90 results about "Hydrazone" patented technology

The application discloses the use of carbon cyanogen - 4 trifluoromethoxy benzyl hydrazone in the prevention and treatment of candida infection, belonging to the technical field of candida infection prevention and treatment. Carbon cyanogen - 4 trifluoromethoxy benzyl hydrazone is used as the only active ingredient for preparing a medicine for preventing or treating diseases caused by candida infection, wherein the candida is candida albicans and / or candida auris; or it is used for preparing a bacteriostatic and / or bactericidal product of candida, wherein the candida is candida albicans and / or candida auris. FCCP shows good inhibition of strain growth, good inhibition of biofilm effect and good mitochondria breaking effect in the antibacterial experiments of various candida (wild type candida albicans, drug resistant candida albicans and drug resistant candida auris). Thus, a new treatment drug for candida albicans and candida auris infection is provided.

The invention discloses an L-carvone hydrazone derivative and an application thereof. The L-carvone hydrazone derivative disclosed by the invention has the advantages of low raw material cost, simple and convenient synthesis route and the like, and the obtained L-carvone hydrazone product has an excellent bacteriostatic effect on rhizoctonia solani, botrytis cinerea, sclerotinia sclerotiorum, fusarium graminearum, valsa mali and phytophthora capsici, and can be used for preventing and treating various plant fungal diseases.

The present invention relates to novel compounds which are useful in agriculture and / or in animal health and in particular to novel isoxazoline compounds, as well as to compositions comprising these compounds. In addition, the present invention relates to the use of a compound or a composition comprising one or more of these compounds in agriculture or animal health and specifically for controlling insect pests or parasitic invertebrate pests. The present invention further relates to intermediate compounds which are useful in preparing the compounds of the present invention.

The invention discloses a preparation method of a fluorine-containing ester-containing triazole compound, which comprises the following steps of: reacting fluorine-containing ester-containing p-toluenesulfonylhydrazone prepared from cheap and easily available starting raw materials (ketone containing trifluoromethyl or difluoromethyl functional groups) with an aromatic amine compound in tert-butyl hydroperoxide and acetonitrile under the promotion condition of iodine to obtain the fluorine-containing ester-containing triazole compound. And the fluorine-containing ester-containing triazole compound is obtained by a cyclization reaction and a'one-pot method '. In the preparation process, an expensive metal catalyst or ligand does not need to be used, so that the problem of toxicity or use safety caused by metal residues or azide compounds in a pharmaceutical process does not exist; in addition, the raw materials used in the process are bulk, cheap and easily available, the reaction system is green and environment-friendly, and the method has the advantages of simple operation steps and post-treatment process and high yield; the subsequent conversion research of the process can be applied to the synthesis of medical intermediates or related similar compounds.

This invention discloses a method for preparing 4-(trifluoromethylsulfinyl)pyrazole compounds, comprising: dissolving terminal alkyne in n-hexane under nitrogen atmosphere, adding anhydrous zinc chloride, and reacting trifluoromethylsulfinyl chloride to obtain α-trifluoromethylalkynyl sulfoxide; adding benzoyl chloride dropwise to a CH2Cl2 solution of phenylhydrazine and triethylamine under nitrogen atmosphere to obtain acylhydrazine; adding carbon tetrachloride to a suspension of acylhydrazine and triphenylphosphine in acetonitrile to obtain hydrazone chloride; and reacting α-trifluoromethylalkynyl sulfoxide, hydrazone chloride, potassium carbonate, and anhydrous ethanol at room temperature to obtain 4-(trifluoromethylsulfinyl)pyrazole compounds. This invention uses inexpensive and readily available raw materials, the entire reaction route is mild and simple to operate, does not require stringent reaction conditions, and most of the reaction process is carried out at room temperature. The product yield is high, and the prepared trifluoromethylalkynyl sulfoxide pyrazole structure has multiple derivatization sites, showing good application prospects.

