CN116264834A - Use of hydroxy purines for the treatment of skin disorders - Google Patents

Use of hydroxy purines for the treatment of skin disorders Download PDF

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Publication number
CN116264834A
CN116264834A CN202180059940.6A CN202180059940A CN116264834A CN 116264834 A CN116264834 A CN 116264834A CN 202180059940 A CN202180059940 A CN 202180059940A CN 116264834 A CN116264834 A CN 116264834A
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group
acid
compound
optionally substituted
dermatitis
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Inventor
陈小新
黄淑娟
刘苗
陈谋
刘志强
刘卓伟
龙超峰
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Guangdong Raynovent Biotech Co Ltd
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Guangdong Raynovent Biotech Co Ltd
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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

Abstract

The invention discloses application of a series of hydroxy purine compounds in preparing medicines for treating skin diseases, and particularly discloses application of a compound shown in a formula (I), tautomer thereof or pharmaceutically acceptable salt thereof in preparing medicines for treating skin diseases.
Figure DDA0004113714070000011

Description

Use of hydroxy purines for the treatment of skin disorders Technical Field
The invention relates to the field of medicines for treating skin diseases, in particular to application of a series of hydroxy purine compounds in preparation of medicines for treating skin diseases, especially atopic dermatitis.
Technical Field
Phosphodiesterases (PDEs) catalyze the hydrolysis of cyclic nucleotides cGMP and cAMP, regulating various physiological responses by controlling the intramolecular concentration of these two important secondary signaling factors. Dysregulation of cyclic nucleotide cGMP and cAMP within the molecule is responsible for many diseases, and there are now a number of drugs that improve and treat diseases by inhibiting PDE activity, such as PDE5 inhibitors for pulmonary hypertension and PDE4 inhibitors for arthritis caused by psoriasis. The phosphodiesterase genes known to date have a total of eleven major classes, each of which can express several subtypes, for a total of over 100 PDE subtypes. Different subtypes have different structures and different tissue distributions, and have very different catalytic activities on cyclic nucleotides cGMP and cAMP, and the physiological functions of regulation are very different.
Tumor necrosis factor alpha (tumor necrosis factor alpha, TNF-alpha) is a cytokine with a variety of biological activities, and has an important impact on the occurrence, development and treatment of a variety of diseases, particularly immune and inflammation related diseases. TNF- α is produced primarily by the monocyte and macrophage lineage, and is involved in the immunomodulation and cytokine network coordination of the body. TNF- α normally plays an important role in immune defenses and immune supervision, but in some cases has adverse effects. Studies have shown that TNF- α overexpression induces the expression of pro-inflammatory cytokines such as interleukin 1 (IL-1), IL-6, etc., increases endothelial cell permeability, upregulates adhesion molecule expression, activates neutrophils and eosinophils, and induces bone synovial cells and chondrocytes to secrete acute phase substances and tissue degrading enzymes, etc., to promote the onset of inflammation. These pathological responses play a very important role in the development and progression of many Immune-mediated inflammatory diseases (Immune-mediated inflammatory diseases, IMID), such AS rheumatoid arthritis (rheumatoid arthritis, RA), psoriatic arthritis (psoriatic arthritis, psA), ankylosing spondylitis (ankylosing spondylitis, AS), inflammatory enteritis (inflammatory bowel disease, IBD), juvenile chronic arthritis (juvenile chronic arthritis, JCA), and vasculitis (vasculitis), among others. Studies have shown that TNF-alpha is an ideal target for the above various IMIDs, and that the use of TNF-alpha antagonists (TNF-alpha inhibitors) to neutralize excess TNF-alpha is also an effective prophylactic and therapeutic approach for some diseases caused by chronic inflammatory lesions, such as steatohepatitis, chronic obstructive pulmonary disease, and the like. TNF- α mab drugs have been shown clinically to be a very effective means of inhibiting TNF- α in the treatment of the above-mentioned inflammation-related disorders.
PDE can mechanistically regulate TNF- α expression, and thus can control TNF- α levels by modulating PDE activity, thereby allowing for the control of inflammatory responses.
Cyclic nucleotides cGMP and cAMP transduce external signals by activating key cellular effectors such as Protein Kinase A (PKA). PKA inhibits the activity of many transcription factors through phosphorylation, including nuclear factor kappa-light chain enhancer (nuclear factor Kappa-light-chain-enhancer of activated T-cells, NFAT) that activates B lymphocytes, and the like. These factors control the expression of inflammatory mediators such as the interleukins IL-2, IL-4, IL-6, IL-31 and tumor necrosis factor TNF- α, which in turn regulate inflammatory responses of cells such as T lymphocytes, helper (Th) 2 cells, etc., such as centromere degranulation, chemotaxis and endothelial cell adhesion. Thus, a decrease in intracellular cAMP levels is associated with the secretion of pro-inflammatory mediators.
Atopic dermatitis (atopic dermatitis, AD) is a common itchy skin disease with a recurrence-remission process, severely affecting the physical and mental health and quality of life of the patient. Epidemiological studies have shown a global incidence of childhood AD of 20% and an adult of 3%. PDE4 levels in inflammatory cells in AD patients were significantly increased. PDE4 is one of the effective targets for the treatment of AD, and PDE4 inhibitors inhibit NFAT and nfkb signaling pathways by inducing an increase in intracellular cAMP, and decrease downstream cytokine and chemokine release. Several in vitro experiments showed a significant reduction in prostaglandin E2, IL-4 and IL-10 production in atopic leukocytes exposed to high-potency PDE4 inhibitors. Subsequent in vivo experiments also confirm this prediction, PDE4 inhibition is significantly reduced in relevant inflammatory parameters after application to AD patients. This potent anti-inflammatory effect in vivo is the rationale for the application of PDE4 inhibitors in the treatment of AD.
Crisabole (AN 2728) is a small molecule boron-based benzoxazoline PDE4 inhibitor that has been shown to improve disease severity in AD patients. Currently, crisabanole was first marketed in 2016 with FDA approval, the first new molecular entity approved by the us FDA for the treatment of atopic dermatitis (eczema) in the past 15 years of 2016. In month 3 of 2020, the U.S. FDA has approved the extension of the crisabanole ointment indication to the 3 month old child suffering from mild to moderate atopic dermatitis, which supplementary approval made it the first local prescription drug also uniquely applicable to the 3 month old child suffering from mild to moderate AD.
