] Another aspect of the present invention provides a method for treating or preventing a disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase, comprising orally administering to a patient in need of such treatment or prevention an effective amount of the following compound, or a pharmaceutically acceptable salt thereof: [ka] Here, the compound is formulated as a suspension.

[0111] In certain embodiments, the suspension is an oral suspension.

[0112] In certain embodiments, the suspension is formulated for oral administration.

[0113] In certain embodiments, the amount of the compound is from about 5 mg / day to about 1525 mg / day.

[0114] In certain embodiments, the amount of the compound is from about 10 mg / day to about 750 mg / day.

[0115] In certain embodiments, the amount of the compound is from about 10 mg / day to about 525 mg / day.

[0116] In certain embodiments, the amount of the compound is about 25 mg / day to about 100 mg / day. In other embodiments, the amount of the compound is about 150 mg / day to about 250 mg / day. In other embodiments, the amount of the compound is about 300 mg / day to about 500 mg / day.

[0117] In certain embodiments, the amount of the compound is about 25 mg / day. In other embodiments, the amount of the compound is about 75 mg / day. In other embodiments, the amount of the compound is about 150 mg / day. In other embodiments, the amount of the compound is about 250 mg / day. In other embodiments, the amount of the compound is about 300 mg / day. In other embodiments, the amount of the compound is about 500 mg / day. In other embodiments, the amount of the compound is about 750 mg / day to about 1000 mg / day.

[0118] In certain embodiments, the amount of the compound is about 1000 mg / day to about 1500 mg / day. In other embodiments, the amount of the compound is about 1000 mg / day. In other embodiments, the amount of the compound is about 1500 mg / day.

[0119] In certain embodiments, the % w / w of the compound in the suspension is from about 25% to about 95% w / w.

[0120] In certain embodiments, the % w / w of the compound in the suspension is about 33% to about 60% w / w. In other embodiments, the % w / w of the compound in the suspension is about 75% to about 90% w / w. In other embodiments, the % w / w of the compound in the suspension is about 90% to about 95% w / w.

[0121] In certain embodiments, the suspension consists of the compound, a wetting agent, and a vehicle.

[0122] In certain embodiments, the amount of compound is administered in a single daily dose, hi other embodiments, the amount of compound is administered in two equal divided doses per day.

[0123] In certain embodiments, the compound is administered once daily (QD). In other embodiments, the amount of compound is administered twice daily (BID).

[0124] In one particular embodiment, 25 mg of the compound is administered twice daily (BID).

[0125] In one particular embodiment, 75 mg of the compound is administered twice daily (BID).

[0126] In certain embodiments, 150 mg of the compound is administered once daily (QD).

[0127] In certain embodiments, treatment continues indefinitely (ie, long-term treatment).

[0128] In certain embodiments, the patient is a human.

[0129] In certain embodiments, the patient is an adult. In other embodiments, the patient is an elderly person. In other embodiments, the patient is a child. In other embodiments, the patient is an infant or toddler. In other embodiments, the patient is male. In other embodiments, the patient is female.

[0130] In certain embodiments, the human is of African, Asian, Caucasian, American Indian, Hispanic / Latino, or Pacific Islander descent.

[0131] In certain embodiments, the concentration of phenylalanine in the patient's blood is reduced compared to a pre-treatment baseline.

[0132] In certain embodiments, the concentration of phenylalanine is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% reduction.

[0133] In certain embodiments, the concentration of phenylalanine is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0134] In certain embodiments, the disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase is phenylketonuria.

[0135] In certain embodiments, the phenylketonuria is classical phenylketonuria. In other embodiments, the phenylketonuria is mild phenylketonuria.

[0136] In certain embodiments, the disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase is hyperphenylalaninemia.

[0137] In certain embodiments, the compound inhibits SLC6A19 in the patient. [Example]

[0138] The invention is described in more detail in the following examples, which do not limit the scope of the invention described in the claims.

