WO2017001434A1 - Composés de type antagonistes des récepteurs du cgrp pour traitement par voie topique de maladies de la peau - Google Patents

Composés de type antagonistes des récepteurs du cgrp pour traitement par voie topique de maladies de la peau Download PDF

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WO2017001434A1
WO2017001434A1 PCT/EP2016/065063 EP2016065063W WO2017001434A1 WO 2017001434 A1 WO2017001434 A1 WO 2017001434A1 EP 2016065063 W EP2016065063 W EP 2016065063W WO 2017001434 A1 WO2017001434 A1 WO 2017001434A1
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compound
rosacea
acne
skin
use according
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PCT/EP2016/065063
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Christelle Nonne
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Galderma Research & Development
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents

Definitions

  • the present invention relates to the use of CGRP receptor antagonist compounds and the pharmaceutical compositions comprising such compounds in dermatological field.
  • CGRP is broadly expressed in the central and peripheral nervous system and is involved in various biological functions. There are more and more evidence that CGRP play a key role as neuromodulator, but it is mostly known as a strong vasodilatator. CGRP activates a heterodimer receptor (CGRP-R) composed of a class B protein-G coupled receptor (CLR or calcitonin-like receptor)) associated with a transmembrane protein modifying the receptor activity (RAMP1 or receptor activity- modifying protein 1).
  • CLR class B protein-G coupled receptor
  • RAMP1 or receptor activity- modifying protein 1 transmembrane protein modifying the receptor activity
  • Many studies have been done on CGRP role and CGRP receptor activity. For instance studies have demonstrated that migraine attack was associated to the release of CGRP by meningeal nociceptors of the trigeminal ganglion and that CGRP could play a key role in migraine attack.
  • CGRP release by face trigeminal nerves could be involved in neurogenic inflammation responsible especially of permanent erythema in type I rosacea. This hypothesis is done knowing that rosacea and migraine are sharing common characteristics such as a neurogenic component with vasodilation phenomenon, the activation of trigeminal nervous system and the release of neuro-inflammatory peptides (CGRP, P substance). CGRP would have its vasodilatator action by acting through smooth muscle cells and sub-cutaneous vessels.
  • telcagepant ([N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-l-(2,2,2- trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-lH-imidazo [4,5-b]pyridin-l-yl)piperidine- 1-carboxamide] also named telcagepant or MK-094 developed by Merck & Co, was the first orally bioavailable CGRP receptor antagonist tested in the clinic with a triptan-like efficacy for the acute treatment of migraine. Because of various toxic effects observed in patients during the clinical development of telcagepant, especially hepatotoxicity, its development has been discontinued.
  • Inflammatory skin diseases relate to skin diseases associated with inflammatory component. There are different types of inflammatory skin disease, classified by their localization, their causes and their symptoms. These skin disorders are common but their diagnosis can be difficult. Indeed, the skin immune system have limited way to respond to internal and external stimuli and many diseases present an inflammatory profile with few distinctive characteristics.
  • Rosacea is a common chronic and progressive inflammatory dermatosis associated with vascular relaxation. Rosacea affects principally central part of the face and is characterized by facial flushes, facial erythema, papules, pustules, telangiectasia and sometimes ocular lesions and rhinophyma. Moreover these primary features are associated with a secondary neurogenic component, more specifically to a cutaneous hyperreactivity of face and neck skin, characterized by the apparition of skin redness, prurit, feelings of itching, burning, stinging, and rough, flaky skin sensations.
  • Rosacea is classified into four subtypes according to the degree of primary features, such as vasomotor flushing, persistent erythema, papules and pustules, telangiectasias:
  • Erythematotelangiectatic rosacea is mainly characterized by vasomotor flushing and persistent central facial erythema (redness). Telangiectasias (visible blood vessels) are commonly observed but are not essential for the diagnosis of this subtype. Central facial edema, burning or stinging sensations and rough, flaky skin are also symptoms that have sometimes been reported. A history of flushing as the only symptom is commonly found in people with erythematotelangiectatic rosacea. Facial flushing is due to the sudden dilatation of the arterioles of the face (which then takes a red appearance) and may be triggered by emotional stress, hot drink, alcohol, spicy food or temperature changes.
