WO2019096113A1 - 一种氘代的含硼的化合物及药物组合物和用途 - Google Patents

一种氘代的含硼的化合物及药物组合物和用途 Download PDF

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WO2019096113A1
WO2019096113A1 PCT/CN2018/115163 CN2018115163W WO2019096113A1 WO 2019096113 A1 WO2019096113 A1 WO 2019096113A1 CN 2018115163 W CN2018115163 W CN 2018115163W WO 2019096113 A1 WO2019096113 A1 WO 2019096113A1
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disease
compound
mmol
group
hydrogen
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French (fr)
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王义汉
刘志强
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深圳市塔吉瑞生物医药有限公司
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    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the invention belongs to the technical field of medicine, and in particular to a substituted boron-containing compound and a composition comprising the same and use thereof. More specifically, the present invention relates to certain anthracene substituted 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxoxaborole These guanidine substituted compounds are useful for treating and/or preventing diseases associated with infection or inflammation, and have superior pharmacokinetic properties.
  • Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are second messengers in the cell and play an important role in cell signaling.
  • cAMP adenosine monophosphate
  • cGMP cyclic guanosine monophosphate
  • ATP adenosine triphosphate
  • GTP guanosine triphosphate
  • cAK guanosine protein kinase
  • Both cAK and cGK consist of a catalytic subunit and a regulatory subunit. Cyclic nucleotides bind to regulatory subunits, releasing catalytic subunits that phosphorylate proteins, causing biological effects within the cell. Phosphodiesterases (PDEs) specifically catalyze hydrolysis with cAMP and cGMP as substrates to produce inactive 5'-AMP and 5'-GMP. The concentration of intracellular cyclic nucleotides is primarily determined by the balance between the synthesis of nucleotide cyclase and the hydrolysis of PDEs. PDEs inhibitors regulate the function of tissues and organs by inhibiting the activity of PDEs and increasing the concentration of cAMP and cGMP in cells.
  • PDEs can be separated by ion exchange chromatography and classified according to the amino acid sequence, enzyme kinetics, catalytic and regulatory properties, substrate specificity, cell distribution, and sensitivity to inhibitors of PDEs. So far, it has been reported that PDEs have at least 11 gene families (PDE1 to PDE11), and each family has 20% to 25% homology, and each family includes a plurality of subfamilies encoded by different genes. There is 70% to 80% homology between them, which are involved in different signaling pathways.
  • PDE4 inhibitors have obvious anti-inflammatory, anti-allergic, anti-platelet activation and anti-infective effects.
  • Crisaborole also known as AN2728 and PF-06930164 and the chemical name is 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxoxaborole , a new non-steroidal phosphodiesterase 4 (PDE-4) inhibitor developed by Anacor Pharmaceuticals (currently acquired by Pfizer) for mild to moderate allergic dermatitis in patients 2 years of age and older The topical treatment was approved by the US Food and Drug Administration (FDA) on December 14, 2016.
  • PDE-4 non-steroidal phosphodiesterase 4
  • the present invention provides a novel PDE4 inhibitor which is deuterated modified with a Crisaborole parent compound, which reduces or eliminates undesirable metabolites by a deuteration strategy; increases the half-life of the parent compound; reduces the dosage required to achieve the desired effect The number of doses required to achieve the desired effect; increase the formation of active metabolites (if formed); reduce the production of harmful metabolites in specific tissues; produce drugs that are more effective for multiple administrations and/or Safer drugs (regardless of whether the multiple drugs are intentional).
  • the present invention discloses a novel hydrazine-substituted boron-containing compound and a composition comprising the same and use thereof, which have better pharmacodynamic/pharmacokinetic properties and can be used for treatment and / or prevent conditions associated with infection or inflammation.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 and X 2 are each independently selected from hydrogen or hydrazine;
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the present invention provides a process for the preparation of a pharmaceutical composition as described above, comprising the steps of: mixing a pharmaceutically acceptable excipient with a compound of the present invention to form a pharmaceutical composition.
  • the invention provides a method of treating and/or preventing an infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention.
  • the infection is selected from the group consisting of: chloronychia, paronychia, erysipelas, fragile nail disease, gonorrhea, swimming pool granuloma, larval migration, rash, leprosy, deep pustular nodules, squeezing Milk nodule, herpetic spasm, acute bacterial periarthritis, chronic periarthritis, sporotrichosis, syphilis, skin tuberculosis, rabbit fever, scrotal disease, nail circumference and nail sputum, band Herpes, nail dystrophy, skin disease, psoriasis, pustular psoriasis, plaque alopecia, pustular keratosis, contact dermatitis, celestial syndrome
  • the invention provides a method of treating and/or preventing a disease associated with inflammation in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention.
  • the inflammation-related disease is selected from the group consisting of arthritis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, neurodegenerative disorders, congestive heart failure, stroke, aorta Stenosis, renal failure, lupus, pancreatitis, allergies, fibrosis, anemia, atherosclerosis, metabolic disease, bone disease, cardiovascular disease, chemotherapy/chemotherapy-related complications, type 1 diabetes, type 2 diabetes, liver disease , gastrointestinal disorders, ophthalmic diseases, allergic conjunctivitis, diabetic retinopathy, Xiaogren's syndrome, uveitis, lung disease, kidney disease, dermatitis, HIV-related cachexia, brain disease, ankylosing spondylitis, Member of
  • the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease and Parkinson's disease.
  • the inflammatory bowel disease is selected from the group consisting of Crohn's disease or ulcerative colitis.
  • the gastrointestinal complication is diarrhea.
  • the liver disease is a member selected from the group consisting of autoimmune hepatitis, hepatitis C, primary biliary cirrhosis, primary sclerosing cholangitis, and fulminant hepatic failure.
  • the gastrointestinal disorder is a member selected from the group consisting of celiac disease and non-specific colitis.
  • the lung disease is a member selected from the group consisting of allergic rhinitis, asthma, chronic obstructive pulmonary disease, chronic granulomatous inflammation, cystic fibrosis, and sarcoidosis.
  • the cardiovascular disease is a member selected from the group consisting of arteriosclerotic heart disease, congestive heart failure, and restenosis.
  • the kidney disease is a member selected from the group consisting of glomerulonephritis and vasculitis.
  • the compound is administered topically.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon 14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • compound of the invention refers to a compound of formula (I).
  • the term also encompasses pharmaceutically acceptable salts, prodrugs, hydrates or solvate compounds, polymorphs, stereoisomers or isotopic variations of the compounds of formula (I).
  • the term "pharmaceutically acceptable salt” means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and reasonable The benefits/hazard ratios are proportional to those salts.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • suitable inorganic and organic acids and inorganic and organic bases include those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • pharmaceutically acceptable non-toxic acid addition salts are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • prodrug includes a compound of the formula (I) which is biologically active or inactive, which, when taken by a suitable method, is metabolized or chemically reacted in the human body, or converted into a compound of the formula (I), or a formula a salt or solution of a compound of (I).
  • the prodrug includes, but is not limited to, the following compounds: an amino acid residue or a polypeptide chain consisting of one or more (eg, 2, 3 or 4) amino acid residues covalently linked by an amide or ester linkage in the present invention The free amino, hydroxyl or carboxyl group of the compound.
  • Amino acid residues include, but are not limited to, 20 natural amino acids usually represented by 3 letter symbols, but also 4-hydroxyproline, hydroxyl lysine, Demosine, isodemosine, 3-methylhistidine, n-amylamine Acid, ornithine and azide sulfones.
  • Other types of prodrugs are also included.
  • a free carboxyl group can be derivatized as an amide or an alkyl ester.
  • free hydroxyl groups are derivatized by the use of groups including, but not limited to, hemisuccinates, phosphates, dimethylaminoacetates, and phosphoryl groups. Oxymethoxymethyl group.
  • Hydroxyl and amino carbamate prodrugs as well as hydroxy carbonate prodrugs, sulfonates and sulfates, are also included. Also included are derivatized hydroxyl groups such as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester, optionally including, but not limited to, ether, amine, and carboxylic acid functional groups. The group is substituted, or wherein the acyl group is an amino acid ester as described above. Prodrugs of this type are described in the following literature: J. Med. Chem. 1996, 39, 10. Free presses can also be derivatized to amides, sulfonamides or phosphoramides. All of these other moieties can incorporate groups including, but not limited to, ether, amine, and carboxylic acid functional groups.
  • polymorph refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state.
  • a drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.
  • the term "subject” includes, but is not limited to, a human (ie, a male or female of any age group, eg, a pediatric subject (eg, an infant, a child, adolescent) or an adult subject (eg, Young adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses , sheep, goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or disease (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a “therapeutically effective amount” of a compound, as used herein, is a quantity sufficient to provide a therapeutic benefit, or one or more associated with a disease, disorder, or condition, in the course of treating a disease, disorder, or condition, unless otherwise stated. Symptoms are delayed or minimized.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.
  • Combination and related terms mean the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit dosage form.
  • the present invention provides a benzimidazole compound of formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, polymorph, stereoisomer or isotopic variation thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 and X 2 are each independently selected from hydrogen or hydrazine;
  • An additional condition is that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 and X 2 is deuterated or deuterated.
  • the compound of formula (I) contains at least one ruthenium atom, more preferably one ruthenium atom, more preferably two ruthenium atoms, more preferably three ruthenium atoms, more preferably four ruthenium atoms, More preferably, five germanium atoms, more preferably six germanium atoms, more preferably seven germanium atoms, more preferably eight germanium atoms, more preferably nine germanium atoms.
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 and X 2 have a strontium isotope content of at least 5% in each deuteration position, preferably More than 10%, more preferably more than 15%, more preferably more than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%, more preferably More than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably more than 65%, more preferably more than 70%, more preferably more than 75%, more preferably more than 80%, more preferably more than 85%, more preferably more than 90%, more preferably more than 95%, more preferably more than 99%.
  • At least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 and X 2 of the compound of formula (I) is preferably ruthenium, more preferably The two contain sputum, more preferably three sputum, more preferably four sputum, more preferably five sputum, more preferably six sputum, more preferably seven sputum, more preferably eight One contains ⁇ , and more preferably nine.
