WO2022042390A1 - Utilisation de composés d'hydroxypurine pour le traitement de maladies de la peau - Google Patents

Utilisation de composés d'hydroxypurine pour le traitement de maladies de la peau Download PDF

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WO2022042390A1
WO2022042390A1 PCT/CN2021/113197 CN2021113197W WO2022042390A1 WO 2022042390 A1 WO2022042390 A1 WO 2022042390A1 CN 2021113197 W CN2021113197 W CN 2021113197W WO 2022042390 A1 WO2022042390 A1 WO 2022042390A1
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compound
acid
group
optionally substituted
skin
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PCT/CN2021/113197
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English (en)
Chinese (zh)
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陈小新
黄淑娟
刘苗
陈谋
刘志强
刘卓伟
龙超峰
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广东众生睿创生物科技有限公司
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Priority to CN202180059940.6A priority Critical patent/CN116264834A/zh
Publication of WO2022042390A1 publication Critical patent/WO2022042390A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • 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
    • A61P17/06—Antipsoriatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms

Definitions

  • the invention relates to the field of medicines for treating skin diseases, in particular to the application of a series of hydroxypurine compounds in the preparation of medicines for treating skin diseases, especially atopic dermatitis.
  • Phosphodiesterase catalyzes the hydrolysis of the cyclic nucleotides cGMP and cAMP, and regulates various physiological responses by controlling the intramolecular concentrations of these two important secondary signaling factors.
  • the abnormal regulation of cyclic nucleotides cGMP and cAMP molecules is the cause of many diseases, and now there are many drugs to improve and treat diseases by inhibiting the activity of PDE, such as PDE5 inhibitors for pulmonary arterial hypertension, PDE4 inhibitors for Arthritis caused by psoriasis.
  • PDE5 inhibitors for pulmonary arterial hypertension PDE4 inhibitors for Arthritis caused by psoriasis.
  • PDE4 inhibitors for Arthritis caused by psoriasis.
  • Tumor necrosis factor alpha (tumor necrosis factor alpha, TNF- ⁇ ) is a cytokine with a variety of biological activities, which has an important impact on the occurrence, development and treatment of various diseases, especially immune and inflammation-related diseases.
  • TNF- ⁇ is mainly produced by monocytes and macrophage cell lines and is involved in the body's immune regulation and cytokine network coordination. Normally, TNF- ⁇ plays an important role in immune defense and immune surveillance, but in some cases it has adverse effects.
  • TNF- ⁇ can induce the expression of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, etc., increase endothelial cell permeability, up-regulate the expression of adhesion molecules, and activate neutralization.
  • pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, etc.
  • IL-1 interleukin-1
  • IL-6 IL-6
  • white blood cells and eosinophils and induce synovial cells and chondrocytes to secrete acute phase substances and tissue degrading enzymes to promote the occurrence of inflammation.
  • TNF- ⁇ is an ideal target for many of the above IMIDs.
  • TNF- ⁇ antagonists TNF- ⁇ inhibitors
  • Neutralizing excess TNF- ⁇ is also an effective prevention and treatment approach.
  • TNF- ⁇ monoclonal antibody has been clinically proved that inhibiting TNF- ⁇ is a very effective means to treat the above-mentioned inflammation-related diseases.
  • PDE can regulate the expression of TNF- ⁇ , so it can control the level of TNF- ⁇ by regulating the activity of PDE, so as to control the inflammatory response.
  • Cyclic nucleotides cGMP and cAMP transduce external signals by activating key cellular effectors such as protein kinase A (PKA).
  • PKA protein kinase A
  • PKA inhibits the activity of many transcription factors through phosphorylation, including the nuclear factor Kappa-light-chain-enhancer of activated T-cells (NFAT), which activates B lymphocytes.
  • NFAT nuclear factor Kappa-light-chain-enhancer of activated T-cells
  • TNF- ⁇ tumor necrosis factor IL-2, IL-4, IL-6, IL-31 and tumor necrosis factor TNF- ⁇
  • T lymphocytes helper T lymphocytes (T-helper, Inflammatory responses of cells such as Th)2 cells, such as neutrophil degranulation, chemotaxis and endothelial cell adhesion.
