US20230029266A1 - MrgprX2 Antagonists for the Treatment of Inflammatory Disorders - Google Patents

MrgprX2 Antagonists for the Treatment of Inflammatory Disorders Download PDF

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US20230029266A1
US20230029266A1 US17/772,467 US202017772467A US2023029266A1 US 20230029266 A1 US20230029266 A1 US 20230029266A1 US 202017772467 A US202017772467 A US 202017772467A US 2023029266 A1 US2023029266 A1 US 2023029266A1
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Ferda Cevikbas
Ashley Jarvis
Laura GLEAVE
Nina Connelly Ursinyova
Ricky CAIN
Wei Tsung Yau
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Evotec UK Ltd
Dermira Inc
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Dermira Inc
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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Definitions

  • AD Atopic dermatitis
  • AD is the most common inflammatory skin disease with an overall prevalence of 6% in adults in the US, and 1-3% of adults and 15-20% of children worldwide. 17.8 million Americans suffer from AD. The disease onset is typically in childhood, and skin manifestations are visible by the age of 1 year in 60% of the patients. Clinical manifestations are erythematous papules and plaques, oozing, crust, hypopigmentation and lichenification. The hallmark symptom of AD, however, is intense chronic itch that persists more than 6 weeks. Despite high prevalence of chronic itch in AD patients, there is no effective first-line treatment available with a good safety profile. Itch has a significant impact on the quality of life of these patients, including sleep impairment, ultimately leading to poor performance at work or school. Health-related quality of life in children is inversely correlated with the severity of the disease. Sleep is affected by persisting nocturnal pruritus.
  • Oral anti-histamines provide modest symptomatic relief due to their sedative effects without directly altering pruritus.
  • Topical calcineurin inhibitors (TCI) as well as topical corticosteroids (TCS) might be helpful in reducing the pruritus.
  • TCI topical calcineurin inhibitors
  • TCS topical corticosteroids
  • their adverse effects skin atrophy, hypopigmentation, and telangiectasia in case of TCS, and the black box warning on TCI regarding skin cancer malignancies
  • itch-scratch cycle which has secondary beneficial effects such as improving the skin barrier and may lead to improvement in skin lesions and erythema.
  • NK1R antagonist aprepitant failed to significantly block itch in humans.
  • MrgprX2 is a promising target due to its promiscuous ligand binding properties to various pruritic mediators. Multiple pruritic mediators known or speculated to be relevant players in the pathogenesis of AD appear to bind MrgprX receptor rather than the cognate receptors.
  • compositions comprising MrgprX2 antagonists and methods for using the MrgprX2 antagonists for the treatment of inflammatory conditions such as AD.
  • the present disclosure provides for compounds that are MrgprX2 antagonists.
  • the present disclosure provides for a composition comprising a topical or oral MrgprX2 antagonist, and a pharmaceutically acceptable excipient.
  • the present disclosure provides for a method for treating an inflammatory disorder, the method comprising administering to a subject in need thereof a topical or oral composition having a therapeutically effective amount of a MrgprX2 antagonist (e.g. a MrgprX2 antagonist according to the present disclosure); and a dermatologically or orally acceptable excipient.
  • a MrgprX2 antagonist e.g. a MrgprX2 antagonist according to the present disclosure
  • a dermatologically or orally acceptable excipient e.g. a dermatologically or orally acceptable excipient.
  • the present disclosure provides a method for reducing inflammation in mammalian skin, the method comprising administering an effective amount of a topical or oral composition including an MrgprX2 antagonist (e.g. a MrgprX2 antagonist according to the present disclosure) and a dermatologically or orally acceptable excipient to a subject in need thereof.
  • an MrgprX2 antagonist e.g. a MrgprX2 antagonist according to the present disclosure
  • a dermatologically or orally acceptable excipient to a subject in need thereof.
  • the present disclosure provides a method for reducing the incidence of or severity of itch in a subject in need thereof, the method comprising administering a therapeutically effective amount of a topical or oral composition including a MrgprX2 antagonist (e.g. a MrgprX2 antagonist according to the present disclosure) to a subject in need thereof.
  • a MrgprX2 antagonist e.g. a MrgprX2 antagonist according to the present disclosure
  • compositions for treating inflammatory conditions e.g., skin disorders characterized by inflammation.
  • the pharmaceutical compositions include compounds that are antagonists of the Mas-related G protein-coupled receptor MrgprX2.
  • MrgprX2 Antagonists for Use in the Compositions and Methods of the Present Disclosure are MrgprX2 Antagonists for Use in the Compositions and Methods of the Present Disclosure
  • the present disclosure provides for a Compound [Compound 1] that is a MrgprX2 antagonist having the Formula I:
  • R A is absent or is selected from H, C 1-3 alkyl, —C( ⁇ O)—NH 2 , —C( ⁇ O)—OH, halogen, phenyl, CN and benzyl;
  • k, q, m and p are each independently 0 or 1;
  • R 3 is H or C 1-3 alkyl
  • R 1 is selected from H; C 1-6 alkyl or C 3-6 cycloalkyl, which is optionally substituted with 1, 2 or 3 independently selected R 50 groups; or a 3-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S, which is optionally substituted with 1, 2 or 3 independently selected R 51 groups, and which optionally comprises a —(C ⁇ O)— group or —S( ⁇ O) 2 — group in the ring;
  • each R 50 is independently selected from hydroxy, —NR 20 N 21 ; —SO 2 R 22 ; C 1-3 haloalkyl; halogen; —C( ⁇ O)—R 26 ; CN; C 3-6 cycloalkyl which is optionally substituted with 1-3 R 25 groups; C 1-3 alkoxy; —C( ⁇ O)—NR 27 R 28 ; C 1-3 hydroxyalkyl; and a 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S, which is optionally substituted with 1, 2 or 3 independently selected R 51 groups, and which optionally comprises a —(C ⁇ O)-group in the ring;
  • each R 20 and R 21 is independently selected from H, C 1-6 alkyl and —SO 2 NR 30 R 31 ;
  • each R 22 is independently C 1-6 alkyl
  • each R 25 is independently selected from hydroxy, C 1-3 haloalkyl and C 1-3 hydroxyalkyl;
  • each R 26 is independently selected from hydroxy, C 1-3 haloalkyl and C 1-6 alkoxy;
  • each R 27 and R 28 is independently selected from H, hydroxy, C 1-3 haloalkyl and C 1-3 alkoxy;
  • each R 51 is independently selected from C 1-6 alkyl; —SO 2 NR 30 R 31 ; —C( ⁇ O)—O—R 32 ; halogen; hydroxy; cyano; C 1-3 hydroxyalkyl; —C( ⁇ O)—NR 33 R 34 ; —C( ⁇ O)—R 35 ; CN; —SO 2 R 22 ; C 1-3 haloalkyl; NR 33 R 34 ; and C 1-3 alkoxy;
  • each R 30 and R 31 is independently selected from H and C 1-6 alkyl
  • each R 32 is independently selected from H and C 1-6 alkyl
  • each R 33 and R 34 is independently selected from H and C 1-6 alkyl
  • each R 35 is independently C 1-6 alkyl
  • R 2 is H, C 1-6 alkyl or C 3-6 cycloalkyl, each optionally substituted with 1, 2 or 3 groups selected from hydroxy, C 1-3 haloalkyl, halogen, C 1-3 alkoxy and CN; or R 2 is —SO 2 (C 1-6 alkyl);
  • R 2 and R 3 together form a —CH 2 —CH 2 — group, such as a ring of formula
  • p is 0 or 1;
  • L 1 is O, CH 2 , —CH(C 1-3 alkyl)-, —C( ⁇ O)—NH—CH 2 —, —C(OH)(CH 3 )—, —CH(OH)—, —(C ⁇ O)—, —N(C 1-6 alkyl)-, or —NH—;
  • a 2 is C 6-10 aryl, C 3-7 cycloalkyl, or a 5-10 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S, wherein each of C 6-10 aryl, C 3-7 cycloalkyl and 5-10 membered heteroaryl is optionally substituted with 1, 2 or 3 independently selected R 60 groups; and
  • each R 60 is independently selected from halogen, CN, hydroxy, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 haloalkyl, —C( ⁇ O)—O—R 35 and C 1-3 alkyl optionally substituted with 1-3 substituents independently selected from hydroxy, CN and C 1-3 alkoxy;
  • the present disclosure further provides compounds as follows:
  • composition 1 comprising a MrgprX2 antagonist and a dermatologically or orally acceptable excipient.