  • Papulopustular rosacea is characterized by persistent central facial erythema and transient inflammatory crops of papules and/or pustules in the center of the face. However, the papules and pustules can also occur in periorificial regions, i.e., around the mouth, nose and eyes.
  • the papulopustular subtype resembles acne vulgaris but comedones (specific of acne) are absent in rosacea. Rosacea and acne may coexist in a same patient, in which case comedones may also be present alongside the papules and pustules suggestive of rosacea. People with papulopustular rosacea sometimes complain of a burning or stinging sensation.
  • PPR is also characterized by the presence of inflammatory infiltrates that accompany flares, along with a heightened immune response involving neutrophilic infiltration and increased gene expression of IL8. This subtype is often observed after or at the same time as ETR (including the presence of telangiectasias).
  • Phymatous rosacea is characterized by a thickening of the skin, irregular surface nodularities and swelling. Patients with this subtype sometimes exhibit prominent, enlarged follicles as well as telangiectasias in the affected areas. The nose is most commonly affected (“rhinophyma”) but phymatous rosacea can also involve other areas such as the chin, the forehead, the cheeks and the ears. This subtype essentially affects men and often occurs after or at the same time as ETR or PPR.
  • Ocular rosacea (or ophthalmic rosacea) exhibits symptoms restricted to the ocular area with blepharitis, conjunctivitis and keratitis. It is characterized by watery or bloodshot eyes (interpalpebral conjunctival hyperemia), foreign body sensation, burning or stinging, dry or itchy eyes, sensitivity to light, blurred vision, conjunctival telangiectasias or eyelid margin telangiectasias or erythema of the eyelid and periocular area. They can occur with or without rosacea. The onset may occur before, during or after the onset of skin lesions.
  • rosacea The pathogenesis of rosacea is complex and not yet completely understood. Its etiology is multifactorial. In addition to exogenous factors (including UV light, temperature changes, alcohol, hormonal or emotional factors), it may be due to a higher density of Demodex folliculorum mites in rosacea patients. Such factors activate neurovascular and/or immune responses, and consequently inflammatory cascades. Intermittent flares may contribute to the chronicity of rosacea as they are associated with prolonged vasodilation, perivascular inflammation, edema and exposure to cytokines and cellular infiltrates. Moreover, many people who get rosacea have family history of the disease, suggesting a possible role of genetic.
  • Typical treatment of rosacea include oral or topical administration of antibiotics such as tetracycline, erythromycin, clindamycin, but also metronidazole (an antibacterial agent), low dose of isotretinoin in severe forms or even anti-infectious agents such as azelaic acid.
  • antibiotics such as tetracycline, erythromycin, clindamycin, but also metronidazole (an antibacterial agent), low dose of isotretinoin in severe forms or even anti-infectious agents such as azelaic acid.
  • metronidazole an antibacterial agent
  • isotretinoin in severe forms or even anti-infectious agents such as azelaic acid.
  • these treatments do not allow treating and/or preventing efficiently all the symptoms associated with rosacea, especially, the neurogenic component such as the skin hyperreactivity and redness.
  • atopic dermatitis, psoriasis and acne belong to the most frequent inflammatory skin diseases.
  • Dermatitis derives from Greek language with "derma” meaning skin and "itis” meaning inflammation. Thus, dermatitis corresponds to skin inflammation that is classified in several specific and distinct types of dermatitis according to the localization, causes and symptoms thereof.
  • Non exhaustive examples of dermatitis are atopic dermatitis, contact dermatitis, herpetiformis dermatitis, acrodermatitis, exfoliative dermatitis, perioral dermatitis, seborrheic dermatitis, eczema, hand eczema.
  • Atopic dermatitis is a condition of the epidermis which affects a large number of individuals genetically predisposed to atopy, including infants, children and pregnant women.
  • Atopic dermatitis is an increasingly common pruritic inflammatory skin disorder due to complex interactions between the genetic predispositions and environmental factors.