  • the compound of formula (I) contains at least one, two, three, four, five, six, seven, eight, nine ruthenium atoms.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen or hydrazine.
  • R 1 and R 2 are deuterium.
  • R 3 and R 4 are deuterium.
  • R 5 , R 6 and R 7 are each independently hydrogen or deuterium.
  • R 5 and R 6 are deuterium.
  • X 1 and X 2 are each independently hydrogen or deuterium.
  • X 1 is deuterium
  • X 2 is deuterium
  • X 1 and X 2 are deuterium.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen or hydrazine", including R 1 being selected from hydrogen or deuterium, and R 2 being selected from hydrogen Or hydrazine, R 3 is selected from hydrogen or hydrazine, and so on, until R 7 is selected from the hydrogen or hydrazine scheme. More specifically, R 1 is hydrogen, R 1 is deuterium, R 2 is hydrogen, R 2 is deuterium, R 3 is hydrogen, R 3 is deuterium, and so on, until R 7 is hydrogen and R 7 is deuterium.
  • X 1 and X 2 are each independently selected from hydrogen or hydrazine
  • X 1 is selected from hydrogen or hydrazine and R 2 is selected from hydrogen or hydrazine. More specifically, it includes a technical scheme in which X 1 is hydrogen, X 1 is hydrazine, X 2 is hydrogen, and X 2 is hydrazine.
  • the invention relates to a compound of formula (I), wherein R 3 , R 4 and R 7 are selected from hydrogen, R 1 , R 2 , R 5 , R 6 , X 1 and X 2 Each is independently selected from hydrogen or hydrazine, with the proviso that the compound contains at least one hydrazine.
  • the invention relates to a compound of formula (I), wherein R 1 -R 4 and R 7 are selected from hydrogen, and R 5 , R 6 , X 1 and X 2 are each independently selected from hydrogen Or hydrazine, with the proviso that the compound contains at least one hydrazine.
  • the invention relates to a compound of formula (I), wherein R 1 -R 4 , R 7 and X 1 are selected from hydrogen, and R 5 , R 6 and X 2 are each independently selected from hydrogen Or hydrazine, with the proviso that the compound contains at least one hydrazine.
  • the invention relates to a compound of formula (I), wherein R 1 -R 4 , R 7 , X 1 and X 2 are selected from hydrogen, and R 5 and R 6 are each independently selected from hydrogen Or hydrazine, with the proviso that the compound contains at least one hydrazine.
  • the invention relates to a compound of formula (I), wherein R 5 and R 6 are selected from the group consisting of ruthenium, R 1 -R 4 , X 1 and X 2 are each independently selected from hydrogen or hydrazine.
  • the invention relates to a compound of formula (I), wherein R 5 and R 6 are selected from hydrazine, R 3 , R 4 and R 7 are selected from hydrogen, R 1 , R 2 , X 1 And X 2 are each independently selected from hydrogen or hydrazine.
  • the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof:
  • the compound does not include a non-deuterated compound.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 0.5 to 2000 mg of the compound of the invention per agent, more preferably from 1 to 500 mg of the compound of the invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable excipient” means a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin) ), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-embedded Seg
  • compositions of the present invention may be administered orally, topically, parenterally, by inhalation or by nebulization or by the rectal unit dosage form, which comprises conventional pharmaceutically acceptable excipients. It is further understood that the optimal mode of administration can be a combination of methods. Oral administration is preferably carried out in the form of a pill, a capsule, an elixir, a syrup, a lozenge, a tablet or the like.
  • parenteral as used herein includes subcutaneous injection, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal, etc. or infusion techniques.
  • the pharmaceutical preparations comprising the compounds of the invention are preferably in a form suitable for oral use, such as tablets, tablets, troches, water or oil suspensions, dispersible powders or granules, hard or soft capsules or syrups or elixirs.
  • Solid dosage forms for oral administration include capsules, tablets, pills, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or solubilizer, for example, starch , lactose, sucrose, glucose, dry diol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, for example, paraffin; An absorption accelerator, for example, a quaternary amine compound; (g) a wetting agent such as cetyl alcohol and
  • Solid dosage forms such as tablets, troches, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • Liquid dosage forms can contain, in addition to the active compound, inert release agents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert release agents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butanediol, dimethylformamide and
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the method of the invention can be applied by topical application of a compound of the invention.
  • compositions of the present invention comprise a fluid or semi-solid vehicle which may include, but is not limited to, polymers, thickeners, buffers, neutralizers, chelating agents, preservatives, surfactants or emulsifiers, antioxidants, waxes or Oils, softeners, sunscreens and solvent or mixed solvent systems.
  • a solvent or mixed solvent system is important for forming because she primarily dissolves the drug. Although it is difficult to add a solvent to the formulation, the optimal solvent or solvent system is capable of maintaining the clinically relevant level of the drug in solution.
  • the topical compositions for use in the subject matter of the present invention can be made into a variety of product types.
  • ком ⁇ онент include, but are not limited to, lotions, creams, gels, sticks, sprays, ointments, pastes, foams, mousses, and cleansers.
  • product types can include several types of carrier systems including, but not limited to, particles, nanoparticles, and liposomes.
  • a disintegrating agent such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.
  • Formulation lotions which are applied to the skin, nails, hair, claws or hoof surface without friction are generally liquid or semi-liquid preparations in which solid fine powders, waxes or liquids are dispersed.
  • Lotions generally comprise a suspending agent which produces a better dispersion and a compound for limiting and maintaining the active agent in contact with the skin, nails, hair, claws or hooves, such as methylcellulose, carboxymethyl-cellulose sodium and the like.
  • Creams comprising an active agent delivered in accordance with the present invention are viscous liquids or semi-solids, either of the oil-in-water or water-in-oil type.
  • the cream base is water washable and comprises an oil phase, an emulsifier and an aqueous phase, an emulsifier and an aqueous phase.
  • Gelling agents can also be used in conjunction with the present invention.
  • the gel is semi-solid.
  • the single-solid phase comprises organic macromolecules substantially uniformly distributed in the carrier liquid, which is typically water, and may be a solvent or a mixture of solvents.
  • Ointments which are semi-solid preparations are generally based on petroleum jelly or other petroleum jelly derivatives.
  • the ointment base should be inert, stable, non-irritating and non-sensitive.
  • Formulations useful in the present invention also include sprays.
  • Sprays generally provide the active agent in water and/or alcohol solutions which can be aerosolized on the skin, nails, hair, claws or hooves for delivery.
  • Such sprays include those which provide a concentration of the active agent solution at the site of administration after delivery, for example, the spray solution may consist essentially of an alcohol or other volatile liquid in which the drug or active agent may be dissolved.
  • the carrier volatilizes leaving a concentrated active agent on the site of administration.
  • the topical pharmaceutical compositions may also contain suitable solid or gel phase carriers.
  • suitable solid or gel phase carriers include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers. Such as polyethylene glycols.
  • the topical pharmaceutical compositions may also contain suitable emulsifying agents, i.e., agents which enhance or facilitate the mixing and suspension of oil-in-water or water-in-oil.
  • suitable emulsifying agents i.e., agents which enhance or facilitate the mixing and suspension of oil-in-water or water-in-oil.
  • the emulsifier used herein may consist of a single emulsifier or may be a nonionic, anionic, cationic or amphoteric surfactant or a mixture of two or more such surfactants; preferably nonionic or anionic Emulsifier.
  • the topical pharmaceutical compositions may also contain suitable softening agents.
  • Softeners are substances used to prevent or slow drying and to protect the skin, nails, hair, claws or hooves.
  • Useful softening agents include, but are not limited to, cetyl alcohol, isopropyl myristate, stearyl alcohol, and the like.
  • the topical pharmaceutical compositions may also contain suitable antioxidants, i.e., substances known to inhibit oxidation.
  • Antioxidants suitable for use in the present invention include, but are not limited to, butylated hydroxytoluene, ascorbic acid, butyl hydroxyanisole, thiodipropionic acid, and tocopherols, and the like, including pharmaceutically acceptable salts and esters of these compounds.
  • the topical pharmaceutical compositions may also contain suitable preservatives.
  • a preservative is a compound that acts as an antimicrobial agent in a pharmaceutical formulation.
  • the effective and acceptable preservatives known in the art as parenteral formulations are benzalkonium chloride, benzethonium chloride, chlorhexidine, phenol, m-cresol, benzyl alcohol, methylparaben. , propyl paraben, chlorobutanol, o-cresol, p-cresol, chlorocresol, phenylmercuric nitrate, thimerosal, benzoic acid and various mixtures thereof.
  • the topical pharmaceutical compositions may also contain suitable chelating agents for complexing with metal cations that do not pass through the lipid bilayer.
  • suitable chelating agents include ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis( ⁇ -aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) and 8-amino- 2[(2-Amino-5-methylphenoxy)methyl]-6-methoxyquinoline-N,N,N',N'-tetraacetic acid tetrapotassium salt (QUIN-2).
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol-bis( ⁇ -aminoethylether)-N,N,N',N'-tetraacetic acid
  • QUIN-2 8-amino- 2[(2-Amino-5-methylphenoxy)methyl]-6-methoxyquinoline-N,N,N',N'
  • the topical compositions may also contain suitable neutralizing agents for adjusting the pH of the formulation to a pharmaceutically acceptable range.
  • the topical compositions may also contain suitable tackifiers. These components are diffusible compounds capable of increasing the viscosity of the polymer-containing solvent by interaction of the active agent with the polymer.
  • the topical compositions may also contain a suitable nail penetration enhancer or one or more suitable solvents.
  • a sustained release system can be used to deliver a compound, such as a translucent substrate of a solid hydrophobic polymer comprising a therapeutic agent.
  • a topical treatment regimen for administration in accordance with the present invention comprises applying the composition directly to the site of application of the skin, nails, hair, claws or hooves, once to several times a day.
  • the formulations of the invention may be used to treat, ameliorate or prevent conditions or conditions associated with bacterial infections, acne, inflammation, and the like.
  • Anti-inflammatory agents include, but are not limited to, menthol, chlorophenyl sulfone, aloe vera, hydrocortisone, and the like.