  • the MrgprX2 antagonist is Compound I, having Formula I described above.
  • topical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammalian skin, e.g., human skin.
  • a medium includes all dermatologically acceptable carriers, diluents or excipients therefor.
  • Stepoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • solvent refers to a form of a compound complexed by solvent molecules.
  • Tautomers refers to two molecules that are structural isomers that readily interconvert.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isoprop
  • the compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centres and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and ( ⁇ ), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallisation.
  • “Dermatologically acceptable excipient” includes without limitation any adjuvant, carrier, vehicle, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier, including those approved by the United States Food and Drug Administration as being acceptable for dermatological use on humans or domestic animals, or which are known, or are suitable for use in dermatological compositions.
  • alkyl is intended to mean a straight or branched carbon radical containing the indicated number of carbon atoms. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, pentyl, isopentyl, t-pentyl, neopentyl, 1-methylbutyl [i.e., —CH(CH 3 )CH 2 CH 2 CH 3 ], 2-methylbutyl [i.e., —CH 2 CH(CH 3 )CH 2 CH 3 ], n-hexyl, and the like.
  • cycloalkyl is intended to mean a saturated ring radical containing the indicated number of carbon atoms. Some embodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • haloalkyl is intended to mean a radical comprising an alkyl group having the indicated number of carbon atoms, substituted with one or more halogens.
  • C 1 -C 6 haloalkyl may be fully substituted in which case it can be represented by the formula C n L 2n+1 , wherein L is a halogen and “n” is 1, 2, 3, 4, 5 or 6.
  • n is 1, 2, 3, 4, 5 or 6.
  • haloalkyl contains 1 to 5 carbons.
  • haloalkyl contains 1 to 4 carbons.
  • haloalkyl contains 1 to 3 carbons. In some embodiments, haloalkyl contains 1 or 2 carbons.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like. When used without a prefix indicating the number of halo substituents, “haloalkyl” groups contain 1, 2 or 3 halogen atoms.
  • hydroxyalkyl is intended to mean a radical comprising an alkyl group having the indicated number of carbon atoms, substituted with one or more hydroxy (i.e., —OH) groups. When used without a prefix indicating the number of hydroxy substituents, “hydroxyalkyl” groups contain 1, 2 or 3 hydroxy groups.
  • halogen is intended to mean to a fluoro, chloro, bromo or iodo group.
  • aryl is intended to mean a ring system containing 6 to 10 carbon atoms, that may contain a single ring or two fused rings, and wherein at least one ring is aromatic. Examples include phenyl, indanyl, and naphthyl.
  • heteroaryl is intended to mean a ring system containing 5 to 14 ring atoms, that may contain a single ring, two fused rings or three fused rings, and wherein at least one ring is aromatic and at least one ring atom is a heteroatom selected from, for example: 0, S and N.
  • Some embodiments contain 5 to 6 ring atoms for example furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
  • Some embodiments contain 8 to 14 ring atoms for example quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl, isobenzofuran, 2,3-dihydrobenzofuranyl, 4H-benzo[1,3]dioxinyl, 3,4-dihydro-1H-isoquinolin
  • cyano means a —CN group.
  • alkoxy means a group of formula —O-alkyl, having the indicated number of carbon atoms.
  • heterocycloalkyl is intended to mean a non-aromatic 3-6-membered heterocyclic ring optionally fused to a 3-6 member saturated, partially unsaturated, or aromatic aryl or heteroaryl ring.
  • non-aromatic 3-6-membered heterocyclic rings include oxirane, azinidine, oxetane, tetrahydrofuran, pyrrolidine, piperidine, tetrahydropyran, morpholine, piperazine, hexahydropyrimidine, hexahydropyridazine, and the like.
  • Heterocycloalkyl groups can contain one or more oxo (i.e.
  • heterocycloalkyl rings include sulfolane, tetrahydro-2H-thiopyran-1,1,-dione, thiomorpholine 1,1-dioxide, 2-pyrrolidione, piperidin-2-one, piperazine-2-one, morpholine -3-one, and the like.
  • heterocycloalkyls having a fused ring include dihydroindoles such as 1,3 dihydroindole.
  • spiroalkyl is intended to mean a structure of two or more rings in which two of the rings share one common atom, and wherein at least one of the rings is a cycloalkyl ring, containing the indicated number of carbon atoms. Examples include spirocyclopropane and spirocyclobutane.
  • the Compounds of the Invention are useful in the treatment of inflammatory disorders, e.g., atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudo-allergic reactions triggered by small molecules for example anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch triggered by systemic diseases, drug-adverse reactions.
  • atopic dermatitis e.g., Asian atopic dermatitis, European atopic dermatitis
  • chronic urticaria triggered by small molecules for example anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch triggered by systemic diseases, drug-adverse reactions.
  • a preferred MrgprX2 antagonist as described herein e.g., a MrgprX2 antagonist as hereinbefore described, e.g., a Compound of Formula I
  • a preferred MrgprX2 antagonist as described herein e.g., a MrgprX2 antagonist as hereinbefore described, e.g., a Compound of Formula I
  • the present disclosure provides for a method [Method 1] for treating an inflammatory disorder, the method comprising administering to a subject in need thereof a topical or oral composition comprising a therapeutically effective amount of a MrgprX2 antagonist (e.g. a MrgprX2 antagonist according to the present disclosure); and a dermatologically or orally acceptable excipient.