  • Atopic dermatitis has a complex etiology that involves abnormal immunological and inflammatory pathways that include defective skin barrier, exposure to environmental agents and neuropsychological factors.
  • the diagnosis of atopic dermatitis is based on clinical presentation of skin erythematous plaques, eruption, and/or lichenification, typically in flexural areas accompanied by intense pruritus and cutaneous hypersensitivity.
  • Pathological examination reveals spongiosis, hyperkeratosis and parakeratosis in acute lesions and marked epidermal hyperplasia, acanthosis, and perivascular accumulation of lymphocytes and mast cells (mastocytes) in chronic lesions.
  • atopic dermatitis has at least two major components corresponding to a damaged skin barrier and a deregulated immune response.
  • atopic dermatitis such as dry skin, erythematous plaques, eruption, lichenification, intense pruritus or cutaneous hypersensitivity and, to a greater extent, to compensate for the epithelial barrier deficiency.
  • pyrrolidone carboxylic acid Teakaoka, JP2004168763
  • citrulline or certain amino acids such as glycine, methionine and alanine
  • glycine, methionine and alanine Harmono et al., WO2005/077349
  • Tezuka (JP08020525) has proposed shampoos containing a complex of sodium montmorillonite with a moisturizing agent, which itself can be urea, amino acids, proteins, proteins, pyrrolidone carboxylic acid or a silk protein hydrolysate.
  • a moisturizing agent which itself can be urea, amino acids, proteins, proteins, pyrrolidone carboxylic acid or a silk protein hydrolysate.
  • Natural or synthetic immune inhibitors, anti-histamine agents, and steroids have also been used in pharmaceutical compositions in order to treat dermatitis atopic by reducing IgE production with the aim to reduce the immune response.
  • cyclosporin A holds the limelight as immune inhibitors or calcineurin inhibitor and is marked by Novartis under the name Sandimmun®.
  • the conventional treating agents for atopic dermatitis using steroid and anti-histamine agents can only temporarily relieve symptoms.
  • Psoriasis is an inflammatory skin disease characterized by red, itchy and scaly skin patches covered with white scales on top with a varying severity. These patches are mostly localized on the knees, elbows, scalp, and on lower back but can also affect other parts of the body. In this pathology, skin cells are quickly multiplied and then accumulated to form psoriatic patches. Psoriasis is characterized by an abnormally excessive and rapid growth of the epidermal skin cells which are replaced every 3-5 days rather than between 28-30 days in normal skin. This abnormal production of skin cells is thought to be due to premature maturation of keratinocytes induced by an inflammatory cascade in the dermis involving dendritic cells, macrophages and T cells.
  • Psoriasis pathology is multifactorial, with genetic pre-dispositions triggered by many environmental factors such as, stress, tobacco, alcohol, interruption of corticosteroids etc.
  • the current available treatments permit mostly to control the symptoms with a limited efficacy and may be use only during short time periods.
  • topical treatments with corticosteroids, or with vitamin D3 analogous, retinoids, fluocinonides etc.
  • these treatments are not really efficient and generate several side effects when used during a long time period such as skin irritations and a pathology aggravation after treatment interruption.
  • This disease affects 2-4% of the population without gender distinction.
  • Acne is also one of the most common inflammatory skin diseases. It is characterized by areas of skin with seborrhea (scaly red skin) and different types of lesions.
  • acne lesions may be divided into non-inflammatory lesions (microcomedones, open and closed comedones), inflammatory lesions (papules, pustules, nodules, cysts) and possibly residual lesions or scarring (atrophic, hypertrophic and keloid scars). Lesions are most likely to occur on the face, neck, chest, shoulders and back, where there is a higher concentration of pilosebaceous units.
  • acne vulgaris commonly referred as "acne” or polymorphic juvenile acne
  • acne is the most common form and starts at puberty. This type of acne can be divided into mild, moderate, moderately severe and severe acne.
  • Conventional treatments for treating acne include topical retinoids which reduce comedone formation and inflammatory response, topical or systemic antibiotics (such as erythromycin, clindamycin and tetracyclines) which aim is to reduce bacteria population and inflammation, benzoyl peroxide (BPO) which is both anti-bacterial and midly comedolytic.