This invention discloses a hydrazone-linked fluorine-substituted covalent organic framework material, its preparation method, and its applications, belonging to the field of semiconductor photocatalysis technology. The material is synthesized by hydrazone condensation of 1,3,5-trifluoro-2,4,6-tris(4-formylphenyl)benzene and terephthalohydrazide, denoted as F-TPDH-COF. A one-step solvothermal synthesis is employed, resulting in a mild, environmentally friendly, low-cost, and easily scalable process. The material obtained by this invention utilizes hydrazone bonds to achieve proton enrichment in acidic media, and fluorine atoms regulate the electronic structure to improve charge separation efficiency. Under pH=2 conditions, the photocatalytic hydrogen peroxide production rate reaches as high as 5825.2 μmolg. ‑1 h ‑1 Its activity and stability are significantly better than most existing COF photocatalytic materials, and it can be used for efficient photocatalytic preparation of hydrogen peroxide in acidic systems, showing good prospects for industrialization.

The invention relates to a polymer for treating a surface, which polymer comprises: n reactive intermediate precursor groups, wherein n is an integer equal to or greater than 3; and m groups which comprise an atom-transfer radical polymerization (ATRP) initiator, wherein m is an integer equal to or greater than 3, wherein the reactive intermediate precursor groups are selected from carbene precursor groups and nitrene precursor groups, wherein the carbene precursor groups are selected from hydrazone groups of formula (A), diazo groups of formula (B) and diazirine groups of formula (C), and the nitrene precursor groups are azide groups of formula (D), wherein R1 is H or -S(O)2R2, and R2 is an unsubstituted or substituted C1-6 alkyl group or an unsubstituted or substituted aryl group. The invention also relates to a process for producing a treated substrate, which treated substrate has a surface suitable for surface -initiated atom-transfer radical polymerization (SIATRP). The invention also relates to a treated substrate having a surface suitable for SIATRP, and to treated substrates obtainable by the aforementioned process of the invention. The invention also relates to a treated substrate which comprises: a substrate, a reacted polymer disposed on a surface of the substrate, and a further polymer, grown by SIATRP, bonded to the reacted polymer.

The invention provides a drug carrier based on N-acetylglucosamine, a drug preparation and a preparation method. The drug carrier based on N-acetylglucosamine comprises N-acetylglucosamine and a cross-linking agent, the cross-linking agent is a compound with an aldehyde group or a ketone group, and the aldehyde group or the ketone group reacts with the deacetylated N-acetylglucosamine to generate one or more of a hydrazide bond, a hydrazone bond or an imine bond. The drug carrier based on N-acetylglucosamine shows remarkable advantages in the aspects of particle size distribution, drug loading capacity, encapsulation efficiency and cumulative drug release rate.

The invention discloses a < 131 > I labeled SNO hydrogel material and a preparation method of the < 131 > I labeled SNO hydrogel material. The hydrogel material is mainly composed of hyaluronic acid, firstly, one kind of hyaluronic acid is modified, API molecules are modified on the side chain of the hyaluronic acid, a reaction site is provided for marking of < 131 > I nuclide, meanwhile, the hyaluronic acid is subjected to oxidation treatment, the hyaluronic acid rich in aldehyde groups becomes a monomer for forming the hydrogel, the hyaluronic acid with another molecular weight is selected, and the molecular weight of the hyaluronic acid is changed into the molecular weight of the hydrogel. ADH rich in hydrazide groups is introduced into a side chain through amidation reaction, a hydrazone bond is formed through reaction of aldehyde groups and hydrazide, and the chemical bond can endow the hydrogel with injectable and self-healing characteristics. Nuclide labeling of the hydrogel is completed for the first time through a chloramine T method, the overall labeling rate reaches about 80%, the hydrogel has good stability under physiological conditions, < 131 > I is not prone to falling off from the hydrogel, and the hydrogel has a good antibacterial effect at 500 mu ci. By constructing a bacterial infection osteoarthritis model, it is verified that the < 131 > I-labeled HA hydrogel has good injectability, the in-situ enrichment capacity of iodine < 131 > I is improved, and therefore the antibacterial efficiency is improved, the method is simple in preparation, the < 131 > I labeling efficiency is high, the method can be widely applied to osteoarthritis caused by bacterial infection, and the application prospect is wide. And a wide prospect is provided for clinical treatment of the disease.