  • a MrgprX2 antagonist e.g. a MrgprX2 antagonist according to the present disclosure
  • a dermatologically or orally acceptable excipient e.g. a dermatologically or orally acceptable excipient.
  • the present disclosure provides a method [Method 2] for reducing inflammation in mammalian skin, the method comprising administering an effective amount of a topical or oral composition including a MrgprX2 antagonist according to the present disclosure and a dermatologically or orally acceptable excipient to a subject in need thereof.
  • a further embodiment provides a method [Method 3] for reducing the incidence of or severity of itch, the method comprising administering a therapeutically effective amount of a topical or oral composition according to any of Compositions 1 and 1.1-1.73.
  • Atopic dermatitis refers to a skin condition involving chronic inflammation, and symptoms of atopic dermatitis include a red, itchy rash. Atopic dermatitis may be present on the skin of any part of the body, but is common on the hands, feet, upper chest, and in the bends of elbows or knees. Additional symptoms of atopic dermatitis may include small raised bumps or thickened, scaly skin.
  • Psoriasis is a chronic skin condition related to an overactive immune response. Psoriasis may be present on may be present on the skin of any part of the body. Symptoms of psoriasis include local inflammation, skin flaking, and thick white or red patches of skin.
  • Alopecia is an autoimmune skin disease, causing hair loss on the scalp, face and sometimes on other areas of the body.
  • alopecia areata, for example, T cell lymphocytes cluster around affected follicles, causing inflammation and subsequent hair loss.
  • “Chronic Urticaria” (Hives) is a common skin rash triggered by many things including certain foods, medications, and stress. Symptoms can include itchy, raised, red, or skin-colored welts on the skin's surface.
  • MrgprX2 Given the role of mast cells in chronic idiopathic urticaria, MrgprX2 partakes a key function in the mast cell activation.
  • Antimicrobial host defense peptides, neuropeptides, major basic protein, eosinophil peroxidase, and some FDA-approved peptidergic drugs activate human MrgprX2.
  • Unique features of MrgprX2 that distinguish it from other GPCRs include their presence both on the plasma membrane and intracellular sites and their selective expression in MCs.
  • MrgprX2 small-molecule inhibitors of MrgprX2 could benefit the treatment of MC-dependent allergic and inflammatory disorders such as chronic urticaria which is currently treated by targeting the IgE axis of mast cell activity.
  • MC-activity relies on ligand binding to MrgprX2 (Subramanian H et al., 2016 , The Journal of Allergy and Clinical Immunology, 138(3), 700-710; https://doi.org/10.1016/j.jaci.2016.04.051) suggesting that targeting MRGPRX2 might indeed be a treatment option for IgE-independent and resistant chronic urticaria.
  • MrgprB2 proadrenomedullin N-terminal peptide 9-20 (PAMP9-20) induced the release of multiple bioactive mediators from mast cells which in turn activated itch-sensing neurons suggesting the mast-cell specific MrgprB2 is key in mast-cell degranulation and related non-histaminergic itch.
  • Mast cell MrgprB2 and MrgrpX2 are activated by SP, compound 48/80 and pseudoallergy inducing drugs such as icatibant (McNeil, B. D.
  • MrgprX2 placed at the center stage of non-histaminergic mast cell activation and various allergic and nonallergic diseases as well as pseudoallergic reactions.
  • Rosecea is condition that causes redness and often small, red, pus-filled bumps on the face. MrgrpX2 has also been identified as the receptor for endogenous host defense peptide, including cathelicidin (LL-37) and ⁇ -defensin (Subramanian, H. et al., 2011 , The Journal of Biological Chemistry, 286(52), 44739-44749; https://doi.org/10.1074/jbc.M111.277152 and Subramanian, H.
  • MrgprX2 may also function in innate immunity by regulating host defense responses.
  • MrgprX2 is activated by peptides such as LL-37 and the neuropeptide PACAP, both of which are crucially involved in rosacea and function as trigger peptides to affect mast cell activity and vasodilation. Together these findings suggest MrgprX2 as an emerging receptor in the pathophysiology of rosacea.
  • “Asthma” is a condition in which a person's airways become inflamed, narrow and swell, and produce extra mucus, which makes it difficult to breathe.
  • Mast cells (MC) which also subside in close vicinity with smooth muscle, T cells and leukocytes, are important effector cells in airway hyperresponsiveness and inflammation, a phenomenon characteristic of asthma.
  • MCT phenotypic switch of MCTC from MCT.
  • the mast cell MCTC population in severe asthma is expressing MrgprX2 (Fajt M. L.
  • “Mammal” or “mammalian” includes humans and both domestic animals such as laboratory animals and household pets, (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • “Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease or condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • a “therapeutically effective amount” is that amount of a compound of invention which is sufficient to inhibit inflammation of the skin.
  • Treating covers the treatment of the disease or condition of interest in a mammal, preferably a human, and includes:
  • the terms “disease,” “disorder,” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
  • the MrgprX2 antagonist e.g. a MrgprX2 antagonist according to the present disclosure
  • the MrgprX2 antagonist is present in the topical composition at a concentration of about 0.05% to about 5% by weight.
  • the pharmaceutical compositions described herein further include a dermatologically acceptable excipient.
  • the dermatologically acceptable excipients may be one or more solvents that solubilize and/or stabilize the active ingredient (e.g., MrgprX2 antagonist) contained therein.
  • the dermatologically acceptable excipients may also include skin penetration enhancers, preservatives, viscosity enhancers, pH adjusters, film forming agents and the like.
  • Non-limiting examples of the suitable excipients include water, PEG 200, PEG 400, ethanol, glycerol, Transcutol P (diethylene glycol monoethyl ether), propylene glycol, 1,3-dimethyl-2-imidazolidinone (DMI), sodium metabisulfite, butylated hydroxytoluene (BHT), benzyl alcohol, sodium benzoate, isopropyl myristate, diisopropyl adipate, crodamol OHS (ethylhexyl hydroxystearate), mineral oil, Betadex, TWEEN 20, Brij S20 (polyoxyethylene (20) stearyl ether).
  • DMI 1,3-dimethyl-2-imidazolidinone
  • BHT butylated hydroxytoluene
  • benzyl alcohol sodium benzoate
  • isopropyl myristate diisopropyl adipate
  • crodamol OHS
  • components of the pharmaceutical formulations described herein can possess multiple functions.
  • a given substance may act as both a viscosity increasing agent and as an emulsifying agent.
  • a suitable dermatologically acceptable excipient may include one or more penetration enhancers (or permeation enhancers), which are substances that promote the diffusion of the therapeutic drugs (e.g., the MrgprX2 antagonists described herein) through the skin barrier. They typically act to reduce the impedance or resistance of the skin to allow improved permeation of the therapeutic drugs. In particular, substances which would perturb the normal structure of the stratum corneum are capable of disrupting the intercellular lipid organization, thus reducing its effectiveness as a barrier.
