CN104844532A - Antiviral compounds, and preparation method and use thereof - Google Patents
Antiviral compounds, and preparation method and use thereof Download PDFInfo
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- CN104844532A CN104844532A CN201410056606.7A CN201410056606A CN104844532A CN 104844532 A CN104844532 A CN 104844532A CN 201410056606 A CN201410056606 A CN 201410056606A CN 104844532 A CN104844532 A CN 104844532A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
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Abstract
The invention provides compounds represented by formula (I). All variables in the formula (I) are defined in the specification. The invention also provides a preparation method and a use of the compounds of the formula (I).
Description
Technical field
The present invention relates to novel antiviral, Preparation Method And The Use.More particularly, the present invention relates to a kind of adamantane compound of novelty, its preparation method and its preparation antiviral in purposes.
Background technology
The most effective treatment plan of current treatment influenza A virus is medicine Oseltamivir Tamiflu (Roche Holding Ag).Oseltamivir is neuraminidase inhibitor, and neuraminidase is responsible for one of important membrane albumen discharging breeding after virus assembly just.But the fancy price of Tamiflu makes most developing countries cannot lay in a large amount of medicines and is supplied to the common people in case flu outbreak.Another kind of Tamiflu outside Tamiflu Rimantadine Rimantadine just.What adamantane compound Rimantadine suppressed is the another kind of viral ion channels albumen being called M2.But along with the diffusion of variation M2 viral ion channels, present anti-Rimantadine virus has accounted for the influenza virus more than 90%.Although Rimantadine is cheap, drug-fast appearance makes it lose the validity of opposing influenza A.
Therefore, still need to develop the Novel adamantine alkyl compound effectively can resisting influenza A.
Summary of the invention
The object of the invention is to develop the Novel adamantine alkyl compound that effectively can suppress variation M2 viral ion channels.This kind of novel adamantane compound will effectively suppress resistance influenza virus.The present invention will have an opportunity to become novel Tamiflu, also can same amantadine, Rimantadine, Oseltamivir together drug combination play the target more effectively suppressing influenza virus.
A first aspect of the present invention provides a kind of formula (I) compound:
R
1be selected from H, OH, substituted or unsubstituted alkoxyl group or amino;
R
2be selected from H, OH, halogen, C
1-8alkyl, C
3-8cycloalkyl, alkoxyl group, N-C
1-4alkyl; Or optionally by C
1-4alkyl, C
3-45-6 unit's aromatic ring that cycloalkyl, alkoxyl group, halogen replace further or heterocycle;
A is 5-6 unit's aromatic ring or heterocycle, and it comprises the heteroatoms that 1-3 is selected from N, O, S;
N1, n2 and n3 are selected from 0,1,2,3 or 4 independently of one another.
According to the present invention one preferred embodiment, in described formula (I) compound:
R
1be selected from H, OH, substituted or unsubstituted alkoxyl group;
R
2be selected from H, C
1-6alkyl, C
3-6cycloalkyl or by C
1-4alkyl, C
3-4cycloalkyl, alkoxyl group or the 5-6 unit's aromatic ring replaced further by halogen or heterocycle;
A is 5 yuan of heterocycles, and it comprises the heteroatoms that 1-3 is selected from N, O, S;
N1, n2 and n3 are selected from 1,2,3 or 4 independently of one another.
According to the present invention's embodiment be more preferably, in described formula (I) compound:
R
1be selected from H or OH;
R
2be selected from the 6 yuan of aromatic rings replaced further by halogen;
A is 5 yuan of heterocycles, and it comprises the heteroatoms that 1-3 is selected from N, O, S;
N1, n2 and n3 are selected from 1,2,3 or 4 independently of one another.
According to the present invention's most preferred embodiment, described formula (I) compound is selected from:
2-[(5-cyclopropyl-3-methylisoxazole)-amino]-diamantane-2}-methyl alcohol;
2-[(5-phenyl-3-methylisoxazole)-amino]-diamantane-methyl alcohol;
2-[(2-methyl-4-picoline)-amino]-diamantane-methyl alcohol;
2-[(2-methyl-5-picoline)-amino]-diamantane-methyl alcohol;
(2-{ [(5-phenyl-isoxzzole-3-methyl)-amino]-methyl-diamantane-2)-methyl alcohol;
(2-{ [(2-picoline-4-methyl)-amino]-methyl diamantane-2)-methyl alcohol;
(2-{ [(2-picoline-5-methyl)-amino]-methyl diamantane-2)-methyl alcohol;
(2-{ [(5-cyclopropyl-3-methylisoxazole)-amino]-methyl diamantane-2)-methyl alcohol;
(2-methyl adamantane-2-methyl)-(5-phenyl isoxzzole-3-methyl) ammonia;
(2-methyl adamantane-2-methyl)-(5-phenyl-1,3,4-thiadiazoles-3-methyl) ammonia;
(2-methyl adamantane-2-)-(5-phenyl isoxzzole-3-methyl) ammonia; Or
(2-methyl adamantane-2-)-(5-phenyl-1,3,4-thiadiazoles-3-methyl) ammonia.
According to the present invention, " alkyl " refers to the unit price with the carbonatoms of specifying, saturated hydrocarbon chain.Such as, C1-C6 alkyl refers to the alkyl with 1 to 6 carbon atoms.In other embodiments, alkyl comprises 1 to 2,3,4 or 5 carbon atoms.Alkyl can optionally be replaced by one or more substituting group described here.Alkyl can be straight or branched.In one embodiment, the alkyl of side chain can have one, two or three side chains.The example of alkyl includes, but are not limited to methyl, methylethyl, ethyl, propyl group (n-propyl and sec.-propyl), methyl-propyl, methyl-propyl, butyl (normal-butyl, isobutyl-and the tertiary butyl), amyl group (n-pentyl, isopentyl and neo-pentyl) and hexyl.
According to the present invention, " alkoxyl group " refers to-O-R, and wherein R is alkyl described herein.In one embodiment, alkoxyl group comprises 1 to 2,3,4 or 5 carbon atoms.The example of alkoxyl group includes, but are not limited to methoxyl group, oxyethyl group and propoxy-.