Figure PCTCN2021113197-APPB-000001
OPA-15406 as another ointment formulation of PDE4 inhibitor has achieved good efficacy in phase I, II clinical trials for AD aged 10-70. The pharmacokinetics of OPA-15406 was also evaluated in phase I and phase II clinical trials, and the compound was highly selective for one PDE4B subtype, but also inhibitory for PDE 2. Overall OPA-15406 proved safe and well tolerated in all studies.
Figure PCTCN2021113197-APPB-000002
European patent EP544391, filed by Kovar pharmaceutical 1992.08.19, discloses the use of pentoxifylline for the topical treatment of psoriasis and atopic dermatitis.
Figure PCTCN2021113197-APPB-000003
Chinese patent ZL201580054840.9, filed by the biotechnology limited company of guangdong, discloses a series of hydroxy purine compounds having PDE2 inhibiting effect in 2017.08.01. The inventors have surprisingly found in subsequent further studies that the series of compounds simultaneously have PDE 4-inhibiting effects and highly inhibit PDE4B isozymes, thereby enabling the treatment of skin diseases, such as atopic dermatitis, etc.
Disclosure of Invention
The invention provides application of a compound shown in a formula (I), a tautomer or a pharmaceutically acceptable salt thereof in preparing a medicament for treating skin diseases,
Figure PCTCN2021113197-APPB-000004
wherein,
the structural unit can be assembled
Figure PCTCN2021113197-APPB-000005
Derivatives substituted by tautomers thereof
Figure PCTCN2021113197-APPB-000006
L 11 Selected from the group consisting of absent, C (R) (R');
r, R' are each independently selected from H, halogen, OH, NH 2 CN, optionally substituted C 1～6 Alkyl or heteroalkyl;
optionally, R, R' can be cyclized with the carbon atom to which it is attached to form a 3-6 membered cycloalkyl, heterocycloalkyl;
a is absent or optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
L 12 selected from optionally substituted C 1～6 Alkyl or heteroalkyl;
R 1 selected from optionally substituted C 1～6 Alkyl, 3-6 membered cycloalkyl or heteroalkyl;
"hetero" means N, O, S, C (=o), S (=o) 2 The number of heteroatoms per group is selected from 1, 2, 3 or 4.
In some aspects of the invention, R, R', A, L described above 12 、R 1 Wherein the substituents are each independently selected from halogen, OH, NH 2 、CN、C 1～6 Alkyl, 3-6 membered cycloalkyl or heteroalkyl, each independently selected from 1, 2 or 3 in number for each radical substituent.
In some aspects of the present invention,
Figure PCTCN2021113197-APPB-000007
preferably is
Figure PCTCN2021113197-APPB-000008
In some aspects of the invention, R, R', A, L described above 12 、R 1 The substituents in (a) are each independently selected from halogen, CF 3 CN, OH, me, et, n-propyl, isopropyl, cyclopropyl,
Figure PCTCN2021113197-APPB-000009
In some embodiments of the invention, each of the R, R' groups is independently selected from H, me, CF 3 、Et。
In some aspects of the invention, L as described above 11 Selected from the group consisting of
Figure PCTCN2021113197-APPB-000010
In some embodiments of the invention, a is selected from optionally substituted: 3-12 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl.
In some embodiments of the invention, a is selected from optionally substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypentyl, phenyl, pyridinyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, bicyclo [1.1.1] pentane, or a bicyclic, spirocyclic, or fused cyclic group selected from any two of the foregoing.
In some embodiments of the invention, a is selected from optionally substituted:
Figure PCTCN2021113197-APPB-000011
Figure PCTCN2021113197-APPB-000012
in some embodiments of the invention, A is selected from
Figure PCTCN2021113197-APPB-000013
Figure PCTCN2021113197-APPB-000014
In some aspects of the invention, L as described above 12 Selected from methylene group,
Figure PCTCN2021113197-APPB-000015
Figure PCTCN2021113197-APPB-000016
In some aspects of the invention, R is as described above 1 Selected from Me, CHF 2 、CF 3 、Et、CH 2 CF 3 Isopropyl group,
Figure PCTCN2021113197-APPB-000017
Cyclopropyl group,
Figure PCTCN2021113197-APPB-000018
Figure PCTCN2021113197-APPB-000019
The invention relates to application of a compound shown in the following formula in preparation of a medicament for treating skin diseases:
Figure PCTCN2021113197-APPB-000020
Figure PCTCN2021113197-APPB-000021
further, the present invention relates to the use of a compound of the formula:
Figure PCTCN2021113197-APPB-000022
Figure PCTCN2021113197-APPB-000023
The invention relates to the use of said compounds for the preparation of a medicament for the treatment of dermatological disorders, preferably atopic dermatitis, psoriasis, contact dermatitis, other eczematous dermatitis, and delayed hypersensitivity reactions; plant and solar dermatitis; seborrheic dermatitis and dermatitis herpetiformis; lichen planus, lichen sclerosus, pyoderma gangrenosum, sarcoidosis, angioedema, vasculitis, toxic erythema, cutaneous eosinophilia, alopecia areata, male pattern baldness, svinter syndrome, wer-Crohn's syndrome, multiple erythema; infectious or non-infectious cellulitis; panniculitis; cutaneous lymphomas, non-melanoma skin cancers or other dysplastic lesions; drug-induced diseases, including fixed drug eruptions.
More preferably, the skin disease is selected from atopic dermatitis.
Further, the invention relates to application of the compound in preparing a medicament for treating skin diseases, wherein the compound is a compound 1 shown in the following formula, the skin diseases are atopic dermatitis,
Figure PCTCN2021113197-APPB-000024
correlation definition
Unless otherwise indicated, the terms and phrases used herein have the following meanings. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure 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. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure 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, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Preferably, the salt is contacted with a base or acid in a conventional manner to isolate the parent compound, thereby regenerating the neutral form of the compound. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the invention wherein the parent compound is modified by salt formation with an acid or by salt formation with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic 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 non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or 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, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalactural, propionic acid, salicylic acid, stearic acid, sulfurous acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and p-toluenesulfonic acid.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, it is preferable to use a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. In addition, 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 invention may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.
Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
Unless otherwise indicated, wedge-shaped keys and dashed-line keys are used
Figure PCTCN2021113197-APPB-000025
Representing the absolute configuration of a stereogenic center, using
Figure PCTCN2021113197-APPB-000026
Representing the relative configuration of a stereogenic center. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomers unless specified otherwise. Likewise, all tautomeric forms are included within the scope of the invention.
The compounds of the 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, (D) -isomers, (L) -isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active agent of the present invention, which does not interfere with the biological activity of the active agent and which does not have toxic or side effects to the host or patient. Representative carriers include water, oils, vegetables and minerals, ointment bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, reference may 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.
The term "excipient" generally refers to a carrier, diluent, and/or other medium required to make an effective pharmaceutical composition.
For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms in accordance with the present invention, an "effective amount" of an active agent in a composition refers to that amount required to achieve the desired effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" refers to any one or more hydrogen atoms on a particular atom being substituted with a substituent, including heavy hydrogen and variants of hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =o), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
When the number of one linking group is 0, such as- (CRR) 0 -it is meant that the linking group is a single bond.
When one of the variables is selected from a single bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in A-L-Z represents a single bond, it is indicated that the structure is actually A-Z.
When one substituent is absent, such as a-X, where X is absent, indicates that the structure is actually a.
Where a bond of a substituent may cross-connect to two atoms on a ring, the substituent may be bonded to any atom on the ring. When none of the listed substituents indicates through which atom it is attached to a compound included in the chemical structural formula but not specifically mentioned, such substituents may be bonded through any of their atoms. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, structural units
Figure PCTCN2021113197-APPB-000027
Meaning that it may be substituted at any one position on the cyclohexyl or cyclohexadiene.
Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C 1 -C 4 ) Alkyl "is intended to include, but is not limited to, trifluoromethyl, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
Examples of haloalkyl groups include, but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl and pentachloroethyl.
"alkoxy" represents an alkyl group as described above having a specified number of carbon atoms attached through an oxygen bridge. C (C) 1-6 Alkoxy includes C 1 、C 2 、C 3 、C 4 、C 5 And C 6 Alkoxy groups of (a). Examples of 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 C 3 、C 4 、C 5 、C 6 And C 7 Cycloalkyl groups. "alkenyl" includes hydrocarbon chains of straight or branched configuration wherein one or more carbon-carbon double bonds are present at any stable position on the chain, such as ethenyl and propenyl.
Unless otherwise specified, the term "hetero" denotes a heteroatom or a heteroatom group (i.e., a heteroatom-containing group of atoms), including atoms other than carbon (C) and hydrogen (H), and groups containing such heteroatoms, including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), =o, =s, -C (=o) O-, -C (=o) -, -C (=s) -, -S (=o), and-S (=o) 2 -and optionally substituted-C (=o) N (H) -, -C (=nh) -, -S (=o) 2 N (H) -or-S (=o) N (H) -.
Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The term ring includes monocyclic, bicyclic, spiro, and fused or bridged rings. The number of atoms on a ring is generally defined as the number of ring elements, for example, "5-7 membered ring" means a ring of 5-7 atoms arranged around the ring. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Thus, "5-7 membered ring" includes, for example, phenyl, pyridyl and piperidinyl; in another aspect, the term "5-7 membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems comprising at least one ring, each of which independently meets the definition set forth above.
Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable heteroatom-or heteroatom-group-containing monocyclic, bicyclic or tricyclic ring which may be saturated, partially unsaturated or unsaturated (aromatic), which contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above-mentioned heterocycles may be fused to one of the carbocyclic rings to form a bicyclic ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., n=o and S (=o) p, p being 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents already defined herein). The heterocycle may be attached to any heteroatom or pendant group of a carbon atom that results in the formation of a stable structure. If the resulting compound is stable, the heterocycles described herein may undergo substitution at the carbon or nitrogen positions. The nitrogen atom in the heterocycle is optionally quaternized. In a preferred embodiment, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. In another preferred embodiment, the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "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 comprising a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents already defined herein). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., n=o and S (=o) p, p being 1 or 2). Notably, the total number of S and O atoms on the aromatic heterocycle does not exceed 1. Bridged rings are also included in the definition of heterocyclic ring. A bridged ring is formed when one or more atoms (i.e., C, O, N or S) join two non-adjacent carbon or nitrogen atoms. Preferred "bridges" in the bridged ring include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. Notably, one bridge always converts a single ring to a tricyclic ring. In bridged rings, substituents on the ring may also be present on the bridge.
Examples of heterocyclic compounds include, but are not limited to: acridinyl, azecinyl, benzimidazolyl, benzofuranyl, benzomercapto-furanyl, benzomercapto-phenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazole, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolyl, 3H-indolyl, isophthalonyl, isoindolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridine, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, phenazinyl, phenothiazine, benzoxanthinyl, phenoxazinyl, phthalazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, and the like purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazoles, pyridoimidazoles, pyridothiazoles, pyridinyl, pyrrolidinyl pyrrolinyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazinyl, 1,2, 4-thiadiazinyl, 1,2, 5-thiadiazinyl, 1,3, 4-thiadiazinyl, thianthrenyl, thiazolyl, isothiazolylthiophene, thienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl and xanthenyl. Also included are fused and spiro compounds.
Unless otherwise specified, the term "hydrocarbyl" or its lower term (e.g., alkyl, alkenyl, alkynyl, aryl, etc.) by itself or as part of another substituent means a straight, branched, or cyclic hydrocarbon radical or combination thereof, which may be fully saturated (e.g., alkyl), mono-or poly-unsaturated (e.g., alkenyl, alkynyl, aryl), which may be mono-or poly-substituted, which may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine), which may include divalent or multivalent radicals having the indicated number of carbon atoms (e.g., C 1 -C 12 Represents 1 to 12 carbons, C 1-12 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 Selected from C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 . ). "hydrocarbyl" includes, but is not limited to, aliphatic and aromatic hydrocarbyl groups including chain and cyclic, specifically including, but not limited to, chain and cyclic alkyl, alkenyl, alkynyl groups, and aromatic hydrocarbyl groups including, but not limited to, 6-12 membered aromatic hydrocarbyl groups, such as benzene, naphthalene, and the like. In some embodiments, the term "hydrocarbyl" refers to a straight or branched chain radical or combination thereof, which may be fully saturated, mono-or polyunsaturated, and may include both divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, and homologs or isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like radicals. 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-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers.