  • penetration enhancers or permeation enhancers
  • These substances could include any lipid material which would partition into the stratum corneum lipids causing a direct effect or any material which would affect the proteins and cause an indirect perturbation of the lipid structure.
  • solvents such as ethanol, can remove lipids from the stratum corneum, thus destroying its lipid organization and disrupting its barrier function.
  • penetration enhancers or barrier function disrupters include, but are not limited to, alcohol-based enhancers, such as alkanols with one to sixteen carbons, benzyl alcohol, butylene glycol, diethylene glycol, glycofurol, glycerides, glycerin, glycerol, phenethyl alcohol, polypropylene glycol, polyvinyl alcohol, and phenol; amide-based enhancers, such as N-butyl-N-dodecylacetamide, crotamiton, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl formamide, and urea; amino acids, such as L- ⁇ -amino acids and water soluble proteins; azone and azone-like compounds, such as azacycloalkanes; essential oils, such as almond oil, amyl butyrate, apricot kernel oil, avocado oil, camphor, castor oil, 1-carvone, coconut oil, corn oil,
  • the topical compositions described herein typically contain one or more carriers, which preferably have a vapor pressure greater than or equal to 23.8 mm Hg at 25° C.
  • Preferred concentration range of a single carrier or the total of a combination of carriers can be from about 0.1 wt. % to about 10 wt. %, more preferably from about 10 wt. % to about 50 wt. %, more specifically from about 50 wt. % to about 95 wt. % of the dermatological composition.
  • the solvent include water (e.g., deionized water) and lower alcohols, including ethanol, 2-propanol and n-propanol.
  • a dermatological composition of the invention can contain one or more hydrophilic co-solvents, which are miscible with water and/or lower chain alcohols and preferably have a vapor pressure less than water at 25° C. ( ⁇ 23.8 mm Hg).
  • the carrier typically has a vapor pressure greater than or equal to the hydrophilic co-solvent as to concentrate the active ingredient (e.g., a MrgprX2 antagonist of the present disclosure) on the skin.
  • a hydrophilic co-solvent may be a glycol, specifically propylene glycol.
  • the propylene glycol can be from the class of polyethylene glycols, specifically polyethylene glycols ranging in molecular weight from 200 to 20000.
  • the solvent would be part of a class of glycol ethers.
  • a hydrophilic co-solvent of the invention would be diethylene glycol monoethyl ether (transcutol).
  • DGME diethylene glycol monoethyl ether
  • transcutol refers to 2-(2-ethoxyethoxy)ethanol ⁇ CAS NO 001893 ⁇ or ethyoxydiglycol.
  • DMI 1,3-dimethyl-2-imidazolidinone
  • the topical compositions described herein may also contain one or more “humectant(s)” used to provide a moistening effect.
  • the humectant remains stable in the composition.
  • Any suitable concentration of a single humectant or a combination of humectants can be employed, provided that the resulting concentration provides the desired moistening effect.
  • the suitable amount of humectant will depend upon the specific humectant or humectants employed.
  • Preferred concentration range of a single humectant or the total of a combination of humectants can be from about 0.1 wt. % to about 70 wt. %, more preferably from about 5.0 wt. % to about 30 wt.
  • Non-limiting examples for use herein include glycerin, polyhydric alcohols and silicone oils. More preferably, the humectant is glycerin, propylene glycol and/or cyclomethicone. Specifically, the filler would be glycerine and/or cyclomethicone.
  • the pharmaceutical compositions include a viscosity enhancing agent or an emulsifier.
  • Gelling agents are used to increase the viscosity of the final composition.
  • Emulsifiers are substances that stabilize an emulsion.
  • the viscosity increasing agent can also act as an emulsifying agent.
  • concentration and combination of viscosity increasing agents will depend on the physical stability of the finished product. Preferred concentration range of a viscosity increasing agent can be from about 0.01 wt. % to about 20 wt. %, more preferably from about 0.1 wt. % to about 10 wt. %, more specifically from about 0.5 wt. % to about 5 wt. % of the dermatological composition.
  • Non-limiting examples of viscosity increasing agents for use herein include classes of celluloses, acrylate polymers and acrylate crosspolymers, such as, hydroxypropyl cellulose, hydroxymethyl cellulose, Pluronic PF127 polymer, carbomer 980, carbomer 1342 and carbomer 940, more preferably hydroxypropyl cellulose, Pluronic PF127 carbomer 980 and carbomer 1342, more specifically hydroxypropyl cellulose (Klucel® EF, GF and/or HF), Pluronic PF127, carbomer 980 and/or carbomer 1342 (Pemulen® TR-1, TR-2 and/or Carbopol® ETD 2020).
  • emulsifiers for use herein include polysorbates, laureth-4, and potassium cetyl sulfate.
  • the topical or oral compositions described herein may contain one or more anti-oxidants, radical scavengers, and/or stabilizing agents, preferred concentration range from about 0.001 wt. % to about 0.1 wt. %, more preferably from about 0.1 wt. % to about 5 wt. % of the dermatological composition.
  • Non-limiting examples for use herein include butylatedhydroxytoluene, butylatedhydroxyanisole, ascorbyl palmitate, citric acid, vitamin E, vitamin E acetate, vitamin E-TPGS, ascorbic acid, tocophersolan and propyl gallate. More specifically the anti-oxidant can be ascorbyl palmitate, vitamin E acetate, vitamin E-TPGS, vitamin E or butylatedhydroxy toluene.
  • the topical or oral compositions described herein may also contain preservatives that exhibit anti-bacterial and/or anti-fungal properties.
  • Preservatives can be present in a gelled dermatological composition of the invention to minimize bacterial and/or fungal over its shelf-life.
  • Preferred concentration range of preservatives in a dermatological composition of the invention can be from about 0.001 wt. % to about 0.01 wt. %, more preferably from about 0.01 wt. % to about 0.5 wt. % of the dermatological composition.
  • Non-limiting examples for use herein include diazolidinyl urea, methylparaben, propylparaben, tetrasodium EDTA, and ethylparaben. More specifically the preservative would be a combination of methylparaben and propylparaben.
  • the topical compositions described herein may optionally include one or more chelating agents.
  • chelating agent or “chelator” refers to those skin benefit agents capable of removing a metal ion from a system by forming a complex so that the metal ion cannot readily participate in or catalyze chemical reactions.
  • the chelating agents for use herein are preferably formulated at concentrations ranging from about 0.001 wt. % to about 10 wt. %, more preferably from about 0.05 wt. % to about 5.0 wt. % of the dermatological composition.
  • Non-limiting examples for use herein include EDTA, disodium edeate, dipotassium edeate, cyclodextrin, trisodium edetate, tetrasodium edetate, citric acid, sodium citrate, gluconic acid and potassium gluconate.
  • the chelating agent can be EDTA, disodium edeate, dipotassium edate, trisodium edetate or potassium gluconate.