According to the present invention, " cycloalkyl " refers to the saturated monocycle alkyl with three to ten carbon atoms with monocycle or multiple carbocyclic fused ring system.In some embodiments, cycloalkyl has three to six carbon atom.The example of cycloalkyl includes, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
According to the present invention, " halogen " refers to fluorine (F), chlorine (C1), bromine (Br) or iodine (I)." halo " refers to halogen group: fluoro (-F), chloro (-C1), bromo (-Br) and iodo (-I).
According to the present invention, " haloalkyl " refers to have one, the alkyl of two or three halogen atoms and its combination.The example of haloalkyl includes, but are not limited to chloromethyl, brooethyl, trifluoromethyl, dichloromethyl.
According to the present invention, " Heterocyclylalkyl " refers to 5,6 or 7 yuan of saturated single heterocycles only comprising a heteroatoms nitrogen, and the nitrogen of Heterocyclylalkyl is replaced by a C1-C3 alkyl.In some embodiments, the nitrogen of Heterocyclylalkyl is methyl substituted by one.In some embodiments, single heterocycle is 6 rings.In some embodiments, the carbon of Heterocyclylalkyl can be replaced by one or two C1-C3 alkyl further.The example of Heterocyclylalkyl includes, but are not limited to pyrrolidyl, piperidyl and azepine base.
According to the present invention, " replace or do not replace " and representing, group (as alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl or heteroaryl) can be unsubstituted, or this group can be replaced by one or more defined substituting group.
According to the present invention, " pharmacy is acceptable " refers to that those are suitable for the contact tissue with human and animal in the scope of sound medical judgment, and there is no too much toxicity, pungency or other problems or complication, the compound, material, composition and the formulation that match with rational interests/Hazard ratio.
The one or more hydrogen atoms combined about " replacement " expression of group and the skeletal atom (such as carbon atom) of group are replaced by defined substituting group.Should be appreciated that term " replacement " comprises Implicit Conditions is to replace according to the atom be substituted and substituent permission valence and this replacement causes stable compound (change, as reset, cyclisation or elimination and enough strong to isolate the compound that can also exist from reaction mixture) namely unautogenously.When describing a kind of group and can comprising one or more substituting group, one or more (when being applicable to) skeletal atom in group can be substituted.In addition, the single skeletal atom in group can be replaced by more than one substituting group, as long as carry out this replacement according to the permission valence of this atom.Substituent example includes, but are not limited to halogeno-group, hydroxyl, amino, amide group ,-SH, cyano group, nitro, sulfanyl, carboxylic acid ,-NH-C (=NH)-NH
2, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, wherein alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl can be substituted further.The substituting group of group that is that be suitable for each replacement or that optionally replace is described at this.
The salt of the application's Chinese style (I) compound, kind is had no particular limits, specifically can enumerate, the inorganic acid addition salts such as such as hydrofluoride, hydrochloride, vitriol, nitrate, perchlorate, phosphoric acid salt, carbonate, supercarbonate, hydrobromate, hydriodate; The organic carboxyl acid additive salt such as acetate, maleate, fumarate, oxalate, lactic acid salt, tartrate, trifluoroacetate; The organic sulfonic acid additive salt such as mesylate, fluoroform sulphonate, esilate, hydroxymethane sulfonic acid salt, isethionate, benzene sulfonate, tosylate, taurate; Front three amine salt, triethylamine salt, pyridinium salt, procaine salt, picoline salt, dicyclohexyl amine salt, N, N, the amine additive salt such as-dibenzyl ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, diethanolamine salt, triethanolamine salt, styroyl benzylamine salts; The basic metal such as sodium salt, sylvite additive salt; The alkaline-earth metal such as magnesium salts, calcium salt additive salt; The amino acid addition salts such as arginic acid salt, lysine salt, Serine salt, glycinate, aspartate, glutaminate.Preferred pharmacy acceptable salt.
As pharmacy acceptable salt, be not limited to specific kind, but can enumerate such as, the inorganic acid addition salts such as hydrochloride, vitriol, carbonate, supercarbonate, hydrobromate, hydriodate; The organic carboxyl acid additive salt such as acetate, maleate, lactic acid salt, tartrate, trifluoroacetate; The organic sulfonic acid additive salt such as mesylate, hydroxymethane sulfonic acid salt, isethionate, benzene sulfonate, tosylate, taurine basin; Front three amine salt, triethylamine salt, pyridinium salt, procaine salt, picoline salt, dicyclohexyl amine salt, N, N, the amine additive salt such as-dibenzyl ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, diethanolamine salt, triethanolamine salt, three (methylol) methane salt, styroyl benzylamine salts; The basic metal such as sodium salt, sylvite additive salt; The amino acid addition salts such as essence oxygen hydrochlorate, lysine salt, Serine salt, glycinate, aspartate, glutaminate.
A second aspect of the present invention is to provide the method for preparation above-mentioned formula (I) compound.Formula (I) compound is substantially by following four kinds of methods preparation.
The method of the first preparation formula (I) compound comprises the steps: 2-diamantane ketone to be converted into cyanamide compound; then cyan-hydrolysis is become acid; then esterification is amino ester compound; Bu Tong amino formula (I) compound replaced is formed, as compound 92,93,94,95 or analogue with last reduction again by alkylation or acylations.
The method of the second preparation formula (I) compound comprises the steps: 2-diamantane ketone to be converted into cyano group compound by second cyaniding; then formic acid ester group is connected; then be amine methyl by cyano reduction; Bu Tong amino formula (I) compound replaced is formed, as compound 98,99,100,101 or analogue with last reduction again by alkylation or acylations.
The method of the third preparation formula (I) compound comprises the steps: 2-diamantane ketone to be converted into cyano group compound by second cyaniding; then alkylated reaction is carried out; then be amine methyl by cyano reduction; Bu Tong amino formula (I) compound replaced is formed, as compound 106,107 or analogue with last reduction again by alkylation or acylations.
The method of the 4th kind of preparation formula (I) compound comprises the steps: 2-diamantane ketone to be converted into tertiary alcohol; then be amino by conversion of hydroxyl; Bu Tong amino formula (I) compound replaced is formed, as compound 109,110 or analogue with last reduction again by alkylation or acylations.