Unless otherwise specified, the term "heterocarbyl" or its lower term (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term means a stable straight-chain, branched-chain, or cyclic hydrocarbon radical, or a combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom. In some embodiments, the term "heterocarbyl" by itself or in combination with another term means a stable straight-chain, branched-chain hydrocarbon radical or combination thereof, consisting of a number of carbon atoms and at least one heteroatom. In one exemplary embodiment, the heteroatomSelected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. 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 remainder of the molecule). Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -CH 2 、-S(＝O)-CH 3 、-CH 2 -CH 2 -S(＝O) 2 -CH 3 、-CH＝CH-O-CH 3 、-CH 2 -CH＝N-OCH 3 and-ch=ch-N (CH 3 )-CH 3 . At most two heteroatoms may be contiguous, e.g. -CH 2 -NH-OCH 3 。
The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in conventional sense to refer to those alkyl groups attached to the remainder of the molecule through an oxygen, amino or sulfur atom, respectively.
Unless otherwise specified, the term "alkyl" is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (e.g. -CH 2 F) Or polysubstituted (e.g. -CF) 3 ) May be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
Unless otherwise specified, the terms "cycloalkyl", "heterocycloalkyl" or their lower terms (e.g., aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, etc.), alone or in combination with other terms, represent, respectively, "hydrocarbyl", "heterocarbyl" of cyclization. In addition, in the case of heterohydrocarbyl or heterocycloalkyls (e.g., heteroalkyl, heterocycloalkyl), the heteroatom may occupy the position where the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclyl groups include 1- (1, 2,5, 6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran indol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl.
Unless otherwise specified, the term "aryl" denotes a polyunsaturated aromatic hydrocarbon substituent, which may be mono-, di-or polysubstituted, and which may be monovalent, divalent or multivalent, and which may be monocyclic or polycyclic (preferably 1 to 3 rings), which are fused together or linked covalently. The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms. In one exemplary embodiment, the heteroatom is selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heteroaryl groups may be attached to the remainder of the molecule through heteroatoms. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolinyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the acceptable substituents described below.
For simplicity, aryl when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like), including those alkyl groups in which a carbon atom (e.g., methylene) has been replaced by, for example, an oxygen atom, such as phenoxymethyl, 2-pyridyloxymethyl 3- (1-naphthyloxy) propyl, and the like.
The term "leaving group" refers to a functional group or atom that may be substituted with another functional group or atom by a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromophenylsulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.
The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "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: a formyl group; acyl groups such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl groups such as t-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and t-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
All solvents used in the present invention are commercially available and can be used without further purification.
The invention adopts the following abbreviations: compound 1 was isomer 2 of example 51 of WO 2016054971; pen is pentoxifylline; INT-747 is 6-ethyl chenodeoxycholic acid; aq represents water; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC represents 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 stands for diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethylsulfoxide; etOAc represents ethyl acetate; etOH stands for ethanol; meOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents tert-butylcarbonyl, an amine protecting group; HOAc stands for acetic acid; naCNBH 3 Represents sodium cyanoborohydride; r.t. stands for room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc 2 O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 Represents thionyl chloride; CS (circuit switching) 2 Represents carbon disulphide; tsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N- (benzenesulfonyl) benzenesulfonamide; NCS represents 1-chloropyrrolidine-2, 5-dione; n-Bu 4 NF represents tetrabutylammonium fluoride; i-PrOH represents 2-propanol; mp represents the melting point; LDA represents lithium diisopropylamide; TMSCF (TMSCF) 3 Represents trifluoromethyl trimethylsilane; ti (Oi-Pr) 4 Represents tetraisopropyl titanate; MSCl represents methanesulfonyl chloride; DMAP represents N, N-dimethyl-4-aminopyridine; TEA represents triethylamine; bnBr represents benzyl bromide; DIEA stands for diisopropylethylamine; BH (BH) 3 DMS stands for borane dimethyl sulfide; DMP represents dessmartin periodate; TBAF represents tetrabutylammonium fluoride; HOBT represents 1-hydroxybenzotriazole; AIBN represents azobisisobutyronitrile; NBS represents N-bromosuccinimide; RT buffer represents reverse transcription buffer; dNTPs represent deoxyribonucleoside triphosphates; PBS represents phosphate buffer; LPS represents bacterial lipopolysaccharide; TNF-alpha represents a tumorNecrosis factor alpha; PBMCs represent peripheral blood mononuclear cells; ELISA stands for enzyme-linked immunosorbent assay.
Figure PCTCN2021113197-APPB-000028
The compounds being prepared by hand or by hand
Figure PCTCN2021113197-APPB-000029
Software naming, commercial compounds are referred to by vendor catalog names.
Drawings
Fig. 1: TNF- α levels in PBMC and Whole blood (white blood) culture supernatants, data expressed as mean.+ -. Standard error (mean.+ -. SEM); * p <0.05, < p <0.01, < p <0.001, < p <0.0001, < one-way variance analysis, new complex pole difference assay, compared to the blank (DMSO); #p <0.05, #p <0.01, #p <0.001, #p <0.0001, t-test, compared to the LPS group;
fig. 2: analysis of inhibition ratio of TNF-alpha by PBMC and whole blood culture detection compounds;
fig. 3: the ear thickness inhibition rate of the mouse ear edema model is less than 0.001 in comparison with the model group, and less than 0.01 in comparison with the model group;
fig. 4: the ear weight inhibition rate of the mouse ear edema model is less than 0.001 in comparison with the model group, and less than 0.01 in comparison with the model group;
fig. 5: weight change rate of mice in each group, p <0.001, p <0.01, p < 0.05;
fig. 6: skin loss score for each group of mice, p <0.0001, p <0.001, p <0.01, p < 0.05;
fig. 7: the weight change of the ilium lymph nodes of each group of mice is that p <0.0001, p <0.001, p <0.01, p < 0.05.
