WO2014177123A1 - Acne medication and method for producing same - Google Patents

Acne medication and method for producing same Download PDF

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Publication number
WO2014177123A1
WO2014177123A1 PCT/DE2013/100190 DE2013100190W WO2014177123A1 WO 2014177123 A1 WO2014177123 A1 WO 2014177123A1 DE 2013100190 W DE2013100190 W DE 2013100190W WO 2014177123 A1 WO2014177123 A1 WO 2014177123A1
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acne
inhibitors
medicament according
mtorci
vitamin
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German (de)
French (fr)
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Bodo C. Melnik
Gunter Thielen
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Melnik Bodo C
Gunter Thielen
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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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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 invention relates to acne medicaments and methods for its production with activation of the transcription factor forkhead box class 01 (FoxO l) and / or inhibition of the kinase mechanistic target of rapamycin complex 1 (TORC 1)
  • Acne is the most common inflammatory skin disease and is found in industrialized countries In adolescents with a prevalence of over 80% and increasingly persists in up to 50% of Americans in the third decade of life. Acne was recognized as a Western civilization disease in 2002, which was hypothetically linked to an excessive activity of the food-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC D), which is currently the annual cost of acne treatment and compensation in the US Unfortunately, there has been a significant need for acne treatment for acne medications.
  • mTORC D food-sensitive kinase mechanistic target of rapamycin complex 1
  • Anti-androgen hormone treatments as acne therapy in women are associated with an increase in risk of thrombosis.
  • isotretinoin 13-cis-retinoic acid
  • isotretinoin 13-cis-retinoic acid
  • isotretinoin 13-cis-retinoic acid
  • teratogenic effects fruit malformation
  • isotretinoin-induced follicular atresia When oral isotretinoin is administered, predisposing individuals may experience a worsening mood with suicidal outcome.
  • the object of the invention is to provide new, more effective and side-effect poorer acne medicines than the known and processes for their preparation.
  • Anti-acne drugs with FoxOl -activating action can be produced, for example, with vitamin D and / or vitamin D analogues as essential ingredients: Vitamin D is an important vitamin with hormone function that significantly influences cell division, cell growth and cell differentiation. Also, the sebocytes and acroinfundibular keratinocytes involved in the pathogenesis of acne respond to 1,25-dihydroxyvitamin D3 (1 .25D3) as these cells express the vitamin D receptor (VDR) as well as vitamin D-metabolizing enzymes. Upon binding of 1 .25D3 to the VDR, it increases the nuclear activity of FoxO proteins (Fox03a and Fox04) and increases their nuclear presence and thus their gene regulatory effect.
  • Vitamin D is an important vitamin with hormone function that significantly influences cell division, cell growth and cell differentiation.
  • the sebocytes and acroinfundibular keratinocytes involved in the pathogenesis of acne respond to 1,25-dihydroxyvitamin D3 (1 .25D3) as these cells express the
  • vitamin D and various vitamin D analogues such as Caicipotriol can be used as a FoxO enhancer to treat acne.
  • Vitamin D intake enhances the expression of DNA damage-inducible transcript 4 (DDIT4).
  • DDIT4 promotes the association and activation of the inhibitory TSC1 / TSC2 complex, which plays a key role in mTORCI inhibition.
  • vitamin D3 is orally administered in doses of 5000 to 10000 units daily of acne patients.
  • acne is topically treated with vitamin D analogs such as calcipotriol, maxacalcitol, and the like. applied externally on a gel or lotion basis at a concentration of 0.001-0.01%, one to three times daily.
  • vitamin D analogs such as calcipotriol, maxacalcitol, and the like.
  • vitamin D or vitamin D analogs in combination, e.g. 500-1000 units of vitamin D daily as well as topical application of 0.005% calcipotriol or other comparable vitamin D analogues.
  • Anti-acne drugs with FoxOl -activating effect are also Milttel, which are produced as an essential part of Leptomycin B (LMB) and LMB analogues.
  • the herbal fungicide leptomycin B (LM B) is known as a specific inhibitor of the nuclear export protein required for chromosomal region maintenance (CRM 1, synonym Eportin-1, XP01). FoxOl has LMB-sensitive nuclear export signal domains. Treatment of cells with LM B leads to an accumulation of FoxO proteins in the nucleus. This increases the desired nuclear anti-acne activity of FoxO transcription factors.
  • leptomycin B as well as LM B analogs are applied in a concentration of 0.1 to 0.50 nM once to three times daily in a suitable base.
  • leptomycin B is topically applied once to twice daily in an ethanolic gel at a concentration of between 0.05 mg / dL to 0.25 mg / dL.
  • Other useful synthetic LM B1 derivatives, such as KOS-2464, can be used in nM concentrations for the topical treatment of acne, and are more closely characterized by reference.
  • LM B and synthetic LM B analogs such as KOS-2464
  • other specific inhibitors of nuclear FoxOl transport inhibiting CRM 1-I are considered for the topical treatment of acne in nanomolar to micromolar concentrations.
  • These substances are shown in FIG. These are the following polycyclic compounds with the abbreviations NSC17474Z, NSC186057T, 52161 77, 51 07769, 5233705, 5160096, NSC891 10Q, 5137877, 5271325, 523648, 5107360, 5217490, NSC354891, 5281 1 54, NSC401366Z, 5213337, NSC293046M , 51 75309, NSC3548891, 5145695, NSC17600N, B6-7-1 and other possible derivatives of these CRM1 inhibitors with FoxOl nuclear export activity.
  • Acne is associated with increased body mass index (BMI) and insulin resistance as a civilization disease.
  • metformin reduces body weight and improves insulin sensitivity, activates AMP kinase (AMPK) and thus leads to an inhibition of the kinase mTORCI.
  • metformin stimulated the activity of Fox03.
  • Fox03 also stimulates the expression of FoxOl and inhibits the activity of the kinase mTORCI by increasing the expression of TSC1 and sestrin3.
  • Another positive effect of metformin in the treatment of acne is the inhibition of leucine-induced translocation of the inactive mTORCI complex to lysosomal cell compartments where Rheb-induced mTORCI activation occurs.
  • the benign and intractable biguanide metformin used in the treatment of type 2 diabetes and insulin resistance, is administered as a basic oral acne therapy at a dose of 500 mg to 2000 mg daily, unless the acne patient is willing to accept his "high-glycemic" Western Neolithic diet To adjust the load and high consumption of milk and milk products of a Paleolithic form of nutrition with reduced consumption of sugars, cereals, as well as milk and milk products.
  • acne can be ameliorated by pharmacological attenuation of the activity of the kinase mTORCI of the cells of the sebaceous follicle.
  • mTORCI inhibitors use natural and synthetic mTORCI inhibitors.
  • the macrolide rapamycin (sirolimus) synthesized by the bacterium Streptomyces hygroscopicus is a physiologically occurring allosteric mTORCl inhibitor, but does not inhibit the ATP-sensitive kinase domain of mTORCI.
  • the inhibition of the ATP-sensitive kinase domain of mTOR can be inhibited by natural plant polyphenols and synthetic mTORKinibs.
  • Herbal mTORCI inhibitors are, for example, curcumin and curcumin derivatives.
  • the naturally occurring curcumin (diferuloylmethane), a polyphenol of the plant Curcuma longa, has antiproliferative effects and inhibits the mTORCI signaling pathway.
  • Curcumin dissociates the mTOR-Raptor complex and can be used by the inventors as an mTORCI inhibitor for oral and topical acne treatment.
  • Curcumin is given to acne patients either orally in capsule form at 250 to 500 mg twice daily with meals, or is used in a 0.5-3% preparation as gel or lotion, also in the form of facial masks for topical acne treatment.
  • 3,3'-Diindolylmethane also inhibits the mTORCI signaling pathway, leading to cell cycle arrest and antiproliferative activity.
  • An oral and topical use is recommended, especially in acne patients who take few vegetables and insufficient amounts of pfanzlichen precursors of 3,3 '-Diindolylmethans to himself.
  • For acne treatment is 3,3'-Diindolylmethan administered in a daily dose of 2 x 200 mg to 500 mg 2x capsules orally at mealtimes, the external treatment with 3,3 '-Diindolylmethan takes the form of 0.5 to 3% strength gels or Lotions or solutions.
  • Genistein is a naturally occurring isoflavone and phytoestrogen from soy and may also inhibit the mTORCI signaling pathway. Genistein is taken orally in a daily dose of 100 to 200 mg in capsule form once to twice daily. A topical application with a concentration of 0.5-5% genistein in the form of gels, lotions and solutions takes place once or twice a day.
  • Silymarin is a natural vegetable flavanolignan isolated from the fruits and seeds of milk thistle (Silybum marianum L. Gaertn.). Silymarin has anti-inflammatory effects and inhibits photocarcinogenesis. Silymarin also inhibits the activity of the kinase mTORCI. In an oral dosage form, silymarin is taken two to three times a day in capsule form per 100 mg. The topical treatment of acne with silymarin is carried out with 0.5 to 1 0% Emulsion / emulsions, gels or alcoholic solutions.
  • Quercetin a bioflavonoid and dual-specific PI3K / mTOR inhibitor, is also considered for oral and topical acne therapy.
  • Fisetin (3,7,3 ', 4'-tetrahydroxyflavone), a naturally occurring polyphenol, belongs to the family of flavonoids and is used in 0.5 to 3% concentration for topical acne treatment.
  • Combinations of said plant mTORCI inhibitors may be combined in another preferred application for oral and topical acne therapy.
  • other polyphenols already described as having anti-acne action such as resveratrol, as well as the grapevine epigallocatechin-3-gallate and their derivatives may also be included in the combination.
  • silymarin is combined with resveratrol.
  • EGCG green tea polyphenol epigallocate-chin-3-gallate
  • Rapamycin (sirolimus) and Rapalog analogs are known immunosuppressants and display anti-inflammatory and anti-proliferative properties. Rapamycin and rapalogues such as everolimus form a complex with the intracellular receptor protein FK506 binding protein 12 (FKBP12). This rapamycin or rapalog FKBP12 complex then binds to mTOR and allosterically blocks its catalytic function.
  • FKBP12 intracellular receptor protein FK506 binding protein 12
  • rapamycin or rapalog FKBP12 complex then binds to mTOR and allosterically blocks its catalytic function.
  • rapamycin (sirolimus) is used at a level of between 0.005% to 0.05% for the topical treatment of acne.