  • Vitamins include, but are not limited to, vitamin B, vitamin E, vitamin A, vitamin D, and the like.
  • Anti-aging agents include, but are not limited to, nicotinamide, retinol and retinoid derivatives, AHA, ascorbic acid, lipoic acid, coenzyme Q10, beta hydroxy acid, salicylic acid, copper-binding peptides, dimethylaminoethyl (DAEA), etc. .
  • Active agents that effectively control or alter keratinization include, but are not limited to, retinoic acid and adapalene.
  • any acceptable mode of administration of the active agent for similar applications is employed.
  • the particular dosage level for any particular patient will depend on a variety of factors, including the activity, age, weight, general health, sex, diet, time of administration, route of administration, and rate of excretion of the particular compound employed.
  • the severity of the particular disease of the therapy and the judgment of the clinician prescribing the prescription It can be administered once or twice daily or 3 or 4 times a day.
  • a typical patient is administered systemically at a dose ranging from 0.1 to 1000 mg/day, preferably from 1 to 500 mg/day, more preferably from 10 to 200 mg/day, even more preferably from 100 to 200 mg/day.
  • the usual dosage range for the body surface area of the patient is in the range of 50-91 mg/m 2 /day.
  • the invention further relates to a method of treating and/or preventing an infection in a subject comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, hydrate or solvent thereof, Compounds, polymorphs, stereoisomers or isotopic variations, or administration of the pharmaceutical compositions described herein.
  • the method involves treating and/or preventing the following infections: chloronychia, paronychia, erysipelas, fragile nail disease, gonorrhea, swimming pool granuloma, larval migration, rash, leprosy, deep touch Pustular nodules, milkmaid nodules, herpetic spasms, acute bacterial periarthritis, chronic periarthritis, sporotrichosis, syphilis, skin tuberculosis, rabbit fever, latent rickets, nail week and Nail sputum, herpes zoster, nail dystrophy, skin disease, psoriasis, pustular psoriasis, plaque alopecia, pustular keratosis, contact dermatitis, celestial syndrome, acral psoriasis dermatitis , lichen planus, idiopathic atrophy in nails, lustrous moss, streaky
  • the invention also relates to a method of treating and or preventing a disease associated with inflammation in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, prodrug thereof, Hydrates or solvates, polymorphs, stereoisomers or isotopic variations, or administration of the pharmaceutical compositions described herein.
  • the method relates to the treatment and/or prevention of inflammation: arthritis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, neurodegenerative disorders, congestive heart failure, stroke, Aortic stenosis, renal failure, lupus, pancreatitis, allergies, fibrosis, anemia, atherosclerosis, metabolic disease, bone disease, cardiovascular disease, chemotherapy/chemotherapy-related complications, type 1 diabetes, type 2 diabetes , liver disease, gastrointestinal disorders, ophthalmic diseases, allergic conjunctivitis, diabetic retinopathy, Xiaogren's syndrome, uveitis, lung disease, kidney disease, dermatitis, HIV-related cachexia, brain disease, ankylosing spine A member of inflammation, leprosy, anemia, and fibromyalgia.
  • the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease and Parkinson's disease; the inflammatory bowel disease is selected from Crohn's disease or ulcerative colitis; the gastrointestinal complication is diarrhea; and the liver disease is selected from the group consisting of autoimmune hepatitis, type C Hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and fulminant hepatic failure; gastrointestinal disorders are selected from celiac disease and non-specific colitis; lung diseases are selected from allergic rhinitis, asthma, chronic obstruction Pulmonary disease, chronic granulomatous inflammation, cystic fibrosis and sarcoidosis; cardiovascular disease is selected from the group consisting of arteriosclerotic heart disease, congestive heart failure and restenosis; kidney disease is selected from glomerulonephritis and vein Tube inflammation.
  • the compounds of the present invention have a number of advantages over non-deuterated compounds known in the art.
  • Advantages of the present invention include: First, the compounds and compositions employing the technical solutions of the present invention provide a more advantageous therapeutic tool for the treatment of infection and inflammation related diseases. Second, the metabolism of the compound in the organism is improved, giving the compound better pharmacokinetic parameter characteristics. In this case, the dosage can be changed and a long-acting preparation can be formed to improve the applicability. Third, the drug concentration of the compound in the animal is increased, and the drug efficacy is improved. Fourth, certain metabolites are inhibited and the safety of the compounds is increased.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • LC-MS (APCI): m / z 254.13 (M + 1) +.
  • LC-MS (APCI): m / z 255.09 (M + 1) +.
  • the compound 23 (0.5 g, 1.28 mmol) was added to a solution of anhydrous tetrahydrofuran (15 ml) under a nitrogen atmosphere, the solution was cooled to -78 ° C, and then n-butyllithium solution (0.61 ml, 2.5 mol) was slowly added dropwise. /L), after the completion of the dropwise addition, the reaction was continued at -78 ° C for 1 h, and then trimethyl borate (0.20 g, 1.92 mmol) was added in one portion.
  • LC-MS (APCI): m / z 254.19 (M + 1) +.
  • PDE4D2 TR-FRET Assay Kit BPS bioscience, Cat. No. 60707, Cyclic-3', 5'-AMP (Sigma, Cat. No. A6885), Tris (amresco, Cat. No. T0497), BSA (Perkin Elmer, Catalog Number CR84-100), Magnesium Chloride (Sigma, Cat. No. M1028), Tween-20 (Solarbio, Cat. No. T8220), Dithiothreitol (Invitrogen, Cat. No. P2325), DMSO (Sigma, Cat. No. D8418), 96-well plate (Nunc, catalog number 249944), 384-well plate (Greiner, catalog number 784075).
  • test compound was dissolved in DMSO to make a 10 mM stock solution. Then, the mother liquid was diluted to 2 mM, and then diluted in a concentration of 3 times in DMSO, and 10 doses were obtained to obtain a working solution.
  • PDE4D2 enzyme activity assay 2.5 uL of 2*PDE4D2 enzyme solution (4 pg/ ⁇ L) and 25 nL of pre-diluted compound of different concentrations were transferred to the side plates, and sealed and mixed for 10 minutes at room temperature, double wells at each concentration. Among them, a negative positive control was set: negative was a blank control and positive was Rolipram. 2.5 ⁇ L of a previously prepared 2x Cyclic-3', 5'-AMP (2 ⁇ M) solution was added to the reaction system and incubated at room temperature for 60 minutes. Then add 5 ⁇ L of AMP glo reagent and continue to incubate for 60 minutes at room temperature.
  • the enzyme activity in the presence of the compound of the present invention at each concentration was measured by an Evnvision microplate reader, and the inhibitory activities of the compounds at different concentrations on the enzyme activity were calculated. Then, according to the four-parameter equation, the inhibitory activity of the enzyme activity under different concentrations of the compound was fitted according to Graphpad 5.0 software, and the IC 50 value was calculated.
  • phosphate buffer 100 mM, pH 7.4.
  • the pH of the solution was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • a solution of the NADPH regeneration system (containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride) was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the metabolic stability of human liver microsomes was evaluated by comparing the compounds of the present invention and their compounds without deuteration, Crisaborole.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 2.