[0139] Example 1. Oral Suspension Formulation of Compound Preparation of oral suspension Compound 1 oral suspensions of various concentrations are prepared for each dose level. Each suspension is prepared for a separate volunteer to administer at a specific dose. All oral suspensions are prepared by adding the diluent OralBlend® SF (Padagis LLC (formerly Perrigo® Company plc)) containing 0.1% w / v sodium lauryl sulfate. The compositions of the various oral suspensions prepared by the compounding pharmacy to provide each dose level: 25 mg, 75 mg, 150 mg, 250 mg, 350 mg, and 500 mg, are shown in Tables 1-7, respectively. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0140] The oral suspension is prepared at the compounding pharmacy using the following procedure. 1. Weigh out the required amount of Compound 1 drug substance into a tared weighing paper / boat. 2. Transfer a weighed amount of Compound 1 to a 50 mL Falcon or equivalent tube. 3. Prepare the vehicle (OralBlend® SF with 0.1% sodium lauryl sulfate) by weighing the appropriate amount of sodium lauryl sulfate and dissolving it in OralBlend® SF with mixing at room temperature. 4. Dispense 25 mL of OralBlend® SF with 0.1% sodium lauryl sulfate into the Falcon tube or equivalent containing the weighed amount of Compound 1 drug substance and seal the tube. 5. Gently vortex the contents of the tube for at least 30 seconds to mix and suspend Compound 1 in OralBlend® SF containing 0.1% sodium lauryl sulfate. 6. Place the tube containing the contents upright. 7. Prior to administering the dose to the subject, gently vortex the contents of the tube by hand to resuspend the Compound 1 particles. 8. Once the contents of the tube have been administered, rinse the tube with 2 x 25 mL of purified water, USP, and administer the rinse to the subject.

[0141] Example 2. Tablet formulation of compound Tablet preparation Two tablet formulations containing Compound 1 in an amount of 75 mg are described in Tables 8 and 9. [Table 8] [Table 9]

[0142] Two coated tablet formulations containing Compound 1 in an amount of 75 mg are listed in Tables 10 and 11. [Table 10] [Table 11]

[0143] Patients will receive a combination of 75 mg and 25 mg tablets to achieve the following final doses (Table 12): Tablets will be administered once daily or twice daily. [Table 12]

[0144] Example 3. Administration of suspension formulation Various doses of Compound 1 suspension (10-170 mg) were administered to healthy volunteers. Changes in amino acid excretion were measured over 24 hours after a single dose (Figure 1). Over the 24 hours after administration, a maximum 14-fold increase in total Phe secretion (10 mg to 142 mg) and a 16-fold increase in Hartnup AA secretion (0.29 g to 4.8 g) were observed (Tables 13A and 13B). [Table 13]

[0145] Various doses of Compound 1 suspension formulation (25 or 75 mg twice daily [BID] or 150 mg once daily [QD]) were administered to healthy volunteers. After 14 days of administration, the plasma concentration of Compound 1 was measured over 24 hours (Figure 2). The plasma concentrations after administration are listed in Table 14. [Table 14-1] [Table 14-2]

[0146] Various doses of Compound 1 suspension (25 or 75 mg twice daily [BID] or 150 mg once daily [QD]) were administered to healthy volunteers. Changes in 24-hour excretion of phenylalanine or total SLC6A19 amino acid substrates (Hartnup amino acids) were measured on days 1, 7, and 14 (Figures 3A and 3B). Urinary excretion of Hartnup amino acids over 24 hours increased from 0.4 gw / PBO to 4.9 gw / 75 mg compound BID (a 13-fold increase) (Table 15A). [Table 15] [Table 16]

[0147] Example 4. Comparison of suspension and tablet formulations Suspension formulations (100 mg, fasted) and tablet formulations (100 mg, fasted or fed) of Compound 1 were administered to healthy volunteers. Plasma concentrations of Compound 1 were measured over a 72-hour period (FIG. 4). Plasma concentrations after administration are listed in Table 16. [Table 17-1] [Table 17-2]

[0148] Incorporation by Reference All United States patents and published United States and international applications cited herein are hereby incorporated by reference.

[0149] equivalent The foregoing specification is sufficient to enable those skilled in the art to practice the present invention. The scope of the present invention should not be limited by the described examples, as each example is intended as a single illustration of one aspect of the invention, and other functionally equivalent embodiments are also within the scope of the present invention. Various modifications of the present invention in addition to those shown and described herein will be apparent to those skilled in the art from the above description and are encompassed within the scope of the appended claims. The benefits and objectives of the present invention are not necessarily encompassed in each embodiment of the present invention.