  • the topical acne treatment is carried out with everolism (RAD001) or 0.005% to a maximum of 0.05%.
  • rapamycin Derviat temsirolimus CCI-779, Torisei
  • Rapamycin Dervia Deforolimus AP23573, Ridaforolimus
  • Rapalog Zotarolimus ABT-578
  • the said rapalogs are combined for therapy optimization and minimization of side effects.
  • the pyrazolopyrimidine PP242 (2- (4-amino-1-isopropyl-1H-pyrazolo [3,4-d] pyrimidin-3-yl) -1H-indol-5-ol) (first selective Inhibitor of the ATP binding domain of mTOR) for the topical treatment of acne, in such a way that in the sebaceous follicle concentrations between 5-10 nM is reached.
  • PP30 mTOR kinase inhibitor
  • NDP-BEZ235 mTOR inhibitor-2-methyl-2- (4- (3-methyl-2-oxo-8- (quinolin-3-yl) -2,3 dihydroimidazo [4,5-c] quinolin-1-yl) phenyl) propane nitrile).
  • Another topical treatment option for acne is the PI3K and mTOR PI-103 dual inhibitor (phenol, 3- [4- (4-morpholinyl) pyndo- [3 ', 2': 4,5] furo- [3,2 -d] pyrimidin-2-yl).
  • the pyridinone quinoline is Torini (benzo [h] -1, 6-naphthyridin-2 (1H) -one, 1 - [4- [4- (1-oxopropyl) -1-piperazinyl] -3- ( trifluoromethyl) phenyl] -9- (3- quinolinyl); mTOR kinase inhibitor) for topical acne therapy.
  • pyrazolopyrimidine WYE-354 is used for topical acne treatment.
  • the pyrazolopyrimidine WYE-1 25132 (urea, N- [4- [1- (1,4-dioxaspiro [4.5] dec-8-yl) -4- (8-oxa-3-azabicyclo) 3.2.1] oct-3-yl) -1H-pyrazolo [3,4-d] pyrimidin-6-yl] phenyl] -N'-methyl) for topical use in acne.
  • Another topical therapy option involves the use of the pyrazolopyrimidine WAY-600 (6- (1H-indol-5-yl) -4-morpholino-1- (1- (pyridin-3-ylmethyl) piperidin-4-yl) -1 H-pyrazolo [3,4-d] pyrimidines; Competitive ATP inhibitor of mTOR).
  • Another topical therapy option describes the use of the pyrazolopyrimidine WYE-687 (methyl 4- (4-morpholino-1- (1- (pyridin-3-ylmethyl) piperidin-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl; Competitive ATP inhibitor of mTOR).
  • pyridopyrimidine Ku-0063794 (2 - ((2R, 6S) -2,6-dimethylmorpholino) -4-morpholino-opyrido [2,3-d] pyrimidine -7-yl) -2-methoxyphenyl; specific mTORCI and mTORC2 inhibitor).
  • INK128 3- (2-aminobenzo [d] oxazol-5-yl) -1-isopropyl-1H-pyrazolo [3,4-d] pyrimidine-4 amin; Competitive ATP inhibitor of mTOR.
  • PF-04691 502 (2-amino-8 - ((1R, 4R) -4- (2-hydroxyethoxy) cyclohexyl) -6- (6-methoxypyridine-3 -yl) -4-methylpyrido [2,3-d] pyrimidin-7 (8H).
  • Palomid 529 (3- (4-methoxybenzyloxy) -8- (1-hydroxyethyl) -2-methoxy-6H-benzo [c] -chromene-6-one).
  • OSI-027 ((1 r, 4r) -4- (4-amino-5- (7-methoxy-1H-indol-2-yl) imidazo [1,5-f] [1, 2 , 4] triazin-7-yl) cyclohexanecarboylxklare).
  • GSK2126458 (2,4-difluoro-N- (2-methoxy-5- (4- (pyridazin-4-yl) quinolin-6-yl) pyridin-3-yl) benzenesulfonamide).
  • Another topical treatment option is the combination of mTOR inhibitors with competitive ATP inhibitors of mTOR.
  • synthetic mTOR inhibitors are combined with natural mTORCI inhibitors, e.g. Torini with curcumin or INK128 with resveratrol or EGCG.
  • Figure 2 is a graph of the FoxO enhancer and TORC1 inhibitor metformin
  • Fig. 3 is an overview of FoxO enhancers and TORC1 inhibitors
  • the teaching of this patent explains the acne therapy by a pharmacological attenuation of the activity of the kinase mTORCI in the area of the cells of the sebaceous follicle of humans.
  • This goal is achieved either indirectly by increasing the nuclear activity of FoxO transcription factors and / or by directly inhibiting mTORCI activity with allosteric mTOR inhibitors or natural or synthetic mTOR inhibitors (TORKinibs).
  • TORKinibs allosteric mTOR inhibitors or natural or synthetic mTOR inhibitors
  • the pharmacological intervention is supported by a dietary intervention in the sense of a Paleolithic diet with reduction of the glycemic load and the insulinotropic, mTORCI-activating endocrine signaling system milk.

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Abstract

The invention relates to novel acne medication and to a method for producing same with a topical as well as systemic application on the basis that acne is a mTORC1-induced sebofollicular skin disease. The elevated signal transduction of the mTORC1 pathway is decreased by activating the transcription factor FoxO1 and other FoxO subtypes using FoxO enhancers such as vitamin D, metformin, leptomycin B, or other CRM1 inhibitors. Another option, which is used in particular in combination with different FoxO enhancers, is the direct inhibition of the kinase mTORC1 using vitamin D and natural plant and/or synthetic allosteric mTORC1 inhibitors from the group of rapalogs and synthetic direct mTORC1 inhibitors. The aim of the therapeutic measures is not the complete deactivation of the mTORC1 signal path, but rather the normalization thereof to a level of human beings with a Paleolithic diet.

Description

Akne-Medikament und Verfahren zu seiner Herstellung  Acne drug and process for its preparation
Die Erfindung betrifft Akne-Medikamente und Verfahren zu seiner Herstellung mit Aktivierung des Transkriptionsfaktors forkhead box class 01 (FoxO l ) und/ oder Hemmung der Kinase mechanistic target of rapamycin complex 1 (TORC 1 ) Akne ist die häufigste entzündliche Hauterkrankung und wird in I ndustriestaaten bei Jugendlichen mit einer Prävalenz von über 80% angetroffen und persistiert zunehmend bei bis zu 50% der US-Amerikaner in der dritten Lebensdekade. Die Akne wurde bereits 2002 als westliche Zivilisationskrankheit erkannt, die mit einer überhöhten Aktivität der Nahrungs-sensitiven Kinase mechanistic target of rapamycin complex 1 (mTORC D in theoretischen Zusammenhang gebracht wurde. In den USA werden aktuell die jährlichen Kosten zur Behandlung der Akne und zum Ausgleich des krankheitsbedingten Produktionsverlustes auf 3 Milliarden US Dollar geschätzt. Es besteht somit ein erheblicher Bedarf zur medikamentösen Behandlung der Akne. Nachhaltige therapeutische I nnovationen von Akne-Medikamenten sind leider seit mehr als 1 5 Jahren ausgeblieben. Alle auf dem Markt befindlichen Akne-Medikamente wurden klinisch empirisch entdeckt und ohne jeglichen Kausalzusammenhang in die Therapie der Akne, meist in Kombination, eingeführt. Die derzeit im Umlauf befindlichen Akne-Medikamente stellen nicht die idealen Wirkstoffe zur Behandlung der Akne dar, da sie durch leichte bis extrem schwere unerwünschte Wirkungen belastet sind, wie z. B. Bleicheffekte an Textilien bei Anwendung von topischem Benzoylperoxid, Antibiotikaresistenzen von Propionibacterium acnes bei topischer Anwendung von Erythromycin, verstärkte Lichtempfindlichkeit mit erhöhter Gefahr des Sonnenbrandes bei Anwendung oraler Tetrazykline, Hautirritationen mit Rötung und Schuppung bei topischer Anwendung von Retinoiden (all-trans-Retinsäure, Adapalen u.a.). Antiandrogene Hormonbehandlungen als Aknetherapie bei Frauen sind mit einer Steigerung des Thromboserisikos assoziiert. Die Anwendung des wirksamsten oral verabfolgten Akne-Medikamentes, Isotretinoin (13-cis-Retinsäure) ist bei unzureichender Kontrazeption mit schweren teratogenen Wirkungen (Fruchtmissbildung) belastet und steht zudem unter begründetem Verdacht, die Fruchtbarkeit (Follikelreserve) weiblicher Patienten infolge Isotretinoin-induzierter Follikelatresie zu vermindern. Bei oraler Einnahme von Isotretinoin kann es möglicher Weise bei disponierten Individuen zu einer Verschlechterung der Stimmungslage mit suizidalem Ausgang kommen. The invention relates to acne medicaments and methods for its production with activation of the transcription factor forkhead box class 01 (FoxO l) and / or inhibition of the kinase mechanistic target of rapamycin complex 1 (TORC 1) Acne is the most common inflammatory skin disease and is found in industrialized countries In adolescents with a prevalence of over 80% and increasingly persists in up to 50% of Americans in the third decade of life. Acne was recognized as a Western civilization disease in 2002, which was hypothetically linked to an excessive activity of the food-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC D), which is currently the annual cost of acne treatment and compensation in the US Unfortunately, there has been a significant need for acne treatment for acne medications. Unfortunately, there have been no lasting therapeutic innovations in acne medication for more than 1.5 years, and all acne medications on the market have become clinically viable empirically discovered and introduced without any causal link in the treatment of acne, usually in combination.The currently circulating acne medications are not the ideal agents for the treatment of acne, as they are burdened by mild to extremely severe adverse effects, such as eg Bleaching effects on textiles using topical benzoyl peroxide, antibiotic resistance of Propionibacterium acnes in topical application of erythromycin, increased photosensitivity with increased risk of sunburn when using oral tetracyclines, skin irritations with redness and scaling in topical application of retinoids (all-trans-retinoic acid, adapalene, etc.) ). Anti-androgen hormone treatments as acne therapy in women are associated with an increase in risk of thrombosis. The application of the most effective oral acne medication, isotretinoin (13-cis-retinoic acid) is in severe contraception with severe teratogenic effects (fruit malformation) burdened and is also under reasonable suspicion to reduce the fertility (follicular reserve) of female patients due to isotretinoin-induced follicular atresia. When oral isotretinoin is administered, predisposing individuals may experience a worsening mood with suicidal outcome.