According to the present invention one preferred embodiment, formula (I) compound is by following four kinds of concrete grammars preparation.
Method one:
2-diamantane ketone (formula (II)) is converted into cyanamide compound (formula (III)) under the methyl alcohol of ammonium chloride, sodium cyanide and the effect of ammoniacal liquor.Hydrogen bromide is hydrolyzed cyano group and becomes acid, then under the effect of methanolic, esterification is amino methyl compound (formula (IV)).Compound 92,93,94,95 or the analogue of Bu Tong amino replacement is formed with last reduction by alkylation or acylations.
Method two:
2-diamantane ketone (formula (II)) is converted into cyano group compound (formula (V)) by second cyaniding.Vinyl chloroformate connects ethyl formate group, is then amine methyl (formula (VI)) by cyano reduction.Compound 98,99,100,101 or the analogue of Bu Tong amino replacement is formed with last reduction by alkylation or acylations.
Method three:
2-diamantane ketone (formula (II)) is converted into cyano group compound (formula (V)) by second cyaniding.Cyano reduction is then amine methyl (formula (VII)) by alkylated reaction.Compound 106,107 or the analogue of Bu Tong amino replacement is formed with last reduction by alkylation or acylations.
Method four:
2-diamantane ketone (formula (II)) is converted into tertiary alcohol (formula (VIII)) by grignard reagent.Then be amino (formula (IX)) by conversion of hydroxyl.Compound 109,110 or the analogue of Bu Tong amino replacement is formed with last reduction by alkylation or acylations.
It will be understood by those skilled in the art that according to the method described in above-mentioned reaction scheme and the following example, other compounds of the present invention can be prepared similarly.Should be appreciated that, provide above-mentioned embodiment and reaction scheme and the following example just illustratively, not there is limitation.
A third aspect of the present invention is to provide a kind of pharmaceutical composition, and it comprises above-mentioned formula (I) compound and its pharmaceutically acceptable carrier or thinner for the treatment of significant quantity.These pharmaceutical compositions are prepared by routine techniques.Exemplary composition of the present invention is combined with the acceptable vehicle of pharmacy, described vehicle can be carrier or thinner, or loaded body dilution, or encapsulating is in the carrier, and it can be tablet, capsule, bag agent, aerosol, solution, suspension, injection or other composition forms.When preparing composition, the routine techniques for the preparation of pharmaceutical composition can be used.Such as, active compound usually with carrier or mixing diluents, or loaded body or thinner dilute, or are encapsulated in carrier or thinner, and it can be tablet, injection, capsule, bag agent, aerosol, solution, suspension or other composition forms.When other carriers are used as thinner, it can be solid, semisolid or fluent material, its carrier as active compound, vehicle or medium.
Suitable carrier and thinner comprise lactose, sucrose, glucose, N.F,USP MANNITOL, sorbyl alcohol, starch (such as W-Gum, yam starch and pregelatinized Starch), cellulose and its derivates (such as Microcrystalline Cellulose), calcium sulfate and secondary calcium phosphate.Described oral dosage form can also comprise tackiness agent.Suitable tackiness agent comprises starch (such as W-Gum, yam starch and pregelatinized Starch), gel, gum arabic, sodium alginate, alginic acid, tragacanth, guar gum, polyvidone and cellulose and its derivates (such as Microcrystalline Cellulose).Described oral dosage form can also comprise disintegrating agent.Suitable disintegrating agent comprises polyvinylpyrrolidone, sodium starch glycolate, croscarmellose, alginic acid and Xylo-Mucine.Described oral dosage form can also comprise lubricant.Suitable lubricant comprises stearic acid, Magnesium Stearate, calcium stearate and talcum.
Tablet and Capsula is most preferred oral dosage unit form, obviously uses solid pharmaceutical carriers in this case.Described compound also can be mixed with is convenient to oral elixir or solution.Described active compound is also optionally mixed with the solution for administered parenterally, such as, by intravenously, intramuscular and subcutaneous administration.In addition, described carrier or thinner can comprise and known in the artly anyly delay releasable material, such as glyceryl monostearate or distearin.In one embodiment, described active compound is incorporated in controlled release preparation, comprises implant and microcapsule delivery system.The compounds of this invention also can with liposome or the administration of nano particle delivery system.Described composition can form like this, and namely they may only at specific physiological location release of active ingredients within one period, or preferably at specific physiological location release of active ingredients.
" the treatment significant quantity " of relevant the compounds of this invention refers to the illness that is enough to treat patient within the scope of sound medical diagnosis but low the amount being enough to avoid the compound of severe side effect (reasonably useful/dangerous than).The safety of compound and effective amount can according to the particular compound (such as considering the effect of compound, effect and transformation period) selected, selected route of administration, connect subject illness, the seriousness connecing subject illness, age, height, body weight and connecing the physical appearance of subject patient, the medical history of patient to be treated, the factor such as time length, the character of synchronous therapeutic, the result for the treatment of of expectation for the treatment of and changing, in any case but determined by skilled doctor.
A fourth aspect of the present invention is to provide the purposes of above-mentioned formula (I) compound in preparation antiviral.
The action target spot of this compound is the M2 proton channel of influenza A virus.This viral protein is also the target spot of amantadine and the Rimantadine compound be once widely used.Although amantadine and the M2 of Rimantadine to variation lost efficacy substantially, before these two kinds of medicines, effective treatment foot of first stream patient was proved using M2 proton channel as the feasibility suppressing first stream virus.And this compound in vitro in Viral Assay to resistance strain as H1N1 and H5N1 has obvious inhibition, absolutely proved the purposes of its compound in preparation antiviral.
Because influenza virus serotype is numerous, simultaneously because virus variation speed is fast, be easy in a short time occur new resistance strain, comprise the variant viral of anti-Tamiflu (at present unique effectively Tamiflu).And this compound for M2 proton channel and the target neuraminidase of Tamiflu be two kinds of diverse albumen, with to reach non-formation height complementary, very will be suitable for combination therapy.
Compare Tamiflu and vaccine development, the synthesis cost of this compound is low, is extremely applicable to developing country, is also applicable to poultry farming, has the feature becoming veterinary drug.