  • topical or oral compositions described herein may include one or more compatible cosmetically acceptable adjuvants commonly used, such as colorants, fragrances, emollients, and the like, as well as botanicals, such as aloe, chamomile, witch hazel and the like.
  • compatible cosmetically acceptable adjuvants commonly used, such as colorants, fragrances, emollients, and the like, as well as botanicals, such as aloe, chamomile, witch hazel and the like.
  • Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver active compound(s) or prodrug(s).
  • Certain organic solvents such as dimethylsulfoxide (DMSO) may also be employed.
  • compositions described herein may be provided in any cosmetically suitable form, preferably as a lotion, a cream, or a ointment, as well as a sprayable liquid form (e.g., a spray that includes the MrgprX2 antagonist in a base, vehicle or carrier that dries in a cosmetically acceptable way without the greasy appearance that a lotion or ointment would have when applied to the skin).
  • a sprayable liquid form e.g., a spray that includes the MrgprX2 antagonist in a base, vehicle or carrier that dries in a cosmetically acceptable way without the greasy appearance that a lotion or ointment would have when applied to the skin.
  • any suitable amount of a MrgprX2 antagonist e.g., a compound according to the present disclosure
  • a MrgprX2 antagonist e.g., a compound according to the present disclosure
  • the stability is over a prolonged period of time, e.g., up to about 3 years, up to 1 year, or up to about 6 months, which is typical in the manufacturing, packaging, shipping and/or storage of dermatologically acceptable compositions.
  • a compound of the present disclosure can be in solution, partially in solution with an undissolved portion or completely undissolved suspension.
  • a compound of the present disclosure can be present in a dermatological composition of the invention in a concentration range from about 0.001 wt.
  • a compound of the present disclosure can be present in a concentration range of from about 0.001 wt. % to about 10 wt. %, from about 0.1 wt. % to about 10 wt. % or from about 1.0 wt. % to about 5.0 wt. % of the dermatological composition.
  • the topical composition comprising a compound of the present disclosure is preferably administered directly to the affected area of the skin (e.g., the skin that itches) of the human in need thereof.
  • compositions when such compositions are in use (e.g., when a dermatological composition comprising a compound of the present disclosure) and a dermatologically acceptable excipient is placed upon the skin of the human in need thereof, the MrgprX2 antagonist of is in continuous contact with the skin of the patient, thereby effecting penetration and treatment.
  • the skin of the human to be treated can be optionally pre-treated (such as washing the skin with soap and water or cleansing the skin with an alcohol-based cleanser) prior to administration of the dermatological composition of the invention.
  • compositions of the invention may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound(s).
  • the topical composition described herein may also be provided in a patch with the topical composition on the side of the patch that directly contacts the skin. Dermatologically acceptable adhesives may be used to affix the patch to the skin for an extended period of time.
  • the pharmaceutical compositions herein are provided for oral administration.
  • solid, semisolid, or liquid dosage forms for oral administration comprising a compound as described herein.
  • suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, pellets, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, enteric coatings, film costing agents, modified release agents, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
  • pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, enteric coatings, film costing agents, modified release agents, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
  • Binders or granulators impart cohesiveness to a tablet to ensure that the tablet remains intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, ethylcellulose, carboxymethylcellulose, methylcellulose, methyl paraben, polyalkyleneoxides, povidone, polyvinylpyrrolidone (PVP), crospovidones, Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethy
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, trehalose, lysine, leucine, lecithin, starch, kaolin, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.
  • the amount of disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co. of Boston, Mass.); and mixtures thereof.
  • the pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
  • Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-free talc.
  • Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
  • a color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate.
  • Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrolidone.
  • Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil.
  • Organic acids include citric and tartaric acid.
  • Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
  • compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
  • Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
  • Enteric coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • the soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid.
  • liquid, semisolid, and solid dosage forms may be encapsulated in a capsule.
  • suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides.
  • Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil.
  • Emulsions may include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs are clear, sweetened, and hydroalcoholic solutions.
  • Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • a dialkylated mono- or poly-alkylene glycol including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as but
  • compositions provided herein for oral administration may be also provided in the forms of liposomes, micelles, microspheres, or nanosystems.
  • Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
  • compositions provided herein may be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the above dosage forms.
  • compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • the active ingredient(s) i.e., the calcium channel blocker, or L-arginine, or a combination of a calcium channel blocker and L-arginine, or pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof
  • a pharmaceutical composition which is an immediate release oral dosage form, preferably but not necessarily including an enteric coating.
  • the active ingredients(s) are administered in a pharmaceutical composition which is an extended release oral dosage form, preferably but not necessarily including an enteric coating.
  • the active ingredients are administered in a pharmaceutical composition which contains both an immediate release dose and an extended release dose or pulsed release dose of the calcium channel blocker, preferably but not necessarily also including an enteric coating.
  • a pharmaceutical composition which contains both an immediate release dose and an extended release dose or pulsed release dose of the calcium channel blocker, preferably but not necessarily also including an enteric coating.
  • Such dual release dosage forms achieve release of an initial dose of active ingredient, followed late in time by another pulsed release, or by a sustained release dose. Methodologies for preparing such dual release dosage forms are well known in the art.
  • the active ingredients are formulated into a controlled release matrix tablet, which contains one or more polymeric matrix materials that promote the sustained, delayed or pulsed release profile.
  • polymeric matrix materials include cellulosic materials as described above, and carbomers, for example those sold by Lubrizol Corporation under the name Carbopol®, for example Carbopol® 71G NF, Carbopol® 971P NF and Carbopol® 974P NF polymers.
  • extended release compositions suitable for use in the methods and compositions of the invention include, for example and not limitation, extended release compositions found in nifedipine formulations such as Adalat CC®, Procardia® XL, Afeditab® CR and Nifedical® XL; and in diltiazem formulations such as Cardizem® CD, Cardizem® LA, Cardizem® SR, Cartia® XT and Dilacor® XR.
  • nifedipine formulations such as Adalat CC®, Procardia® XL, Afeditab® CR and Nifedical® XL
  • diltiazem formulations such as Cardizem® CD, Cardizem® LA, Cardizem® SR, Cartia® XT and Dilacor® XR.
  • the present disclosure provides pharmaceutical compositions for oral administration, for use in treating the conditions and disorders described herein.
  • compositions provided herein contain therapeutically effective amounts of one or more of the compounds provided herein that are useful in the prevention, treatment, or amelioration of one or more of the symptoms of diseases or disorders described herein and a vehicle.
  • Vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration, preferably topically, orally or via injection.
  • the compounds may be formulated as the sole active ingredient in the composition or may be combined with other active ingredients.
  • the active compound is included in the vehicle in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated.
  • the therapeutically effective concentration may be predicted empirically by testing the compounds in in vitro and in vivo systems well known to those of skill in the art and then extrapolated there from for dosages for humans. Human doses are then typically fine-tuned in clinical trials and titrated to response.
  • the concentration of active compound in the composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of diseases or disorders as described herein.