Die Aufgabe der Erfindung ist es, neue, wirksamerer und nebenwirkungsärmerer Akne-Medikamente als die bekannten sowie Verfahren zu ihrer Herstellung zur Verfügung zu stellen. The object of the invention is to provide new, more effective and side-effect poorer acne medicines than the known and processes for their preparation.
Die Lösung dieser Aufgabe ergibt sich daraus, dass es gelungen ist, einen gemeinsamen grundlegenden Wirkmechanismus aller bekannten Akne-Medikamente abzuleiten, der es erlaubt neue, innovative Substanzen und Substanzkombinationen mit neuen als auch altbekannten Akne-Medikamenten vorzunehmen und damit eine kausale, medizinisch optimierte und nebenwirkungsärmere zielgerichtete Aknetherapie durchzuführen. Es werden Substanzen und Substanzkombinationen zur Herstellung eine Aknemedikaments izur Verfügung gestellt, die als Aktivierer des nuklearen Transkriptionsfaktors forkhead box class 01 (FoxOD und/ oder als Hemmer der metabolisch regulativen Kinase mechanistic (mammalian) target of rapamycin complex 1 (mTORCI ) ihre Anti-Akne- Wirkung entfalten. The solution to this problem arises from the fact that it has managed to derive a common basic mechanism of action of all known acne drugs, which allows to make new, innovative substances and substance combinations with new as well as well-known acne medications and thus a causal, medically optimized and perform less-targeted, targeted acne therapy. Substances and combinations of compounds for the production of an acne medicament are provided as anti-acne activators of the nuclear transcription factor forkhead box class 01 (FoxOD and / or inhibitor of the metabolically regulatory kinase mechanistic (mammalian) target of rapamycin complex 1 (mTORCI) - unfold their effect.
Anti-Akne-Medikamente mit FoxOl -aktivierender Wirkung können beispielsweise mit Vitamin D und/ oder Vitamin D-Analoga als wesentlichem Bestanteil hergestellt werden: Vitamin D ist ein wichtiges Vitamin mit Hormonfunktion, dass Zellteilung, Zellwachstum und Zelldifferenzierung maßgeblich beeinflusst. Auch die an der Pathogenese der Akne beteiligten Sebozyten und akroinfundibulären Keratinozyten sprechen auf 1 ,25- Dihydroxyvitamin D3 (1 .25D3) an, da diese Zellen den Vitamin D-Rezeptor (VDR) als auch Vitamin D-metabolisiernde Enzyme exprimieren. Nach Bindung von 1 .25D3 an den VDR erhöht dieser die nukleare Aktivität von FoxO-Proteinen (Fox03a und Fox04) und steigert deren Präsenz im Zellkern und somit ihre generegulatorische Wirkung. Daher können Vitamin D sowie verschiedene Vitamin D-Analoga wie Caicipotriol als FoxO-Enhancer zur Therapie der Akne verwendet werden. Vitamin D-Zufuhr steigert die Expression von DNA damage-inducible transcript 4 (DDIT4). DDIT4 fördert die Assoziation und Aktivierung des inhibitorisch wirksamen TSC1/TSC2-Komplexes, der für die mTORCI -Hemmung eine zentrale Rolle spielt. In einer bevorzugten Anwendung wird Vitamin D3 in Dosen von täglich 5000 bis 1 0000 Einheiten Aknepatienten oral verabreicht. Anti-acne drugs with FoxOl -activating action can be produced, for example, with vitamin D and / or vitamin D analogues as essential ingredients: Vitamin D is an important vitamin with hormone function that significantly influences cell division, cell growth and cell differentiation. Also, the sebocytes and acroinfundibular keratinocytes involved in the pathogenesis of acne respond to 1,25-dihydroxyvitamin D3 (1 .25D3) as these cells express the vitamin D receptor (VDR) as well as vitamin D-metabolizing enzymes. Upon binding of 1 .25D3 to the VDR, it increases the nuclear activity of FoxO proteins (Fox03a and Fox04) and increases their nuclear presence and thus their gene regulatory effect. Therefore, vitamin D and various vitamin D analogues such as Caicipotriol can be used as a FoxO enhancer to treat acne. Vitamin D intake enhances the expression of DNA damage-inducible transcript 4 (DDIT4). DDIT4 promotes the association and activation of the inhibitory TSC1 / TSC2 complex, which plays a key role in mTORCI inhibition. In a preferred application, vitamin D3 is orally administered in doses of 5000 to 10000 units daily of acne patients.
In einer weiteren bevorzugten Anwendungsform wird Akne topisch mit Vitamin D- Analoga wie Calcipotriol, Maxacalcitol u.a. in einer Gel- oder Lotio-Grundlage mit einer Konzentration von 0,001 -0,01 % ein bis dreimal täglich äußerlich aufgetragen. In another preferred embodiment, acne is topically treated with vitamin D analogs such as calcipotriol, maxacalcitol, and the like. applied externally on a gel or lotion basis at a concentration of 0.001-0.01%, one to three times daily.
In einer weiteren Modifikation erfolgt eine orale und topische Anwendung von Vitamin D bzw. Vitamin D-Analoga in Kombination, z.B. oral täglich 500-1000 Einheiten Vitamin D sowie zusätzlich topische Anwendung von 0,005 % Calcipotriol oder anderen vergleichbaren Vitamin D-Analoga. In a further modification, oral and topical application of vitamin D or vitamin D analogs in combination, e.g. 500-1000 units of vitamin D daily as well as topical application of 0.005% calcipotriol or other comparable vitamin D analogues.
Anti-Akne-Medikamente mit FoxOl -aktivierender Wirkung sind auch Milttel, die als wesentlichem Bestandteil aus Leptomycin B (LMB) und LMB-Analoga hergestellt werden. Das pflanzliche Fungizid Leptomycin B (LM B) ist als spezifischer Inhibitor des nukleären Exportproteins required for chromosome region maintenance (CRM 1 , Synonym Eportin-1 , XP01 ) bekannt. FoxOl verfügt über LMB-sensitive nukleäre Exportsignaldomänen. Durch Behandlung von Zellen mit LM B kommt es zu einer Akkumulation von FoxO-Proteinen im Zellkern. Hierdurch erhöht sich die gewünschte nukleäre Anti-Akne- Aktivität der FoxO-Transkriptionsfaktoren. Anti-acne drugs with FoxOl -activating effect are also Milttel, which are produced as an essential part of Leptomycin B (LMB) and LMB analogues. The herbal fungicide leptomycin B (LM B) is known as a specific inhibitor of the nuclear export protein required for chromosomal region maintenance (CRM 1, synonym Eportin-1, XP01). FoxOl has LMB-sensitive nuclear export signal domains. Treatment of cells with LM B leads to an accumulation of FoxO proteins in the nucleus. This increases the desired nuclear anti-acne activity of FoxO transcription factors.
In einer bevorzugten topischen Anwendung wird Leptomycin B (LMB) als auch LM B- Analoga in einer Konzentration von 0, 1 bis 0,50 nM ein- bis dreimal täglich in geeigneter Grundlage appliziiert. In einer weiteren bevorzugten Anwendung wird Leptomycin B in einem ethanolischen Gel in einer Konznetration zwischen 0,05 mg/dL bis 0,25 mg/dL einmal bis zweimal täglich topisch angewendet. Weitere nutzbare synthetische LM B1 -Derivative wie KOS-2464 können in nM Konzentrationen zur topischen Behandlung der Akne zur Anwendung kommen und sind unter Referenz näher charaktierisert. Unabhängig von LM B und synthetischen LM B-Analoga wie KOS-2464 kommen weitere spezifische, den nukleären FoxOl -Transport hemmende CRM 1 -I nhibitoren zur topischen Behandlung der Akne in nanomolarer bis mikromolarer Konzentration in Betracht. Diese Substanzen sind in der Figur 1 dargestellt. Es handelt sich um die folgenden polyzyklischen Verbindungen mit den Kurzbezeichnungen NSC17474Z, NSC186057T, 52161 77, 51 07769, 5233705, 5160096, NSC891 1 0Q, 5137877, 5271325, 523648, 5107360, 5217490, NSC354891 , 5281 1 54, NSC401366Z, 5213337, NSC293046M, 51 75309, NSC3548891 , 5145695, NSC17600N, B6-7-1 und weitere mögliche Derivate dieser CRM1 -lnhibitoren mit Hemmwirkung des nukleären FoxOl -Exports. Akne ist als Zivilisationskrankheit mit erhöhtem Body Mass Index (BMI) und I nsulinresistenz assoziiert. Das altbekannte Antidiabetikum Metformin reduziert das Körpergewicht und verbessert die Insulinsensitivität, aktiviert die AMP-Kinase (AMPK) und führt damit zu einer Hemmung der Kinase mTORCI . In Gliomazellen stimulierte Metformin die Aktivität von Fox03. Fox03 stimuliert darüber hinaus die Expression von FoxOl und hemmt via Steigerung der Expression von TSC1 und Sestrin3 die Aktivität der Kinase mTORCI . Ein weiterer positiver Effekt von Metformin bei der Behandlung von Akne ist die Hemmung der Leucin-induzierten Transkolation des inaktiven mTORCI - Komplexes zu lysosomalen Zellkompartimenten, wo die Rheb-induzierte mTORCI - Aktivierung erfolgt. Das in der Behandlung des Typ2-Diabetes und bei Insulinresistenz erprobte und nebenwirkungsarme Biguanid Metformin wird als orale Basistherapie der Akne in einer Dosis von 500 mg bis 2000 mg täglich verabfolgt, sofern der Aknepatient nicht bereit ist, seine "Westliche" neolithische Ernährungsweise mit hoher glykämischer Last und hohem Konsum von Milch und Milchprodukten einer paläolithisch geprägten Ernährungsform mit vermindertem Konsum von Zuckern, Getreide, sowie Milch- und Milchprodukten anzupassen. In a preferred topical application, leptomycin B (LMB) as well as LM B analogs are applied in a concentration of 0.1 to 0.50 nM once to three times daily in a suitable base. In another preferred application, leptomycin B is topically applied once to twice daily in an ethanolic gel at a concentration of between 0.05 mg / dL to 0.25 mg / dL. Other useful synthetic LM B1 derivatives, such as KOS-2464, can be used in nM concentrations for the topical treatment of acne, and are more closely characterized by reference. Regardless of LM B and synthetic LM B analogs such as KOS-2464, other specific inhibitors of nuclear FoxOl transport inhibiting CRM 1-I are considered for the topical treatment of acne in nanomolar to micromolar concentrations. These substances are shown in FIG. These are the following polycyclic compounds with the abbreviations NSC17474Z, NSC186057T, 52161 77, 51 07769, 5233705, 5160096, NSC891 10Q, 5137877, 5271325, 523648, 5107360, 5217490, NSC354891, 5281 1 54, NSC401366Z, 5213337, NSC293046M , 51 75309, NSC3548891, 5145695, NSC17600N, B6-7-1 and other possible derivatives of these CRM1 inhibitors with FoxOl nuclear export activity. Acne is associated with increased body mass index (BMI) and insulin resistance as a civilization disease. The well-known antidiabetic agent metformin reduces body weight and improves insulin sensitivity, activates AMP kinase (AMPK) and thus leads to an inhibition of the kinase mTORCI. In glioma cells, metformin stimulated the activity of Fox03. Fox03 also stimulates the expression of FoxOl and inhibits the activity of the kinase mTORCI by increasing the expression of TSC1 and sestrin3. Another positive effect of metformin in the treatment of acne is the inhibition of leucine-induced translocation of the inactive mTORCI complex to lysosomal cell compartments where Rheb-induced mTORCI activation occurs. The benign and intractable biguanide metformin, used in the treatment of type 2 diabetes and insulin resistance, is administered as a basic oral acne therapy at a dose of 500 mg to 2000 mg daily, unless the acne patient is willing to accept his "high-glycemic" Western Neolithic diet To adjust the load and high consumption of milk and milk products of a Paleolithic form of nutrition with reduced consumption of sugars, cereals, as well as milk and milk products.