Detailed Description
All compounds of the present disclosure were prepared by the preparation method disclosed in WO 2016054971.
Experimental example 1: in vitro evaluation of PDE4B phosphodiesterase inhibition Activity
The purpose of the experiment is as follows: the reaction products AMP or GMP were detected by fluorescence polarization (BellBrook, madison WI) and fluorescent tracers compete with AMP or GMP for binding to the antibodies, resulting in a change in the fluorescence polarization value. Calculation of PDE4B phosphodiesterase inhibition Activity (IC) of test Compounds 50 Values).
Experimental materials: 10mM tris (hydroxymethyl) aminomethane hydrochloride buffer, pH 7.5,5mM magnesium chloride, 0.01% polyoxyethylene lauryl ether, 1mM dithiothreitol and 1% DMSO.
Reagent:
AMP2/GMP2 assay kit:BellBrook Cat#3015-1K PDE1A:
SignalChem(Richmond,Canada)Cat#P89-30H PDE2A:
SignalChem Cat#P90-30G
PDE4B:SignalChem Cat#P92-31BG
IBMX:EMD Millipore(Billerica,MA)Cat#410957
Methoxyquinazoline:EMD Millipore Cat#475250
BRL-50481:R&D Systems(Minneapolis,MN)Cat#2237
Zaprinast:R&D Systems Cat#0947
pentoxifylline
All reagents were purchased from Sigma-Aldrich (St. Louis, mo.).
Reaction concentration:
enzymes Amount of enzyme in the test (pM) Substrate(s) Amount of substrate in assay (uM)
PDE4B 40 cAMP 1
Background-no enzyme only other all components
Time at room temperature for 1 hour
The conversion rate is 5-20%
Sample preparation and dilution:
compound 1 or pentoxifylline was added to DMSO to prepare 25mM samples for use. Transfer 6. Mu.L of 25mM of the sample to be tested, add to the solution of Echo plate (LabCyte cat#LP-0200) in DMSO (6. Mu.L) and make a 2-fold dilution of the sample. The 2-fold serial dilution of the compound sample was added directly to the reaction as follows without any additional intermediate dilution steps.
The experimental process comprises the following steps:
1. preparing a required enzyme solution by using a freshly prepared reaction buffer;
2. Transferring 1.5X enzyme solution and adding into the reaction hole; 10. Mu.L/well;
3. transferring 60nL of the compound to be tested by using an objective technology (Echo 550; labCyte Inc.Sunnyvale, CA), adding the compound to an enzyme solution, slowly mixing, and incubating for 20min at room temperature;
4. preparing and transferring a 3X substrate solution, and adding a reaction hole to initiate a reaction; 5. Mu.L/well;
5. reacting for 1 hour at room temperature, adding a detection agent, slowly mixing at room temperature, and incubating for 90min;
EnVision 2102 reads fluorescence polarized signal (Perkin Elmer, waltham MA; ex/Em=FP 620/S688/P688 nm);
7. standard curves of AMP and GMP were prepared by 3-fold dilution at 10 μm concentration, detection reagent was added, and signal detection method was as described above;
8. fluorescence polarization intensity was converted to nM concentration by AMP/GMP standard curve, and then enzyme was calculated relative to DMSO blank (no inhibitor)Inhibitory Activity IC was calculated using Prism software package (GraphPad Software, san Diego California, USA) 50 Values and curves.
Experimental results:
TABLE 1 test results of PDE4B phosphodiesterase inhibition Activity
Test article (Compound prepared in each example) PDE4B phosphodiesterase inhibition Activity (IC 50)
Compound 1 16.6μM
Pentoxifylline 78.8μM
Conclusion: 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.
Experimental example 2: in vitro evaluation of the effect of Compounds on LPS-induced human PBMC and Whole blood TNF- α secretion
The purpose of the experiment is as follows: the influence of the compound and pentoxifylline on the secretion of TNF-alpha by human blood and human peripheral blood mononuclear cells induced by bacterial lipopolysaccharide LPS is detected and used for evaluating the in vitro anti-inflammatory activity.
Experimental materials:
whole blood of normal people is donated by Shanghai Minkangde New drug development Limited company for 4 months in 2016 for 1 day, 30mL, heparin sodium is anticoagulated, and an informed consent is signed;
heparin sodium anticoagulation tube, purchased from BD company, cat No.: 367878, lot number: 4314542;
RPMI 1640, available from Gibco corporation under the trade designation: 224400-089, lot number: 1699742;
fetal Bovine Serum (FBS), purchased from Gibco company under the trade designation: 10099-141, lot number: 1618863;
the culture solution is RPMI 1640 containing 10% FBS;
LPS, available from Sigma, cat: l2630, lot 114M4009U, stock solution (1 mg/mL), stored in-80℃refrigerator;
dexamethasone (Dexamethasone, dex), available from J & K Chemical company under the trade designation: 308890, lot number: LMA0N14, stock solution (500. Mu.M), stored in-20deg.C refrigerator;
PBS, available from Corning corporation, cat: 21-031-CVR, lot number: 21031469R;
Lymphocyte isolate Lymphoprep, available from STEMCELL Inc., cat: 07851, lot number: 12HES21;
DMSO, available from Sigma, cat: d2650, lot number: RNBD9495;
u bottom 96 well plate, purchased from Costar company, cat: 3799.