Embodiment
Embodiment 1: compound the synthesis of 2-[(5-cyclopropyl-3-methylisoxazole)-amino]-diamantane-2}-methyl alcohol (92):
20 grams of 2-diamantane ketone (0.13 mole) join in 300 ml methanol, then add 21.5 grams of ammonium chlorides (0.4 mole) and 50 milliliters of ammoniacal liquor.After becoming clarification Deng solution, add 10 grams of sodium cyanides (0.2 mole).Reaction mixture is heated to 50 DEG C of reactions 24 hours, uses dichloromethane extraction three times after being then as cold as room temperature.The organic layer washing of 200 milliliters once removes remaining sodium cyanide, then anhydrous sodium sulfate drying.Solvent concentration, residuum by silicagel column (petrol ether/ethyl acetate=10: 1) purifying obtain 15 digest close a (productive rate 63%).
1h NMR (400MHz, DMSO-d
6): δ 1.67-2.05 (m, 12H), 2.21 (s, 2H), 3.34 (s, 1H), 8.42 (s, 3H).
20 g of compound a (0.11 mole) join in 100 milliliters of acetic acid and 300 milliliter of 48% Hydrogen bromide, are then heated to 125 DEG C of reactions 3 days.Be as cold as concentrating under reduced pressure after room temperature, remaining solid water and ethanol are washed, and obtain 25 g of compound b (crude product) after elutant is concentrated.LC-MS：196.1[M+H]
+.
25 g of compound b (crude product) join in 300 ml methanol, then add 50 milliliters of thionyl chlorides (0.69 mole).Be heated to reflux temperature, react 5 days.Be as cold as concentrating under reduced pressure after room temperature, the saturated sodium hydrogen carbonate solution of residuum adjusts pH=7.Then methylene dichloride (300mLx3) is used to extract three times.With the saturated common salt washing of 100 milliliters after organic layer merges, then use anhydrous sodium sulfate drying.Steam solvent, residuum obtains compound 2.5 g of compound c (productive rate 11%) by silicagel column (methylene dichloride) purifying.
1h NMR (400MHz, CDCl
3): δ 1.52-2.08 (m, 12H), 2.197-2.239 (m, 2H), 3.693 (s, 3H).
Under room temperature, sodium Metal 99.5 (2.0g, 87mmol) is dissolved in 50 milliliters of ethanol.After solution is cooled to 0 DEG C, slowly add methylcyclopropyl groups ketone (7.31g, 87mmol) and diethyl oxalate (12.7g, 87mmol).Question response liquid rises to room temperature, separately adds 50 milliliters of ethanol.At room temperature react after 1 hour, be slowly heated to 80 DEG C and react again and make to react completely for 1 hour.Evaporate ethanol, the residuum hydrochloric acid of 1 mol/L is transferred to pH=1.Then wash three times (30mL x3) by ethyl acetate extraction.Organic phase merges rear dried over sodium sulfate, filters, and filtrate is concentrated obtains 13.5 g of compound 92-a (productive rate 84%).
1H NMR(400MHz，CDCl
3)：δ1.03-1.09(m，2H)，1.18-1.24(m，2H)，1.33-1.38(m，3H)，1.86-1.92(m，1H)，4.30-4.37(m，2H)，6.46-6.47(m，1H)，14.6(brs，1H)。
92-a (6.46g, 35mmol) and oxammonium hydrochloride (7.31g, 105mmol) are joined 100 milliliters of ethanol) in.Reaction solution evaporates ethanol after refluxing 3 hours.Dilute with water residuum, adds ethyl acetate (50mL x3) and extracts three times.Merge organic phase, after concentrated, column chromatography purification (solvent ratios sherwood oil is than ethyl acetate 20: 1) obtains 4.0 g of compound 92-b (productive rate 63%).
1H NMR(400MHz，CDCl
3)：δ0.96-1.00(m，2H)，1.07-1.13(m，2H)，1.33-1.40(m，3H)，2.05-2.09(m，1H)，4.34-4.43(m，2H)，6.26-6.29(m，1H)。
92-b (1.81g, 10mmol) is dissolved in tetrahydrofuran (THF) (30mL), adds lithium aluminum hydride (0.76g, 20mmol) at-10 DEG C.React 2 hours after reaction solution being risen to room temperature.Add 10% sodium hydroxide (1mL) and distilled water (1.5mL) cancellation reaction.Filter, filtrate is concentrated obtains thick product, then prepares 1.2 g of compound 92-c (productive rate 86%) through RPLC.
1H NMR(300MHz，DMSO-d
6)：δ0.82-0.87(m，2H)，1.00-1.06(m，2H)，2.06-2.13(m，1H)，4.40-4.42(d，J＝5.7Hz，2H)，5.35-5.39(t，J＝5.9Hz，1H)，6.14(s，1H)。
92-c (0.56g, 4mmol), Methanesulfonyl chloride (0.46g, 8mmol) and trolamine (2mL, 12mmol) are dissolved in dichloro 20 milliliters of methane, stirred overnight at room temperature.Reaction solution adds dichloromethane extraction twice (20mL x2) with after 20 ml water dilutions, and organic phase extracts rear dried over sodium sulfate, obtains 0.5 gram of 92-d (productive rate 79%) after purifying.LC-MS：218[M+H]
+。
92-d (1.6g, 10mmol), 2-aminoadamantan-2-methyl-formiate (1.1g, 5.5mmol) and salt of wormwood (2.1g, 15mmol) be dissolved in dimethyl formamide (30mL), microwave heating 130 DEG C reaction 4 hours.Reaction terminates the dilution of rear use 100 ml water, is then extracted with ethyl acetate three times (100mL x 3).The organic phase merged concentrates, and obtains 0.3 g of compound 92-e (productive rate 18%) through preparing plate purifying.LC-MS：331[M+H]
+。
92-e (0.3g, 0.9mmol) is dissolved in 20 milliliters of tetrahydrofuran (THF)s, then adds lithium aluminum hydride (0.11g, 2.8mmol).Stirring at room temperature is reacted after 1 hour with water (1mL) and 0% sodium hydroxide (1mL) cancellation.Filter, the resistates after filtrate concentrates obtains 0.15 gram of { 2-[(5-cyclopropyl, 3-methylisoxazole)-amino]-diamantane }-methyl alcohol (productive rate 61%) by preparing plate purifying.