Nach Ansicht der Erfinder kann Akne durch pharmakologische Abschwächung der Aktivität der Kinase mTORCI der Zellen des Talgdrüsenfollikels gebessert werden. Als mTORCI -Hemmer kommen natürliche und synthetische mTORCI -lnhibitoren zur Anwendung. Das vom Bakterium Streptomyces hygroscopicus synthetisierte Makrolid Rapamycin (Sirolimus) ist ein physiologisch vorkommender allosterischer mTORCl - Hemmer, der jedoch nicht die ATP-sensitive Kinase-Domäne von mTORCI hemmt. Die Hemmung der ATP-sensitiven Kinase-Domäne von mTOR kann durch natürliche pflanzliche Polyphenole und synthetische mTORKinibs gehemmt werden. According to the inventors, acne can be ameliorated by pharmacological attenuation of the activity of the kinase mTORCI of the cells of the sebaceous follicle. When mTORCI inhibitors use natural and synthetic mTORCI inhibitors. The macrolide rapamycin (sirolimus) synthesized by the bacterium Streptomyces hygroscopicus is a physiologically occurring allosteric mTORCl inhibitor, but does not inhibit the ATP-sensitive kinase domain of mTORCI. The inhibition of the ATP-sensitive kinase domain of mTOR can be inhibited by natural plant polyphenols and synthetic mTORKinibs.
Pflanzliche mTORCI -Hemmer sind beispielsweise Curcumin und Curcumin-Derivate. Das natürlich vorkommende Curcumin (Diferuloylmethan), ein Polyphenol der Pflanze Curcuma longa, weist antiproliferative Effekte auf und hemmt den mTORCI -Signalweg. Curcumin dissoziiert den mTOR-Raptor-Komplex und kann aus Sicht der Erfinder als ein mTORCI -lnhibitor zur oralen und topischen Behandung der Akne eingesetzt werden. Curcumin wird Aknepatienten hierzu entweder oral in Kapselform mit je 250 bis 500 mg zweimal täglich zu den Mahlzeiten verabreicht oder kommt in einer 0,5 - 3%igen Zuberei- tung als Gel oder Lotio, auch in Form von Gesichtsmasken zur topischen Aknebehandlung zur Anwendung. Herbal mTORCI inhibitors are, for example, curcumin and curcumin derivatives. The naturally occurring curcumin (diferuloylmethane), a polyphenol of the plant Curcuma longa, has antiproliferative effects and inhibits the mTORCI signaling pathway. Curcumin dissociates the mTOR-Raptor complex and can be used by the inventors as an mTORCI inhibitor for oral and topical acne treatment. Curcumin is given to acne patients either orally in capsule form at 250 to 500 mg twice daily with meals, or is used in a 0.5-3% preparation as gel or lotion, also in the form of facial masks for topical acne treatment.
Auch 3,3'-Diindolylmethan hemmt den mTORCI -Signalweg, führt zu Zellzyklusarrest und wirkt antiproliferativ. Eine orale und topische Anwendung wird empfohlen, insbesondere bei Aknepatienten, die wenig Gemüse und damit unzureichende Mengen der pfanzlichen Vorstufen des 3,3'-Diindolylmethans zu sich nehmen. Zur Aknebehandlung wird 3,3'-Diindolylmethan in einer Tagesdosis von 2x 200 mg bis 2x 500 mg in Kapselform oral zu den Mahlzeiten verabreicht, die externe Behandlung mit 3,3'-Diindolylmethan erfolgt in Form 0,5 bis 3%iger Gele oder Lotionen oder Lösungen. 3,3'-Diindolylmethane also inhibits the mTORCI signaling pathway, leading to cell cycle arrest and antiproliferative activity. An oral and topical use is recommended, especially in acne patients who take few vegetables and insufficient amounts of pfanzlichen precursors of 3,3 '-Diindolylmethans to himself. For acne treatment is 3,3'-Diindolylmethan administered in a daily dose of 2 x 200 mg to 500 mg 2x capsules orally at mealtimes, the external treatment with 3,3 '-Diindolylmethan takes the form of 0.5 to 3% strength gels or Lotions or solutions.
Genistein ist ein natürlich vorkommendes Isoflavon und Phytoestrogen von Soja und kann ebenfalls den mTORCI -Signalweg hemmen. Genistein wird oral in einer Dosis von täglich je 100 bis 200 mg in Kapselform ein bis zweimal täglcih eingenommen. Eine topische Anwendung mit einer Konzentration von 0.5-5% Genistein in Form von Gelen, Lotionen und Lösungen erfolgt ein bis zweimal am Tag. Genistein is a naturally occurring isoflavone and phytoestrogen from soy and may also inhibit the mTORCI signaling pathway. Genistein is taken orally in a daily dose of 100 to 200 mg in capsule form once to twice daily. A topical application with a concentration of 0.5-5% genistein in the form of gels, lotions and solutions takes place once or twice a day.
Silymarin ist ein natürliches pflanzliches Flavanolignan, das aus den Früchten und Samen der Milchdistel (Silybum marianum L. Gaertn.) isoliert wird. Silymarin wirkt antientzündlich und hemmt die Photokarzinogenese. Auch Silymarin hemmt die Aktivität der Kinase mTORCI . In einer oralen Anwendungsform wird Silymarin zwei bis dreimal täglich in Kapselform je 100 mg eingenommen. Die topische Behandlung der Akne mit Silymarin erfolgt mit 0,5 bis 1 0%igen ΟΑΛ/ Emulsionen, Gelen oder alkoholischen Lösungen. Silymarin is a natural vegetable flavanolignan isolated from the fruits and seeds of milk thistle (Silybum marianum L. Gaertn.). Silymarin has anti-inflammatory effects and inhibits photocarcinogenesis. Silymarin also inhibits the activity of the kinase mTORCI. In an oral dosage form, silymarin is taken two to three times a day in capsule form per 100 mg. The topical treatment of acne with silymarin is carried out with 0.5 to 1 0% Emulsion / emulsions, gels or alcoholic solutions.
Quercetin, ein Bioflavonoid und dualspezifischer PI3K/ mTOR-lnhibitor, kommt ebenfalls zur oralen und topischen Aknetherapie in Betracht. Quercetin, a bioflavonoid and dual-specific PI3K / mTOR inhibitor, is also considered for oral and topical acne therapy.
Fisetin (3,7,3',4'-Tetrahydroxyflavon), ein natürlich vorkomendes Polyphenol, gehört zur Familie der Flavonoide und wird in 0,5 bis 3%iger Konzentration zur topischen Aknebehandlung eingesetzt. Fisetin (3,7,3 ', 4'-tetrahydroxyflavone), a naturally occurring polyphenol, belongs to the family of flavonoids and is used in 0.5 to 3% concentration for topical acne treatment.
Kombinationen der genannten pflanzlichen mTORCI -Hemmer können in einer weiteren bevorzugten Anwendungsweise zur oralen und topischen Aknetherapie kombiniert werden. In die Kombination mit einbezogen werden können vorteilhafterweise auch andere, bereits mit Anti-Akne-Wirkung beschriebenen Polyphenole wie Resveratrol sowie der Grüteewirkstoff Epigallocatechin-3-gallat sowie deren Derivate. Combinations of said plant mTORCI inhibitors may be combined in another preferred application for oral and topical acne therapy. Advantageously, other polyphenols already described as having anti-acne action, such as resveratrol, as well as the grapevine epigallocatechin-3-gallate and their derivatives may also be included in the combination.
I n einer besonders empfehlenswerten Präparation werden Silymarin mit Resveratrol kombiniert. In a particularly recommended preparation, silymarin is combined with resveratrol.
In einer weiteren bevorzugten Präparation erfolgt eine Kombination von Silymarin mit Resveratrol (Trans-3,4',5-Trihydroxystilben) und dem Grüntee-Polyphenol Epigallocate- chin-3-gallat (EGCG). In a further preferred preparation, a combination of silymarin with resveratrol (trans-3,4 ' , 5-trihydroxystilbene) and the green tea polyphenol epigallocate-chin-3-gallate (EGCG).
Weitere vorteilhafte Kombinationspartner der genannten natürlichen mTORCI -Inhibitoren sind Myricetin und Kaempferol. Further advantageous combination partners of said natural mTORCI inhibitors are myricetin and kaempferol.
