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Treatment of skin disorders
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A technology for dermatological diseases and compounds, applied in the field of dermatological compounds and their pharmaceutical compositions, which can solve problems such as unmet medical needs in treatment and therapy
Pending Publication Date: 2020-06-19
TORQUR AG
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However, physicians still consider topical application of rapamycin and its analogs, especially on children's faces, to be undesirable
[0020] Therefore, for skin diseases caused by excessive angiogenesis and / or fibrogenesis (such as angiofibromas and periungual fibromas) (and therefore especially associated with tuberous sclerosis (TSC), other hereditary skin diseases and complex There is a high unmet medical need for the treatment and therapy of vascular abnormalities associated with skin diseases
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[0374] Preparation of compounds of the present invention
[0375] The compounds of the present invention may be synthesized by synthetic routes comprising methods analogous to those well known in the chemical arts, particularly the description contained herein with respect to light. Furthermore, the synthesis of the compounds of the present invention and the intermediates used in said synthesis of the compounds of the present invention have been described in WO2016 / 075130 and in the application PCT / EP2017 / 025137 filed on May 17, 2017. Starting materials are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art.
[0376] In preparing compounds of the invention, it may be desirable to protect remote functionality (eg, primary or secondary amines) of intermediates. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation method. Suitable ami...
example 1
[0386] Preparation of Intermediate Compounds and Compounds of the Invention
[0387] Preparation of intermediate compounds
[0388] Intermediate compounds used to produce compounds of formula (I) were prepared using the following methods. Said methods for the preparation of said intermediates and the synthesis of exemplified intermediates for the preparation of compounds of the invention have been described in WO 2016 / 075130 and in application PCT / EP2017 / 025137 filed on May 17, 2017 . Therein, these methods are numbered and referred to as "Method 1", "Method 2" and so on, and intermediates exemplified and synthesized by the methods are referred to as "i1", "i2" and so on. This numbering is used to distinguish intermediates from compounds of formula (I). When referring to compounds of formula (I), compound numbers such as "1", "2", "1*", "2*" etc. without the prefix "i" are used. The same numbering concepts and the same specific references and reference numbers for specific...
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[0579] In vitro mTOR binding assay and intracellular Western Blot
[0580] In vitro mTOR binding assay
[0581] mTOR with a GST tag at the N-terminus (Cat. No. PR8683B; 0.45 mg / ml; truncated version: amino acids 1360-2549), 647-labeled Kinase Tracer 314 (Cat. No. PV6087), LanthaScreen Eu-anti-GST Tag antibody (Cat. No. PV5594) were purchased from Life Technologies. 1x mTOR Kinase Buffer consists of 50mM HEPES (pH 7.5), 5mM MgCl 2 , 1 mM EGTA and 0.01% Pluronic F-127 (Sigma Cat# P2443-250G).
[0582]The mTOR binding assay was performed on 10-point 4-fold serial dilutions of each compound (in duplicate) in 384-well plates (highest concentration 10 μmol / L and lowest concentration 40 pmol / L). For the LanthaScreen kinase binding assay, 5 μl of the test compound was concentrated to 3x the final concentration, 5 μl of the 9 nM GST-mTOR / 6 nM Eu-anti-GST antibody mixture and 5 μl of the 30 nM tracer 314 solution were mixed together to obtain a Final concentrations of 3 nM GST-mTOR...
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Abstract
The present invention relates to a compound of formula (I), wherein X<1>, X<2> and X<3> are, independently of each other, N or CH; with the proviso that at least two of X<1>, X<2> and X<3> are N; Y isN or CH; W is H or F; with the proviso that when W is F, then X<1>, X<2> and X<3> are N; R<1> and R<2> are independently of each other (i) a morpholinyl of formula (II) wherein the arrow denotes thebond in formula (I); and wherein R<3> and R<4> are independently of each other H, C1-C3alkyl optionally substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(O)0-C1- C2alkyl; or R<3> and R<4> form together a bivalent residue -R<5>R<6>- selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-0-CH2-, -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II); or (ii) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally substituted by 1 to 3 R<7>; wherein R<7> isindependently at each occurrence C1-C3alkyl optionally substituted with one or two OH, C1-C2fluoroalkyl, C1- C2alkoxyC1-C3alkyl, C3-C6cycloalkyl; or two R<7> substituents form together a bivalent residue -R<8>R<9>- selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-0-CH2- or -0- CH2CH2-0-; with the proviso that at least one of R<1> and R<2> is a morpholinyl of formula II; andprodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts thereof, for use in a method of treating a skin disorder in a subject, wherein said skin disorder is a genodermatosis,a vascular anomaly or a skin disorder selected from scleroderma, sclerodermatous chronic graft-versus-host disease, lichen sclerosus, lichen planus, lichen ruber planus and scars.
Description
[0001] In particular the present invention relates to compounds and pharmaceutical compositions thereof for use in the treatment of a skin disorder in a subject, wherein said skin disorder is a genetic disease skin disease, a vascular abnormality or a skin disease selected from the group consisting of scleroderma, scleroderma-like Chronic graft versus host disease, lichen sclerosus, lichen planus, lichen planus, angiofibromas (preferably facial angiofibromas), and scarring. Background technique [0002] Mammalian target of rapamycin (mTOR) is a large serine / threonine-specific protein kinase that can associate with a protein-binding partner to form one of two functionally distinct mTOR complexes that regulate different cellular Process of mTORC1 and mTORC2. mTOR can be inhibited by inhibition of upstream kinases such as PI3K and / or AKT or by direct inhibition of mTOR kinase by allosteric (rapamycin) or ATP site-directed inhibitors (Saxton RA, Sabatini DM (2017) Cell "168:960-9...
Claims
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Application Information
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