The invention relates to the technical field of pesticides, and particularly discloses a quality-improving and yield-increasing pesticide composition and a preparation method thereof. The quality-improving and yield-increasing pesticide composition is composed of a drug-loading core and an intelligent response shell wrapping the drug-loading core, the drug-loading core is metal-doped hollow carbon microspheres loaded with pesticide active ingredients, and the intelligent response shell is a cyclodextrin-adipic dihydrazide cross-linked network formed through host-guest interaction and dynamic covalent bonding. According to the invention, the acid sensitivity of hydrazone bonds and the enzyme sensitivity of cyclodextrin skeletons are utilized to construct a dual-signal response controlled release mechanism, so that pesticide is ensured to be released in an explosive manner only in a dual environment in which low pH and specific enzyme exist at a pathogenic bacterium infection point at the same time, and'mistaken release 'caused by environmental fluctuation is greatly avoided; the composition has multiple functions of high drug loading capacity, synergistic sterilization, nutrition supplement and the like, and the raw materials are biodegradable and environment-friendly.

The present disclosure pertains to a molecule that is operable to release a nitroxyl (HNO) upon irradiation. The nitroxyl may be operable to convert to nitrous oxide (N2O). The present disclosure also pertains to methods of releasing nitroxyl from a molecule of the present disclosure by irradiating the molecule. The released nitroxyl may then convert to nitrous oxide. The present disclosure also pertains to methods of administering at least one of nitroxyl or nitrous oxide to a subject by (1) administering a molecule of the present disclosure to the subject; and (2) irradiating the molecule, where the irradiation results in the release of nitroxyl from the molecule. The released nitroxyl may then convert to nitrous oxide.

The application discloses a kind of endoplasmic reticulum of tumor cell can be targeted N -(2-hydroxypropyl) methacrylamide (HPMA) polymer-drug conjugate. The chemotherapeutic drug carried by the HPMA polymer is at least one of doxorubicin, epirubicin, pirarubicin, cisplatin, oxaliplatin, camptothecin, paclitaxel, gemcitabine, methotrexate, vinblastine, mitoxantrone, irinotecan, and the linker for connecting the drug and the HPMA polymer is at least one of hydrazone bond, amide bond, ester bond, disulfide bond, and ketosulfenyl bond. The HPMA polymer-drug conjugate targets the drug to the endoplasmic reticulum through receptor-ligand interaction, can cause severe endoplasmic reticulum stress, thereby transporting a large amount of calnexin to the tumor cell membrane surface, greatly improving the immunogenicity of tumor cells, and promoting tumor immunotherapy.

This invention relates to the field of polymer fine chemical materials and the synthesis technology of special functional waterborne coatings, specifically to an aldehyde-capturing self-healing waterborne coating and its preparation method. The invention discloses an aldehyde-capturing self-healing waterborne coating and its preparation method. This coating uses a side-chain carboxylated ketone-containing waterborne polyurethane-acrylate composite emulsion as the core film-forming material, forming dynamic hydrazone crosslinks with adipic acid dihydrazide, and introducing an epoxy-amine permanent crosslinking network. The side-chain carboxyl groups are derived from maleic anhydride grafted and undergo ring-opening transformation upon contact with water, and are covalently fixed to the polymer side chains, preventing the migration of small molecule acids and ensuring coating storage stability. After the coating cures, environmental moisture triggers the dissociation of side-chain carboxyl groups, releasing protons and catalyzing the dynamic exchange of hydrazone bonds, achieving room-temperature self-healing. Excess hydrazone groups in the coating capture aldehyde pollutants, and the newly generated hydrazone bonds introduce polar groups and crosslinking sites, enhancing network stability.

This invention provides a biomimetic periodontal complex multilayer hydrogel tissue engineering scaffold, its preparation method, and its application, relating to the technical field of tissue engineering scaffolds. The biomimetic periodontal complex multilayer hydrogel tissue engineering scaffold comprises, from the inside out, a cementum repair layer, a periodontal ligament repair layer, and an alveolar bone repair layer; the cementum repair layer and the alveolar bone repair layer include a mineralized hydrogel layer; wherein the raw materials for preparing the mineralized hydrogel layer include modified hyaluronic acid, methacrylamide type I collagen, and hydroxyapatite; the alveolar bone repair layer includes a non-mineralized hydrogel layer; wherein the raw materials for preparing the non-mineralized hydrogel layer include modified hyaluronic acid, methacrylamide type I collagen, and fibrin I. This invention precisely matches the mechanical and biological requirements of each layer of the periodontal complex through a three-layer structure, a reversibly hydrazone-regulated viscoelastic gradient, and a differentiated biochemical microenvironment of nHAp / FBN1.

