Nova Patents
EP2649984A1

Compounds which inhibit neuronal exocytosis

Abstract

Compounds of general formula (I):          R1-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-R2     (I) their stereoisomers, mixtures thereof, their cosmetically or pharmaceutically acceptable salts and/or its functionally equivalent variants, preparation processes, cosmetic or pharmaceutical compositions which contain them and their use in medicine, particularly in the treatment and/or prevention of pain, inflammation, itching, neurological, compulsive and/or neuropsychiatric diseases and/or disorders and in processes of treatment and/or care of the skin, hair and/or mucous membranes mediated by neuronal exocytosis.

EP2649984A1, drawing sheet 1
Sheet 1 of 46

Term

Projected expiry 13 April 2032.

  1. Priority and filed
  2. Published
  3. Today
  4. Projected expiry

15 claims: 8 independent, 7 dependent

  1. 1
    A compound of general formula (I):R1-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-R2     (I) their stereoisomers, mixtures thereof, their cosmetically or pharmaceutically acceptable salts and/or its functionally equivalent variants, characterized in that: AA1 is selected from the group formed by -Arg-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;AA2 is selected from the group formed by -His-, -Lys- and -Asp-;AA3 is selected from the group formed by -Leu-, -Ile-, -Met-, -MetO-, -MetO2- and -Phe-;AA4 is selected from the group formed by -Ala- and -Asp-;AA5 is selected from the group formed by -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;AA6 is selected from the group formed by -Met-, -MetO-, -MetO2-, -Tyr- and -Trp-;W, X, Y, Z are amino acids and are independently selected from amongst themselves;n, m, p and q are independently selected from amongst themselves and have a value of 0 or 1;n+m+p+q is smaller or equal to 2;with the condition that if AA1 is -Gln-, AA2 is -Asp-, AA3 is -Ile-, AA5 is -Arg- and AA6 is -Tyr-, then AA4 is -Asp-;with the condition that if AA1 is -Gln-, AA2 is -Asp-, AA3 is -Ile-, AA5 is -Arg- andAA6 is -Trp-, then AA4 is -Ala-;with the condition that if X is -Leu-, AA1 is -Glu-, AA2 is -Lys-, AA3 is -Phe-, AA5 is -Glu-, AA6 is -Tyr- and n+p+q is 0, then AA4 is -Asp-;with the condition that if X is -Gly-, AA1 is -Asp-, AA2 is -His-, AA3 is -Leu-, AA5 is -Arg- and AA6 is -Met-, then AA4 is -Ala-;with the condition that if W is -Tyr-, X is -Thr-, AA1 is -Asp-, AA2 is -Lys-, AA3 is -Ile-, AA5 is -Arg- and AA6 is -Tyr-, then AA4 is -Ala-;with the condition that if X is -Ser-, AA1 is -Glu-, AA2 is -Lys-, AA3 is -Leu-, AA5 is -Gln-, AA6 is -Trp- and Y is -Leu-, then AA4 is -Ala-;with the condition that if X is -Asn-, AA1 is -Arg-, AA2 is -Asp-, AA3 is -Leu-, AA5 is -Arg-, AA6 is -Met- and Y is -Ala-, then AA4 is -Asp-;with the condition that if AA1 is -Gln-, AA2 is -Asp-, AA3 is -Met-, AA5 is -Asn-, AA6 is -Trp-, Y is -Val- and Z is -Met-, then AA4 is -Asp-;and with the condition that if AA1 is -Lys-, AA2 is -Lys-, AA3 is -Leu-, AA4 is -Ala-, AA5 is -Lys- and AA6 is -Met-, then n+m+p+q is smaller than 2;R1 is selected from the group formed by H, a polymer derived from polyethylene glycol, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R5-CO-, wherein R5 is selected from the group formed by H, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heteroarylalkyl;R2 is selected from the group formed by -NR3R4, -OR3 and -SR3, wherein R3 and R4 are independently selected from the group formed by H, a polymer derived from polyethylene glycol, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl;and R1 and R2 are not α-amino acids.
  2. 7
    Cosmetic or pharmaceutical composition which comprises at least one compound of general formula (I), their stereoisomers, mixtures thereof, their cosmetically or pharmaceutically acceptable salts and/or its functionally equivalent variants, according to any of claims 1 to 6, together with at least one cosmetically or pharmaceutically acceptable excipient or adjuvant.
  3. 9
    Composition according to any of claims 7 to 8, wherein this composition is presented in a formulation selected from the group formed by creams, multiple emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balsams, foams, lotions, gels, cream gels, hydroalcoholic solutions, hydroglycolic solutions, hydrogels, liniments, sera, soaps, shampoos, conditioners, serums, polysaccharide films, ointments, mousses, pomades, powders, bars, pencils, sprays, aerosols, capsules, gelatin capsules, soft capsules, hard capsules, tablets, sugar coated tablets, pills, powders, granules, chewing gum, solutions, suspensions, emulsions, syrups, elixirs, jellies and gelatins.
  4. 10