  • the experimental results show that the compound of the present invention can significantly improve metabolic stability as compared with the undeuterated compound Crisaborole.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

Abstract

一种如式(I)所示的氘取代的5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、多晶型、立体异构体或同位素变体，包含化合物的药物组合物。式(I)的化合物是磷酸二酯酶4抑制剂。化合物或药物组合物用于制备治疗和/或预防感染以及多种与炎症相关的疾病的药物的用途。

Description

[根据细则37.2由ISA制定的发明名称]　一种氘代的含硼的化合物及药物组合物和用途 技术领域
本发明属于医药技术领域，尤其涉及一种取代的含硼的化合物及包含该化合物的组合物及其用途。更具体而言，本发明涉及某些氘取代的5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯，这些氘取代的化合物可用于治疗和/或预防与感染或炎症相关的疾病，且具有更优良的药代动力学性质。
背景技术
环磷腺苷(cAMP)和环磷鸟苷(cGMP)是细胞内的第二信使，对细胞的信号传导起着重要作用。当外来信号(神经递质、激素、光和气味等)作用于细胞膜上受体时，核苷酸环化酶被激活，作用于三磷酸腺苷(ATP)和三磷酸鸟苷(GTP)，分别生成cAMP和cGMP。它们作为第二信使，通过腺(鸟)苷酸蛋白激酶(cAK或cGK)调节细胞功能。cAK和cGK均由催化亚单位和调节亚单位组成。环核苷酸和调节亚单位结合，释放催化亚单位，后者使蛋白磷酸化，引起细胞内的生物效应。磷酸二酯酶(PDEs)能特异性地以cAMP和cGMP为底物，催化水解生成无活性的5’-AMP和5’-GMP。细胞内环核苷酸的浓度主要由核苷酸环化酶的合成和PDEs水解作用之间的平衡决定。PDEs抑制剂则是通过抑制PDEs的活性，提高细胞内cAMP和cGMP的浓度，从而调节组织器官的功能。
通过离子交换层析可将PDEs分离，并根据PDEs的氨基酸顺序、酶动力学特征、催化和调节特性、底物特异性、细胞分布和对抑制剂的敏感性进行分类。迄今为止，已报道PDEs至少有11个基因家族(PDE1～PDE11)，各家族之间有20％～25％的同源性，每个家族又包括多个由不同的基因编码的亚族，相互之间存在70％～80％的同源性，分别参与不同的信号传导通路。研究表明，PDEs抑制剂对靶器官的药理作用主要在于两个方面：(1)直接抑制PDEs的活性，提高环核苷酸的细胞内水平；(2)对PDEs活性的反馈性抑制效应。其中，PDE4抑制剂具有明显抗炎、抗过敏、抗血小板活化、抗感染作用。
Crisaborole，又名AN2728和PF-06930164并且化学名为5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯，是Anacor制药公司(现被Pfizer收购)研发的一款新型的非甾类磷酸二酯酶4(PDE-4)抑制剂，用于2岁及以上患者的轻度至中度过敏性皮炎的局部治疗药物，于2016 年12月14日获得美国食品药品监督管理局(FDA)批准上市。
因此，本领域仍需开发对适用作PDE4抑制剂且具有更好地药效学/药代动力学的化合物。本发明提供一款新型的以Crisaborole为母体化合物进行氘代修饰的PDE4抑制剂，通过氘代策略降低或消除不希望的代谢物；增加母体化合物的半衰期；减少实现所希望的效果所需要的剂量数目；减少实现所希望的效果所需要的剂量数量；增加活性代谢物的形成(如果形成的话)；减少在特定组织中有害代谢物的产生；产生对于多重用药而言更有效的药物和/或更安全的药物(不论该多重用药是否有意向的)。
发明内容
针对以上技术问题，本发明公开了一种新的氘取代的含硼的化合物及包含该化合物的组合物及其用途，其具有更好地药效学/药代动力学性能，可用于治疗和/或预防与感染或炎症相关的病症。
对此，本发明采用以下技术方案：
本发明的第一方面，提供了式(I)化合物：
Figure PCTCN2018115163-appb-000001
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、X 1和X 2各自独立地选自氢或氘；
附加条件是R 1、R 2、R 3、R 4、R 5、R 6、R 7、X 1和X 2中至少一个是氘代的或氘；
或其药学上可接受的盐、前药、水合物或溶剂化合物、多晶型、立体异构体或同位素变体。
在另一方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物。在具体实施方案中，本发明化合物以有效量提供在所述药物组合物中。在具体实施方案中，本发明化合物以治疗有效量提供。在具体实施方案中，本发明化合物以预防有效量提供。
在另一方面，本发明提供了一种如上所述的药物组合物的制备方法，包括以下步骤：将药学上可接受的赋形剂与本发明化合物进行混合，从而形成药物组合物。
在另一方面，本发明提供了在需要其的受试者中治疗和/或预防感染的方法，所述方法包括给 予受试者有效剂量的本发明化合物。在具体实施方案中，所述感染选自：chloronychia、甲沟炎、类丹毒、脆甲症、淋病、游泳池肉芽肿、幼虫移行匍行疹、麻风病、触染性深脓疱结节、挤奶工结节、疱疹性瘭疽、急性细菌性甲周炎、慢性甲周炎、孢子丝菌病、梅毒、皮肤疣结核、兔热病、潜蚤病、指甲周和指甲下疣、带状疱疹、指甲营养不良、皮肤病、银屑病、脓疱性牛皮癣、斑性脱发、脓疱性角化不全、接触性皮炎、菜特尔综合症、肢端牛皮癣形皮炎、扁平苔癣、指甲中的特发性萎缩病、光泽苔癣、条纹状苔癣、炎性线性疣状表皮痣、秃顶、天疱疮、大疱性类天疱疮、获得性大疱性表皮松解、达里埃病、毛发红糠疹、掌跖角化病、接触性湿疹、多形红斑、疥疮、巴泽克斯综合征、全身性硬皮病、系统性红斑狼疮、慢性红斑狼疮、皮肌炎、孢子丝菌病、真菌性角膜炎、扩散性眼真菌病、内生性眼真菌病、瘢痕疙瘩性芽生菌病、足菌病、毛结节菌病、花斑癣、体癣、股癣、脚癣、须癣、头癣、黑色小孢子菌病、耳真菌病、黄癣、着色真菌病和叠瓦癣中的成员。在具体实施方案中，口服、皮下、静脉内或肌肉内给药所述化合物。在具体实施方案中，长期给药所述化合物。
在另一方面，本发明提供了在需要其的受试者中治疗和/或预防与炎症相关的疾病的的方法，所述方法包括给予受试者有效剂量的本发明化合物。在具体实施方案中，所述的与炎症相关的疾病选自关节炎、风湿性关节炎、炎症性肠病、银屑病、多发性硬化、神经变性病症、充血性心力衰竭、中风、主动脉瓣狭窄、肾衰竭、狼疮、胰腺炎、过敏症、纤维化、贫血、动脉粥样硬化、代谢病、骨病、心血管病、化疗/化疗相关并发症、I型糖尿病、II型糖尿病、肝病、胃肠道病症、眼科疾病、过敏性结膜炎、糖尿病性视网膜病、肖格伦综合征、葡萄膜炎、肺病、肾脏疾病、皮炎、HIV-相关恶病质、脑型疾，强直性脊柱炎、麻风病、贫血和纤维肌痛中的成员。在具体实施方案中，所述的神经变性病症选自阿尔兹海默病和帕金森病中的成员。在具体实施方案中，所述的炎性肠病选自克罗恩病或溃疡性结肠炎中的成员。在具体实施方案中，所述的胃肠并发症为腹泻。在具体实施方案中，所述的肝病为选自自身免疫性肝炎、丙型肝炎、原发性胆汁性肝硬变、原发性硬化性胆管炎和爆发性肝衰竭中的成员。在具体实施方案中，所述的胃肠病症为选自乳糜泻和非特异性结肠炎中的成员。在具体实施方案中，所述的肺病为选自过敏性鼻炎、哮喘、慢性阻塞性肺疾病、慢性肉芽肿性炎症、囊性纤维化和结节病中的成员。在具体实施方案中，所述的心血管疾病为选自动脉硬化性心脏病、充血性心力衰竭和再狭窄中的成员。在具体实施方案中，所述的肾脏疾病为选自肾小球肾炎和脉管炎中的成员。在具体实施方案中，局部施用所述化合物。
具体实施方式
定义
本文中，如无特别说明，“氘代”指化合物或基团中的一个或多个氢被氘所取代；氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
本文中，如无特别说明，“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015％)的化合物。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H， 3H， 13C， 14C， 15N， 17O， 18O， 31P， 32P， 35S， 18F以及 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳14，即 14C，它们的制备和检测比较容易，是同位素中的首选。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用示例中的方案可以制备。
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种“立体异构体”形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
如本文所用，术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的药学上可接受的盐、前药、水合物或溶剂化合物、多晶型、立体异构体或同位素变体。
如本文所用，术语“药学上可接受的盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等，并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。
本发明化合物的药学上可接受的盐包括衍生自合适的无机和有机酸和无机和有机碱的盐。药学上可接受的无毒的酸加成盐的实例是与无机酸形成的盐，例如盐酸、氢溴酸、磷酸、硫酸和高氯酸，或与有机酸形成的盐，例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸。也包括使用本领域常规方法形成的盐，例如，离子交换方法。其它药学上可接受的盐包括：已二酸盐、海藻酸 盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐，等等。衍生自合适的碱的药学上可接受的盐包括碱金属、碱土金属、铵和N +(C 1-4烷基) 4盐。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐，等等。如果合适的话，其它的药学上可接受的盐包括与反离子形成的无毒的铵盐、季铵盐和胺阳离子，反离子例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”指本发明化合物与水进行配位形成的配合物。