  • T-helper helper T lymphocytes
  • Th2 cells such as neutrophil degranulation, chemotaxis and endothelial cell adhesion.
  • AD Atopic dermatitis
  • PDE4 is one of the effective targets for the treatment of AD.
  • PDE4 inhibitors reduce the release of downstream cytokines and chemokines by inducing the increase of intracellular cAMP and the activation of PKA to inhibit the NFAT and NF ⁇ B signaling pathways.
  • Crisaborole (AN2728) is a small molecule borylbenzoxolane PDE4 inhibitor that has been shown to improve disease severity in AD patients.
  • Crisaborole was approved by the FDA for the first time in 2016 and is the first new molecular entity approved by the US FDA for the treatment of atopic dermatitis (eczema) in the past 15 years in 2016.
  • the U.S. FDA approved the extension of Crisaborole ointment to 3-month-old children with mild-to-moderate atopic dermatitis, making it the first and only 3-month-old with mild to moderate atopic dermatitis.
  • Topical prescription drugs for children with moderate AD are examples of topical prescription drugs for children with moderate AD.
  • OPA-15406 as another PDE4 inhibitor ointment formulation, has achieved good efficacy in Phase I and Phase II clinical trials for AD 10 to 70 years old.
  • the pharmacokinetics of OPA-15406 which is highly selective for one PDE4B subtype, but also inhibits PDE2, was also evaluated in Phase I and II clinical trials. Overall, OPA-15406 was shown to be safe and well tolerated in all studies.
  • European Patent EP544391 filed by Teva Pharmaceuticals on August 19, 1992, discloses pentoxifylline for topical treatment of psoriasis and atopic dermatitis.
  • Chinese patent ZL201580054840.9 applied by Guangdong Zhongsheng Ruichuang Biotechnology Co., Ltd., disclosed a series of hydroxypurine compounds on 2017.08.01, which have the effect of inhibiting PDE2.
  • the present invention provides the application of the compound represented by formula (I), its tautomer or its pharmaceutically acceptable salt in the preparation of a medicine for treating skin diseases,
  • L 11 is selected from absent, C(R)(R');
  • R and R' are independently selected from H, halogen, OH, NH 2 , CN, optionally substituted C 1-6 alkyl or heteroalkyl;
  • R, R' can be cyclized together with the carbon atoms to which they are attached to form a 3-6 membered cycloalkyl, heterocycloalkyl;
  • A is absent, or optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • L 12 is selected from optionally substituted C 1-6 alkyl or heteroalkyl
  • R 1 is selected from optionally substituted C 1-6 alkyl, 3-6 membered cycloalkyl or heteroalkyl;
  • the substituents in the above R, R', A, L 12 , R 1 are independently selected from halogen, OH, NH 2 , CN, C 1-6 alkyl, 3-6 membered cycloalkane or heteroalkyl, the number of substituents per group is independently selected from 1, 2, or 3.
  • the substituents in the above R, R', A, L 12 , R 1 are independently selected from halogen, CF 3 , CN, OH, Me, Et, n-propyl, isopropyl, cyclopropyl,
  • R and R' are independently selected from H, Me, CF 3 and Et.
  • the above L 11 is selected from
  • the above A is selected from optionally substituted: 3- to 12-membered cycloalkyl or heterocycloalkyl, 5- to 12-membered aryl or heteroaryl.
  • the above A is selected from optionally substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypentyl, phenyl, pyridyl, pyrazinyl, oxazolyl , isoxazolyl, thiazolyl, bicyclo[1.1.1]pentane, or bicyclyl, spirocyclyl, or parcyclyl selected from any two of the foregoing groups.