The application relates to the technical field of pharmaceutical chemistry, and discloses a sulfuryl hydrazone compound, a preparation method thereof and anti-tumor application. The compound is synthesized from isatin derivatives and sulfuryl hydrazine through two-step nucleophilic substitution-elimination reaction, has a chemical structure as shown in formula (I), and is characterized by 1H NMR, 13C NMR and HRMS. The sulfuryl hydrazone compound has significant inhibitory activity on A549 (lung cancer), HepG2 (liver cancer) and Hela (cervical cancer) three human cancer cell strains, the value of some compounds is as low as 0.03 micromole / L, the compound can induce cell apoptosis by mediating ROS generation in tumor cells, inhibiting the NF-kappa B signal pathway and activating Caspase-3 activity, and can effectively inhibit cancer cell migration and colony formation. The compound has a mild synthesis process, simple operation and wide substrate applicability, can be used as a potential anti-tumor active ingredient, can be used for preparing drugs for resisting lung cancer, liver cancer, cervical cancer and other tumors, and can provide new candidate compounds and technical support for cancer treatment.

The invention discloses a synthesis method of 1, 1-diarylethene, which comprises the following steps: by taking aryl fluorosulfonate and sulfonyl hydrazone as raw materials, in the presence of a palladium catalyst, a ligand, alkali and an organic solvent, heating to carry out coupling reaction, and after the reaction is finished, carrying out post-treatment to obtain a 1, 1-diarylethene compound. The method has the advantages that the aryl fluorosulfonate reagent is easy to prepare and store, the reaction selectivity is high, the functional group compatibility is good, the substrate application range is wide and the like, and the yield is as high as 91%. As the 1, 1-diarylethene compound is an important functional molecular skeleton structure, the 1, 1-diarylethene compound has very wide application in the fields of fine chemical engineering and pharmacy; therefore, the method has great application value and social and economic benefits.

The invention relates to the technical field of compound synthesis, in particular to (Z)-p-toluenesulfonyl hydrazone derivatives and a preparation method thereof. The (E)-p-toluenesulfonyl hydrazone derivative, a photosensitizer and a solvent are mixed and react under illumination to obtain the (Z)-p-toluenesulfonyl hydrazone derivative. The photosensitizer selected by the method is green and low in cost, free of heavy metal residues, wide in substrate application range, high in isomerization efficiency, short in reaction time and good in cis-product stability, the system is easy for amplified production, the high-purity hydrazone compound and the photoisomerization product thereof can be efficiently, mildly and greenly prepared, and the method is suitable for industrial production. The application potential in the fields of drug synthesis, precise drug delivery and functional materials is obviously improved.

The invention belongs to the technical field of pest control, and relates to application of an azo compound as an arginine kinase inhibitor and prevention and control of ampullaria gigas. The azo compound 4-[2-(2-isopropyl-5-methylphenoxy) ethyoxyl]-3-methoxybenzaldehyde (4, 6-dipyrrolidine-1-yl-1, 3, 5-triazine-2-yl) hydrazone obtained through screening can be jointly and stably combined with arginine kinase through multiple types of non-covalent interaction, and the function of an arginine kinase inhibitor is played. When the azo compound provided by the invention is used for preventing and treating ampullaria gigas, an excellent poisoning effect is shown, the activity of the azo compound is higher than that of an existing arginine kinase inhibitor quercetin, and the azo compound is good in selectivity and low in toxicity to vertebrates compared with a traditional molluscicide metaldehyde.

This invention relates to the field of drug delivery systems, and discloses a nanoparticle for photodynamic therapy and its preparation method. The nanoparticle has a core-shell-corona composite structure, comprising, from the inside out: a core layer composed of NaYF4 upconversion nanoparticles; a middle layer: a mesoporous Zr-MOF layer; a shell layer: a pH-responsive polymer layer formed by linking folic acid to polyethylene glycol-polycaprolactone block copolymer via hydrazone bonds; and a targeting corona layer comprising dual targeting ligands, namely a bicyclic [6.1.0]nonyne-functionalized iRGD peptide and an azide-functionalized anti-EGFR nanobody 7D12. The nanoparticles of this invention possess advantages such as high stability, strong targeting, and high photosensitizer loading, and can efficiently generate reactive oxygen species.