1H NMR(400MHz，CDCl
3)：δ0.93-0.97(m，2H)，1.02-1.07(m，2H)，1.63-1.70(m，6H)，1.84-1.94(m，8H)，1.98-2.03(m，1H)，3.64-3.65(d，J＝5.2Hz，4H)，5.90(s，1H)。
Embodiment 2: the synthesis of compound { 2-[(5-phenyl-3-methylisoxazole)-amino]-diamantane }-methyl alcohol (93):
Phenylacetylene (20g, 0.2mol) and ethyl nitroacetate (66.4g, 0.5mol) are dissolved in 500 milliliters of chloroforms, then add 11.2 grams of triethylenediamines (DABCO, 0.1 mole).Solution is heated to 70 DEG C of reactions 72 hours.Cool to room temperature, adds 200 ml water dilutions, sodium bicarbonate aqueous solution (100mL), saturated aqueous common salt (100mL).Organic phase is collected, dry, removes solvent, thick product column chromatography purification (sherwood oil: ethyl acetate=300: 1) obtain 30 g of compound 93-a (productive rate 71%).
1hNMR (400MHz, CDCl
3): δ 1.41-1.45 (t, J=7.0Hz, 3H), 4.43-4.48 (m, 2H), 6.91 (s, 1H), 7.46-7.49 (m, 3H), 7.78-7.81 (m, 2H).
93-a (1.4g, 6.4mmol) is dissolved in methyl alcohol (25mL), and slowly add aqueous sodium hydroxide solution (1.0g, 26mmol, in30mL water), reaction solution at room temperature reacts 3 hours.The hydrochloric acid that residuum adds 2 mol/L adjusts to pH=2.Add methylene dichloride (3x50mL) extraction.Merge organic phase washing, dry, remove solvent, thick product column chromatography purification (sherwood oil: ethyl acetate=200: 1) obtain 1.1g compound 93-b (productive rate 92%).
1H NMR(400MHz，DMSO-d
6)：δ6.99(s，1H)，7.50-7.53(m，3H)，7.81-7.84(m，2H)，8.92(brs，1H)。
By 93-b (0.19g, 1mmol), 2-aminoadamantan-2-methyl-formiate (0.21g, 1mmol), HATU (0.76g, 2mmol) and DIEA (0.39g, 3mmol) be dissolved in dimethyl formamide (5mL), stirred overnight at room temperature.Dilution that reaction solution adds water (10mL), divide and add ethyl acetate (3x30mL) extraction for three times, collect organic phase, by dried over sodium sulfate, filter, steam except ethyl acetate, thick product column chromatography purification (sherwood oil: ethyl acetate=20: 1) obtain 0.23 g of compound 93-c (productive rate 63%).
1H NMR(300MHz，CDCl
3)：δ1.76-1.88(m，8H)，2.04-2.09(m，4H)，2.65(s，2H)，3.75(s，3H)，6.91(s，1H)，7.07(s，1H)，7.46-7.49(m，3H)，7.76-7.79(m，2H)。
93-c (0.15g, 0.39mmol) is dissolved in 10 milliliters of tetrahydrofuran (THF)s, at room temperature adds lithium aluminum hydride (0.18g, 3.9mmol).Reaction solution use water (1mL) and 10% sodium hydroxide (1mL) cancellation after stirring at room temperature 1h.Filter, filtrate is concentrated obtains 0.1 g of compound 93-d (productive rate 90%).LC-MS：353[M+H]
+。
93-d (100mg, 0.28mmol) solution, in tetrahydrofuran (THF) (10mL), then adds borane dimethylsulf iotade (1.0M, 0.4mL, 0.4mmol).Reaction is warmed up to 50 DEG C of stirrings and spends the night.Reaction solution methyl alcohol (2mL) and concentrated hydrochloric acid (0.1mL) cancellation.After concentrated, thick product RPLC is prepared purifying and is obtained 40 milligrams of { 2-[(5-phenyl, 3-methylisoxazole)-amino]-diamantane }-methyl alcohol (93, productive rate 45%).
1H NMR(400MHz，CDCl
3)：δ1.67-1.72(m，6H)，1.88-1.95(m，8H)，3.69(s，2H)，3.78(s，2H)，6.54(s，1H)，7.44-7.47(m，3H)，7.77-7.79(m，2H)。
Embodiment 3: the synthesis of compound { 2-[(2-methyl-4-picoline)-amino]-diamantane }-methyl alcohol (94):
The synthetic method of { 2-[(2-methyl-4-picoline)-amino]-diamantane }-methyl alcohol (94) is similar with the synthetic method of { 2-[(5-phenyl-3-methylisoxazole)-amino]-diamantane }-methyl alcohol (93), instead of above-mentioned 93-b with 2-methyl-isonicotinic acid, obtain 35 milligrams of sterlings through identical three-step reaction.
1H NMR(400MHz，CDCl
3)：δ1.67-1.73(m，6H)，1.88-1.94(m，8H)，3.56(s，3H)，3.59(s，2H)，3.68(s，2H)，7.09(d，J＝5.2Hz，1H)，7.16(s，1H)，8.44(d，J＝4.8Hz，1H)。
Embodiment 4: the synthesis of compound { 2-[(2-methyl-5-picoline)-amino]-diamantane }-methyl alcohol (95):
6-methyinicotinate (0.15g, 1mmol) solution, in methyl alcohol (10mL), adds sodium hydroxide (0.16g, 4mmol, in1 mL water).Reaction solution at room temperature stirring reaction 3 hours.Concentrated, the residuum hydrochloric acid of 2 mol/L is transferred to pH=2, then uses dichloromethane extraction three times (3x10mL).Organic phase saturated aqueous common salt (10mL) washs once, and anhydrous sodium sulfate drying obtains 95-a (0.1g, productive rate 83%) after concentrated.LC-MS：138[M+H]
+。
{ 2-[(2-methyl-5-picoline)-amino]-diamantane }-methyl alcohol (95) synthesis is below similar with the synthetic route of { 2-[(5-phenyl-3-methylisoxazole)-amino]-diamantane }-methyl alcohol (93), instead of above-mentioned 93-b with 2-methyl-isonicotinic acid, obtain 60 milligrams of sterlings through identical three-step reaction.