  • the above-mentioned A is selected from optionally substituted:
  • the above-mentioned A is selected from
  • L 12 is selected from methylene
  • R 1 is selected from Me, CHF 2 , CF 3 , Et, CH 2 CF 3 , isopropyl, cyclopropyl,
  • the present invention specifically relates to the application of the compound of the following formula in the preparation of a medicine for the treatment of skin diseases:
  • the present invention relates to the application of the compound of the following formula in the preparation of a medicine for the treatment of skin diseases:
  • the present invention relates to the application of the compound in the preparation of medicaments for treating skin diseases, preferably atopic dermatitis, psoriasis, contact dermatitis, other eczematous dermatitis, and delayed hypersensitivity; vegetative and solar Dermatitis; seborrheic dermatitis, dermatitis herpetiformis; lichen planus, lichen sclerosus, lichen atrophicus, pyoderma gangrenosum, cutaneous sarcoidosis, angioedema, vasculitis, toxic erythema, cutaneous eosinophilia , localized alopecia, male pattern baldness, Sweet's syndrome, Wer-Ke syndrome, erythema multipleis; infectious or non-infectious cellulitis; panniculitis; cutaneous lymphoma, non-melanoma skin cancer or Other dysplastic lesions; drug-induced disorders, including fixed drug eruptions.
  • skin diseases preferably atopic derma
  • the above-mentioned skin disease is selected from atopic dermatitis.
  • the present invention relates to the application of the compound in the preparation of a medicine for treating skin diseases, the compound is compound 1 represented by the following formula, and the skin disease is atopic dermatitis,
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc.
  • inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate,
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound.
  • the parent form of a compound differs from its various salt forms by certain physical properties, such as solubility in polar solvents.
  • pharmaceutically acceptable salts pertain to derivatives of compounds of the present invention wherein the parent compound is modified by salt formation with an acid or salt formation with a base.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include conventional nontoxic salts or quaternary ammonium salts of the parent compound, such as those formed from nontoxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxy, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, bismuth Xinafoic acid, pantothenic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferably used.
  • the compounds provided herein also exist in prodrug forms.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention.
  • prodrugs can also be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention relates to all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient.
  • Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, tackifiers, penetration enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • excipient generally refers to a carrier, diluent and/or other medium required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating the target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
  • Ketone substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent's bond can be cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring.
  • substituent When a listed substituent does not indicate through which atom it is attached to a compound included in the general formula but not specifically mentioned, such substituent may be bonded through any of its atoms. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, structural unit Indicates that it can be substituted at any position on cyclohexyl or cyclohexadiene.
  • halo or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl.
  • halo( C1 - C4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like Wait.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above-mentioned alkyl groups having the specified number of carbon atoms attached through an oxygen bridge.
  • C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy.
  • alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and S- pentoxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. 3-7 cycloalkyl includes C3, C4 , C5 , C6 and C7 cycloalkyl.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds are present at any stable site on the chain, such as vinyl and propenyl.
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. So-called rings include monocyclic, bicyclic, spirocyclic, paracyclic or bridged rings.
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means 5-7 atoms arranged around it. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms.
  • 5-7 membered ring includes, for example, phenyl, pyridyl, and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but not phenyl .
  • ring also includes ring systems containing at least one ring, wherein each "ring" independently meets the above definition.
  • heterocycle or “heterocyclyl” means a stable heteroatom or heteroatom-containing monocyclic, bicyclic, or tricyclic ring, which may be saturated, partially unsaturated, or unsaturated ( aromatic), which contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a carbocycle to form a bicyclic ring.
  • Nitrogen atoms can be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein).
  • the heterocycle can be attached to any heteroatom or pendant carbon atom to form a stable structure.
  • the heterocycles described herein may undergo substitution at the carbon or nitrogen positions if the resulting compound is stable.
  • the nitrogen atoms in the heterocycle are optionally quaternized.
  • a preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred solution is that the total number of S and O atoms in the heterocycle does not exceed 1.
  • aromatic heterocyclic group or “heteroaryl” means a stable aromatic 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • Nitrogen atoms can be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein).