Rapamycin (Sirolimus) und Rapalog-Analoga (Rapalogs) sind bekannte Immunsuppressiva und entfalten anti-flammatotische und anti-proliferative Eigenschaften. Rapamycin und Rapaloge wie Everolimus bilden einen Komplex mit dem intrazellulären Rezeptorprotein FK506 binding protein 12 (FKBP12). Dieser Rapamycin bzw. Rapalog-FKBP12-Komplex bindet dann an mTOR und blockiert in allosterischer Weise dessen katalytische Funktion. In einer bevorzugten Anwendung wird Rapamycin (Sirolimus) in einer Konzentration zwischen 0,005% bis 0,05% zur topischen Behandlung der Akne eingesetzt. In einer weiteren vorteilhaften Anwendung erfolgt die topische Aknebehandlung mit Everolismus (RAD001 ) oder 0,005% bis maximal 0,05% . Eine weitere Option zur topischen Aketherapie bietet das Rapamycin-Derviat Temsirolimus (CCI-779, Torisei). Eine weitere topische Therapieoption bietet das Rapamycin-Derviat Deforolimus (AP23573, Ridaforolimus). Eine weitere topische Therapieoption bietet das Rapamycin-Derviat 32-Deoxy-rapamycin (SAR943). Eine weitere topische Therapieoption bietet das Rapalog Zotarolimus (ABT-578). I n einer weiteren bevorzugten Anwendungsform werden die genannten Rapaloge zur Therapieoptimierung und Minimierung der Nebenwirkungen kombiniert. Rapamycin (sirolimus) and Rapalog analogs (Rapalogs) are known immunosuppressants and display anti-inflammatory and anti-proliferative properties. Rapamycin and rapalogues such as everolimus form a complex with the intracellular receptor protein FK506 binding protein 12 (FKBP12). This rapamycin or rapalog FKBP12 complex then binds to mTOR and allosterically blocks its catalytic function. In a preferred application, rapamycin (sirolimus) is used at a level of between 0.005% to 0.05% for the topical treatment of acne. In a further advantageous application, the topical acne treatment is carried out with everolism (RAD001) or 0.005% to a maximum of 0.05%. Another option for topical acne therapy is the rapamycin Derviat temsirolimus (CCI-779, Torisei). Another topical treatment option is Rapamycin Dervia Deforolimus (AP23573, Ridaforolimus). Another topical therapy option is rapamycin derviat 32-deoxy-rapamycin (SAR943). Another topical therapy option is the Rapalog Zotarolimus (ABT-578). In a further preferred embodiment, the said rapalogs are combined for therapy optimization and minimization of side effects.
Seit wenigen Jahren stehen weitere synthetische kleinmolekulare mTORCI -Inhibitoren zur Verfügung, die die ATP-sensitive katalytische Domäne von mTOR kompetitiv hemmen. In einer bevorzugten Therapieform wird das Pyrazolopyrimidin PP242 (2-(4-amino-1 -isopropyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)-1 H-indol-5-ol) (erster selektiver Inhibitor der ATP-Bindungsdomäne von mTOR) zur topischen Therapie der Akne angewendet, in der Weise, dass im Talgdrüsenfollikel Konzentrationen zwischen 5-10 nM erreicht wird. For a few years, additional synthetic small-molecule mTORCI inhibitors have been available that competitively inhibit the ATP-sensitive catalytic domain of mTOR. In a preferred form of therapy, the pyrazolopyrimidine PP242 (2- (4-amino-1-isopropyl-1H-pyrazolo [3,4-d] pyrimidin-3-yl) -1H-indol-5-ol) (first selective Inhibitor of the ATP binding domain of mTOR) for the topical treatment of acne, in such a way that in the sebaceous follicle concentrations between 5-10 nM is reached.
In einer weiteren bevorzugten topischen Anwendung wird PP30 (mTOR-Kinase-lnhibitor) zur topischen Therapie der Akne angewendet, in der Weise, dass im Talgdrüsenfollikel Konentrationen zwischen 50-125 nM erreicht werden. Eine weitere topische Aknetherapie benennt den dualen PI3K und mTOR-lnhibitor BEZ235 (NVP-BEZ235) (2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro- imidazo[4,5-c]quinolin-1 -yl)phenyl)propan-nitril). In a further preferred topical application, PP30 (mTOR kinase inhibitor) is used for the topical treatment of acne in such a way that concentrations between 50-125 nM are achieved in the sebaceous follicle. Another topical acne therapy names the dual PI3K and mTOR inhibitor BEZ235 (NVP-BEZ235) (2-methyl-2- (4- (3-methyl-2-oxo-8- (quinolin-3-yl) -2,3 dihydroimidazo [4,5-c] quinolin-1-yl) phenyl) propane nitrile).
Eine weitere topische Therapieoption bei Akne stellt der duale PI3K- und mTOR-lnhibitor PI-103 (Phenol, 3-[4-(4-morpholinyl)pyndo-[3',2':4,5]furo-[3,2-d]pyrimidin-2-yl) dar. Another topical treatment option for acne is the PI3K and mTOR PI-103 dual inhibitor (phenol, 3- [4- (4-morpholinyl) pyndo- [3 ', 2': 4,5] furo- [3,2 -d] pyrimidin-2-yl).
In einer weitere Anwendungsform wird das Pyridinonqinolin Torini (Benzo[h]-1 ,6- naphthyridin-2(1 H)-one, 1 -[4-[4-(1 -oxopropyl)-1 -piperazinyl] -3-(trifluoromethyl)phenyl]-9-(3- quinolinyl); mTOR-Kinase-l nhibitor) zur topischen Aknetherapie verwendet. In another embodiment, the pyridinone quinoline is Torini (benzo [h] -1, 6-naphthyridin-2 (1H) -one, 1 - [4- [4- (1-oxopropyl) -1-piperazinyl] -3- ( trifluoromethyl) phenyl] -9- (3- quinolinyl); mTOR kinase inhibitor) for topical acne therapy.
In einer weiteren topischen Anwendung kommt das Pyrazolopyrimidin WYE-354 zur topischen Anwendung bei Akne zum Einsatz. In another topical application, pyrazolopyrimidine WYE-354 is used for topical acne treatment.
In einer weiteren topischen Anwendung wird das Pyrazolopyrimidin WYE-1 25132 (Urea,N-[4-[1 -(1 ,4-dioxaspiro[4.5]dec-8-yl)-4-(8-oxa-3-azabicyclo [3.2.1 ]oct-3-yl)-1 H-pyrazolo [3,4-d]pyrimidin-6-yl]phenyl]-N'-methyl) zur topischen Anwendung bei Akne verwendet. In another topical application, the pyrazolopyrimidine WYE-1 25132 (urea, N- [4- [1- (1,4-dioxaspiro [4.5] dec-8-yl) -4- (8-oxa-3-azabicyclo) 3.2.1] oct-3-yl) -1H-pyrazolo [3,4-d] pyrimidin-6-yl] phenyl] -N'-methyl) for topical use in acne.
Eine weitere topische Therapieoption beinhaltet die Anwendung des Pyrazolopyrimidins WAY-600 (6-(1 H-indol-5-yl)-4-morpholino-1 -(1 -(pyridin-3-ylmethyl)piperidin-4-yl)-1 H-pyrazolo [3,4-d]pyrimidine; Kompetitiver ATP-Inhibitor von mTOR). Another topical therapy option involves the use of the pyrazolopyrimidine WAY-600 (6- (1H-indol-5-yl) -4-morpholino-1- (1- (pyridin-3-ylmethyl) piperidin-4-yl) -1 H-pyrazolo [3,4-d] pyrimidines; Competitive ATP inhibitor of mTOR).
Eine weitere topische Therapieoption beschreibt die Anwendung des Pyrazolopyrimidins WYE-687 (Methyl 4-(4-morpholino-1 -(1 -(pyridin-3-ylmethyl)piperidin-4-yl)-1 H-pyrazolo[3,4- d]pyrimidin-6-yl; Kompetitiver ATP-Inhibitor von mTOR). Another topical therapy option describes the use of the pyrazolopyrimidine WYE-687 (methyl 4- (4-morpholino-1- (1- (pyridin-3-ylmethyl) piperidin-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-6-yl; Competitive ATP inhibitor of mTOR).
Eine weitere Option der topischen Therapie mit mTORKinibs ist die topische Verwendung des Pyridopyrimidins Ku-0063794 (5-(2-((2R,6S)-2,6-dimethylmorpholino)-4-morpholin- opyrido[2,3-d]pyrimidin-7-yl)-2-methoxyphenyl; spezifischer mTORCI - und mTORC2- Inhibitor). Another option of topical therapy with mTORKinibs is the topical use of the pyridopyrimidine Ku-0063794 (5- (2 - ((2R, 6S) -2,6-dimethylmorpholino) -4-morpholino-opyrido [2,3-d] pyrimidine -7-yl) -2-methoxyphenyl; specific mTORCI and mTORC2 inhibitor).
Eine weitere Option der topischen Therapie mit mTORKinibs ist die topische Verwendung von INK128 (3-(2-Aminobenzo[d]oxazol-5-yl)-1 -isopropyl-1 H-pyrazolo[3,4-d]pyrimidin-4- amin; Kompetitiver ATP-Inhibitor von mTOR). Another option of topical therapy with mTORKinibs is the topical use of INK128 (3- (2-aminobenzo [d] oxazol-5-yl) -1-isopropyl-1H-pyrazolo [3,4-d] pyrimidine-4 amin; Competitive ATP inhibitor of mTOR).
Eine weitere Option der topischen Therapie mit mTORKinibs ist die topische Verwendung von PF-04691 502 (2-Amino-8-((1 r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin- 3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H). Another option of topical therapy with mTORKinibs is the topical use of PF-04691 502 (2-amino-8 - ((1R, 4R) -4- (2-hydroxyethoxy) cyclohexyl) -6- (6-methoxypyridine-3 -yl) -4-methylpyrido [2,3-d] pyrimidin-7 (8H).