  • topical or systemic antibiotics such as erythromycin, clindamycin and tetracyclines
  • BPO benzoyl peroxide
  • Using multiple agents (combined therapy) has been recommended to target as many pathophysiologic factors of acne.
  • Oral isotretinoin which targets all the pathophysiological factors involved in acne, is used in most severe and refractory cases because of serious side effects (such as teratogenicity or depression).
  • these available therapies are harsh on the skin and can cause dryness, irritation, or redness.
  • the invention provides a safe treatment to discontinue or decrease skin inflammation, especially linked to a neurogenic inflammation.
  • the invention provides a long-term effect with limited toxic effects especially regarding hep ato toxicity.
  • CGRP antagonist compounds have been described by Merck & Co in EP1 638 969 Bl, as orally bioavailable drugs useful for treating acute migraine. These compounds are derived from benzodiazepine lead compound, optimized for leading to potent CGRP receptor antagonist compounds.
  • CGRP receptor antagonist compounds of family (I) can be effective for treating and/or preventing inflammatory skin pathologies with a neurogenic component by topical application. More specifically, compounds of formula (I), particularly telcagepant (MK-094) can be effective for treating and/or preventing skin inflammatory rosacea, especially type I rosacea, atopic dermatitis, psoriasis and/or acne by topical application.
  • compounds of formula (I) particularly telcagepant (MK-094) can be effective for treating and/or preventing skin inflammatory rosacea, especially type I rosacea, atopic dermatitis, psoriasis and/or acne by topical application.
  • the topical application of MK094 allows to decrease the blood vessel dilation by a significant reduction of the blood perfusion with a dose and time dependant manner. Therefore the topical application of compound of formula (I) such as MK094 is useful for treating and/or preventing type I erythema characterized by erythema and skin flushing induced by excessive blood vessel dilatation.
  • the present invention relates to CGRP receptor antagonist compound of formula (I) for topical application. More specifically the present invention relates to CGRP receptor antagonist compound of formula (I) for topical application for treating and/or preventing inflammatory skin pathologies with a neurogenic component.
  • the present invention relates to CGRP receptor antagonist compound of formula (I) for topical application for treating and/or preventing rosacea, atopic dermatitis, psoriasis, and/or acne.
  • the CGRP receptor antagonist compound useful for the present invention is a compound of formula (I).
  • This invention is also directed to a pharmaceutical composition for topical application, comprising at least one CGRP receptor antagonist compound of formula (I) and a pharmaceutically acceptable vehicle for the treatment and/or the prevention of skin inflammatory pathologies with a neurogenic component and especially rosacea, atopic dermatitis, psoriasis and/or acne.
  • CGRP receptor antagonist compound of formula (I) for treating and/or preventing skin inflammatory disorders with a neurogenic component allows to obtain a significant biological activity of CGRP receptor antagonist and a significant skin bioavailability with a significant hepatic metabolism instability allowing to avoid the toxic side effects observed by oral route.
  • the present application concerns CGRP receptor antagonist compounds of formula (I) for treating and/or preventing skin inflammatory pathologies with a neurogenic component, by topical application. More specifically the present invention concerns CGRP receptor antagonist compounds of formula (I) for treating and/or preventing rosacea, atopic dermatitis, psoriasis, and/or acne by topical application.
  • telcagepant MK-094 is the preferred compound.
  • the present invention is also directed to a pharmaceutical composition for topical application, comprising at least one CGRP receptor antagonist compound of formula (I) and a pharmaceutically acceptable vehicle for the treatment and/or the prevention of skin inflammatory pathologies with a neurogenic component, and especially rosacea, atopic dermatitis, psoriasis, and/or acne.
  • a pharmaceutical composition for topical application comprising at least one CGRP receptor antagonist compound of formula (I) and a pharmaceutically acceptable vehicle for the treatment and/or the prevention of skin inflammatory pathologies with a neurogenic component, and especially rosacea, atopic dermatitis, psoriasis, and/or acne.