experimental operation:
(1) PBMC isolation
a) Strictly following the procedure provided in the Lymphprep product specification: the whole blood is diluted in equal volume by using PBS containing 2% FBS, and is spread on the upper layer of lymphocyte separation liquid, so that a good interface is maintained, and the mixing of the blood and the lymphocyte separation liquid is avoided:
b) Centrifuging 800g PBMC for 30 minutes at normal temperature, and regulating the speed up and down of the centrifuge to the minimum;
c) Collecting a cloud and fog layer between the plasma layer and the lymphocyte separation liquid layer, and washing for 2 times by using a culture solution;
d) The culture solution is resuspended to 10mL, the Vi-CELL count is carried out, and the CELL concentration is adjusted to 2.5x10 6 /mL。
(2) Test and control compound formulations
a) Preparation of compound stock solution: compound 1 and pentoxifylline are respectively added into DMSO with corresponding volumes to prepare 100mM stock solution;
b) Preparing a compound intermediate solution: compound 1 and pentoxifylline stock solutions were 100mM in concentration, and compound stock solutions were diluted to 30mM,10mM,3mM,1mM,300 μm,100 μm, respectively, using DMSO;
c) Preparing a compound working solution: stock solutions and intermediate solutions of compound 1 and pentoxifylline, including 100mM,30mM,10mM,3mM,1mM, 300. Mu.M, 100. Mu.M, were 250-fold diluted in cell culture medium to give concentrations of 400. Mu.M, 120. Mu.M, 40. Mu.M, 12. Mu.M, 4. Mu.M, 1200nM,400nM, 4-fold final culture concentration.
(3) Preparation of LPS working solution
LPS stock solution (1 mg/mL) was first diluted 1000-fold with PBS to give 1. Mu.g/mL solution;
a) For PBMC stimulation (4 ng/mL): diluting the 1ug/mL solution 250 times by using the culture solution to 4ng/mL, wherein the concentration is 4 times of the final culture concentration;
b) For whole blood stimulation (4 ng/mL): the culture solution was diluted 50-fold to 20ng/mL with 1. Mu.g/mL of the solution, and the final concentration of the culture was 4-fold.
(4) Preparation of dexamethasone (Dex) and vehicle working solution
Dexamethasone (Dex) 500. Mu.M stock solution was 1250-fold diluted to 400nM using cell culture broth as Dex working solution at 4-fold final culture concentration.
(5) PBMC and whole blood culture
a) PBMC culture:
adding 50 mu L/hole of a compound 1 to be tested, a control compound, pentoxifylline, dexamethasone (Dex) working solution and vehicle (DMSO) working solution respectively;
LPS (4 nM) working solution 50. Mu.L/well;
PBMC suspension (2.5x10) 6 /mL), 100 μl/well addition;
for each sample, the final volume of each well was 200. Mu.L, and less than 200. Mu.L of added culture medium was made up to 200. Mu.L/well. Wells designated PBS 200 μl of PBS was added per well.
b) Whole blood culture:
adding 50 mu L/hole of a compound 1 to be tested, a control compound, pentoxifylline, dexamethasone (Dex) working solution and vehicle (DMSO) working solution respectively;
LPS (20 nM) working solution 50. Mu.L/well;
blood, 50 μl/well; serum-free RPMI 1640 50 μl/well;
for each sample, the final volume of each well was 200. Mu.L, and less than 200. Mu.L of added culture medium was made up to 200. Mu.L/well. Wells designated PBS 200 μl of PBS was added per well;
c) Culturing:
placing the culture plate in CO 2 In the incubator, culture was performed for 24 hours.
(6) Supernatant collection and detection of TNF-alpha levels
a) After 24 hours of incubation of PBMC and whole blood, culture supernatants were harvested, about 150 μl of supernatant was harvested per well, collected into 96-well plates, and stored at-80 ℃ for ELISA detection;
b) Before ELISA detection, supernatant samples were taken out of the refrigerator at-80℃and thawed at room temperature, and after thawing, the samples were diluted 3-fold and TNF- α levels were detected according to ELISA kit instructions.
Experimental results:
TABLE 2 detection value of TNF-a (pg/ml)
Figure PCTCN2021113197-APPB-000030
Figure PCTCN2021113197-APPB-000031
TABLE 3 inhibition results (%)
Figure PCTCN2021113197-APPB-000032
Conclusion: as shown in Table 2, dexamethasone (Dex) at 100nM concentration has obvious inhibition effect (inhibition rate 98.3%) on TNF-alpha secretion in LPS stimulated whole blood, and at the same concentration has a certain inhibition effect on TNF-alpha secretion in PBMC, but the inhibition effect is lower than that of whole blood (inhibition rate 37.2%). As shown in Table 3, FIG. 1 and FIG. 2, pentoxifylline showed significant inhibition (39.8% inhibition) of TNF- α secretion in whole blood at 100. Mu.M concentration, no significant inhibition was seen at concentrations of 30. Mu.M and below 30. Mu.M, compound 1 showed significant inhibition of 80.1% and 48.4% at concentrations of 100. Mu.M and 30. Mu.M, respectively, and no significant inhibition at concentrations of 10. Mu.M and below. In PBMC cultures, pentoxifylline showed significant inhibition of TNF- α secretion at 100. Mu.M, with a significant difference in inhibition rates of 27.1%, no significant inhibition was seen at doses of 30. Mu.M or less, whereas in this system, compound 1 showed significant inhibition at 100. Mu.M and 30. Mu.M, with significant differences in inhibition rates of 83.1% and 68.1%, respectively, and 27.7% was detected at 10. Mu.M. It follows that the lowest effective dose of compound 1 is lower than that of pentoxifylline and is more potent in inhibiting TNF- α than pentoxifylline at the same dose.
Experimental example 3 pharmacodynamic study of PMA-induced model of ear edema in mice
The purpose of the experiment is as follows: stimulation with PMA induces the release of the inflammatory factors TNF- α, IL-6 and IL-1β and increases vascular permeability, resulting in acute inflammatory edema in the ears of mice, and the anti-inflammatory effects of the test drugs were evaluated using a mouse model.
Experimental model: model of PMA-induced mouse ear edema
Experimental animals: CD-1 female mouse (Chengdu Daoshuo animal technology Co., ltd.)
Experimental reagent:
1. acetone (Chengdu long-chain chemical reagent Co., ltd.);
2. absolute ethanol (Chengdu Kelong chemical reagent plant);
12-tetradecanoate 13-phorbol acetate (phorbol ester, PMA, TPA)
Crisaboole (AN 2728) (Probiotics, inc. of Chengdu-know)
The experimental method comprises the following steps:
20 CD-1 female mice were ordered, 3 of which were ready for use. Animals reached the day, and were randomized by body weight, 5 per group. The adaptation period was 5 days after the animals reached the facility. During the adaptation period, the health of the animals was monitored daily. If any abnormalities or infections are found, the mice need to be knocked out of the test group.