1H NMR(400MHz，CDCl
3)：δ1.67-1.72(m，6H)，1.89-1.94(m，8H)，2.55(s，3H)，3.58(s，2H)，3.69(s，2H)，7.13(d，J＝8.0Hz，1H)，7.58-7.60(m，1H)，8.44(d，J＝1.6Hz，1H)。
Embodiment 5: the synthesis of compound (2-{ [(5-phenyl-isoxzzole-3-methyl)-amino]-methyl }-diamantane-2)-methyl alcohol (98):
Compound 43a (24 grams; 0.16 mole) join in 1,2-ethylene dichloride (1.5 liters) and ethanol (15 milliliters), then under the protection of nitrogen, add p-toluenesulfonyl isonitrile (TosMIC; 40 grams, 0.2 mole).Reaction mixture ice-water bath cools.Potassium tert.-butoxide (46.4 grams, 0.4 mole) is by the mixture that slowly adds above.After adding, reaction mixture stirs and spends the night in 40 degree of situations. then filter out solid.Filtrate be distilled out of rear residuum passed through column purification (petrol ether/ethyl acetate=30: 1) obtain compound 43b (23 grams, 88%).
1h NMR (400MHz, CDCl
3): δ 1.72-2.16 (m, 14H), 2.893 (s, 1H).
The tetrahydrofuran (THF) (100 milliliters) of the drying of Diisopropylamine (20 milliliters, 0.14 mole) cools to subzero 78 degree.Slowly add tetrahydrofuran (THF) (30 milliliters) solution of butyllithium (62 milliliters, 0.15 mole).Then be raised to stirring at room temperature half hour, then be cooled to subzero 78 degree.Then compound 43b (6.44 grams, 40 mmoles) tetrahydrofuran (THF) (50 milliliters) solution be added in LDA solution above. after reaction mixture is stirred 2 hours, the Vinyl chloroformate (26 milliliters, 0.24 mole) of new distillation is stirred when room temperature and is spent the night in the solution adding above slowly.Then reaction mixture is poured in frozen water is extracted with ethyl acetate.Organic layers with water and saturated common salt washing, then steam solvent with after anhydrous sodium sulfate drying.Residuum by silicagel column (petrol ether/ethyl acetate=200: 1) purifying is to compound 43c (6.6 grams, 71%).
1h NMR (400MHz, CDCl
3): δ 1.259-1.335 (m, 3H), 1.688-1.869 (m, 10H), 2.222-2.254 (d, 2H), 2.546 (s, 1H), 4.262-4.316 (m, 2H).
Under room temperature, lithium aluminium hydride (13g, 0.34mol) slowly joins in tetrahydrofuran (THF) (500 milliliters) solution of compound 43c (6.6 grams, 28 mmoles).After adding, reaction mixture stirs and spends the night in 70 degree of situations, then adds water (20 milliliters) and 15% sodium hydroxide (10 milliliters) successively.Filter out solid, filtrate being concentrated obtains compound 43 (5 grams, 90%) .LC-MS:196.1 [M+H]
+.
1h NMR (400MHz, CDCl
3): δ 1.565-2.096 (m, 14H), 3.121 (s, 2H), 3.915 (s, 2H).
At 0 DEG C, lithium aluminum hydride (0.76g, 20mmol) joins in tetrahydrofuran (THF) (50mL) solution of compound 98-a (2.2g, 10mmol).Then room temperature is risen to, with water (6mL) and 10% sodium hydroxide (2mL) cancellation after reaction 2h.Filter, the resistates after filtrate concentrates obtains compound 98-b (1.3g, productive rate 74%) through column chromatography purification (solvent ratios sherwood oil is than ethyl acetate: 10/1-3/1).LC-MS：176[M+H]
+。
Compound 98-b (1.1g, 6.3mmol), methane sulfonyl chloride (1.44g, 12.6mmol) and triethylamine (2.6mL, 19mmol) are dissolved in methylene dichloride (25mL), stirred overnight at room temperature.Add methylene dichloride (50mL) dilution rear water (30mL) and saturated aqueous common salt (30mL) respectively wash once.Organic phase with sodium sulfate is dry, obtains 98-c (1.2g) after concentrated.LC-MS：254[M+H]
+。
Amino-2 methyl-adamantyl-methyl alcohol (0.4g, 2mmol) of compound 98-c (0.5g, 2mmol), 2-and salt of wormwood (0.88g, 6mmol) are dissolved in dimethyl formamide (10mL), stirred overnight at room temperature.Add water (20mL) dilution after completion of the reaction, add ethyl acetate (3x30mL) and extract three times.Organic phase is concentrated removes solvent, prepares plate purifying and obtains target compound (2-{ [(5-phenyl-isoxzzole-3-methyl)-amino]-methyl }-diamantane-2)-methyl alcohol (98) (0.12g, productive rate 17%).
1H NMR(300MHz，DMSO-d
6)：δ1.52(d，4H)，1.56-1.65(m，4H)，1.84(s，2H)，1.97(d，4H)，3.36(s，2H)，3.76(s，2H)，4.39(s，2H)，7.14(s，1H)，7.55-7.58(m，3H)，7.86-7.89(m，2H)，8.81(brs，2H)。
Embodiment 6: the synthesis of compound (2-{ [(2-picoline-4-methyl)-amino]-methyl } diamantane-2)-methyl alcohol (99):
2-methylnicotinic acid (7g, 51mmol) is dissolved in methyl alcohol (100mL), at 0 DEG C, slowly drip thionyl chloride (8mL, 70mmol), then by reaction solution temperature rising reflux 2h.React complete, low pressure is steamed except methyl alcohol, with sodium bicarbonate aqueous solution, residual solution is adjusted to neutrality, pH=8.Add ethyl acetate (3x50mL) to quench and wash three times.Organic phase saturated common salt is washed, dry, obtains the 99-a of 8g after purifying.