  • a therapeutically effective dosage should be from about 0.0001 mg to about 1000 mg per day. In some embodiments, 0.001-50 mg of active ingredient (MgrprX2 antagonist as described herein) per kilogram of body weight per day, delivered topically, orally or by injection as descried herein.
  • the MgrprX2 antagonist is administered at a dosage of up to 1500 mg/day, for example 1200 mg/day, 900 mg/day, 850 mg/day, 800 mg/day, 750 mg/day, 700 mg/day, 650 mg/day, 600 mg/day, 550 mg/day, 500 mg/day, 450 mg/day, 400 mg/day, 350 mg/day, 300 mg/day, 250 mg/day, 200 mg/day, 150 mg/day, 1000 mg/day, 50 mg/day, 25 mg/day, 10 mg/day, or 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.75, 0.5, 0.25, 0.10, 0.05 or 0.01 mg/day.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data or subsequent clinical testing. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
  • Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from vehicle or carrier may be prepared. Methods for preparation of these compositions are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975 or later editions thereof.
  • oral dosage forms of the invention that contain the MrgprX2 antagonists of the present disclosure will typically be administered at dosages described above.
  • the daily dose is administered once per day.
  • the dosage form is an extended release composition.
  • the daily dose is administered in a single dose. In other embodiments, the daily dose is administered in smaller increments given multiple times per day, for example twice or three times per day, in amounts that combined equal the daily values above
  • the daily dose is administered in a single dose that provides efficacy for up to 12, up to 18, or up to 24 hours.
  • topical formulations including the compounds of the present disclosure will contain the MgrprX2 antagonist at a concentration of from 0.001% to 20% by weight of the composition, for example 0.001%-10%, for example 0.001%-8%, for example 0.001%-5%, for example 0.001%-4%, for example 0.001%-3%, for example 0.001%-2%, for example 0.001%-1%, by weight of the of the composition.
  • the compounds or derivatives may be packaged as articles of manufacture containing packaging material, a compound or derivative thereof provided herein, which is effective for treatment, prevention or amelioration of one or more symptoms of the diseases or disorders, supra, within the packaging material, and a label that indicates that the compound or composition or derivative thereof, is used for the treatment, prevention or amelioration of one or more symptoms of the diseases or disorders, supra.
  • packaging materials for use in packaging products are well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.
  • packaging materials include, but are not limited to, blister packs, bottles, tubes, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • a wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease or disorder described herein.
  • reaction mixture was washed with sat. aq. NaHCO3, passed through a TELOS phase separator, concentrated under reduced pressure and purified by prep HPLC (Method D) to afford the title compound as a colorless gum (77 mg).
  • Step 1 To tert-butyl (2R)-2-[[5-[(3-fluorophenyl)methyl]thiazol-2-yl]carbamoyl]pyrrolidine-1-carboxylate (Compound E035, 697 mg, 1.67 mmol) was added 4 M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol), and stiffed at RT for 1 hr.
  • Step 2 (2R)—N-[5-[(3-fluorophenyl)methyl]thiazol-2-yl]pyrrolidine-2-carboxamide hydrochloride (Intermediate I01, 77%, 100 mg, 0.225 mmol) was converted to the free base (SCX-2 cartridge, washing MeOH, eluting with 7N NH3/MeOH) and to this was added formaldehyde (37%, 34 ⁇ L, 0.338 mmol) and acetic acid (1.3 ⁇ L, 0.0225 mmol) in DCE (2 mL). This was stirred for 1 hr before the addition of sodium triacetoxyborohydride (72 mg, 0.338 mmol) and the resulting mixture was stirred at 70° C. overnight.
  • Step 1 5-bromothiazol-2-amine hydrobromide (1.00 g, 3.85 mmol) and cesium carbonate (3.13 g, 9.61 mmol) were suspended in acetonitrile (5 mL) and the mixture was warmed to 70° C. A solution of 3-fluorophenol (462 ⁇ L, 5.10 mmol) in acetonitrile (25 mL) was added dropwise over 15 minutes. Upon complete addition the mixture was stirred at 70° C. for 1 hour, then at 60° C. for 16 hours overnight. The mixture was diluted with MeOH (20 mL) and the remaining solids were filtered off and discarded.
  • Step 2 5-(3-fluorophenoxy)thiazol-2-amine (45 mg, 0.214 mmol) was dissolved in DCM (2 mL) and 4-methyloxane-4-carboxylic acid (35 mg, 0.243 mmol) was added, followed by DIPEA (75 ⁇ L, 0.429 mmol) and finally HATU (98 mg, 0.258 mmol). The mixture was stirred at RT for a total of 20 hours and then warmed to 35° C. for 4 hours. Water (2 mL) was added and the organic layer was separated using a Telos phase separator cartridge.
  • Step 1 2,5-difluorobenzaldehyde (0.23 mL, 2.15 mmol) was dissolved in THF-Anhydrous (10 mL) and the reaction was cooled to ⁇ 78° C. 1.6 M butyllithium (1.7 mL, 2.69 mmol) was then added dropwise and after stirring for 15 minutes at ⁇ 78° C., tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate (500 mg, 1.79 mmol) was added and the reaction mixture was continued to be stirred at this temperature for 30 minutes.
  • Step 2 tert-butyl N-[5-[(2,5-difluorophenyl)-hydroxy-methyl]thiazol-2-yl]carbamate (225 mg, 0.644 mmol) was suspended in DCM (5 mL) and 2,2,2-trifluoroacetic acid (0.69 mL, 9.02 mmol) was added (at which point the solution became homogeneous) followed by triethylsilane (0.82 mL, 5.15 mmol) and the reaction was stirred at RT over the weekend.
  • Step 3 4-methyloxane-4-carboxylic acid (25 mg, 0.177 mmol) was dissolved in DCM (2 mL) and N-ethyl-N-isopropyl-propan-2-amine (0.09 mL, 0.53 mmol) was added followed by 1-[bis(dimethylamino)methylidene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (67 mg, 0.177 mmol). After stirring for 10 minutes, 5-[(2,5-difluorophenyl)methyl]thiazol-2-amine (40 mg, 0.177 mmol) was added and the reaction was stirred at RT overnight.
  • reaction mixture was washed with sat. aq. NaHCO 3 , passed through a TELOS phase separator, concentrated under reduced pressure and purified by prep HPLC (Method D) to afford the title compound as a pale pink gum (26 mg).
  • Step 1 A stiffed solution of aqueous ethylamine (70%, 2.1 mL, 25.8 mmol) was cooled to 0° C. and a solution of (2S)-2-methyloxirane (1.00 g, 17.2 mmol) in water (2 mL) was added dropwise. The reaction mixture was allowed to warm up to RT and was stiffed overnight. The reaction mixture was then evaporated to dryness to afford (2S)-1-(ethylamino)propan-2-ol (Intermediate I02) as a colorless liquid (1.55 g).