  • the present invention is directed to the use of a CGRP receptor antagonist of formula (I) for the manufacture of a medicament destined to treat and/or prevent skin inflammatory pathologies with a neurogenic component by topical application.
  • Another aspect of the invention is directed to a process for treating and/or preventing skin inflammatory pathologies with a neurogenic component, comprising the topical administration of at least one compound of formula (I).
  • the present invention is further directed to a method for the manufacture of a medicament comprising at least a compound of formula (I) with a pharmaceutical carrier or diluent for treating and/or preventing skin inflammatory pathologies with a neurogenic component and more especially type I rosacea, atopic dermatitis, psoriasis, and/or acne.
  • the present invention also relates to a method for treating and or preventing skin inflammatory pathologies with a neurogenic component and more especially type I rosacea, atopic dermatitis, psoriasis, and/or acne, by topical administration of a composition comprising the compound of formula (I) and more precisely MK094.
  • compounds for use in topically treating and/or preventing a skin inflammatory pathology with a neurogenic component are compounds of formula (I):
  • R is selected from:
  • the compounds of formula (I) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention.
  • the compounds of formula (I) and their isomeric forms are useful according the present invention. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art.
  • Racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • Halo or halogen as used herein are intended to include chloro, fluoro, bromo and iodo.
  • alkyl is intended to mean linear or branched structures having no carbon-to-carbon double or triple bonds.
  • Cl-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that Cl-6alkyl specifically includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, tert-butyl, pentyl and hexyl.
  • Cycloalkyl is an alkyl, part or all of which which forms a ring of three or more atoms.
  • aryl is intended to mean mono- or bi-cycle with 6 to 12 atoms of carbon of formula C n H( n-2 ).
  • heterocycloalkyl is a cycloalkyl group as defined herein, comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • CGRP receptor antagonist compounds of formula (I) are described by Merck & Co in EP1 638 969 Bl at page 11 to page 29, more specifically by examples 1 to 9 and in table E-4.
  • pharmaceutically acceptable vehicle refers to a vehicle appropriated for topical application, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives wherein the parent compound is modified by making acid or base salts thereof.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • salts may be prepared from pharmaceutically acceptable nontoxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • the salts are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of formula (I) are meant to also include the pharmaceutically acceptable salts.
  • compounds for treating and/or preventing skin inflammatory pathology with a neurogenic inflammation are compounds of formula (I):
  • R is selected from: -CH2CF3, -CH2CH2F, -CH2CHF2, -CH2CH2CF3 and pharmaceutically acceptable salts and individual stereoisomers thereof.
  • the preferred CGRP receptor antagonist is compound of formula (I) for treating and/or preventing skin inflammatory pathologies with a neurogenic inflammation wherein R is -CH2CF3.
  • CGRP receptor antagonist compound of formula (I) for treating and/or preventing skin inflammatory pathologies with a neurogenic inflammation is Telcagepant (MK-094) and its pharmaceutically acceptable salts and individual stereoisomers thereof.
  • telcagepant MK094
  • telcagepant MK094
  • MK094 having the following chemical name: [N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo- 1 -(2,2,2- trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-l-yl)piperidine- 1-carboxamide] and the CAS registry number 781649-09-0.
  • pharmaceutical composition refers preferably to a dermatological composition which can be topically applied. More specifically “pharmaceutical composition” relates to a pharmaceutical composition comprising a CGRP receptor antagonist compound of formula (I) and a vehicle suitable for a topical application, for the treatment and/or the prevention of skin inflammatory pathology with a neurogenic component. Telcagepant being the preferred CGRP receptor antagonist compound of formula (I) and rosaea, especially type I rosacea being the preferred skin inflammatory pathology with a neurogenic component.
  • CGRP receptor antagonist compounds of formula (I), preferably telcagepant, and the form of the pharmaceutical composition for the treatment and/or the prevention of a particular skin inflammatory pathology with a neurogenic component can be made depending on the type and severity of the pathology, location of the affected area, and form of the pharmaceutical composition. A person of ordinary skill in the art will be able to determine these different parameters.