  • Bridged rings are also included in the definition of heterocycle.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
  • Preferred "bridges" in bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In bridged rings, substituents on the ring may also appear on the bridge.
  • heterocyclic compounds include, but are not limited to: acridinyl, azacinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxanyl oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, Carboline, chromanyl, chromene, cinnolinyldecahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] tetrahydrofuranyl, furanyl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl
  • hydrocarbyl or its subordinate concepts (such as alkyl, alkenyl, alkynyl, aryl, etc.) by itself or as part of another substituent means straight chain, branched chain or cyclic Hydrocarbon radicals or combinations thereof, can be fully saturated (such as alkyl), mono- or polyunsaturated (such as alkenyl, alkynyl, aryl), can be mono- or polysubstituted, and can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine), and may include divalent or polyvalent radicals with the specified number of carbon atoms (such as C1 -C12 for 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C4
  • Hydrocarbyl includes but is not limited to aliphatic hydrocarbon groups and aromatic hydrocarbon groups
  • the aliphatic hydrocarbon groups include chain and cyclic groups, specifically including but not limited to chain and cyclic alkyl, alkenyl, alkynyl groups
  • the aromatic hydrocarbon groups include but are not limited to Not limited to 6-12-membered aromatic hydrocarbon groups, such as benzene, naphthalene, etc.
  • the term “hydrocarbyl” refers to straight or branched chain radicals or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and may include divalent and polyvalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) Methyl, cyclopropylmethyl, and homologues or isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl and other atomic groups.
  • Unsaturated hydrocarbon groups have one or more double or triple bonds, examples of which include but are not limited to vinyl, 2-propenyl, butenyl, crotyl, 2-prenyl, 2-(butadienyl) , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term means a stable straight, branched chain A cyclic or cyclic hydrocarbon radical or a combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
  • heterohydrocarbyl by itself or in combination with another term refers to a stable straight chain, branched chain hydrocarbon radical, or a combination thereof, consisting of a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized.
  • the heteroatoms B, O, N, and S can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, eg -CH2 -NH- OCH3 .
  • alkoxy alkylamino and alkylthio (or thioalkoxy) are conventional expressions and refer to those alkanes which are attached to the rest of the molecule through an oxygen, amino or sulfur atom, respectively base group.
  • alkyl is used to denote a straight or branched chain saturated hydrocarbon group, which may be monosubstituted (eg -CH2F ) or polysubstituted (eg -CF3 ), may be monovalent (eg methyl), divalent (eg methylene), or polyvalent (eg methine).
  • alkyl groups examples include methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, s-butyl) , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • cycloalkyl refers to any one of the groups listed above.
  • heterocycloalkyl or subordinate concepts thereof (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl , heterocycloalkynyl, etc.) by themselves or in combination with other terms represent cyclized “hydrocarbyl”, “heterohydrocarbyl”, respectively.
  • a heteroatom may occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclyl groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuranindol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • aryl refers to a polyunsaturated aromatic hydrocarbon substituent, which may be mono-, di- or polysubstituted, mono-, di-, or polyvalent, which may be monocyclic or Polycyclic rings (preferably 1 to 3 rings) fused together or covalently linked.