The specific grouping information is shown in the following table, the grouping time is the grouping administration of normal mice in the selected state before the animal molding is started, and the table 4 is the experimental grouping condition table after the formal administration is started.
Table 4 table of experimental grouping conditions
Figure PCTCN2021113197-APPB-000033
The skin on the front and back of the right ear of the mouse was stimulated by applying PMA (20. Mu.L/piece, 0.25mg/mL in acetone). Each group was treated in the same manner as in table 4 (60 μl/piece in acetone: ethanol (=2:3)) at the same position on the front and back sides of the right ear of the mouse 30min before PMA stimulation and 30min after stimulation. After 6 hours of PMA stimulation, the mice were then sacrificed by cervical dislocation, tissues of the same parts of the left and right ears of the mice were taken using a punch (d=8 mm), and thicknesses of the left and right ears of the mice were measured using a micrometer.
Experimental results:
TABLE 5 mouse ear edema inhibition rate table
Figure PCTCN2021113197-APPB-000034
Figure PCTCN2021113197-APPB-000035
The results show that after the local application of PMA stimulation induces the release of inflammatory factors TNF-alpha, IL-6 and IL-1 beta and increases vascular permeability to cause acute inflammatory edema of the ears of mice, both the compound 1 and the AN2728 can inhibit the inflammatory edema, as shown in figures 3 and 4, the ear thickness inhibition rate and the weight inhibition rate of the ear edema model of the mice of the compound 1 are both greater than those of the AN2728 at the dose of 1mg/ear, which indicates that the inhibition effect of the compound 1 is obviously superior to that of the AN2728, and the compound 1 has good anti-inflammatory effect and potential atopic dermatitis treatment effect.
EXAMPLE 4 pharmacodynamic Studies in DNCB-induced mice model of atopic dermatitis
The purpose of the experiment is as follows: pharmacodynamic study of test drugs in DNCB-induced mice model of atopic dermatitis
Experimental model: DNCB-induced female BALB/c mice model of atopic dermatitis
Experimental animals: female BALB/c mouse (Beijing vitamin Torilhua laboratory animal technology Co., ltd.)
Experimental reagent:
1. compound 1 (Guangdong Zhongsheng Rui Chuang technology biological Co., ltd.)
2. Acetone (Chengdu long-connected chemical reagent Co., ltd.)
3. Olive oil (Chengdu Corp chemical Co., ltd.)
4.1-chloro-2, 4-Dinitrobenzene (DNCB) (Sigma-Aldrich)
5.Tacrolimus(MedChemExpress)
Crisaboole (AN 2728) (Probiotics, inc. of Chengdu Zhi Gong Lai)
The experimental method comprises the following steps:
grouping animals: the animals are randomly grouped according to weight, the specific grouping information is shown in the following table, the grouping time is the grouping administration of the mice in a normal state is selected before the animal molding is started, and the following table is a formal administration experiment grouping condition table after the starting of the administration.
TABLE 6 Experimental grouping Condition Table
Figure PCTCN2021113197-APPB-000036
Figure PCTCN2021113197-APPB-000037
Modeling AD mice: 50 female BALB/c mice were randomly grouped according to body weight, randomly divided into 6 groups, 6 in the normal group and 8 in each of the other groups. The skin hair on the back of the mice was shaved 2 days before the start of the test, with an area of about 8cm 2 The mice were sensitized on the back skin with 200 μl (0.5%) DNCB solution applied 1 time a day for D1, D2, D3 days; the mice were challenged with 200 μl (1%) DNCB solution from D14 to the back skin, 2 times a week for 4 weeks. The normal group was treated with the same volume of vehicle (acetone: olive oil=3:1).
AD mice were dosed: mice back skin was smeared with 200 μl of 1.5% na 2728 or 0.5%, 1.5% compound 1 solution starting from D14, 2 times daily for 4 weeks, and the model group was treated with the same volume of vehicle (acetone: olive oil=3:1). Tacrolimus group was dosed at 200. Mu.L, 0.1% bid, after the first week, the second week, and the fourth week at a dose of 200. Mu.L, 0.5% bid.
Dissecting and sampling: after 48h from the last 200 μl of 1% dncb solution, the AD mice were collected from the orbits, and then the mice were sacrificed by cervical dislocation and their back skin tissue was fixed with 10% neutral formalin solution.
Mouse skin tissue inflammation score (EASI): skin status scores were observed and photographed before each sensitization, and the judgment was made according to 4 symptoms: drying/desquamation, hemorrhage/erythema, ulceration/exfoliation, edema, each symptom was scored according to 0 (none), 1 (mild), 2 (moderate), 3 (severe), the final score being the sum of 4 symptoms, and the skin tissue inflammation score being 0-12 points.
Size and weight of the subiliac lymph node: the mice were dissected for subiliac lymph node size and weight.
And (3) data processing: the animal experimental data of each group are described by mean ± standard error (x±sd). The data were analyzed for significance using a Kruskal-Wallis One-way One-factor anova. P <0.05 is statistically significant for the differences. All statistical analyses were done using SPSS11 software.
Experimental results:
1. clinical observations and body weight
As shown in fig. 5, mice in the model group had a slight decrease in body weight, associated with DNCB modeling stimulation, compared to the normal group, and had significant differences in D25, D32, and D35. Compared to the model group, the Tacrolimus group mice had a tendency to decrease in body weight (D28 significantly decreased) 2 weeks prior to dosing and began to return to body weight at weeks 3,4 of dosing. The other dosing groups had no difference in body weight change compared to the model group.