  • the choice of the concentration of CGRP receptor antagonist compounds of formula (I), preferably MK-094, and the form of the pharmaceutical composition for the treatment and/or the prevention of a particular skin inflammatory pathology with a neurogenic component can be made depending on the type and severity of the pathology, location of the affected area, and form of the pharmaceutical composition. A person of ordinary skill in the art will be able to determine these different parameters.
  • the compound of formula (I) and especially MK-094 can be used in a composition from 0.001 to 10 , preferentially from 0.001 to 5 , more preferentially from 0.3 to 3 , and even more preferentially at 3 % relative to the total weight of the composition.
  • the pharmaceutical composition is advantageously administered by topical application and, therefore, is in a form suitable for topical application to the skin.
  • it may be in the form of an optionally gelled, oily solution, an optionally two-phase dispersion of the lotion type, an emulsion obtained by dispersion of a fatty phase in an aqueous phase (OAV) or vice versa (W/O), or a triple emulsion (W/OAV or 0/W/O) or a vesicular dispersion of ionic and/or non-ionic type.
  • This topical composition may be in anhydrous form, in aqueous form or in the form of an emulsion.
  • a composition in the form of an emulsion obtained by dispersion of a fatty phase in an aqueous phase is preferably used.
  • This composition may be more or less fluid and may be in the form of salves, emulsions, creams, milks, ointments, impregnated pads, syndets, solutions, gels, sprays or aerosols, foams, suspensions, lotions or sticks.
  • the composition used in the present invention is in the form of an emulsion, of a cream, of a lotion type, of a gel, or of a solution, and more preferably in the form of an emulsion.
  • the pharmaceutical composition according to the present invention can be administered in combination with, or comprise an additional active ingredient or additive.
  • the additional active ingredient is preferably selected from the group comprising antibiotics, antibacterial, antivirrals, antiparasitics, antifungals, anesthetics, analgesics, antiallergic agents, retinoids, free-radical scavengers, anti-pruriginous, the keratolytic agents, antiseborrheic, antihistaminic, sulfides, immunosuppressant products and antiproliferative agents, corticosteroids, intravenous immunoglobulin, anti-angiogenic, antiinflammatory and/or a mixture thereof.
  • the additive is preferably selected from the group consisting of sequestering agents, chelating agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, dyes, conventional acids, or bases, organic or inorganic, perfumes, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, soothing and protective agents of the skin, penetrating agents, emulsifiers, gelling agents and a mixture thereof.
  • treatment refers to an improvement, the prophylaxis of a disease or disorder, or at least one symptom can be discerned therefrom.
  • treatment or “treating” means an improvement, prevention of at least one measurable physical parameter associated with the disease or disorder being treated, which is not necessarily discernible in the subject.
  • treatment or “treating” refers to inhibiting or slowing the progression of a disease or disorder, physically, e.g., stabilization of a discernible symptom, physiologically, for example, stabilization of a physical parameter, or both.
  • treatment or “treating” refers to delaying the onset of a disease or disorder.
  • compounds of interest are administered as a preventive measure.
  • prevention or “preventing” refers to a reduction in the risk of acquiring a disease or disorder specified.
  • the present invention is directed to any mammal, particularly humans, male or female.
  • skin inflammatory pathologies with a neurogenic component refers to skin inflammatory pathologies with a neurogenic component chosen among type I erythematous rosacea, type II papulopustular rosacea, atopic dermatitis, hand chronic eczema, psoriasis (vulgaris, scalp, arthritic, pustular, guttate), facial erythema, pudic erythema, hives, utricaria (acute, chronic), any kind of pruritus (for instance senile pruritus, prurigo nodularis) and acne.
  • a neurogenic component chosen among type I erythematous rosacea, type II papulopustular rosacea, atopic dermatitis, hand chronic eczema, psoriasis (vulgaris, scalp, arthritic, pustular, guttate), facial erythema, pudic erythema, hives, u
  • the skin inflammatory pathologies with a neurogenic component are chosen among type I erythematous rosacea, atopic dermatitis, vulgaris and scalp psoriasis, prurit senile, acne and prurigo nodularis.