  • heteroaryl refers to an aryl group (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from B, N, O, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrrolyl oxazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl azolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene base, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-
  • aryl when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals in which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, etc.), including wherein a carbon atom (eg, methylene) has been replaced by, for example, oxygen Atoms are substituted for those alkyl groups such as phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl groups (eg acetyl); arylmethyl groups such as benzyl (Bn), p- Methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl groups (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p- Methoxybenzyl (PMB), 9-fluoren
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • Compound 1 is isomer 2 in Example 51 of WO2016054971; Pen. is pentoxifylline; INT-747 is 6-ethylchenodeoxycholic acid; aq represents water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl) )-N'-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether ; DIAD for diisopropyl azodicarboxylate; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; EtOAc for ethoxybenzoic acid
  • FIG. 1 Levels of TNF- ⁇ in culture supernatant of PBMC and whole blood (Whole blood), data are expressed as mean ⁇ standard error (Mean ⁇ SEM); *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, ****p ⁇ 0.0001, one-way ANOVA, new multiple range test, compared with blank group (DMSO); #p ⁇ 0.05, ##p ⁇ 0.01, ###p ⁇ 0.001, ####p ⁇ 0.0001, t-test, compared with LPS group;
  • Figure 2 Analysis of the inhibitory rate of compounds on TNF- ⁇ detected by PBMC and whole blood culture
  • Figure 3 Inhibition rate of ear thickness in mouse ear edema model, compared with the model group, ***p ⁇ 0.001, **p ⁇ 0.01;
  • Figure 4 Inhibition rate of ear weight in mouse ear edema model, compared with model group, ***p ⁇ 0.001, **p ⁇ 0.01;
  • Figure 7 Changes in the weight of inferior iliac lymph nodes of mice in each group, ****p ⁇ 0.0001, ***p ⁇ 0.001, **p ⁇ 0.01, *p ⁇ 0.05.
  • reaction product AMP or GMP was detected by fluorescence polarization method (BellBrook, Madison WI).
  • the fluorescent tracer competed with AMP or GMP to bind with the antibody, resulting in the change of the fluorescence polarization value.
  • the inhibitory activity (IC 50 value) of the compounds to be tested against PDE4B phosphodiesterase was calculated.
  • AMP2/GMP2 assay kit BellBrook Cat#3015-1K PDE1A:
  • Methoxyquinazoline EMD Millipore Cat#475250
  • the standard curve of AMP and GMP was prepared by 3-fold dilution of 10 ⁇ M concentration, and the detection agent was added, and the signal detection method was as described above;
  • Test sample (compound prepared in each example) PDE4B phosphodiesterase inhibitory activity (IC 50 ) Compound 1 16.6 ⁇ M Pentoxifylline 78.8 ⁇ M
  • the compounds of the present invention have significant and even unexpected PDE4B protease inhibitory activity, and the inhibitory activity is significantly higher than that of pentoxifylline.
  • Heparin sodium anticoagulation tube purchased from BD company, item number: 367878, batch number: 4314542;
  • RPMI 1640 purchased from Gibco, item number: 224400-089, batch number: 1699742;
  • Fetal bovine serum purchased from Gibco Company, item number: 10099-141, batch number: 1618863;
  • the culture medium is RPMI 1640 containing 10% FBS;
  • LPS purchased from Sigma, item number: L2630, batch number 114M4009U, stock solution (1mg/mL), stored in -80°C refrigerator;
  • Dexamethasone (Dexamethasone, Dex), purchased from J&K Chemical Company, item number: 308890, batch number: LMAON14, stock solution (500 ⁇ M), stored in a refrigerator at -20 °C;
  • PBS purchased from Corning Company, item number: 21-031-CVR, batch number: 21031469R;
  • Lymphoprep Lymphocyte Separation Solution, purchased from STEMCELL Company, Item No.: 07851, Lot No.: 12HES21;
  • DMSO purchased from Sigma, item number: D2650, batch number: RNBD9495;
  • U-bottom 96-well plate purchased from Costar Company, item number: 3799.
  • the culture medium was resuspended to 10 mL, Vi-CELL was counted, and the cell concentration was adjusted to 2.5 ⁇ 10 6 /mL.
  • c) Preparation of compound working solution the stock solution and intermediate solution of compound 1 and pentoxifylline, including 100mM, 30mM, 10mM, 3mM, 1mM, 300 ⁇ M, 100 ⁇ M, were diluted 250 times in cell culture medium respectively, and the concentration was prepared as 400 ⁇ M, 120 ⁇ M, 40 ⁇ M, 12 ⁇ M, 4 ⁇ M, 1200nM, 400nM, 4 times the final concentration of the culture.