Claims

1. The following compounds, or their pharmaceutically acceptable salts 【Chemistry 1】 A composition for treating or preventing a disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase in a patient, characterized in that an effective amount of the compound, or a pharmaceutically acceptable salt thereof, is used to be administered orally. A composition comprising the compound, or a pharmaceutically acceptable salt thereof, formulated as a tablet.

2. The amount of the aforementioned compound Approximately 5 mg / day to approximately 1025 mg / day; About 75 mg / day to about 1025 mg / day; About 100 mg / day to about 500 mg / day; Approximately 200 mg / day to approximately 300 mg / day; or Approximately 300 mg / day to approximately 400 mg / day The composition according to claim 1.

3. The composition according to claim 2, wherein the amount of the compound is approximately 300 mg / day.

4. The % w / w of the compound in the aforementioned tablet is, Approximately 5% to 30% w / w; Approximately 5% to approximately 10% w / w; or Approximately 20% to 30% w / w The composition according to claim 1 or 2.

5. The composition according to claim 1 or 2, wherein the tablet is a coated tablet.

6. The composition according to claim 3, wherein the amount of the compound is administered in two equal daily divisions.

7. The composition according to claim 6, wherein 150 mg of the compound is administered twice daily (BID).

8. 25 mg of the compound is administered twice daily (BID); 75 mg of the compound is administered twice daily (BID); or 150 mg of the compound is administered once daily (QD). The composition according to claim 1.

9. The following compounds, or their pharmaceutically acceptable salts 【Chemistry 2】 A composition for treating or preventing a disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase in a patient, characterized in that an effective amount of the compound, or a pharmaceutically acceptable salt thereof, is used to be administered orally. A composition comprising the compound or a pharmaceutically acceptable salt thereof, formulated as a suspension.

10. The amount of the aforementioned compound Approximately 5mg / day to approximately 1525mg / day About 10 mg / day to about 750 mg / day; Approximately 10 mg / day to approximately 525 mg / day; or Approximately 300mg / day to approximately 500mg / day The composition according to claim 9.

11. The composition according to claim 10, wherein the amount of the compound is approximately 300 mg / day.

12. The % w / w of the compound in the suspension is Approximately 25% to 95% w / w; Approximately 33% to 60% w / w; Approximately 75% to approximately 90% w / w; or Approximately 90% to 95% w / w The composition according to claim 9 or 10.

13. The composition according to claim 11, wherein the amount of the compound is administered in two equal daily divisions.

14. The composition according to claim 13, wherein 150 mg of the compound is administered twice daily (BID).

15. 25 mg of the compound is administered twice daily (BID); 75 mg of the compound is administered twice daily (BID); or 150 mg of the compound is administered once daily (QD). The composition according to claim 9.

16. The composition according to any one of claims 1 to 3, 6 to 11, and 13 to 15, characterized in that the treatment continues indefinitely.

17. The aforementioned patient is a human being; The patient is an adult; The aforementioned patient is elderly; The patient in question is a child; The patient is an infant or toddler; The aforementioned patient is male; The aforementioned patient is female; The patient is a human being, and the human being is of African, Asian, Caucasian, Native American, Hispanic / Latino, or Pacific Islander descent. The composition according to any one of claims 1 to 3, 6 to 11, and 13 to 15.

18. The concentration of phenylalanine in the patient's blood decreases compared to the pre-treatment baseline; The concentration of phenylalanine is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 2 5%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50 %, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75% , decrease by at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%; or The concentration of phenylalanine decreases by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. The composition according to any one of claims 1 to 3, 6 to 11, and 13 to 15.

19. The aforementioned disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase, Phenylketonuria; Classical phenylketonuria; Mild phenylketonuria; or Hyperphenylalaninemia The composition according to any one of claims 1 to 3, 6 to 11, and 13 to 15.

20. The composition according to any one of claims 1 to 3, 6 to 11, and 13 to 15, wherein the compound inhibits SLC6A19 in the patient.

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