  • 1H NMR 250 MHz, Methanol-d4) ⁇ 4.00-3.72 (m, 1H), 2.78-2.29 (m, 4H), 1.23-0.98 (m, 6H).
  • Step 2 To a cooled (0° C.) solution of (4-nitrophenyl) carbonochloridate (49 mg, 0.245 mmol) in anhydrous THF (1 mL) was added a solution of 5-[(3-chlorophenyl)methyl]thiazol-2-amine (50 mg, 0.223 mmol) and pyridine (20 ⁇ L, 0.245 mmol) in anhydrous THF (2 mL) and the reaction was warmed up to RT and stirred at this temperature for 1 h.
  • Step 1 To a solution of cesium carbonate (1.46 g, 4.47 mmol) and 3,5-difluorophenol (400 mg, 2.98 mmol) in DMF-Anhydrous (10 mL) was added ethyl 2-chloro-1,3-thiazole-5-carboxylate (629 mg, 3.28 mmol) and the reaction was stirred at 80° C. for 1 hr. Water (50 mL) was added to the reaction which caused solid to crash out. This was isolated by vacuum filtration and oven dried for 1.5 hr to afford ethyl 2-(3,5-difluorophenoxy)thiazole-5-carboxylate (892 mg) as an orange solid.
  • Step 2 To a solution of ethyl 2-(3,5-difluorophenoxy)thiazole-5-carboxylate (850 mg, 2.98 mmol) in THF (23.4 mL) was added 2 M LiOH (3.0 mL, 5.96 mmol) and the reaction mixture was stirred at 40° C. for 3 hr and then stirred at RT overnight. The reaction was concentrated under reduced pressure and to this was added water (20 mL). The reaction mixture was acidified with 2 M HCl, extracted with EtOAc (3 ⁇ 20 mL) and concentrated under reduced pressure to afford 2-(3,5-difluorophenoxy)thiazole-5-carboxylic acid (685.7 mg) as a yellow solid.
  • 1H NMR 500 MHz, DMSO-d6) ⁇ 7.89 (s, 1H), 7.38-7.32 (m, 2H), 7.32-7.26 (m, 1H). (OH not observed).
  • Step 3 To a solution of 2-(3,5-difluorophenoxy)thiazole-5-carboxylic acid (100 mg, 0.389 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.15 mL, 0.855 mmol) in 1,4-Dioxane-Anhydrous (5 mL) was added DPPA (0.10 mL, 0.467 mmol) and the reaction was stirred at RT for 1 hr. To the reaction mixture was added (2S)-1-(ethylamino)propan-2-ol (Intermediate I02, 88%, 91 mg, 0.778 mmol) and stirred at 100° C. for 16 hr.
  • Step 1 To a stirred solution of 3-fluorophenylacetonitrile (1.00 g, 7.40 mmol) in DMF-Anhydrous (10 mL) was added dichloromagnesium (719 mg, 7.40 mmol) followed by sulfanylsodium hydrate (1:1) (1.11 g, 14.8 mmol). The mixture was stirred at RT for a total of 21 hours. The reaction mixture was washed with water and extracted with ethyl acetate (2 ⁇ ). The combined organic layers were washed with water, brine, and dried (hydrophobic filter) and concentrated to dryness under reduced pressure.
  • Step 2 A stirred solution of 2-(3-fluorophenyl)thioacetamide (300 mg, 1.77 mmol) and ethyl 2-chloro-3-oxopropanoate (320 mg, 2.13 mmol) in 1,4-Dioxane (6 mL) was heated to 100° C. for a total of 21 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified (silica gel 60, 10 g cartridge, eluent: acetone-heptane 0-20%) gave ethyl 2-[(3-fluorophenyl)methyl]thiazole-5-carboxylate as an orange liquid (265 mg).
  • Step 3 To a stirred solution of ethyl 2-[(3-fluorophenyl)methyl]thiazole-5-carboxylate (265 mg, 0.999 mmol) in THF (2.5 mL) was added 2 M aqueous lithium hydroxide (1.0 mL, 2.00 mmol) and the mixture was stirred at RT for 3 hours. The reaction mixture was washed with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate (2 ⁇ ).
  • Step 4 To a stirred solution of 2-[(3-fluorophenyl)methyl]thiazole-5-carboxylic acid (146 mg, 0.615 mmol) in tert-butanol (1.5 mL) was added triethylamine (257 ⁇ L, 1.85 mmol) followed by [azido(phenoxy)phosphoryl]oxybenzene (133 ⁇ L, 0.615 mmol) and the reaction mixture heated to 90° C. for 2.5 hours. Further [azido(phenoxy)phosphoryl]oxybenzene (53 ⁇ L, 0.246 mmol) and triethylamine (103 ⁇ L, 0.738 mmol) were added and the mixture was stirred for a further 2.5 hours.
  • Step 5 tert-butyl N-[2-[(3-fluorophenyl)methyl]thiazol-5-yl]carbamate (83 mg, 0.269 mmol) was dissolved and stirred in 4 M 1,4-dioxane hydrochloride (3.4 mL, 13.5 mmol) for 24 hours. The reaction mixture was washed with aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (2 ⁇ ). The combined organic layers were washed with brine, dried (hydrophobic filter) and concentrated to dryness under reduced pressure to give 2-[(3-fluorophenyl)methyl]thiazol-5-amine as a brown syrup (44 mg, 59% yield, 75% purity).
  • Step 6 To a stirred solution of 2-[(3-fluorophenyl)methyl]thiazol-5-amine (22 mg, 0.106 mmol) in THF-Anhydrous (1 mL) was added N,N-dimethylpyridin-4-amine (1.3 mg, 0.0106 mmol) and N-ethyl-N-isopropyl-propan-2-amine (37 ⁇ L, 0.211 mmol) followed by 2-methylpropanoyl 2-methylpropanoate (26 ⁇ L, 0.158 mmol) and the reaction mixture was heated to 80° C. for 3.5 hours.
  • N,N-dimethylpyridin-4-amine 1.3 mg, 0.0106 mmol
  • N-ethyl-N-isopropyl-propan-2-amine 37 ⁇ L, 0.211 mmol
  • 2-methylpropanoyl 2-methylpropanoate 26 ⁇ L, 0.158 mmol
  • Step 1 To a stirred solution of 5-methyl-1,3-thiazole-2-carboxylic acid (500 mg, 3.49 mmol) in DMF-Anhydrous (10 mL) was added dipotassium carbonate (965 mg, 6.99 mmol) followed by iodoethane (309 ⁇ L, 3.84 mmol) and the suspension was stirred at 40 C for 4 h. The reaction mixture was then diluted with water and extracted twice with EtOAc.
  • Step 2 To a stirred solution of ethyl 5-methylthiazole-2-carboxylate (335 mg, 1.96 mmol) in DCE (6 mL) was added 1-bromopyrrolidine-2,5-dione (383 mg, 2.15 mmol) followed by benzoyl benzenecarboperoxoate (75%, 1.3 mg, 3.91 ⁇ mol) and the reaction was heated to 75° C. for 1.5 h. It was then cooled to RT, washed with water and the aqueous layer was extracted with DCM.