Ein weiterer potentieller mTORCI -Inhibitor zur Aknetherapie ist Palomid 529(3-(4- Methoxybenzyloxy)-8-(1 -hydroxyethyl)-2-methoxy-6H-benzo[c]-chromen-6-on). Eine weitere Option ist OSI-027 ((1 r,4r)-4-(4-Amino-5-(7-methoxy-1 H-indol-2-yl)imidazo[1 ,5- f][1 ,2,4]triazin-7-yl)cyclohexanecarboylxsäure). Another potential mTORCI inhibitor for acne therapy is Palomid 529 (3- (4-methoxybenzyloxy) -8- (1-hydroxyethyl) -2-methoxy-6H-benzo [c] -chromene-6-one). Another option is OSI-027 ((1 r, 4r) -4- (4-amino-5- (7-methoxy-1H-indol-2-yl) imidazo [1,5-f] [1, 2 , 4] triazin-7-yl) cyclohexanecarboylxsäure).
Eine weitere Option ist GSK2126458 (2,4-Difluoro-N-(2-methoxy-5-(4-(pyridazin-4- yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamid). Another option is GSK2126458 (2,4-difluoro-N- (2-methoxy-5- (4- (pyridazin-4-yl) quinolin-6-yl) pyridin-3-yl) benzenesulfonamide).
Eine weitere topische Therapieoption besteht in der Kombination von mTOR-lnhibitoren mit kompetitiven ATP-Inhibitoren von mTOR. In einer weiteren topischen Therapieform werden zur Verminderung pharmakologischer Nebenwirkungen synthetische mTOR-lnhibitoren mit natürlichen mTORCI -Inhibitoren kombiniert wie z.B. Torini mit Curcumin oder INK128 mit Resveratrol oder EGCG. Another topical treatment option is the combination of mTOR inhibitors with competitive ATP inhibitors of mTOR. In another topical therapy, to reduce pharmacological side effects, synthetic mTOR inhibitors are combined with natural mTORCI inhibitors, e.g. Torini with curcumin or INK128 with resveratrol or EGCG.
Viele weitere Kombinationen sind entsprechend der Lehre dieses Patents möglich und sinnvoll. Many other combinations are possible and useful according to the teachings of this patent.
Vorteilhaft sind auch die verschiedenen Verfahren zur Herstellung aller oben genannten Akne-Medikamente, bei denen als wesentliche Bestandteile Substanzen oder Substanzkombinationen verwendet werden, die als Aktivierer des nukleären Transkriptionsfaktors forkhead box class 01 (FoxOl ) und/ oder als Hemmer der metabolisch regulativen Kinase mechanistic (mammalian) target of rapamycin complex 1 (mTORCI ) arbeiten und dadurch eine Anti-Akne-Wirkung entfalten. Also advantageous are the various processes for the preparation of all of the abovementioned acne medicaments, in which substances or substance combinations are used as activators of the nuclear transcription factor forkhead box class 01 (FoxOl) and / or as an inhibitor of the metabolically regulative kinase mechanistic ( mammalian) target of rapamycin complex 1 (mTORCI) and thereby develop an anti-acne effect.
Auch die Verwendung von diesen Substanzen oder Substanzkombinationen zur Herstellung der oben genannten Akne-Medikamente liefert eine neue therapeutische Anwendung, die bislang vollkommen unbekannt war. Also, the use of these substances or combinations of substances for the preparation of the above-mentioned acne drugs provides a new therapeutic application that was previously completely unknown.
Die nachfolgenden Figuren zeigen: Fig. 1 polyzyklischen Verbindungen als die den nukleären FoxOl -Transport hemmende CRM1 -Inhibitoren, 1 shows polycyclic compounds as the nuclear FoxOl transport-inhibiting CRM1 inhibitors,
Fig. 2 ein Schaubild zum FoxO-enhancer und TORC1 -Hemmer Metformin, und Fig. 3 eine Übersicht der FoxO-enhancer und TORC1 -Hemmer Figure 2 is a graph of the FoxO enhancer and TORC1 inhibitor metformin, and Fig. 3 is an overview of FoxO enhancers and TORC1 inhibitors
Die Lehre dieses Patents erklärt die Aknetherapie durch eine pharmakologische Abschwächung der Aktivität der Kinase mTORCI im Bereich der Zellen des Talgdrüsenfollikels des Menschen. Dieses Ziel wird entweder indirekt durch Erhöhung der nukleären Aktivität der FoxO-Transkriptionsfaktoren erreicht und/ oder durch direkte Hemmung der mTORCI -Aktivität mit allosterischen mTOR-lnhibitoren oder natürlichen oder synthetischen mTOR-lnhibitoren (TORKinibs). Die pharmakologische Intervention wird unterstützt durch eine diätetische Intervention im Sinne einer paläolithischen Diät mit Verminderung der glykämischen Last und des insulinotropen, mTORCI -aktivierenden endokrinen Signalsystems Milch. The teaching of this patent explains the acne therapy by a pharmacological attenuation of the activity of the kinase mTORCI in the area of the cells of the sebaceous follicle of humans. This goal is achieved either indirectly by increasing the nuclear activity of FoxO transcription factors and / or by directly inhibiting mTORCI activity with allosteric mTOR inhibitors or natural or synthetic mTOR inhibitors (TORKinibs). The pharmacological intervention is supported by a dietary intervention in the sense of a Paleolithic diet with reduction of the glycemic load and the insulinotropic, mTORCI-activating endocrine signaling system milk.

Claims

P a t e n t a n s p r ü c h e P a n t a n s p r e c h e
Akne-Medikament, dadurch gekennzeichnet, dass zu seiner Herstellung Substanzen oder Substanzkombinationen verwendet sind, die als Aktivierer des nuklearen Transkriptionsfaktors forkhead box class 01 (FoxOl ) und/ oder als Hemmer der metabolisch regulativen Kinase mechanistic (mammalian) target of rapamycin complex 1 (mTORCD wirken, wodurch eine Anti-Akne-Wirkung erzeugbar ist. Acne medication, characterized in that substances or combinations of substances are used for its production which act as activators of the nuclear transcription factor forkhead box class 01 (FoxOl) and / or as inhibitors of the metabolically regulatory kinase mechanistic (mammalian) target of rapamycin complex 1 (mTORCD act, whereby an anti-acne effect is produced.
Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als Substanz mit FoxOl -aktivierender Wirkung Vitamin D und/ oder Vitamin D-Analoga verwendet wird. Acne medication according to claim 1, characterized in that vitamin D and / or vitamin D analogues are used for its production as substance with FoxOl-activating effect.
Akne-Medikament nach Anspruch 2, dadurch gekennzeichnet, dass Vitamin D3 in Dosen von täglich 5000 bis 10000 Einheiten bei Aknepatienten oral anwendbar ist. Acne medication according to claim 2, characterized in that vitamin D3 in doses of 5,000 to 10,000 units per day is orally applicable in acne patients.
Akne-Medikament nach Anspruch 2, dadurch gekennzeichnet, dass Vitamin D und/ oder Vitamin D-Analoga wie Calcipotriol, Maxacalcitol topisch in einer Gel- oder Lotio-Grundlage mit einer Konzentration von 0,001 -0,01 % vorliegt. Acne medication according to claim 2, characterized in that vitamin D and / or vitamin D analogues such as calcipotriol, maxacalcitol is present topically in a gel or lotion base with a concentration of 0.001-0.01%.
Akne-Medikament nach Anspruch 2, dadurch gekennzeichnet, dass es ein bis dreimal täglich äußerlich auftragbar ist. Acne medication according to claim 2, characterized in that it is externally applicable one to three times a day.
Akne-Medikament nach Anspruch 2, dadurch gekennzeichnet, dass eine orale und eine topische Anwendung von Vitamin D und/ oder Vitamin D-Analoga in Kombination Verwendung findet. Acne medication according to claim 2, characterized in that an oral and a topical application of vitamin D and / or vitamin D analogues is used in combination.
Akne-Medikament nach Anspruch 6, dadurch gekennzeichnet, dass eine Dosierung von oral täglich 500-1000 Einheiten Vitamin D sowie eine topische Anwendung von 0,005 % Calcipotriol oder vergleichbaren Vitamin D-Analoga erfolgt. Acne medication according to claim 6, characterized in that a dosage of orally daily 500-1000 units of vitamin D and a topical application of 0.005% calcipotriol or comparable vitamin D analogues takes place.
8. Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als Substanz mit Fox01 -aktivierender Wirkung Leptomycin B (LM B) und/ oder auch LMB-Analoga Verwendung findet. 9. Akne-Medikament nach Anspruch 8, dadurch gekennzeichnet, dass Leptomycin B (LM B) und/ oder LM B-Analoga in einer Konzentration von 0, 1 bis 0,50 nM vorliegt. 8. acne drug according to claim 1, characterized in that for its production as a substance with Fox01 -activating action Leptomycin B (LM B) and / or LMB analogues is used. 9. acne medicament according to claim 8, characterized in that leptomycin B (LM B) and / or LM B analogues in a concentration of 0, 1 to 0.50 nM is present.
10. Akne-Medikament nach Anspruch 9, dadurch gekennzeichnet, dass es ein- bis dreimal täglich in geeigneter Grundlage applizierbar ist. 10. acne medicament according to claim 9, characterized in that it can be administered one to three times a day in a suitable basis.
1 1 . Akne-Medikament nach Anspruch 8, dadurch gekennzeichnet, dass Leptomycin B in einem ethanolischen Gel in einer Konzentration zwischen 0,05 mg/dL bis 0,25 mg/dL vorliegt. 12. Akne-Medikament nach Anspruch 1 1 , dadurch gekennzeichnet, dass es einmal bis zweimal täglich topisch anwendbar ist. 1 1. Acne medication according to claim 8, characterized in that leptomycin B is present in an ethanolic gel in a concentration between 0.05 mg / dL to 0.25 mg / dL. 12. acne medicament according to claim 1 1, characterized in that it is topically applicable once to twice daily.
13. Akne-Medikament nach Anspruch 8, dadurch gekennzeichnet, dass zu seiner Herstellung synthetische LMB1 -Derivative in nM-Konzentrationen zur topischen Behandlung der Akne anwendbar sind. 13. acne medicament according to claim 8, characterized in that for its preparation synthetic LMB1 -derivative in nM concentrations for the topical treatment of acne are applicable.
14. Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als Substanz den nukleären FoxOl -Transport hemmende CRM 1 - Inhibitoren zur topischen Behandlung der Akne in nanomolarer bis mikromolarer Konzentration Verwendung finden. 14. acne medicament according to claim 1, characterized in that for its preparation as a substance the nuclear FoxOl transport inhibiting CRM 1 - inhibitors for the topical treatment of acne in nanomolar to micromolar concentration find use.