术语“前药”包括其本身可以是具有生物活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式(I)的一类化合物，或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不限于)以下化合物：氨基酸残基或由一个或多个(如2、3或4个)氨基酸残基组成的多肽链通过酰胺或酯键共价连接在本发明化合物的游离氨基、羟基或羧基上。氨基酸残基包括但不限于20个通常用3个字母符号表示的天然氨基酸，而且还包括4-羟基脯氨酸、羟基赖氨酸、Demosine、isodemosine、3-甲基组氨酸、正缬氨酸、鸟氨酸和氮氨酸砜。也包括其他类型的前药。例如，游离羧基可衍生为酰胺或烷基酯。如Advanced Drug Delivery Reviews 1996,19,115中所述，游离羟基通过使用以下基团来进行衍生化，所述基团包括但不限于半琥珀酸酯、磷酸酯、二甲基氨基乙酸酯和磷酰基氧基甲氧基碳基。羟基和氨基的氨基甲酸酯前药，以及羟基的碳酸酯前药、磺酸酯和硫酸酯，也包括在内。还包括羟基的衍生化如(酰基氧基)甲基和(酰基氧基)乙基醚，其中所述酰基可以是烷基酯，任选被包括但不限于醚、胺和羧酸官能团的基团取代，或者其中所述酰基是如上述的氨基酸酯。该类型的前药描述在以下文献中：J.Med.Chem.1996,39,10.游离按也可以被衍生化为酰胺、磺酰胺或磷酰胺。所有这些其他部分可掺入包括但不限于醚、胺和羧酸官能团的基团。
术语“多晶型”是指化学药物分子的不同排列方式，一般表现为药物原料在固体状态下的存在形式。一种药物可以多种晶型物质状态存在，同一种药物的不同晶型，在体内的溶解和吸收可能不同， 从而会对制剂的溶出和释放产生影响。
如本文所用，术语“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在另一些实施方案中，受试者是非人动物。
“疾病”、“障碍”和“病症”在本文中可以互换地使用。
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括受试者开始患有具体疾病、障碍或疾病之前发生的作用(“预防性治疗”)。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药物动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗和预防性治疗有效量。
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗有益处的数量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化。化合物的治疗有效量是指单独使用或与其他疗法联用的治疗剂的数量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其他治疗剂的治疗效能的数量。
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的数量，或足以预防与疾病、障碍或病症有关的一或多种症状的数量，或防止疾病、障碍或病症复发的数量。化合物的预防有效量是指单独使用或与其它药剂联用的治疗剂的数量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的数量，或增强其它预防药剂的预防效能的数量。
“组合”以及相关术语是指同时或依次给药本发明的治疗剂。例如，本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药，或与另一治疗剂一起呈单一单位剂型同时给药。
化合物
本发明提供式(I)的苯并咪唑化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、 多晶型、立体异构体或同位素变体：
Figure PCTCN2018115163-appb-000002
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、X 1和X 2各自独立地选自氢或氘；
附加条件是R 1、R 2、R 3、R 4、R 5、R 6、R 7、X 1和X 2中至少一个是氘代的或氘。
作为本发明的优选实施方案，式(I)中化合物至少含有一个氘原子，更加地一个氘原子，更佳地二个氘原子，更佳地三个氘原子，更佳地四个氘原子，更佳地五个氘原子，更佳地六个氘原子，更佳地七个氘原子，更佳地八个氘原子，更佳地九个氘原子。
作为本发明的优选实施方案，氘在氘代位置的氘同位素含量至少是大于天然氘同位素含量0.015％，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。
具体地说，在本发明中R 1、R 2、R 3、R 4、R 5、R 6、R 7、X 1和X 2，各氘代位置中氘同位素含量至少是5％，较佳地大于10％，更佳地大于15％，更佳地大于20％，更佳地大于25％，更佳地大于30％，更佳地大于35％，更佳地大于40％，更佳地大于45％，更佳地大于50％，更佳地大于55％，更佳地大于60％，更佳地大于65％，更佳地大于70％，更佳地大于75％，更佳地大于80％，更佳地大于85％，更佳地大于90％，更佳地大于95％，更佳地大于99％。
在另一具体实施方案中，式(I)中化合物的R 1、R 2、R 3、R 4、R 5、R 6、R 7、X 1和X 2，至少其中一个含氘，更佳地两个含氘，更佳地三个含氘，更佳地四个含氘，更佳地五个含氘，更佳地六个含氘，更佳地七个含氘，更佳地八个含氘，更佳地九个含氘。具体而言，式(I)中化合物至少含有一个、两个、三个、四个、五个、六个、七个、八个、九个氘原子。
作为本发明的优选实施方案，R 1、R 2、R 3和R 4各自独立地选自氢或氘。
在另一优选实施方案中，R 1和R 2是氘。
在另一优选实施方案中，R 3和R 4是氘。
作为本发明的优选实施方案，R 5、R 6和R 7各自独立地是自氢或氘。
在另一优选实施方案中，R 5和R 6是氘。
作为本发明的优选实施方案，X 1和X 2各自独立地是自氢或氘。
在另一优选实施方案中，X 1为氘。
在另一优选实施方案中，X 2为氘。
在另一优选实施方案中，X 1和X 2为氘。
在具体实施方案中，“R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地选自氢或氘”包括R 1选自氢或氘，R 2选自氢或氘，R 3选自氢或氘，以此类推，直至R 7选自氢或氘的技术方案。更具体地，包括R 1为氢、R 1为氘，R 2为氢、R 2为氘，R 3为氢、R 3为氘，以此类推，直至R 7为氢、R 7为氘的技术方案。
在具体实施方案中，“X 1和X 2各自独立地选自氢或氘”包括X 1选自氢或氘，R 2选自氢或氘的技术方案。更具体地，包括X 1为氢、X 1为氘，X 2为氢、X 2为氘的技术方案。
作为本发明的优选实施方案，本发明涉及一种式(I)的化合物，其中R 3、R 4和R 7选自氢，R 1、R 2、R 5、R 6、X 1和X 2各自独立地选自氢或氘，附加条件是所述化合物至少含有一个氘。
作为本发明的优选实施方案，本发明涉及一种式(I)的化合物，其中R 1-R 4和R 7选自氢，R 5、R 6、X 1和X 2各自独立地选自氢或氘，附加条件是所述化合物至少含有一个氘。
作为本发明的优选实施方案，本发明涉及一种式(I)的化合物，其中R 1-R 4、R 7和X 1选自氢，R 5、R 6和X 2各自独立地选自氢或氘，附加条件是所述化合物至少含有一个氘。
作为本发明的优选实施方案，本发明涉及一种式(I)的化合物，其中R 1-R 4、R 7、X 1和X 2选自氢，R 5和R 6各自独立地选自氢或氘，附加条件是所述化合物至少含有一个氘。
作为本发明的优选实施方案，本发明涉及一种式(I)的化合物，其中R 5和R 6选自氘，R 1-R 4、X 1和X 2各自独立地选自氢或氘。
作为本发明的优选实施方案，本发明涉及一种式(I)的化合物，其中R 5和R 6选自氘，R 3、R 4和R 7选自氢，R 1、R 2、X 1和X 2各自独立地选自氢或氘。
作为本发明的优选实施方案中，所述化合物选自下组化合物或其药学上可接受的盐：
Figure PCTCN2018115163-appb-000003
Figure PCTCN2018115163-appb-000004
在另一优选实施方案中，所述化合物不包括非氘代化合物。
药物组合物和施用方法
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的活性组分。在一些实施方案中，所述药物组合物包含治疗有效量的活性组分。在一些实施方案中，所述药物组合物包含预防有效量的活性组分。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有0.5-2000mg本发明化合物/剂，更佳地，含有1-500mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的赋形剂”是指不会破坏一起调配的化合物的药理学活性的无毒载体、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载体、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明的组合物可以通过口服、局部、非肠道，通过吸入或喷雾剂或通过直肠以的单位剂型给药，所述的单位剂型包含常规的药学上可接受的赋形剂。进一步理解最佳给药方式可以为方法的组合。特别优选以丸剂、胶囊、酏剂、糖浆剂、锭剂、药片等形式进行口服。本文所用的术语非肠道包括皮下注射、真皮内、血管内(例如静脉内)、肌内、脊柱、鞘内注射等或输注技术。
包含本发明化合物的药物制剂优选为适合于口服应用的形式，例如为片剂、药片、锭剂、水或油混悬液，可分散粉末或颗粒，硬或软胶囊或糖浆剂或酏剂。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增溶剂，例如，淀粉、乳糖、蔗糖、葡萄糖、干露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如，石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如，鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其他本领域 公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性释放剂，如水或其他溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
局部用制剂
在一个优选的实施方案中，可以通过局部施用本发明化合物应用本发明的办法。
本发明组合物包含流体或半固体媒介物，它们可以包括但不限于聚合物、增稠剂、缓冲剂、中和剂、螯合剂、防腐剂、表面活性剂或乳化剂、抗氧化剂、蜡或油、软化剂、防晒剂和溶剂或混合溶剂系统。溶剂或混合溶剂系统对成形而言是重要的，因为她主要使药物溶解。尽管难以将溶剂添加到制剂中，但是最佳溶剂或溶剂系统还是能够维持药物在溶液中的临床相关水平。可以将用于本发明主题的局部用组合物制成各种产品类型。它们包括但不限于洗剂、霜剂、凝胶、棒、喷雾剂、软膏剂、糊剂、泡沫、摩丝和清洁剂。这些产品类型可以包括几种类型的载体系统，包括但不限于颗粒、纳米粒和脂质体。如果需要，可以加入崩解剂，诸如交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐，诸如藻酸钠。