  • Step 3 (3-fluorophenyl)boronic acid (180 mg, 1.29 mmol), ethyl 5-(bromomethyl)thiazole-2-carboxylate (70%, 400 mg, 1.12 mmol) and Na2CO3 (475 mg, 4.48 mmol) were suspended in dioxane (8 mL) and the mixture was degassed with N2 for 5 mins. Pd(PPh3)4 (129 mg, 0.112 mmol) was then added and the reaction mixture was stirred in a sealed tube at 100 C for 16 h. It was then cooled to RT, diluted with EtOAc and water and filtered through Celite. The organic layer was separated and the aqueous was extracted twice with EtOAc.
  • Step 4 To a solution of ethyl 5-[(3-fluorophenyl)methyl]thiazole-2-carboxylate (60%, 315 mg, 0.712 mmol) in THF (5 mL) was added 2 M LiOH (0.71 mL, 1.42 mmol) and the reaction mixture was stirred at RT for 1 h. The reaction was concentrated under reduced pressure and to this was added water (5 mL). The reaction mixture was acidified with 2 M HCl to pH 1-2 resulting in precipitation of a grey solid. This was filtered, washed with 2M HCl and air-dried to afford 5-[(3-fluorophenyl)methyl]thiazole-2-carboxylic acid as a grey solid (125 mg).
  • Step 5 To a stirred solution of 5-[(3-fluorophenyl)methyl]thiazole-2-carboxylic acid (95%, 40 mg, 0.160 mmol), and HATU (73 mg, 0.192 mmol) in DMF (1.5 mL) was added N-ethyl-N-isopropyl-propan-2-amine (84 ⁇ L, 0.481 mmol) followed by propan-2-amine (21 ⁇ L, 0.240 mmol) and the resulting reaction mixture was stirred at RT for 1 h. Water was then added (10 mL) resulting in formation of a precipitate.
  • Step 1 Thiourea (1 g, 13.14 mmol) was suspended in EtOH (20 mL) and 1,1-dimethoxy-N,N-dimethylmethanamine (2.1 ml, 15.81 mmol) was added. The mixture was heated to reflux with stirring at 90° C. for 2 hours. After cooling to RT, the resultant precipitate was filtered off, washed with diethyl ether (2 ⁇ 5 mL) and dried in a vacuum oven to afford dimethylaminomethylenethiourea (1.48 g, 86% yield) as a pale yellow crystalline solid.
  • 1H NMR 250 MHz, DMSO-d6) ⁇ 8.61 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 3.13 (s, 3H), 3.02-2.95 (m, 3H).
  • Step 2 Dimethylaminomethylenethiourea (250 mg, 1.91 mmol) and 2-bromo-1-phenylethanone (380 mg, 1.91 mmol) were combined in ethanol (10 mL) and triethylamine (266 ⁇ L, 1.91 mmol) was added. The mixture was heated to reflux at 90° C. for 16 hours overnight. The mixture was concentrated under vacuum and the residue was partitioned between EtOAc (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated and the aqueous was extracted with further EtOAc (3 ⁇ 10 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated under vacuum. It was then loaded on to a SCX column (5 g) and eluted with 7 N NH 3 in MeOH. This was concentrated under reduced pressure to afford 5-benzoyl-1,3-thiazol-2-amine (376 mg) as a brown solid
  • Step 3 N-(5-benzoyl-1,3-thiazol-2-yl)-2-methylpropanamide.
  • 5-benzoyl-1,3-thiazol-2-amine 376 mg, 1.10 mmol
  • DCM 3 mL
  • 2-methylpropanoyl chloride 127 ⁇ L, 1.22 mmol.
  • the reaction mixture was stirred for 1 hr at RT. Upon completion, it was washed with water and passed through a TELOS phase separator and concentrated under reduced pressure.
  • Step 4 N-[5-(1-hydroxy-1-phenyl-ethyl)thiazol-2-yl]-2-methyl-propanamide.
  • N-(5-benzoylthiazol-2-yl)-2-methyl-propanamide 100 mg, 0.365 mmol
  • MeMgBr 0.46 mL, 0.73 mmol
  • MeMgBr 0.46 mL, 0.73 mmol
  • Step 5 N-[5-(1-hydroxy-1-phenyl-ethyl)thiazol-2-yl]-2-methyl-propanamide (37 mg, 0.127 mmol) was dissolved in 2,2,2-trifluoroacetic acid (1.0 mL, 13.5 mmol) and the reaction was heated to 80° C. for 5 minutes. Solvent was removed under reduced pressure and the resulting residue was dissolved in IPA (5 mL). Ammonium formate (80 mg, 1.27 mmol) and palladium on carbon (10%) (14 mg, 0.0127 mmol) were added and the reaction was heated to 80° C. for 16 h.
  • 2,2,2-trifluoroacetic acid 1.0 mL, 13.5 mmol
  • Step 1 4-aminothiophene-2-carboxylic acid (100.0 mg, 0.7 mmol), 1-[bis(dimethylamino)methylidene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (265.6 mg, 0.7 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.24 mL, 1.40 mmol) were mixed in Acetonitrile (4 mL) followed by phenylmethanamine (0.23 mL, 2.1 mmol) and stiffed at RT overnight. Solvents were removed in vacuo, and the crude reaction mixture purified using prep HPLC (Method G) to afford 4-amino-N-benzyl-thiophene-2-carboxamide (110 mg) as a yellow oil.
  • Method 1 4-aminothiophene-2-carboxylic acid
  • Step 2 4-amino-N-benzyl-thiophene-2-carboxamide (85.0 mg, 0.18 mmol) was dissolved in THF (5 mL), mixed with N-ethyl-N-isopropyl-propan-2-amine (0.064 mL, 0.366 mmol), N,N-dimethylpyridin-4-amine (22 mg, 0.183 mmol) and 2-methylpropanoyl 2-methylpropanoate (43 mg, 0.274 mmol) and stirred in a sealed vial at 80° C. for 18 hours.
  • UV spectra were recorded at 215 nm using a Waters Acquity PDA detector spectrum range: 200-400 nm, ELS data was collected using a Water Acquity ELS detector (where fitted) were reported. Mass spectra were obtained using a Waters SQD (MSQ1) or Waters Acquity QDA (MSQ2). Data were integrated and reported using Waters MassLynx and OpenLynx software.
  • Potent and selective hMrgpMRGPRX2 compounds have been generated from compounds identified during a high throughput screening (HTS) campaign and followed up with cycles of structure activity based medicinal chemistry efforts. These compounds were characterized in recombinant hMrgpMRGPRX2 expressing cells for their antagonist activity and the potency was confirmed in the human mast cell line LAD-2, where the target is endogenously expressed.
  • the assays used to determine potencies are functional read-out looking at intracellular calcium mobilization using the FLIPRTM technology.

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