2. Skin damage score (EASI)
As shown in fig. 6, mice were scored for skin lesions prior to each DNCB sensitization. 30% of mice in the D14 model group (sensitization stage) have an animal skin loss score of 1-3 points, and the degree of skin loss is reduced compared with that of D7, and the score of the sensitization stage is reduced and is consistent with the prior modeling data. D21 (1 week on dosing), compound 1.5% had a significant decrease in the trend compared to the model group; d28 (2 weeks of dosing), there was no significant difference between each dosing group compared to the model group; d35 (3 weeks of dosing), tacrolimus group, AN 2728.5% and compound 1.5%/1.5% all had a significant decrease in trend compared to the model group. D41 (4 weeks of dosing), tacrolimus, AN 2728.5% and compound 1 high dose 1.5% all had a significant trend down compared to the model group.
3. Organ coefficient-subiliac lymph node
As shown in fig. 7, the model group showed a significant increase in the subiliac lymph nodes compared to the normal group after 4 weeks of administration. The Tacrolimus group had a decreasing trend but no statistical significance compared to the model group. There was a significant decrease in both the AN2728, 1.5% and compound 1, 0.5% and 1.5% groups compared to the model group. See in particular the following table.
TABLE 7 weight and skin thickness (mean+ -SD) of the sub-iliac lymph nodes of each group of animals
Figure PCTCN2021113197-APPB-000038
Remarks: one-way ANONA, compared to AD model p < 0.05, p < 0.01, p < 0.001, p < 0.0001.
In summary, in the pharmacodynamics study in the DNCB-induced mouse atopic dermatitis model, the compounds 1, tacrolimus and AN2728 all have AN improving effect on atopic dermatitis, and the skin damage score of the compound 1 is lower than that of AN2728 under the condition of 1.5%, which indicates that the effect of inhibiting atopic dermatitis of the compound 1 is significantly better than that of AN2728, and the compound 1 has a remarkable improving effect on the symptoms of the DNCB-induced mouse atopic dermatitis and a potential effect of treating atopic dermatitis.

Claims (11)

  1. The application of a compound shown in a formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof in preparing a medicament for treating skin diseases,
    Figure PCTCN2021113197-APPB-100001
    Wherein,
    the structural unit can be assembled
    Figure PCTCN2021113197-APPB-100002
    Derivatives substituted by tautomers thereof
    Figure PCTCN2021113197-APPB-100003
    L 11 Selected from the group consisting of null, C (R) (R');
    r, R' are each independently selected from H, halogen, OH, NH 2 CN, optionally substituted C 1～6 Alkyl or heteroalkyl;
    optionally, R, R' can be cyclized with the carbon atom to which it is attached to form a 3-6 membered cycloalkyl, heterocycloalkyl;
    a is absent or selected from optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
    L 12 selected from optionally substituted C 1～6 Alkyl or heteroalkyl;
    R 1 selected from optionally substituted C 1～6 Alkyl, 3-6 membered cycloalkyl or heteroalkyl;
    "hetero" means N, O, S, C (=o), S (=o) 2 The number of heteroatoms per group is selected from 1, 2, 3 or 4.
  2. The use according to claim 1, wherein R, R', A, L 12 、R 1 Wherein the substituents are each independently selected from halogen, OH, NH 2 、CN、C 1～6 Alkyl, 3-6 membered cycloalkyl or heteroalkyl, each independently selected from 1, 2 or 3 in number of substituents per group; preferably R, R', A, L 12 、R 1 Wherein the substituents are each independently selected from halogen, CF 3 CN, OH, me, et, n-propyl, isopropyl, cyclopropyl,
    Figure PCTCN2021113197-APPB-100004
  3. The use according to claim 1 or 2, wherein R, R' are each independently selected from H, me, CF 3 、Et；
    Preferably L 11 Selected from the group consisting of
    Figure PCTCN2021113197-APPB-100005
  4. Use according to claim 1 or 2, wherein a is selected from optionally substituted: 3-12 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl;
    preferably, a is selected from optionally substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypentyl, phenyl, pyridinyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, bicyclo [1.1.1] pentanyl, or a bicyclic, spirocyclic, or fused cyclic group selected from any two of the foregoing groups;
    more preferably, a is selected from optionally substituted:
    Figure PCTCN2021113197-APPB-100006
    Figure PCTCN2021113197-APPB-100007
    most preferably, A is selected from
    Figure PCTCN2021113197-APPB-100008
    Figure PCTCN2021113197-APPB-100009
  5. The use according to claim 1 or 2, wherein L 12 Selected from methylene group,
    Figure PCTCN2021113197-APPB-100010
    Figure PCTCN2021113197-APPB-100011
  6. Use according to claim 1 or 2, wherein R 1 Selected from Me, CHF 2 、CF 3 、Et、CH 2 CF 3 Isopropyl group,
    Figure PCTCN2021113197-APPB-100012
    Cyclopropyl group,
    Figure PCTCN2021113197-APPB-100013
  7. Use according to claim 1 or 2, wherein
    Figure PCTCN2021113197-APPB-100014
    Preferably is
    Figure PCTCN2021113197-APPB-100015
  8. Use of a compound of the formula:
    Figure PCTCN2021113197-APPB-100016
    Figure PCTCN2021113197-APPB-100017
  9. use of a compound of the formula:
    Figure PCTCN2021113197-APPB-100018
    Figure PCTCN2021113197-APPB-100019
  10. the use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of a dermatological disorder selected from atopic dermatitis, psoriasis, contact dermatitis, other eczematous dermatitis, and delayed hypersensitivity reactions; plant and solar dermatitis; seborrheic dermatitis and dermatitis herpetiformis; lichen planus, lichen sclerosus, pyoderma gangrenosum, sarcoidosis, angioedema, vasculitis, toxic erythema, cutaneous eosinophilia, alopecia areata, male pattern baldness, svinter syndrome, wer-Crohn's syndrome, multiple erythema; infectious or non-infectious cellulitis; panniculitis; cutaneous lymphomas, non-melanoma skin cancers or other dysplastic lesions; drug-induced diseases, including fixed drug eruptions; preferably, the skin disease is selected from atopic dermatitis.
  11. The use of compound 1 in the manufacture of a medicament for the treatment of a dermatological disorder, characterized in that the dermatological disorder is atopic dermatitis,
    Figure PCTCN2021113197-APPB-100020
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IL99368A (en) * 1991-09-02 1996-01-19 Teva Pharma Compositions for topical treatment of psoriasis and atopic dermatitis comprising a xanthine derivative
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