  • the skin inflammatory pathology with a neurogenic component according to the present invention is rosacea and especially type I erythemateous rosacea, atopic dermatitis, psoriasis, and/or acne.
  • Type I erythemateous rosacea is mainly characterized by vasomotor flushing and persistent central facial erythema (redness) and telangiectasias (visible blood vessels). Central facial edema, burning or stinging sensations and rough, flaky skin are also symptoms that have sometimes been reported. Flushing is the only symptom commonly found in people with type I erythemateous rosacea. Facial flushing is due to the sudden dilatation of the arterioles of the face (which then takes a red appearance) and may be triggered by emotional stress, hot drink, alcohol, spicy food or temperature changes.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de type antagoniste des récepteurs du CGRP de formule (I) pour application topique destiné au traitement et/ou à la prévention de pathologies inflammatoires de la peau présentant une composante neurogène. Plus spécifiquement, la présente invention concerne un composé de type antagoniste des récepteurs du CGRP de formule (I) pour application topique destiné au traitement et/ou à la prévention de la rosacée et en particulier de la rosacée de type I, de la dermatite atopique, du psoriasis et/ou de l'acné. Le composé préféré selon la présente invention est : [N-[(3R,6S)-6-(2,3-Difluorophényl)-2-oxo-1-(2,2,2-trifluoroéthyl)azépane-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)pipéridine-1-carboxamide], également connu sous le nom de telcagepant.
PCT/EP2016/065063 2015-06-29 2016-06-28 Composés de type antagonistes des récepteurs du cgrp pour traitement par voie topique de maladies de la peau WO2017001434A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018236873A1 (fr) * 2017-06-19 2018-12-27 President And Fellows Of Harvard College Méthodes et compositions pour le traitement d'une infection microbienne
WO2023034467A3 (fr) * 2021-09-02 2023-04-13 Pfizer Ireland Pharmaceuticals Antagonistes du cgrp pour traiter des affections cutanées

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0734729A1 (fr) * 1995-03-28 1996-10-02 L'oreal Utilisation d'un antagoniste de CGRP pour traiter les rougeurs cutanées d'origine neurogène et composition obtenue
US20010051157A1 (en) * 1995-01-26 2001-12-13 Lionel Breton Therapeutic/cosmetic compositions comprising cgrp antagonists for treating sensitive human skin
WO2004014351A2 (fr) * 2002-08-12 2004-02-19 Birkir Sveinsson Utilisation de composes antagonistes du cgrp pour le traitement du psoriasis
WO2004092166A2 (fr) * 2003-04-15 2004-10-28 Merck & Co., Inc. Antagonistes des recepteurs cgrp
WO2010002763A1 (fr) * 2008-06-30 2010-01-07 Merck & Co., Inc. Formes pharmaceutiques posologiques solides telcagepant potassique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010051157A1 (en) * 1995-01-26 2001-12-13 Lionel Breton Therapeutic/cosmetic compositions comprising cgrp antagonists for treating sensitive human skin
EP0734729A1 (fr) * 1995-03-28 1996-10-02 L'oreal Utilisation d'un antagoniste de CGRP pour traiter les rougeurs cutanées d'origine neurogène et composition obtenue
WO2004014351A2 (fr) * 2002-08-12 2004-02-19 Birkir Sveinsson Utilisation de composes antagonistes du cgrp pour le traitement du psoriasis
WO2004092166A2 (fr) * 2003-04-15 2004-10-28 Merck & Co., Inc. Antagonistes des recepteurs cgrp
WO2010002763A1 (fr) * 2008-06-30 2010-01-07 Merck & Co., Inc. Formes pharmaceutiques posologiques solides telcagepant potassique

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018236873A1 (fr) * 2017-06-19 2018-12-27 President And Fellows Of Harvard College Méthodes et compositions pour le traitement d'une infection microbienne
US11400136B2 (en) 2017-06-19 2022-08-02 President And Fellows Of Harvard College Methods and compositions for treating a microbial infection
WO2023034467A3 (fr) * 2021-09-02 2023-04-13 Pfizer Ireland Pharmaceuticals Antagonistes du cgrp pour traiter des affections cutanées

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