The invention relates to a COF adsorbent rich in N and S sites and a preparation method and application thereof, and belongs to the technical field of composite adsorption materials. According to the invention, 1, 3, 5-tri (3-hydrazino) triazine and 2, 2 '-bithiophene-5, 5'-dicarboxaldehyde are used as raw materials, and the COF adsorbent MEBD with a hydrazone bond connection structure is synthesized through a condensation polymerization reaction, and the structural formula is shown in the specification. The COF adsorbent MEBD rich in N and S sites can be used for efficiently and selectively adsorbing gold ions from a solution, and the adsorbent has excellent adsorption capacity and high cyclic regeneration capacity.

The present invention relates to a family of N-acylhydrazonic compounds structurally derived from 1-methyl-1H-imidazole-2-carboxaldehyde, or pharmaceutically acceptable salts thereof, and the use of said compounds to prevent and / or treat amyloid (such as Alzheimer's, Parkinson's and type 2 diabetes) and non-amyloid (such as cataracts) degenerative aggregopathies These compounds act as attenuators of the metal-protein interaction, preventing and / or decreasing protein oligomerization through competition with the target peptide or protein for the binding of physiological metal ions and, possibly, by modulating the protein-protein interaction itself. The invention also details four compounds specifically described as examples of N-acylhydrazones derived from 1-methyl-1H-imidazole-2-carboxaldehyde, namely: 1-methyl-1H-imidazole-2-carboxaldehyde isonicotinoyl hydrazone, 1-methyl-1H-imidazole-2-carboxaldehyde benzoyl hydrazone, 1-methyl-1H-imidazole-2-carboxaldehyde 2-furoyl hydrazone and 1-methyl-1H-imidazole-2-carboxaldehyde 2-thiophenyl hydrazone. The current application also comprises pharmaceutical compositions.

The invention relates to the technical field of rubber protective materials, and discloses a synergistically modified ethylene propylene diene monomer glove material with high chemical medium permeation resistance and a preparation method thereof. The glove material comprises synergistically modified ethylene propylene diene monomer rubber, zinc oxide, dicumyl peroxide, sulfur, an accelerant, an anti-aging agent, carbon black, a silane coupling agent and an organic solvent, wherein the synergistically modified ethylene propylene diene monomer rubber constructs a multi-crosslinking system synergistically by introducing a hydrazine hydrazone dynamic covalent network, a coordination structure and an organic-inorganic hybrid structure. The preparation method comprises the following steps: preparing synergistically modified ethylene propylene diene monomer rubber, preparing a rubber compound and rubber cement, and carrying out dip forming on a mold to form the glove material with the multi-layer compact structure. Through multi-scale synergistic modification, the chemical medium permeation resistance, the air tightness, the mechanical property and the aging resistance of the material are remarkably improved, the preparation process is simple, and the material is suitable for the field of high-end dry box protection.

The application discloses a preparation method of imino hydrazone intermediate, and the method comprises the step of reducing and hydrogenating a nitro hydrazone compound in the presence of a catalyst. The application determines suitable metal catalysts, relative proportions of the catalysts, reaction temperature, hydrogen pressure and reaction time through screening; and the method of the application overcomes the pollution problem caused by large amount of hazardous waste emissions in the prior art, and is a process for producing intermediate I with reduced three-waste emissions and green environmental protection.

The invention relates to the technical field of pesticides, in particular to a continuous synthesis process and device for a prothioconazole intermediate, and the continuous synthesis process at least comprises the following steps: synthesizing hydrazone from a BL-6 oil phase and formaldehyde in a continuous formation hydrazone reactor; synthesizing a BL-7 mixed phase from hydrazone, a thiocyanate aqueous solution and a dilute acid aqueous solution in a continuous ring-closing static tubular reactor; carrying out phase separation on the BL-7 mixed phase in a continuous phase separation reactor to obtain a BL-7 oil phase and a salt water phase; and the BL-7 oil phase is directly subjected to synthesis of prothioconazole without desolvation. Precise preparation of the key intermediate BL-7 is achieved through the modular continuous flow reaction system, compared with a traditional kettle type process, the continuous production period is shortened to 1 / 6 of that of an original process, the raw material utilization rate is increased by 20%, the three-waste generation amount is reduced by 50%, the risk of enrichment of highly toxic substances such as thiocyanic acid in the traditional process is effectively avoided, and the modular continuous flow reaction system is more suitable for industrial production.