  • the LPS stock solution (1 mg/mL) was diluted 1000-fold with PBS to make a 1 ⁇ g/mL solution;
  • PBMC stimulation (4ng/mL): use culture medium to dilute 1ug/mL solution 250 times to become 4ng/mL, which is 4 times the final culture concentration;
  • Dexamethasone (Dex) 500 ⁇ M stock solution was diluted 1250-fold to 400 nM using cell culture medium, which was used as Dex working solution, which was 4 times the final culture concentration.
  • test compound 1 0.05 ⁇ L/well of test compound 1, control compound pentoxifylline, dexamethasone (Dex) working solution and vehicle (DMSO) working solution respectively;
  • PBMC suspension (2.5 ⁇ 10 6 /mL), 100 ⁇ L/well was added;
  • Each sample was double well, and the final volume of each well was 200 ⁇ L, and the culture medium was added to make up to 200 ⁇ L/well if the volume was less than 200 ⁇ L. Add 200 ⁇ L of PBS to each well marked with PBS.
  • test compound 1 0.05 ⁇ L/well of test compound 1, control compound pentoxifylline, dexamethasone (Dex) working solution and vehicle (DMSO) working solution respectively;
  • Each sample was double well, and the final volume of each well was 200 ⁇ L, and the culture medium was added to make up to 200 ⁇ L/well if the volume was less than 200 ⁇ L. Add 200 ⁇ L of PBS to each well marked with PBS;
  • the supernatant sample was taken out from the -80°C refrigerator, thawed at room temperature, and then diluted 3 times after thawing, and the TNF- ⁇ level was detected according to the instructions of the ELISA kit.
  • dexamethasone (Dex) at 100nM concentration has a significant inhibitory effect on the secretion of TNF- ⁇ in LPS-stimulated whole blood (inhibition rate 98.3%), and at the same concentration in PBMC, it can inhibit the secretion of TNF- ⁇ .
  • the secretion of - ⁇ also has a certain inhibitory effect, but the inhibitory effect is lower than that of whole blood (the inhibition rate is 37.2%).
  • PMA stimulation can induce the release of inflammatory factors TNF- ⁇ , IL-6 and IL-1 ⁇ and increase vascular permeability, resulting in acute inflammatory edema in the ear of mice.
  • the mouse model was used to evaluate the effect of the test drugs. Anti-inflammatory effect.
  • mice Twenty CD-1 female mice were ordered, 3 of which were spare. On the day of arrival, animals were randomly divided into groups of 5 animals according to their body weight. After the animals arrived at the facility, the acclimation period was 5 days. During the acclimation period, the health of the animals was monitored daily. If any abnormality or infection is found, the mouse needs to be excluded from the experimental group.
  • the specific grouping information is shown in the following table.
  • the grouping time is before the start of animal modeling. Select normal mice to start grouping and administering.
  • Table 4 is a table of experimental groupings after the official administration begins.
  • mice Female BALB/c mice (Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.)
  • Animal grouping randomly grouped according to body weight.
  • the specific grouping information is shown in the following table.
  • the grouping time is before the start of animal modeling, and normal mice are selected to start grouping and administration.
  • the following table is the experimental grouping situation table after the official administration begins.
  • the Tacrolimus group was given 200 ⁇ L, 0.1% bid in the first week, the second week, and the dose was adjusted to 200 ⁇ L, 0.5% bid in the third week and the fourth week.
  • AD mice 48h after the last challenge with 200 ⁇ L 1% DNCB solution, AD mice were collected blood from the orbit, and then the mice were sacrificed by cervical dislocation, and the back skin tissue was collected and fixed with 10% neutral formalin solution.
  • EASI Mouse skin tissue inflammation score: observe the skin condition score and take pictures before each sensitization, and judge according to 4 symptoms: dryness/scalding, hemorrhage/red rash, ulceration/exfoliation, edema, each symptom is based on 0 (none), 1 (mild), 2 (moderate), and 3 (severe) were scored, and the final score was the sum of the 4 symptoms, and the skin tissue inflammation score ranged from 0 to 12.