1 5. Akne-Medikament nach Anspruch 14, dadurch gekennzeichnet, dass die CRM 1 - Inhibitoren aus polyzyklischen Verbindungen mit den Kurzbezeichnungen NSC17474Z, NSC186057T, 5216177, 5107769, 5233705, 51 60096, NSC891 1 0Q, 5137877, 5271325, 523648, 51 07360, 521 7490, NSC354891 , 5281 1 54,1 5. acne drug according to claim 14, characterized in that the CRM 1 - inhibitors of polycyclic compounds with the short names NSC17474Z, NSC186057T, 5216177, 5107769, 5233705, 51 60096, NSC891 1 0Q, 5137877, 5271325, 523648, 51 07360 , 521 7490, NSC354891, 5281 1 54,
NSC401366Z, 5213337, NSC293046M, 5175309, NSC3548891 , 5145695,NSC401366Z, 5213337, NSC293046M, 5175309, NSC3548891, 5145695,
NSC17600N, B6-7-1 und aus möglichen Derivaten dieser CRM 1 -lnhibitoren bestehen. NSC17600N, B6-7-1 and consist of possible derivatives of these CRM 1 -nnhibitoren.
6. Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als Aktivierer des nukleären Transkriptionsfaktors forkhead box class 01 (FoxOD und gleichzeitig als Hemmer der metabolisch regulativen Kinase mechanistic (mammalian) target of rapamycin complex 1 (mTORCD als Substanz Metformin verwendet wird. 6. acne drug according to claim 1, characterized in that for its production as an activator of the nuclear transcription factor forkhead box class 01 (FoxOD and simultaneously used as an inhibitor of the metabolically regulatory kinase mechanistic (mammalian) target of rapamycin complex 1 (mTORCD substance metformin becomes.
17. Akne-Medikament nach Anspruch 16, dadurch gekennzeichnet, dass Biguanid Metformin in einer Dosis von 500 mg bis 2000 mg täglich verabreichbar ist. 17. acne medicament according to claim 16, characterized in that biguanide metformin in a dose of 500 mg to 2000 mg daily administered.
18. Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als Substanz mTORCI -Hemmer als natürliche und synthetische mTORCI -Inhibitoren zur Anwendung kommen. 18. acne medicament according to claim 1, characterized in that for its preparation as a substance mTORCI inhibitors as natural and synthetic mTORCI inhibitors are used.
19. Akne-Medikament nach Anspruch 1 8, dadurch gekennzeichnet, dass die Hemmung der ATP-sensitiven Kinase-Domäne von mTOR durch natürliche pflanzliche Polyphenole und synthetische mTORKinibs erfolgt. 19. acne medicament according to claim 1 8, characterized in that the inhibition of the ATP-sensitive kinase domain of mTOR by natural plant polyphenols and synthetic mTORKinibs takes place.
20. Akne-Medikament nach Anspruch 18, dadurch gekennzeichnet, dass pflanzliche mTORCI -Hemmer aus Curcumin (Diferuloylmethan), einem Polyphenol der Pflanze Curcuma longa und/ oder aus Curcumin-Derivaten besteht. 20. acne medicament according to claim 18, characterized in that plant mTORCI inhibitors of curcumin (diferuloylmethane), a polyphenol of the plant Curcuma longa and / or curcumin derivatives.
21 . Akne-Medikament nach Anspruch 20 dadurch gekennzeichnet, dass Curcumin und/ oder Curcumin-Derivate oral und/ oder zur topischen Behandung der Akne einsetzbar sind. 21. Acne medication according to claim 20, characterized in that curcumin and / or curcumin derivatives can be used orally and / or for the topical treatment of acne.
22. Akne-Medikament nach Anspruch 21 , dadurch gekennzeichnet, dass Curcumin Aknebetroffenen in Kapselform mit je 250 bis 500 mg zweimal täglich zu den Mahlzeiten verabreichbar ist. 22. acne medicament according to claim 21, characterized in that curcumin Aknebrooffenen in capsule form with 250 to 500 mg administered twice daily with meals.
23. Akne-Medikament nach Anspruch 21 , dadurch gekennzeichnet, dass Curcumin in einer 0,5 - 3%igen Zubereitung als Gel oder Lotion, oder in Form von Gesichtsmasken zur topischen Aknebehandlung anwendbar ist. 23. acne medicament according to claim 21, characterized in that curcumin is applicable in a 0.5 - 3% preparation as a gel or lotion, or in the form of facial masks for topical acne treatment.
24. Akne-Medikament nach Anspruch 1 r dadurch gekennzeichnet, dass zu seiner Herstellung als Substanz mTO Cl-Hemmar 3,3'-DiindoMmethan zur Anwendung kommt. 24. acne medicament according to claim 1 r characterized in that is used for its preparation as a substance mTO Cl-Hemmar 3,3'-DiindoMmethan used.
25. Akne-Medikament nach Anspruch 24, dadurch gekennzeichnet, dass 3,3'- Diindolylmethan in einer Tagesdosis von 2x 200 mg bis 2x 500 mg in Kapselfcrm zu den Mahlzeiten verabreichbar ist. 25. acne medicament according to claim 24, characterized in that 3,3'-diindolylmethane in a daily dose of 2x 200 mg to 2x 500 mg in capsule crem at meals is administered.
26. Akne-Medikament nach Anspruch 24, dadurch gekennzeichnet, dass die externe topische Behandlung mit 3,3 -Diindolylmethan in Form 0,5 bis 3%iger Gele oder Lotionen oder. Lösungen durchführbar ist. 26. acne medicament according to claim 24, characterized in that the external topical treatment with 3,3-di-indolylmethane in the form of 0.5 to 3% gels or lotions or. Solutions is feasible.
27. Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als Substanz mTORCI -Hemmer Genistein als natürlich vorkommendes Isoflavon und Phytoestrogen von Soja zur Anwendung kommt. 27. acne drug according to claim 1, characterized in that for its production as a substance mTORCI inhibitor genistein comes as a naturally occurring isoflavone and phytoestrogen from soybean used.
28. Akne-Medikament nach Anspruch 27, dadurch gekennzeichnet, dass Genistein in einer Dosis von täglich je 100 bis 200 mg in Kapselform ein bis zweimal täglich verabrelchbar ist. 28. acne medication according to claim 27, characterized in that genistein in a daily dose of 100 to 200 mg in capsule form once or twice daily verabrelchbar.
29. Akne-Medikament nach Anspruch 27, dadurch gekennzeichnet, dass die topische Behandlung mit einer Konzentration von 0,5-5% Genistsin in Form von Gelen, Lotionen und Lösungen ein bis zweimal am Tag durchführbar ist. 30. Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als Substanz mTORCI -Hemmer Silymarin, ein natürliches pflanzliches Flavanolignan, zur Anwendung kommt. 29. acne medicament according to claim 27, characterized in that the topical treatment with a concentration of 0.5-5% Genistsin in the form of gels, lotions and solutions one to twice a day is feasible. 30. acne medicament according to claim 1, characterized in that for its preparation as a substance mTORCI inhibitor silymarin, a natural vegetable flavanolignan, is used.
31. Akne-Medikament nach Anspruch 30, dadurch gekennzeichnet, dass Silymarin in einer oralen Anwendungsform zwei bis dreimal täglich in Kapselform je 100 mg verabreichbar ist. 31. Acne medicament according to claim 30, characterized in that silymarin can be administered in an oral application form two to three times a day in capsule form per 100 mg.
32. Akne-Medikament nach Anspruch 30, dadurch gekennzeichnet, dass Silymarin bei topischer Behandlung in 0,5 bis 10%igen O/W Emulsionen, Gelen oder alkoholischen Lösungen zur Anwendung kommt. 32. acne medicament according to claim 30, characterized in that silymarin at topical treatment in 0.5 to 10% O / W emulsions, gels or alcoholic solutions is used.
Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als mTORCI -Hemmer Quercetin, ein Bioflavonoid, zur Anwendung kommt. Acne medication according to claim 1, characterized in that quercetin, a bioflavonoid, is used for its production as mTORCI inhibitor.
Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als Substanz mTORCI -Hemmer Fisetin (3,7,3',4'-Tetrahydroxyflavon), ein natürlich vorkomendes Polyphenol aus der Familie der Flavonoide, zur Anwendung kommt. Acne medication according to claim 1, characterized in that fisetin (3,7,3 ', 4'-tetrahydroxyflavone), a naturally occurring polyphenol from the family of flavonoids, is used for its preparation as substance mTORCI inhibitor.
Akne-Medikament nach Anspruch 34, dadurch gekennzeichnet, dass Fisetin bei topischer Behandlung in 0,5 bis 3% iger Konzentration zur Anwendung kommt. Acne medication according to claim 34, characterized in that fisetin is used in topical treatment in 0.5 to 3% concentration.
Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als Substanz pflanzliche mTORCI -Hemmer die Substanzen Curcumin, Curcumin-Derivate, 3,3'-Diindolylmethan, Genistein, Silymarin, Quercetin oder Fisetin zusammen mit bereits mit Anti-Akne-Wirkung beschriebenen Polyphenolen wie Resveratrol und/ oder dem Grünteewirkstoff Epigallocatechin-3-gallat sowie deren Derivaten kombinierbar sind. Acne medication according to claim 1, characterized in that for producing the same substance as vegetable mTORCI inhibitor, the substances curcumin, curcumin derivatives, 3,3 '-Diindolylmethan, genistein, silymarin, quercetin, fisetin, or together with already having anti-acne Effect described polyphenols such as resveratrol and / or the green tea epigallocatechin-3-gallate and their derivatives can be combined.
37. Akne-Medikament nach Anspruch 36, dadurch gekennzeichnet, dass zu seiner Herstellung als Substanzen Silymarin mit Resveratrol miteinander kombiniert sind. 37. Acne medicament according to claim 36, characterized in that silymarin with resveratrol are combined with one another for its preparation as substances.
38. Akne-Medikament nach Anspruch 36, dadurch gekennzeichnet, dass zu seiner Herstellung als Substanzen Silymarin mit Resveratrol (Trans-3,4',5-Trihydroxystilben) und dem Grüntee-Polyphenol Epigallocatechin-3-gallat (EGCG) miteinander kombiniert sind. 38. acne medicament according to claim 36, characterized in that for its preparation as substances silymarin with resveratrol (trans-3,4 ' , 5-trihydroxystilbene) and the green tea polyphenol epigallocatechin-3-gallate (EGCG) are combined.