LC-MS：152[M+H]
+。
(2-{ [(2-picoline-4-methyl)-amino]-methyl } diamantane-2)-methyl alcohol (99) below synthesis similar with the synthetic route of (2-{ [(5-phenyl-isoxzzole-3-methyl)-amino]-methyl }-diamantane-2)-methyl alcohol (98), replace 98-a with 99-a, obtain 100 milligrams of products according to the same terms through three-step reaction.
1H NMR(300MHz，DMSO-d
6)：δ＝1.52(d，4H)，1.66(d，4H)，1.82-1.98(m，6H)，2.49(t，J＝1.65Hz，3H)，3.16(s，2H)，3.72(s，2H)，4.27(s，2H)，7.50(d，1H)，7.55(s，1H)，8.61(d，1H)，8.72(brs，2H)。
Embodiment 7: the synthesis of compound (2-{ [(2-picoline-5-methyl)-amino]-methyl } diamantane-2)-methyl alcohol (100):
The synthesis of compound ((2-{ [(2-picoline-5-methyl)-amino]-methyl } diamantane-2)-methyl alcohol (100) is similar with the synthetic route of (2-{ [(5-phenyl-isoxzzole-3-methyl)-amino]-methyl }-diamantane-2)-methyl alcohol (98), replace 98-a with 6-methyinicotinate, obtain 100 milligrams of products according to the same terms through three-step reaction
1H NMR(300MHz，DMSO-d
6)：δ1.45(d，4H)，1.62(s，4H)，1.76-1.97(m，6H)，2.42(s，3H)，2.69(s，2H)，3.62(s，2H)，3.66(s，2H)，7.17(dd，1H)，7.58-7.619(s，1H)，8.35(s，1H)。
Embodiment 8: the synthesis of compound (2-{ [(5-cyclopropyl-3-methylisoxazole)-amino]-methyl } diamantane-2)-methyl alcohol (101):
The synthesis of compound (2-{ [(5-cyclopropyl-3-methylisoxazole)-amino]-methyl } diamantane-2)-methyl alcohol (101) is similar with the synthetic route of (2-{ [(5-phenyl-isoxzzole-3-methyl)-amino]-methyl }-diamantane-2)-methyl alcohol (98), replace 98-a with 101-a, obtain 60 milligrams of products according to the same terms through three-step reaction.
1H NMR(300MHz，CDCl
3)：δ0.94-0.97(m，2H)，1.01-1.06(m，2H)，1.55-1.62(m，4H)，1.70(s，4H)，1.89-2.08(m，6H)，2.97(s，2H)，3.78(s，2H)，3.86(s，2H)，5.90(s，1H)。
Embodiment 9: the synthesis of compound (2-methyl adamantane-2-methyl)-(5-phenyl isoxzzole-3-methyl) ammonia (106)
Under nitrogen protection, in the glycol dimethyl ether (500mL) and ethanol (150mL) solution of 2-diamantane ketone (24g, 0.66mol), add Methyl benzenesulfonyl methyl isocyanide (40g, 0.2mol).Reaction system ice-water bath cools, slowly add potassium tert.-butoxide (46.4g again, 0.4mol), then reaction system is spent the night in 50 degrees Celsius of stirring heating, filter, filtrate is concentrated obtains crude product, then through silica gel column chromatography (petrol ether/ethyl acetate=50: 1-30: 1) purifying obtains compound a (23g, 88% productive rate).
1H NMR(300MHz，CDCl
3)：δ1.71-1.76(m，6H)，1.86-1.93(m，4H)，2.12-2.16(m，4H)，2.89(s，1H)。
Under nitrogen protection, n-Butyl Lithium (2.5M, 100mL, 0.25mol) is slowly dripped in ether (150mL) solution in zero degrees celsius to Diisopropylamine (35ml, 0.25mol).Stir after 15 minutes, in above-mentioned system, compound a (8.1g is added in subzero 20 degrees Celsius, ether (100mL) solution 50mmol), stir after 15 minutes, add methyl iodide (16mL again, 0.25mol), continue to stir one hour at subzero 20 degrees Celsius, remove cryostat, by reaction system in stirring at room temperature 0.5 hour, add water (200mL) termination reaction wherein, and extract 3 times with ether (100mL), organic layer merges, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product, again through silicagel column (petrol ether/ethyl acetate=30: 1-20: 1) purifying obtains compound b (8g, 91% productive rate).
1H NMR(400MHz，CDCl
3)：δ1.50(s，3H)，1.62-1.65(m，2H)，1.72(s，2H)，1.79-1.94(m，8H)，2.24-2.28(m，2H)。
To compound b (0.36g, ammoniacal liquor (3mL) and Raney Ni (0.5g) is added in methyl alcohol (25mL) solution 2mmol), then reaction system is reacted 3 hours in 60 degrees Celsius under 50psi hydrogen pressure, system is chilled to room temperature, filter, filtrate concentrate drying obtains compound c (0.3g, 81% productive rate).H NMR(300MHz，DMSO-d
6)：δ0.96(s，3H)，1.46-2.09(m，17H)。
By compound 98-c (0.5g, 2mmol), compound c (0.93g, 5.2mmol) with salt of wormwood (1.1g, 7.8mmol) be added to N respectively, in dinethylformamide (10mL), reaction mixture was 80 degrees Celsius of stirring reactions 8 hours, dilute with water (20mL) and extract three times by ethyl acetate (20mL), merge organic phase, concentrate and obtain thick product, obtain compound 106 (0.4g, 49% productive rate) through preparation purification.LC-MS：337.2[M+H]
+.
1H NMR(300MHz，CDCl
3)：δ1.10(s，3H)，1.33-1.34(m，6H)，1.52-1.83(m，4H)，1.96-2.07(m，4H)，2.72(s，2H)，3.92(s，2H)，6.53(s，1H)，7.42-7.48(m，3H)，7.76-7.79(m，2H)。
Embodiment 10: the synthesis of compound (2-methyl adamantane-2-methyl)-(5-phenyl-1,3,4-thiadiazoles-3-methyl) ammonia (107)
To benzoyl hydrazine (10.5g, chloroacetyl chloride (7.4ml is slowly dripped in ethyl acetate (150mL) solution 77mmol), ethyl acetate (50ml) solution 93mmol), mixture reflux 0.5 hour, be chilled to room temperature, filter, after the washing of filter cake ethyl acetate, drying obtains compound 107a (9g, 55% productive rate).