在无摩擦下施用于皮肤、指甲、毛发、爪或蹄表面的制剂洗剂一般为液体或半-液体制剂，其中分散了固体细粉、蜡或液体。洗剂一般包含产生更好分散体的悬浮剂和用于局限于和保持活性剂接触皮肤、指甲、毛发、爪或蹄的化合物，例如甲基纤维素、羧甲基-纤维素钠等。
包含按照本发明递送的活性剂的霜剂为粘性液体或半固体，为水包油型或油包水型。霜剂基质 为可用水洗的并且包含油相，乳化剂和水相、乳化剂和水相。
凝胶剂也可以与本发明结合使用。正如局部药物制剂领域技术人员可以理解的，凝胶为半固体。单一-固相包含基本上均匀分布在载体液体中的有机大分子，所述的载体液体一般为水，而且可以为溶剂或溶剂混合物。
为半固体制剂的软膏剂一般基于凡士林油或其他凡士林油衍生物。就载体或媒介物而言，软膏剂基质应为惰性的，稳定的无刺激性和非敏感性的。
本发明有用的制剂还包括喷雾剂。喷雾剂一般提供在水和/或醇溶液中的活性剂，可以使该制剂在皮肤、指甲、毛发、爪或蹄雾化以便递送。这类喷雾剂包括为在递送后的给药部位上提供活性剂溶液浓度配置的那些，例如喷雾剂溶液可以主要由醇或其他类挥发性液体组成，其中可以溶解有药物或活性剂。在递送至皮肤、指甲、毛发、爪或蹄时，载体挥发，从而在给药部位上遗留浓缩的活性剂。
局部用药物组合物还可以包含合适的固体或凝胶相载体。这类载体的实例包括但不限于碳酸钙、磷酸钙、各种糖类、淀粉、纤维素衍生物、明胶和聚合物。诸如聚乙二醇类。
局部用药物组合物还可以包含合适的乳化剂，即强化或有利于混合和悬浮水包油或油包水的试剂。本文所用的乳化剂可以由单一乳化剂组成或可以为非离子型，阴离子型，阳离子型或两性表面活性剂或两种或多种这类表面活性剂混合物；本文优选使用非离子型或阴离子型乳化剂。
局部用药物组合物还可以包含合适的软化剂。软化剂为用于防止或减缓干燥以及用于保护皮肤、指甲、毛发、爪或蹄的物质。有用的软化剂包括但不限于鲸蜡醇、肉豆蔻酸异丙酯、十八烷醇等。
局部用药物组合物还可以包含合适的抗氧化剂，即已知抑制氧化的物质。适用于本发明的抗氧化剂包括但不限于丁羟甲苯、抗坏血酸、丁基羟基茴香醚、硫代二丙酸和生育酚类等，包括这些化合物的药学上可接受的盐和酯类。
局部用药物组合物还可以包含合适的防腐剂。防腐剂为添加到药物制剂中其抗微生物剂作用的化合物。在本领域已知为非肠道制剂中有效和可接受的防腐剂中有苯扎氯铵、苄索氯胺、氯已定、苯酚、间-甲酚、苄醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、氯丁醇、邻-甲酚、对-甲酚、氯甲酚、硝酸苯汞、硫柳汞、苯甲酸及其各种混合物。
局部用药物组合物还可以包含合适的螯合剂以便与不通过脂双层的金属阳离子复合。合适的螯合剂的实例包括乙二胺四乙酸(EDTA)、乙二醇-双(β-氨乙基醚)-N,N,N’,N’-四乙酸(EGTA)和8-氨基-2[(2-氨基-5-甲基苯氧基)甲基]-6-甲氧基喹啉-N,N,N’,N’-四乙酸四钾盐(QUIN-2)。
局部用药组合物还可以包含合适的用于将制剂pH调整至药学上可接受范围内的中和剂。
局部用药组合物还可以包含合适的增粘剂。这些成分为能够通过活性剂与聚合物的相互作用增加含聚合物的溶剂的粘度的可扩散化合物。
局部用药组合物还可以包含合适的指甲穿透促进剂或一种或多种合适的溶剂。
另外，可以使用缓释系统递送化合物，诸如包含治疗剂的固体疏水性聚合物的半透明基质。
按照本发明施用的局部治疗方案包括将所述的组合物直接施用于皮肤、指甲、毛发、爪或蹄的施用部位，每日一次到几次。
本发明的制剂可以用于治疗，改善或预防与细菌感染、痤疮、炎症等相关的情况或病症。
额外的活性剂
下面是可以加入到本发明的局部用药制剂中的实例。
抗炎药包括但不限于薄荷脑、氯苯砜、芦荟、氢化可的松等。
维生素包括但不限于维生素B、维生素E、维生素A、维生素D等和维生素衍生物。
防老剂包括但不限于烟酰胺、视黄醇和类视色素衍生物，AHA，抗坏血酸、硫辛酸、辅酶Q10，β羟基酸、水杨酸、铜结合肽类、二甲氨基乙基(DAEA)等。
有效控制或改变角化的活性剂包括但不限于维甲酸和阿达帕林。
给药
一般而言，通过任何可接受的用于类似应用的活性剂给药方式。然而，可以理解用于任何特定患者的具体剂量水平取决于各种因素，包括所用具体化合物的活性、年龄、体重，一般健康状况、性别、膳食、给药时间、给药途径和排泄速度、进行疗法的特定疾病的严重性和开据处方的临床医师的判断。可以每天一次或每天两次或每天达3或4次给药。
常用患者全身给药剂量范围在0.1-1000mg/天，优选1-500mg/天，更优选10-200mg/天，甚至更优选100-200mg/天。就患者身体表面积而言所述的常用剂量范围在50-91mg/m 2/天。
本发明化合物的治疗适应症
本发明还涉及治疗和/或预防受试者感染的方法，其包括向所述受试者给药治疗有效量的本发明的化合物或其药学上可接受的盐、前药、水合物或溶剂合物、多晶型、立体异构体或同位素变体，或给药本发明所述的药物组合物。在一个实施方案中，所述方法涉及治疗和/或预防以下感染：chloronychia、甲沟炎、类丹毒、脆甲症、淋病、游泳池肉芽肿、幼虫移行匍行疹、麻风病、触染 性深脓疱结节、挤奶工结节、疱疹性瘭疽、急性细菌性甲周炎、慢性甲周炎、孢子丝菌病、梅毒、皮肤疣结核、兔热病、潜蚤病、指甲周和指甲下疣、带状疱疹、指甲营养不良、皮肤病、银屑病、脓疱性牛皮癣、斑性脱发、脓疱性角化不全、接触性皮炎、菜特尔综合症、肢端牛皮癣形皮炎、扁平苔癣、指甲中的特发性萎缩病、光泽苔癣、条纹状苔癣、炎性线性疣状表皮痣、秃顶、天疱疮、大疱性类天疱疮、获得性大疱性表皮松解、达里埃病、毛发红糠疹、掌跖角化病、接触性湿疹、多形红斑、疥疮、巴泽克斯综合征、全身性硬皮病、系统性红斑狼疮、慢性红斑狼疮、皮肌炎、孢子丝菌病、真菌性角膜炎、扩散性眼真菌病、内生性眼真菌病、瘢痕疙瘩性芽生菌病、足菌病、毛结节菌病、花斑癣、体癣、股癣、脚癣、须癣、头癣、黑色小孢子菌病、耳真菌病、黄癣、着色真菌病和叠瓦癣等。
本发明还涉及治疗和或预防受试者中与炎症相关的疾病的方法，其包括向所述受试者给药治疗有效量的本发明的化合物或其药学上可接受的盐、前药、水合物或溶剂合物、多晶型、立体异构体或同位素变体，或给药本发明所述的药物组合物。在一个实施方案中，所述方法涉及治疗和/或预防以下炎症：关节炎、风湿性关节炎、炎症性肠病、银屑病、多发性硬化、神经变性病症、充血性心力衰竭、中风、主动脉瓣狭窄、肾衰竭、狼疮、胰腺炎、过敏症、纤维化、贫血、动脉粥样硬化、代谢病、骨病、心血管病、化疗/化疗相关并发症、I型糖尿病、II型糖尿病、肝病、胃肠道病症、眼科疾病、过敏性结膜炎、糖尿病性视网膜病、肖格伦综合征、葡萄膜炎、肺病、肾脏疾病、皮炎、HIV-相关恶病质、脑型疾，强直性脊柱炎、麻风病、贫血和纤维肌痛中的成员。
优选神经变性病症选自阿尔兹海默病和帕金森病；炎性肠病选自克罗恩病或溃疡性结肠炎；胃肠并发症为腹泻；肝病为选自自身免疫性肝炎、丙型肝炎、原发性胆汁性肝硬变、原发性硬化性胆管炎和爆发性肝衰竭；胃肠病症为选自乳糜泻和非特异性结肠炎；肺病为选自过敏性鼻炎、哮喘、慢性阻塞性肺疾病、慢性肉芽肿性炎症、囊性纤维化和结节病；心血管疾病为选自动脉硬化性心脏病、充血性心力衰竭和再狭窄；肾脏疾病为选自肾小球肾炎和脉管炎。
本发明的化合物与现有技术中已知的非氘代化合物相比，具有一系列优点。本发明的优点包括：第一，采用本发明技术方案的化合物和组合物为感染和炎症相关的疾病的治疗提供了更有利的治疗工具。第二，改进了化合物在生物体中的代谢，使化合物具有更好的药代动力学参数特性。在这种情况下，可以改变剂量并形成长效制剂，改善适用性。第三，提高了化合物在动物体内的药物浓度，提高了药物疗效。第四，抑制了某些代谢产物，提高化合物的安全性。
实施例
下面结合具体实施例，作进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～100℃，优选0℃～80℃)下进行。反应时间通常为0.1-60小时，优选地为0.5-24小时。
实施例1 5-(4-氰基苯氧基)-1,3-二氢-1-羟基-3-d-2,1-苯并氧杂硼杂环戊二烯(化合物L-1)的制备。
Figure PCTCN2018115163-appb-000005
采用以下路线进行合成：
Figure PCTCN2018115163-appb-000006
步骤1化合物3的合成
依次将化合物1(2.0g，16.5mmol)、化合物2(3.3g，16.5mmol)和碳酸钾(3.4g，24.8mmol)加入至DMF(20ml)溶液中，该反应液在100℃下搅拌约10h，点板分析直到原料反应完全。反应液冷却至室温，加水(15ml)淬灭反应，用乙酸乙酯(30ml×2)萃取，有机相再用饱和氯化钠洗涤2次，收集有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝10:1)，得到白色固体产物3.8g，收率76％。
步骤2化合物4的合成
在0℃条件下，将NaBD 4(0.16g，3.97mmol)缓慢加到化合物3(1.0g，3.31mmol)的甲醇(15ml)溶液中，完毕后继续反应0.5h。加入1M的盐酸(10ml)淬灭反应，二氯甲烷(20ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂得到白色固体产品0.9g，收率90％。
步骤3化合物5的合成
依次将化合物4(0.90g，3.0mmol)、3,4-二氢-2H-吡喃(0.30g，3.56mmol)、对甲苯磺酸吡啶盐(PPTS，0.075g，0.30mmol)加入至二氯甲烷(20ml)溶液中，室温搅拌10h。加水(10ml) 淬灭反应，二氯甲烷(15ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：乙酸乙酯/石油醚(v/v)＝1:30)得到无色油状物1.0g，收率87％。
步骤4化合物L-1的合成
氮气氛围下，将化合物5(0.3g，0.77mmol)加入至无水四氢呋喃(15ml)溶液中，将溶液降温至-78℃，然后再慢慢滴加正丁基锂溶液(0.34ml，2.5mol/L)，滴加完继续在-78℃下反应1h，再一次性加入三甲基硼酸酯(0.12g，1.15mmol)，加完后反应液自然升至室温反应10h，再加入盐酸(5ml，6mol/L)，搅拌2h，加水(10ml)淬灭反应，二氯甲烷(15ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：乙酸乙酯/石油醚(v/v)＝1:3)，得到白色固体产物60mg，收率31％。LC-MS(APCI):m/z＝253.12(M+1) +。 1H NMR(400MHz,DMSO-d 6)δ9.22(s,1H),7.86(d,J＝8.9Hz,2H),7.81(d,J＝8.0Hz,1H),7.16(dd,J＝5.4,3.5Hz,3H),7.10(dd,J＝8.0,1.8Hz,1H),4.96(s,1H).