    Composition according to any of claims 7 to 9, wherein this composition also comprises at least one cosmetically or pharmaceutically acceptable adjuvant selected from the group formed by agents which inhibit neuronal exocytosis, anticholinergic agents, agents which inhibit muscular contraction, anti-aging agents, anti-wrinkle agents, antiperspirant agents, anti-inflammatory agents and/or analgesics, anti-itching agents, calming agents, anesthetic agents, inhibitors of acetylcholine-receptor aggregation, agents that inhibit acetylcholinesterase, skin relaxant agents, melanin synthesis stimulating or inhibiting agents, whitening or depigmenting agents, propigmenting agents, self-tanning agents, NO-synthase inhibiting agents, 5α-reductase inhibiting agents, lysyl- and/or prolyl hydroxylase inhibiting agents, antioxidants, free radical scavengers and/or agents against atmospheric pollution, reactive carbonyl species scavengers, anti-glycation agents, antihistamine agents, antiviral agents, antiparasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, skin conditioners, humectants, substances that retain moisture, alpha hydroxy acids, beta hydroxy acids, moisturizers, epidermal hydrolytic enzymes, vitamins, amino acids, proteins, pigments, colorants, dyes, biopolymers, gelling polymers, thickeners, surfactants, softening agents, emulsifiers, binding agents, preservatives, agents able to reduce or treat bags under the eyes, exfoliating agents, keratolytic agents, flaking agents, antimicrobial agents, antifungal agents, fungistatic agents, bactericidal agents, bacteriostatic agents, agents stimulating the synthesis of dermal or epidermal macromolecules and/or capable of inhibiting or preventing their degradation, collagen synthesis-stimulating agents, elastin synthesis-stimulation agents, decorin synthesis-stimulation agents, laminin synthesis-stimulation agents, defensin synthesis-stimulating agents, chaperone synthesis-stimulating agents, cAMP synthesis-stimulating agents, AQP-3 modulating agents, aquaporin synthesis modulating agents, proteins from the aquaporin family, hyaluronic acid synthesis-stimulating agents, glycosaminoglycan synthesis-stimulating agents, fibronectin synthesis-stimulating agents, sirtuin synthesis-stimulating agents, sirtuin activating agents, heat shock proteins, heat shock protein synthesis-stimulating agents, agents stimulating the synthesis of lipids and components of the stratum corneum, ceramides, fatty acids, agents that inhibit collagen degradation, matrix metalloproteinase inhibitory agents, agents that inhibit elastin degradation, agents that inhibit serine proteases, agents stimulating fibroblast proliferation, agents stimulating keratinocyte proliferation, agents stimulating adipocyte proliferation, agents stimulating melanocyte proliferation, agents stimulating keratinocyte differentiation, agents stimulating or delaying adipocyte differentiation, antihyperkeratosis agents, comedolytic agents, anti-psoriasis agents, DNA repair agents, DNA protecting agents, stabilizers, agents for the treatment and/or care of sensitive skin, firming agents, anti-stretch mark agents, binding agents, agents regulating sebum production, lipolytic agents or agents stimulating lipolysis, adipogenic agents, agents modulating PGC-1α expression, agents modulating PPARγ, agents which increase or reduce the triglyceride content of adipocytes, anti-cellulite agents, agents which inhibit the activity of PAR-2, agents stimulating healing, coadjuvant healing agents, agents stimulating reepithelialization, coadjuvant reepithelialization agents, cytokine growth factors, agents acting on capillary circulation and/or microcirculation, agents stimulating angiogenesis, agents that inhibit vascular permeability, venotonic agents, agents acting on cell metabolism, agents to improve dermal-epidermal junction, agents inducing hair growth, hair growth inhibiting or retardant agents, hair loss retardant agents, preservatives, perfumes, cosmetic and/or absorbent and/or body odor masking deodorants, chelating agents, plant extracts, essential oils, marine extracts, agents obtained from a biotechnological process, mineral salts, cell extracts, sunscreens and organic or mineral photoprotective agents active against ultraviolet A and/or B rays and/or infrared A rays, or mixtures thereof.
  5. 11
    Compound of general formula (I), their stereoisomers, mixtures thereof, their cosmetically or pharmaceutically acceptable salts and/or its functionally equivalent variants, as defined in any of claims 1 to 6, for its use in medicine.
  6. 12