39. Akne-Medikament nach Anspruch 36, dadurch gekennzeichnet, dass zu seiner Herstellung als Substanzen Myricetin und Kaempferol miteinander kombiniert sind. 39. Acne medication according to claim 36, characterized in that for its production as substances Myricetin and Kaempferol are combined.
40. Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als mTORCI -Hemmer die Substanzen Rapamycin (Sirolimus), mit Everolismus, Temsirolimus (CCI-779, Torisei) als Rapamycin-Derviat, Deforolimus (AP23573, Ridaforolimus) als Rapamycin-Derviat, 32-Deoxy-rapamycin (SAR943) als Rapamycin-Derviat, Rapalog Zotarolimus (ABT-578) allein oder in einer Kombination verwendet sind. 40. Acne medication according to claim 1, characterized in that for its production as mTORCI inhibitors the substances rapamycin (sirolimus), with everolism, temsirolimus (CCI-779, Torisei) as rapamycin Derviat, Deforolimus (AP23573, Ridaforolimus) as Rapamycin-Derviat, 32-deoxy-rapamycin (SAR943) are used as rapamycin-Derviat, Rapalog Zotarolimus (ABT-578) alone or in combination.
41 . Akne-Medikament nach Anspruch 40, dadurch gekennzeichnet, dass zur topischen Behandlung der Akne Rapamycin (Sirolimus) in einer Konzentration zwischen 0,005% bis 0,05% anwendbar ist. 41. Acne medication according to claim 40, characterized in that the topical treatment of acne rapamycin (sirolimus) in a concentration between 0.005% to 0.05% is applicable.
42. Akne-Medikament nach Anspruch 40, dadurch gekennzeichnet, dass zur topischen Behandlung der Akne Everolismus (RAD001 ) in einer Konzentration zwischen 0,005% bis maximal 0,05% anwendbar ist. 42. Acne medication according to claim 40, characterized in that for the topical treatment of acne Everolismus (RAD001) in a concentration between 0.005% to a maximum of 0.05% is applicable.
43. Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als mTORCI -Hemmer die synthetischen mTOR Kinase-I nhibitoren Pyrazolopyrimidin PP242 (2-(4-amino-1 -isopropyl-1 H-pyrazolo[3,4-d]pyrimidin-3-yl)- 1 H-indol-5-ol), PP30 (mTOR-Kinase-l nhibitor), BEZ235 (NVP-BEZ235) (2-methyl-2-(4- (3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1 -yl)phenyl)propan- nitril), PI-1 03 (Phenol, 3-[4-(4-morpholinyl)pyrido-[3,,2' :4,5]furo-[3,2-d]pyhmidin-2-yl), Pyridinonqinolin Torini (Benzo[h]-1 ,6-naphthyridin-2(1 H)-one, 1 -[4-[4-(1 -oxopropyl)-1 - piperazinyl] -3-(trifluoromethyl)phenyl]-9-(3-quinolinyl), Pyrazolopyrimidin WYE-354, Pyrazolopyrimidin WYE-1 251 32 (Urea, N-[4-[ 1 -(1 ,4-dioxaspiro[4.5]dec-8-yl)-4-(8-oxa-3- azabicyclo [3.2.1 ]oct-3-yl)-1 H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl]-N '-methyl), Pyra- zolopyrimidins WAY-600 (6-(1 H-indol-5-yl)-4-morpholino-1 -(1 -(pyridin-3-ylmethyl) piperidin-4-y l)-1 H-pyrazolo[3,4-d]pyrimidine, Pyrazolopyrimidins WYE-687 (Methyl 4- (4-morpholino-1 -(1 -(pyridin-3-ylmethyl)piperidin-4-yl)-1 H-pyrazolo[3,4-d]pyrimidin-6-yl, Pyridopyrimidins Ku-0063794 (5-(2-((2R,6S)-2,6-dimethylmorpholino)-4- morpholinopyrido[2,3-d]pyrimidin-7-yl)-2-methoxyphenyl, I N K1 28 (3-(2-43. Acne medicament according to claim 1, characterized in that for its preparation as mTORCI inhibitor the synthetic mTOR kinase inhibitors pyrazolopyrimidine PP242 (2- (4-amino-1-isopropyl-1H-pyrazolo [3,4- d] pyrimidin-3-yl) -1H-indol-5-ol), PP30 (mTOR kinase inhibitor), BEZ235 (NVP-BEZ235) (2-methyl-2- (4- (3-methyl) 2-oxo-8- (quinolin-3-yl) -2,3-dihydroimidazo [4,5-c] quinolin-1-yl) phenyl) propane nitrile), PI-1 03 (phenol, 3- [4 - (4-morpholinyl) pyrido [3 , 2 ': 4,5] furo [3,2-d] pyhmmy-2-yl), pyridinone quinoline, Torini (benzo [h] -1, 6-naphthyridine-2 (1H) -one, 1 - [4- [4- (1 -oxopropyl) -1-piperazinyl] -3- (trifluoromethyl) phenyl] -9- (3-quinolinyl), pyrazolopyrimidine WYE-354, pyrazolopyrimidine WYE- 1 251 32 (urea, N- [4- [1 - (1,4-dioxaspiro [4.5] dec-8-yl) -4- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl ) -1 H -pyrazolo [3,4- d] pyrimidin-6-yl] phenyl] -N'-methyl), pyrazolopyrimidine WAY-600 (6- (1H-indol-5-yl) -4- morpholino-1 - (1- (pyridin-3-ylmethyl) piperidin-4-yl) -1 H -pyrazolo [3,4-d] pyrimidines, Pyrazo lopyrimidines WYE-687 (Methyl 4- (4-morpholino-1- (1- (pyridin-3-ylmethyl) piperidin-4-yl) -1 H -pyrazolo [3,4-d] pyrimidin-6-yl, pyridopyrimidine Ku-0063794 (5- (2 - ((2R, 6S) -2,6-dimethylmorpholino) -4-morpholinopyrido [2,3-d] pyrimidin-7-yl) -2-methoxyphenyl, IN K1 28 (3 (2-
Aminobenzo[d]oxazol-5-yl)-1 -isopropyl-1 H-pyrazolo[3,4-d]pyrimidin-4-amin, PF- 04691 502 (2-Amino-8-((1 r,4r)-4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3- yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H), Palomid 529(3-(4-Methoxybenzyloxy)-8-(1 - hydroxyethyl)-2-methoxy-6H-benzo[c]-chromen-6-on), OSI-027 ((1 r,4r)-4-(4-Amino-5- (7-methoxy-1 H-indol-2-yl)imidazo[1 ,5-f][1 ,2,4]triazin-7-yl)cyclohexanecarboylxsäure), GSK2126458 (2,4-Difluoro-N-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3- yDbenzenesulfonamid) allein oder in einer Kombination von mTOR-lnhibitoren mit kompetitiven ATP-Inhibitoren von mTOR verwendet sind. Aminobenzo [d] oxazol-5-yl) -1-isopropyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine, PF-04691 502 (2-amino-8 - ((1R, 4R) -4- (2-hydroxyethoxy) cyclohexyl) -6- (6-methoxypyridin-3-yl) -4-methylpyrido [2,3-d] pyrimidine-7 (8H), palomide 529 (3- (4-methoxybenzyloxy) -8- (1 - hydroxyethyl) -2-methoxy-6H-benzo [c] -chromene-6-one), OSI-027 ((1R, 4R) -4- (4-amino-5- (7-methoxy-1H-indole -2-yl) imidazo [1,5-f] [1,2,4] triazin-7-yl) cyclohexanecarboxylic acid), GSK2126458 (2,4-difluoro-N- (2-methoxy-5- (4- (4-yl) pyridinazin-4-yl) quinolin-6-yl) pyridine-3-yenbenzenesulfonamide) are used alone or in a combination of mTOR inhibitors with competitive ATP inhibitors of mTOR.
44. Akne-Medikament nach Anspruch 1 , dadurch gekennzeichnet, dass zu seiner Herstellung als mTORCI -Hemmer synthetische mTOR-lnhibitoren mit natürlichen mTORCI -lnhibitoren kombiniert sind. 44. acne medicament according to claim 1, characterized in that for its production as mTORCI inhibitors synthetic mTOR inhibitors are combined with natural mTORCI -nnhibitoren.
45. Akne-Medikament nach Anspruch 44, dadurch gekennzeichnet, dass Torini mit Curcumin oder INK1 28 mit Resveratrol oder EGCG in einer Kombination verwendet sind. 46. Verfahren zur Herstellung eines Akne-Medikaments nach einem der Ansprüche 1 - 45, dadurch gekennzeichnet, dass als wesentlicher Bestandteil dieses Akne- Medikaments Substanzen oder Substanzkombinationen verwendet werden, die als Aktivierer des nukleären Transkriptionsfaktors forkhead box class 01 (FoxOD und/ oder als Hemmer der metabolisch regulativen Kinase mechanistic (mammalian) target of rapamycin complex 1 (mTORCI ) arbeiten und dadurch eine Anti-Akne-45. acne medicament according to claim 44, characterized in that Torini with curcumin or INK1 28 with resveratrol or EGCG are used in a combination. 46. A process for the preparation of an acne medicament according to any one of claims 1-45, characterized in that substances or substance combinations are used as an essential component of this acne drug, which activates the nuclear transcription factor forkhead box class 01 (FoxOD and / or as Inhibitors of the metabolically regulatory kinase mechanistic (mammalian) target of rapamycin complex 1 (mTORCI) work and thereby produce an anti-acne
Wirkung entfalten. Unfold their effect.
Verwendung von Substanzen oder Substanzkombinationen nach einem der vorge¬ nannten Ansprüche 1 - 45 zur Herstellung eines Akne-Medikaments, die als Aktivierer des nukleären Transkriptionsfaktors forkhead box class 01 (FoxOD und/ oder als Hemmer der metabolisch regulativen Kinase mechanistic (mammalian) target of rapamycin complex 1 (mTORCI ) fungieren. Use of substances or combinations of substances according to any one of the ¬ called Claims 1-45 for preparing a acne medicament, which (as Activators of the nuclear transcription factor forkhead box class 01 FoxOD and / or mechanistic as inhibitors of metabolic regulatory kinase (mammalian) target of rapamycin complex 1 (mTORCI) act.
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