  • the body weight of the mice in the model group has a slight downward trend, and there are significant differences at D25, D32, and D35.
  • the weight loss is related to the stimulation of DNCB modeling.
  • the body weight of the mice in the Tacrolimus group showed a downward trend (D28 decreased significantly) 2 weeks before administration, and the body weight began to recover at the 3rd and 4th week after administration. There was no difference in body weight between the other administration groups and the model group.
  • mice were scored for skin lesions before each DNCB sensitization.
  • the skin lesions of 30% of the mice in the D14 model group (sensitization stage) were scored 1-3 points, and the degree of skin lesions showed a downward trend compared with D7.
  • D21 (administered for 1 week), compared with the model group, the compound 1 1.5% group had a significant downward trend;
  • D28 (administered for 2 weeks), compared with the model group, there was no significant difference in each administration group;
  • D35 (administered for 2 weeks) drug for 3 weeks), compared with the model group, the Tacrolimus group, AN2728 1.5% and compound 1 0.5%/1.5% all had a significant downward trend.
  • D41 (administration for 4 weeks), compared with the model group, the Tacrolimus group, 1.5% of AN2728 and 1.5% of compound 1 high-dose group had a significant downward trend.
  • the inferior iliac lymph nodes in the model group were significantly enlarged compared with the normal group.
  • the Tacrolimus group showed a downward trend, but it was not statistically significant.
  • the AN2728 1.5% and compound 1 0.5% and 1.5% groups had a significant downward trend. See the table below for details.

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Abstract

La présente invention concerne des utilisations d'une série de composés d'hydroxypurine dans la préparation de médicaments pour le traitement de maladies de la peau. L'invention concerne spécifiquement des utilisations d'un composé représenté par la formule (I) et un tautomère ou un sel pharmaceutiquement acceptable de celui-ci dans la préparation de médicaments pour le traitement de maladies de la peau.
PCT/CN2021/113197 2020-08-25 2021-08-18 Utilisation de composés d'hydroxypurine pour le traitement de maladies de la peau WO2022042390A1 (fr)

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Citations (5)

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CA2076699A1 (fr) * 1991-09-02 1993-03-03 Anat Eitan Composition pour le traitement topique du psoriasis et d'une dermatite atopique
CN1162919A (zh) * 1994-08-25 1997-10-22 赫彻斯特股份公司 含环孢菌素a或fk506或雷怕霉素和黄嘌呤衍生物的组合制剂
CN105566324A (zh) * 2014-10-09 2016-05-11 四川好医生药业集团有限公司 羟基嘌呤类化合物及其应用
WO2017071606A1 (fr) * 2015-10-29 2017-05-04 南京明德新药研发股份有限公司 Utilisation médicale d'un composé d'hydroxylpurine
WO2017071607A1 (fr) * 2015-10-29 2017-05-04 南京明德新药研发股份有限公司 Forme cristalline d'un composé de 4h-pyrazolo [1,5-a] benzoimidazole, procédé de préparation de ce composé et d'un intermédiaire de celui-ci

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CA2076699A1 (fr) * 1991-09-02 1993-03-03 Anat Eitan Composition pour le traitement topique du psoriasis et d'une dermatite atopique
CN1162919A (zh) * 1994-08-25 1997-10-22 赫彻斯特股份公司 含环孢菌素a或fk506或雷怕霉素和黄嘌呤衍生物的组合制剂
CN105566324A (zh) * 2014-10-09 2016-05-11 四川好医生药业集团有限公司 羟基嘌呤类化合物及其应用
WO2017071606A1 (fr) * 2015-10-29 2017-05-04 南京明德新药研发股份有限公司 Utilisation médicale d'un composé d'hydroxylpurine
WO2017071607A1 (fr) * 2015-10-29 2017-05-04 南京明德新药研发股份有限公司 Forme cristalline d'un composé de 4h-pyrazolo [1,5-a] benzoimidazole, procédé de préparation de ce composé et d'un intermédiaire de celui-ci

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