    A compound of general formula (I),          R1-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-R2     (I) their stereoisomers, mixtures thereof, their cosmetically or pharmaceutically acceptable salts and/or its functionally equivalent variants, characterized in that:AA1 is selected from the group formed by -Arg-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;AA2 is selected from the group formed by -His-, -Lys- and -Asp-;AA3 is selected from the group formed by -Leu-, -Ile-, -Met-, -MetO-, -MetO2- and -Phe-;AA4 is selected from the group formed by -Ala- and -Asp-;AA5 is selected from the group formed by -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;AA6 is selected from the group formed by -Met-, -MetO-, -MetO2-, -Tyr- and -Trp-;W, X, Y, Z are amino acids and are independently selected from amongst themselves;n, m, p and q are independently selected from amongst themselves and have a value of 0 or 1;n+m+p+q is smaller or equal to 2;R1 is selected from the group formed by H, a polymer derived from polyethylene glycol, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R5-CO-, wherein R5 is selected from the group formed by H, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heteroarylalkyl;R2 is selected from the group formed by -NR3R4, -OR3 and -SR3, wherein R3 andR4 are independently selected from the group formed by H, a polymer derived from polyethylene glycol, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl;andR1 and R2 are not α-amino acids, for its use in the treatment and/or prevention of pain, inflammation, itching, hyperhidrosis and/or of neurological, compulsive and/or neuropsychiatric diseases and/or disorders which are improved by the inhibition of neuronal exocytosis selected from the group formed by muscular spasticity, dystonia, focal dystonia, blepharospasm, torsion dystonia, cervical dystonia or torticollis, laryngeal dystonia or spasmodic dysphonia, oromandibular dystonia, extremity dystonia, writer's cramp, musician's cramp, foot dystonia, bruxism, facial scoliosis, hemifacial spasm, tics, strabismus, segmentary dystonia, Meige's syndrome, multifocal dystonia, hemidystonia, dopamine-responsive dystonia, Segawa's dystonia, trembling, Parkinson's disease, nervous impingements, Alzheimer's disease and Tourette's syndrome.
  7. 13
    Use of a compound of general formula (I),          R1-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-R2     (I) their stereoisomers, mixtures thereof, their cosmetically or pharmaceutically acceptable salts and/or its functionally equivalent variants, characterized in that:AA1 is selected from the group formed by -Arg-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;AA2 is selected from the group formed by -His-, -Lys- and -Asp-;AA3 is selected from the group formed by -Leu-, -Ile-, -Met-, -MetO-, -MetO2- and -Phe-;AA4 is selected from the group formed by -Ala- and -Asp-;AA5 is selected from the group formed by -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;AA6 is selected from the group formed by -Met-, -MetO-, -MetO2-, -Tyr- and -Trp-;W, X, Y, Z are amino acids and are independently selected from amongst themselves;n, m, p and q are independently selected from amongst themselves and have a value of 0 or 1;n+m+p+q is smaller or equal to 2;R1 is selected from the group formed by H, a polymer derived from polyethylene glycol, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R5-CO-, wherein R5 is selected from the group formed by H, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heteroarylalkyl;R2 is selected from the group formed by -NR3R4, -OR3 and -SR3, wherein R3 andR4 are independently selected from the group formed by H, a polymer derived from polyethylene glycol, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl;andR1 and R2 are not α-amino acids, for the cosmetic, non-therapeutic treatment and/or care of the skin, hair and/or mucous membranes.
  8. 15
    Compound of general formula (I),          R1-Wn-Xm-AA1-AA2-AA3-AA4-AA5-AA6-Yp-Zq-R2     (I) their stereoisomers, mixtures thereof, their cosmetically or pharmaceutically acceptable salts and/or its functionally equivalent variants, characterized in that:AA1 is selected from the group formed by -Arg-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;AA2 is selected from the group formed by -His-, -Lys- and -Asp-;AA3 is selected from the group formed by -Leu-, -Ile-, -Met-, -MetO-, -MetO2- and -Phe-;AA4 is selected from the group formed by -Ala- and -Asp-;AA5 is selected from the group formed by -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;AA6 is selected from the group formed by -Met-, -MetO-, -MetO2-, -Tyr- and -Trp-;W, X, Y, Z are amino acids and are independently selected from amongst themselves;n, m, p and q are independently selected from amongst themselves and have a value of 0 or 1;n+m+p+q is smaller or equal to 2;R1 is selected from the group formed by H, a polymer derived from polyethylene glycol, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R5-CO-, wherein R5 is selected from the group formed by H, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heteroarylalkyl;R2 is selected from the group formed by -NR3R4, -OR3 and -SR3, wherein R3 and R4 are independently selected from the group formed by H, a polymer derived from polyethylene glycol, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl;andR1 and R2 are not α-amino acids, for its use in the inhibition of neuronal exocytosis.
Independent claims8