The present application belongs to the technical field of animal model construction, and relates to a insomnia animal model construction method and application with the characteristics of body deficiency, fever and emotional irritability. The application of uncoupling agent as a modeling agent in the construction of insomnia animal model with the characteristics of body deficiency, fever and emotional irritability; the uncoupling agent is carbonic acid cyanide-4-trifluoromethoxy benzyl hydrazone, carbonyl cyanide m-chlorophenyl hydrazone or benzalazoline. The present application uses mice as model animals, uses uncoupling agent as a modeling agent, and suspends or dissolves the modeling agent, then gives the mice intragastric administration once a day, and lasts for 1-4 weeks, to construct a "deficiency and irritability insomnia" insomnia animal model with the characteristics of body deficiency, fever and emotional irritability. The present application has a high degree of consistency with the traditional Chinese medicine theory, and can be well used for the screening and evaluation of anti-insomnia chemical drugs, anti-insomnia traditional Chinese medicine compounds and anti-insomnia health care products.

The invention discloses a nitrogen heterocyclic ring substituted azopyridone dye and a preparation method thereof, and belongs to the technical field of fine chemical engineering. The structural general formula of the azopyridone dye is shown in the specification (an azo formula and a hydrazone formula are both established), wherein X1, X2, X3, X4 and X5 are respectively and independently selected from one of nitro, hydrogen, halogen atoms, cyano, methyl, isopropyl and methoxyl; r substituent is selected from one of the following structures; an R substituent group is introduced to the N site of pyridone, so that the problem that the solubility of the azopyridone dye in an organic solvent is relatively low can be effectively solved. The solubility of the azopyridone dye disclosed by the invention in an organic solvent is greater than or equal to 5g / 100g, the dye ensures excellent light and heat resistance stability, the color coordinates meet the standard yellow range, and the azopyridone dye has the feasibility of preparing optical devices and full-color high-stability display materials.

The application belongs to the field of organic chemical medicine, and relates to a synthesis method of N-alkylated pyridine-2-ketone derivatives. The application takes a sulfuryl hydrazone derivative and a pyridine-2-ketone derivative as raw materials, takes a rhodium salt as a catalyst, takes a base as an additive, further adds a proper solvent, seals argon gas reaction, reacts for a certain time at a certain temperature, removes the solvent by reducing pressure after the reaction is finished, and separates the target product through silica gel column chromatography or recrystallization. The synthesis of N-alkylated pyridine-2-ketone derivatives is realized. The method has the following advantages: the raw material is easy to obtain, the stable sulfuryl hydrazone derivative is used as a carbene precursor, and the method is safer; the substrate has wide adaptability, the reaction operation is simple, the reaction efficiency is high, the method is more in line with the requirements of green chemistry, and the derivative product has certain enantioselectivity.

The application provides a preparation method of an atazanavir intermediate and relates to the technical field of organic synthesis. The application takes p-halogenated toluene as a starting material, uses NiCl2(dppe), tetraphenylphosphonium palladium or PdCl2(dppe) as a catalyst, and obtains N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone through Grignard coupling reaction, substitution reaction, Sommelet reaction (aldehyde) and aldehyde amine condensation reaction, and finally obtains the target product atazanavir intermediate 2-[4-(2-pyridyl)benzyl]-hydrazine carboxylic acid tert-butyl ester through hydrogenation reduction reaction. Compared with the prior art, the starting material and the catalyst (especially NiCl2(dppe)) used in the application are cheap and easy to obtain, so that the synthesis cost is reduced, and the product yield and purity of the method are high, the purity is greater than 99% (HPLC), and the highest single impurity is less than 0.1%.

The present invention relates to novel compounds which are useful in agriculture and / or in animal health and / or household and in particular to novel isoxazoline compounds, as well as to compositions comprising these compounds. In addition, the present invention relates to the use of a compound or a composition comprising one or more of these compounds in agriculture or animal health or household and specifically for controlling insect pests or parasitic invertebrate pests or household pests. The present invention further relates to intermediate compounds which are useful in preparing the compounds of the present invention.