实施例2 5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯-4,6-d 2(化合物L-2)的制 备。
Figure PCTCN2018115163-appb-000007
采用以下路线进行合成：
Figure PCTCN2018115163-appb-000008
步骤1化合物6的合成
在0℃条件下，将NaBH 4(0.22g，5.97mmol)缓慢滴加到化合物2(1.0g，4.98mmol)的甲醇(15ml)溶液中，滴加完毕后继续反应0.5h。加入1M的盐酸(10ml)淬灭反应，二氯甲烷(20ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂得到白色固体产品0.93g，收率92％。
步骤2化合物7的合成
依次将化合物6(1.3g，6.4mmol)、氘代氢氧化钠(NaOD，0.32g，7.7mmol)加入至重水(15 ml)溶液中，该反应液在微波180℃搅拌反应1.5h，反应液冷却至室温，用1M的盐酸调pH值5左右，用乙酸乙酯(30ml×2)萃取，有机相再用饱和氯化钠洗涤2次，收集有机相，无水硫酸钠干燥，除去溶剂，得到白色固体产物1.1g，收率84％。
步骤3化合物8的合成
依次将化合物1(0.78g，6.44mmol)、化合物7(1.1g，5.37mmol)和碳酸钾(1.1g，8.05mmol)加入至DMF(20ml)溶液中，该反应液在100℃下搅拌约10h，点板分析直到原料反应完全。反应液冷却至室温，加水(15ml)淬灭反应，用乙酸乙酯(30ml×2)萃取，有机相再用饱和氯化钠洗涤2次，收集有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝10:1)，得到白色固体产物1.2g，收率74％。
步骤4化合物9的合成
依次将化合物8(1.2g，3.92mmol)、3,4-二氢-2H-吡喃(0.40g，4.71mmol)、对甲苯磺酸吡啶盐(PPTS，0.10g，0.4mmol)加入至二氯甲烷(20ml)溶液中，室温搅拌10h。加水(10ml)淬灭反应，二氯甲烷(15ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：乙酸乙酯/石油醚(v/v)＝1:30)得到无色油状物1.3g，收率85％。
步骤5化合物L-2的合成
氮气氛围下，将化合物9(0.5g，1.28mmol)加入至无水四氢呋喃(15ml)溶液中，将溶液降温至-78℃，然后再慢慢滴加正丁基锂溶液(0.61ml，2.5mol/L)，滴加完继续在-78℃下反应1h，再一次性加入三甲基硼酸酯(0.20g，1.92mmol)，加完后反应液自然升至室温反应10h，再加入盐酸(6ml，6mol/L)，搅拌2h，加水(10ml)淬灭反应，二氯甲烷(15ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：乙酸乙酯/石油醚(v/v)＝1:3)，得到白色固体产物85mg，收率26％。LC-MS(APCI):m/z＝254.07(M+1) +。 1H NMR(400MHz,DMSO-d 6)δ9.22(s,1H),7.85(d,J＝8.9Hz,2H),7.79(s,1H),7.14(d,J＝8.9Hz,2H),4.96(s,2H).
实施例3 5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯-3,3-d 2(化合物L-3)的制 备。
Figure PCTCN2018115163-appb-000009
采用以下路线进行合成：
Figure PCTCN2018115163-appb-000010
步骤1化合物11的合成
在0℃条件下，将LiAlD 4(0.21g，5.19mmol)缓慢加到化合物10(1.0g，4.33mmol)的四氢呋喃(15ml)溶液中，完毕后继续反应0.5h。加入1M的盐酸(10ml)淬灭反应，二氯甲烷(20ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂得到白色固体产品0.8g，收率78％。
步骤2化合物12的合成
依次将化合物1(0.57g，4.68mmol)、化合物11(0.8g，3.90mmol)和碳酸钾(0.80g，5.85mmol)加入至DMF(20ml)溶液中，该反应液在100℃下搅拌约10h，点板分析直到原料反应完全。反应液冷却至室温，加水(15ml)淬灭反应，用乙酸乙酯(30ml×2)萃取，有机相再用饱和氯化钠洗2次，收集有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝10:1)，得到白色固体产物0.86g，收率71％。
步骤3化合物13的合成
依次将化合物12(0.86g，2.81mmol)、3,4-二氢-2H-吡喃(0.28g，3.37mmol)、对甲苯磺酸吡啶盐(PPTS，0.07g，0.3mmol)加入至二氯甲烷(20ml)溶液中，室温搅拌10h。加水(10ml)淬灭反应，二氯甲烷(15ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：乙酸乙酯/石油醚(v/v)＝:1:30)得到无色油状物0.82g，收率75％。
步骤4化合物L-3的合成
氮气氛围下，将化合物13(0.4g，1.02mmol)加入至无水四氢呋喃(15ml)溶液中，将溶液降温至-78℃，然后再慢慢滴加正丁基锂溶液(0.50ml，2.5mol/L)，滴加完继续在-78℃下反应1h，再一次性加入三甲基硼酸酯(0.16g，1.54mmol)，加完后反应液自然升至室温反应10h，再加入盐酸(6ml，6mol/L)，搅拌2h，加水(10ml)淬灭反应，二氯甲烷(15ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：乙酸乙酯/石油醚(v/v)＝1:3)，得到白色固体产物55mg，收率21％。LC-MS(APCI):m/z＝254.13(M+1) +。 1H NMR(500MHz, DMSO-d 6)δ9.20(s,1H),7.84(d,J＝8.7Hz,2H),7.78(d,J＝8.0Hz,1H),7.14(d,J＝8.5Hz,3H),7.09(dd,J＝8.0,2.0Hz,1H).
实施例4 5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯-3,4,6-d 3(化合物L-4)的 制备。
Figure PCTCN2018115163-appb-000011
采用以下路线进行合成：
Figure PCTCN2018115163-appb-000012
步骤1化合物14的合成
在0℃条件下，将NaBD 4(0.23g，5.97mmol)缓慢滴加到化合物2(1.0g，4.98mmol)的甲醇(15ml)溶液中，完毕后继续反应0.5h。加入1M的盐酸(10ml)淬灭反应，二氯甲烷(20ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂得到白色固体产品0.94g，收率93％。
步骤2化合物15的合成
依次将化合物14(1.0g，4.90mmol)、NaOD(0.24g，5.88mmol)加入至重水(15ml)溶液中，该反应液在微波180℃搅拌反应1.5h，反应液冷却至室温，用1M的盐酸调pH值5左右，用乙酸乙酯(30ml×2)萃取，有机相再用饱和氯化钠洗2次，收集有机相，无水硫酸钠干燥，除去溶剂，得到白色固体产物0.76g，收率77％。
步骤3化合物16的合成
依次将化合物1(0.43g，3.50mmol)、化合物15(0.6g，2.91mmol)和碳酸钾(0.61g，4.37mmol)加入至DMF(20ml)溶液中，该反应液在100℃下搅拌约10h，点板分析直到原料反应完全。反应液冷却至室温，加水(15ml)淬灭反应，用乙酸乙酯(30ml×2)萃取，有机相再用饱和氯化钠洗2次，收集有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：石油醚 /乙酸乙酯(v/v)＝10:1)，得到白色固体产物0.6g，收率68％。
步骤4化合物17的合成
依次将化合物16(0.50g，1.63mmol)、3,4-二氢-2H-吡喃(0.17g，1.95mmol)、对甲苯磺酸吡啶盐(PPTS，0.04g，0.17mmol)加入至二氯甲烷(20ml)溶液中，室温搅拌10h。加水(10ml)淬灭反应，二氯甲烷(15ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：乙酸乙酯/石油醚(v/v)＝1:30)得到无色油状物0.52g，收率81％。
步骤5化合物L-4的合成
氮气氛围下，将化合物17(0.3g，0.77mmol)加入至无水四氢呋喃(15ml)溶液中，将溶液降温至-78℃，然后再慢慢滴加正丁基锂溶液(0.34ml，2.5mol/L)，滴加完继续在-78℃下反应1h，再一次性加入三甲基硼酸酯(0.12g，1.15mmol)，加完后反应液自然升至室温反应10h，再加入盐酸(5ml，6mol/L)，搅拌2h，加水(10ml)淬灭反应，二氯甲烷(15ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：乙酸乙酯/石油醚(v/v)＝1:3)，得到白色固体产物50mg，收率26％。LC-MS(APCI):m/z＝255.09(M+1) +。 1H NMR(400MHz,DMSO-d 6)δ9.21(s,1H),7.85(d,J＝8.9Hz,2H),7.79(s,1H),7.14(d,J＝8.9Hz,2H),4.94(s,1H).
实施例5 5-(4-氰基苯氧基-2,6-d 2)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊二烯(化合物L-5)的 制备。
Figure PCTCN2018115163-appb-000013
采用以下路线进行合成：
Figure PCTCN2018115163-appb-000014
步骤1化合物18的合成
依次将化合物1(3.0g，27.0mmol)、氘代盐酸(1.1g，29.7mmol)加入至重水(15ml)溶液中，该反应液在微波180℃搅拌反应0.5h，反应液冷却至室温，用碳酸钠溶液调pH值7左右，用乙酸乙酯(30ml×2)萃取，有机相再用饱和氯化钠洗2次，收集有机相，无水硫酸钠干燥，除去溶剂，得到红棕色液体2.8g，收率93％。
步骤2化合物19的合成
依次将化合物18(2.0g，17.7mmol)、盐酸(20ml，2mmol)加入至水(15ml)溶液中，搅拌，该溶液降至0℃，然后慢慢滴加亚硝酸钠(10ml，1.5g，21.2mmol)水溶液，加完后继续在0℃下反应1h，再滴加碘化钾(10ml，4.4g，26.5mmol)水溶液，加完后自然升至室温反应4h，反应完全后，用乙酸乙酯(30ml×2)萃取，有机相再用饱和氯化钠洗2次，收集有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：石油醚)，得到无色液体2.6g，收率65％。
步骤3化合物20的合成
氮气氛围下，将化合物19(3.0g，13.4mmol)，氰化锌(3.2g，26.8mmol)，四三苯基磷钯(1.54g，1.34mmol)加入至无水DMF(80ml)溶液中，将溶液升至120℃下反应5h，加水(50ml)淬灭反应，二氯甲烷(50ml×3)萃取，合并有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：石油醚)，得到油状物0.7g，收率42％。
步骤4化合物21的合成
依次将化合物20(1.2g，9.75mmol)、化合物2(2.0g，9.75mmol)和碳酸钾(2.10g，14.6mmol)加入至DMF(20ml)溶液中，该反应液在100℃下搅拌约10h，点板分析直到原料反应完全。反应液冷却至室温，加水(15ml)淬灭反应，用乙酸乙酯(30ml×2)萃取，有机相再用饱和氯化钠洗2次，收集有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙 酯(v/v)＝10:1)，得到白色固体产物2.1g，收率70％。
步骤5化合物22的合成
在0℃条件下，将NaBH 4(0.24g，5.92mmol)缓慢滴加到化合物21(1.5g，4.93mmol)的甲醇(15ml)溶液中，完毕后继续反应0.5h。加入1M的盐酸(10ml)淬灭反应，二氯甲烷(20ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂得到白色固体产品1.4g，收率94％。
步骤6化合物23的合成
依次将化合物22(1.0g，3.27mmol)、3,4-二氢-2H-吡喃(0.33g，3.92mmol)、对甲苯磺酸吡啶盐(PPTS，0.08g，0.33mmol)加入至二氯甲烷(20ml)溶液中，室温搅拌10h。加水(10ml)淬灭反应，二氯甲烷(15ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：乙酸乙酯/石油醚(v/v)＝1:30)得到无色油状物1.1g，收率86％。
步骤7化合物L-5的合成
氮气氛围下，将化合物23(0.5g，1.28mmol)加入至无水四氢呋喃(15ml)溶液中，将溶液降温至-78℃，然后再慢慢滴加正丁基锂溶液(0.61ml，2.5mol/L)，滴加完继续在-78℃下反应1h，再一次性加入三甲基硼酸酯(0.20g，1.92mmol)，加完后反应液自然升至室温反应10h，再加入盐酸(6ml，6mol/L)，搅拌2h，加水(10ml)淬灭反应，二氯甲烷(15ml×2)萃取，合并有机相，无水硫酸钠干燥，除去溶剂，浓缩液进行柱分离(洗脱剂：乙酸乙酯/石油醚(v/v)＝1:3)，得到白色固体产物95mg，收率29％。LC-MS(APCI):m/z＝254.19(M+1) +。 1H NMR(400MHz,DMSO-d 6)δ9.22(s,1H),7.79(d,J＝7.9Hz,1H),7.14(s,3H),7.09(d,J＝8.1Hz,1H),4.96(s,2H).
生物活性测试。
(1)激酶抑制作用
试剂和耗材：
PDE4D2 TR-FRET Assay Kit试剂盒(BPS bioscience,目录号60707)，Cyclic-3’,5’-AMP(Sigma,目录号A6885)，Tris(amresco,目录号T0497)，BSA(Perkin Elmer,目录号CR84-100)，氯化镁(Sigma,目录号M1028),Tween-20(Solarbio,目录号T8220),二硫苏糖醇(Invitrogen,目录号P2325),DMSO(Sigma,目录号D8418)，96孔板(Nunc,目录号249944)，384孔板(Greiner,目录号784075)。
具体实验方法：
使用PDE4D2 TR-FRET Assay Kit试剂盒采用AMP-Glo法测定PDE4D2抑制剂活性
化合物配制：将受试化合物溶于DMSO配成10mM母液。然后，将母液用稀释到2mM后， 在DMSO中3倍浓度梯度稀释，10个剂量，得到工作液。
PDE4D2酶活性检测：将2.5uL的2*PDE4D2酶溶液(4pg/μL)与25nL预先稀释配制的不同浓度的化合物转移到侧定板中，室温下密封混合10分钟，每个浓度双复孔。其中设置阴阳性对照：阴性为空白对照，阳性为Rolipram。加入2.5μL预先制备的2x Cyclic-3’,5’-AMP(2μM)溶液至反应体系中，室温下孵育60分钟。之后加入5μL AMP glo试剂继续室温孵育60分钟。反应完毕加入10μL AMP检测试剂，室温孵育60分钟后，通过Evnvision酶标仪检测，测定在各浓度的本发明化合物存在下的酶活力，并计算不同浓度的化合物对酶活力的抑制活性。之后根据四参数方程，根据Graphpad 5.0软件对不同浓度化合物下酶活力的抑制活性进行拟合，计算出IC 50值。
在上述激酶抑制实验中测试了本发明化合物和未经氘代的化合物Crisaborole，发现本发明化合物对PDE4D2激酶具有更强效或相当的活性。代表性实施例化合物对激酶的抑制作用的结果归纳于如下表1中。
表1：
实施例化合物 PDE4D2 IC 50(nM)
Crisaborole 1.32
L-1 1.25
L-2 1.06
L-3 1.35
L-4 1.29
L-5 1.45
(2)代谢稳定性评价
微粒体实验：人肝微粒体：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science；氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制：精密称取一定量的实施例化合物的粉末，并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM，pH7.4)的配制：取预先配好的150mL的0.5M磷酸二氢钾和700mL的0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁，pH为7.4。
配制NADPH再生系统溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D，3.3mM氯 化镁)，使用前置于湿冰上。
配制终止液：含有50ng/mL盐酸普萘洛尔和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL人肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL 0.25mM的的工作液中，混匀。
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生系统置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL NADPH再生系统溶液，作为0min样品。再向孵育板每孔加入80μL的NADPH再生系统溶液，启动反应，开始计时。相应化合物的反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。
数据分析：通过LC-MS/MS系统检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t 1/2和CL int，其中V/M即等于1/蛋白浓度。
Figure PCTCN2018115163-appb-000015
对本发明化合物及其没有氘代的化合物Crisaborole同时测验比较，评价其在人肝微粒体的代谢稳定性。作为代谢稳定性的指标的半衰期及肝固有清除率如表2所示。实验结果表明：与未经氘代的化合物Crisaborole相比，本发明化合物可以明显改善代谢稳定性。
表2：
实施例化合物 t 1/2(min) CL int(μL/min/mg)
Crisaborole 60.6 22.9
L-1 66.6 20.8
L-2 65.4 21.2
L-3 84.9 16.3
L-4 89.1 15.6
L-5 83.2 16.7
(3)大鼠药代动力学实验
6只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组3只，经静脉或口服单个剂量的化合物(口服10mg/kg)，比较其药代动力学差异。
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。
大鼠吸入乙醚后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL 1％肝素盐溶液。使用前，试管于60℃烘干过夜。在最后一个时间点血样采集完成之后，大鼠乙醚麻醉后处死。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃ 5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，标明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
实验表明，本发明化合物在动物体内具有更好的药代动力学性质，因此具有更好的药效学和治疗效果。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (12)

  1. 一种式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、多晶型、立体异构体或同位素变体：
    Figure PCTCN2018115163-appb-100001
    其中，
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、X 1和X 2各自独立地选自氢或氘；
    附加条件是R 1、R 2、R 3、R 4、R 5、R 6、R 7、X 1和X 2中至少一个是氘代的或氘。
  2. 根据权利要求1所述的化合物，其中，R 3、R 4和R 7选自氢。
  3. 根据权利要求1或2所述的化合物，其中，R 1和R 2选自氢。
  4. 根据权利要求1-3中任一项所述的化合物，其中，X 1选自氢。
  5. 根据权利要求1-4中任一项所述的化合物，其中，X 2选自氢。
  6. 根据权利要求1-5中任一项所述的化合物，其中，R 5和R 6选自氘。
  7. 根据权利要求1所述的化合物，其中所述化合物选自下述化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、多晶型、立体异构体或同位素变体：
    Figure PCTCN2018115163-appb-100002
    Figure PCTCN2018115163-appb-100003
  8. 一种药物组合物，其含有药学上可接受的赋形剂和如权利要求1～7任意一项所述的式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、多晶型、立体异构体或同位素变体。
  9. 一种如权利要求1～7任意一项所述的式(I)的化合物，或其药学上可接受的盐、前药、水合物或溶剂化合物、多晶型、立体异构体或同位素变体，或者如权利要求8所述的药物组合物在制备治疗和/或预防与感染或炎症的相关的疾病的药物中的用途。
  10. 根据权利要求9所述的用途，其中所述的与感染相关的疾病选自chloronychia、甲沟炎、 类丹毒、脆甲症、淋病、游泳池肉芽肿、幼虫移行匍行疹、麻风病、触染性深脓疱结节、挤奶工结节、疱疹性瘭疽、急性细菌性甲周炎、慢性甲周炎、孢子丝菌病、梅毒、皮肤疣结核、兔热病、潜蚤病、指甲周和指甲下疣、带状疱疹、指甲营养不良、皮肤病、银屑病、脓疱性牛皮癣、斑性脱发、脓疱性角化不全、接触性皮炎、菜特尔综合症、肢端牛皮癣形皮炎、扁平苔癣、指甲中的特发性萎缩病、光泽苔癣、条纹状苔癣、炎性线性疣状表皮痣、秃顶、天疱疮、大疱性类天疱疮、获得性大疱性表皮松解、达里埃病、毛发红糠疹、掌跖角化病、接触性湿疹、多形红斑、疥疮、巴泽克斯综合征、全身性硬皮病、系统性红斑狼疮、慢性红斑狼疮、皮肌炎、孢子丝菌病、真菌性角膜炎、扩散性眼真菌病、内生性眼真菌病、瘢痕疙瘩性芽生菌病、足菌病、毛结节菌病、花斑癣、体癣、股癣、脚癣、须癣、头癣、黑色小孢子菌病、耳真菌病、黄癣、着色真菌病和叠瓦癣中的成员。
  11. 根据权利要求9所述的用途，其中所述的与炎症相关的疾病选自关节炎、风湿性关节炎、炎症性肠病、银屑病、多发性硬化、神经变性病症、充血性心力衰竭、中风、主动脉瓣狭窄、肾衰竭、狼疮、胰腺炎、过敏症、纤维化、贫血、动脉粥样硬化、代谢病、骨病、心血管病、化疗/化疗相关并发症、I型糖尿病、II型糖尿病、肝病、胃肠道病症、眼科疾病、过敏性结膜炎、糖尿病性视网膜病、肖格伦综合征、葡萄膜炎、肺病、肾脏疾病、皮炎、HIV-相关恶病质、脑型疾，强直性脊柱炎、麻风病、贫血和纤维肌痛中的成员。
  12. 根据权利要求11所述的方法，其中所述的神经变性病症选自阿尔兹海默病和帕金森病中的成员；所述的炎性肠病选自克罗恩病或溃疡性结肠炎中的成员；所述的胃肠并发症为腹泻；所述的肝病为选自自身免疫性肝炎、丙型肝炎、原发性胆汁性肝硬变、原发性硬化性胆管炎和爆发性肝衰竭中的成员；所述的胃肠病症为选自乳糜泻和非特异性结肠炎中的成员；所述的肺病为选自过敏性鼻炎、哮喘、慢性阻塞性肺疾病、慢性肉芽肿性炎症、囊性纤维化和结节病中的成员；所述的心血管疾病为选自动脉硬化性心脏病、充血性心力衰竭和再狭窄中的成员；且所述的肾脏疾病为选自肾小球肾炎和脉管炎中的成员。
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