1H NMR(300MHz，DMSO-d
6)：δ4.20(s，2H)，7.47-7.58(m，3H)，7.86-7.89(m，2H)，10.37(s，1H)，10.52(s，1H)。
By compound 107a (19g, 89mmol) with lawesson reagent (40g, toluene (1L) vlil 98mmol) 3 hours, be chilled to room temperature, reaction mixture use water (1L) dilutes, separate toluene organic phase, residue aqueous phase ethyl acetate (300mL) extracts three times, merge above-mentioned organic layer, concentrated, obtain crude product, then passed through silicagel column (petrol ether/ethyl acetate=20: 1) purifying obtains compound 107b (16g, 84% productive rate).
1h NMR (400MHz, CDCl
3): δ 4.984 (s, 2H), 7.492-7.510 (m, 3H), 7.950-7.974 (m, 2H).
By compound 107b (0.42g, 2mmol), compound c (0.54g, 3mmol) with salt of wormwood (0.84g, 6mmol) be added to N respectively, in dinethylformamide (5mL), reaction mixture spends the night at 80 degrees Celsius of stirring reactions, dilute with water (20mL) and extract three times by ethyl acetate (20mL), merge organic phase, concentrate and obtain thick product, then obtain compound 107 (0.4g, 57% productive rate) through preparation purification.LC-MS：354.2[M+H]
+.
1H NMR(300MHz，CDCl
3)：δ1.07(s，3H)，1.43-1.49(m，6H)，1.61(s，2H)，1.74-1.79(m，2H)，1.93-2.03(m，4H)，2.65(brs，3H)，4.13(s，2H)，7.53-7.55(m，3H)，7.93-7.96(m，2H)。
Embodiment 11: the synthesis of compound (2-methyl adamantane-2-)-(5-phenyl isoxzzole-3-methyl) ammonia (109)
When zero degrees celsius, 2-diamantane ketone (45g is slowly added in tetrahydrofuran (THF) (100mL) solution of methyl-magnesium-bromide (diethyl ether solution of 3M, 110mL, 0.33mol), 0.3mol), reaction system is in stirred overnight at room temperature, and add water termination reaction, and extracts three times with ether (100mL), merge organic layer, with anhydrous sodium sulfate drying, vacuum-concentrcted obtains compound a (35g, 70% productive rate).
1H NMR(400MHz，CDCl
3)：δ1.33(s，3H)，1.44-1.56(m，3H)，1.67-1.87(m，10H)，2.17(d，J＝12.4Hz，2H)。
Added by compound a (13g, 0.08mol) in chloroform/hydrochloric acid (120mL/120mL), reaction system is spent the night in 50 degrees Celsius of stirrings, and then reaction system concentrate drying obtains compound b (11g, 76% productive rate).
1h NMR (400MHz, DMSO-d
6): δ 1.62-1.82 (m, 11H), 1.94-2.04 (m, 4H), 2.32 (d, J=12.8Hz, 2H).
When zero degrees celsius, to compound b (11g, 59mmol), azide trimethyl silane (16mL, tin tetrachloride (6mL is added in methylene dichloride (100mL) solution 120mmol), 50mmol), reaction system is heated to backflow 24 hours, add water (500mL) termination reaction and extract three times with methylene dichloride (150mL), organic layer merges, and with anhydrous sodium sulfate drying, vacuum concentration obtains crude product, crude product purified by silica gel post (PE) purifying obtains compound c (10g, 86% productive rate).
1H NMR(400MHz，CDCl
3)：δ1.47(s，3H)，1.56-1.59(m，2H)，1.69-1.74(m，6H)，1.82-1.91(m，4H)，2.14(d，J＝11.6Hz，2H)。
To compound c (0.4g, 20% palladium hydroxide (60mg) and hydrazine hydrate (0.2mL is added in methyl alcohol (20mL) solution 2.1mmol), 4.1mmol), then reaction system thermal backflow 2 hours, be chilled to room temperature, filter, filtrate is so concentrated that to be dried to compound d (0.11g, 31% productive rate).
1H NMR(400MHz，DMSO-d
6)：δ1.13(s，3H)，1.40-1.44(m，4H)，1.57-1.61(m，4H)，1.71-1.92(m，6H)，2.16(d，J＝10.8Hz，2H)。
By compound 98-c (0.57g, 3mmol), compound d (0.99g, 6mmol) with salt of wormwood (1.26g, 9mmol) be added to N respectively, in dinethylformamide (20mL), reaction mixture spends the night at 85 degrees Celsius of stirring reactions, dilute with water (50mL) and extract three times by ethyl acetate (30mL), merge organic phase, concentrate and obtain thick product, obtain compound 109 (0.4g, 32% productive rate) through preparation purification.LC-MS：323.2[M+H]
+.
1H NMR(300MHz，CDCl
3)：δ1.10(s，3H)，1.33-1.34(m，6H)，1.52-1.83(m，4H)，1.96-2.07(m，4H)，2.72(s，2H)，3.92(s，2H)，6.53(s，1H)，7.42-7.48(m，3H)，7.76-7.79(m，2H)。
Embodiment 12: the synthesis of compound (2-methyl adamantane-2-)-(5-phenyl-1,3,4-thiadiazoles-3-methyl) ammonia (110)
By compound 107b (0.66g, 3.2mmol), compound d (0.66g, 4mmol) with salt of wormwood (1.32g, 9.6mmol) be added to N respectively, in dinethylformamide (10mL), reaction mixture spends the night at 85 degrees Celsius of stirring reactions, dilute with water (30mL) and extract three times by ethyl acetate (20mL), merge organic phase, concentrate and obtain thick product, obtain compound 110 (0.4g, 32% productive rate) through preparation purification.LC-MS：340.2[M+H]
+.
1H NMR(300MHz，CDCl
3)：δ1.22(s，3H)，1.42(d，J＝12.0Hz，2H)，1.64-1.66(m，6H)，1.79(d，J＝16.4Hz，2H)，1.92(d，J＝12.0Hz，2H)，2.34(d，J＝8.0Hz，2H)，2.71-2.75(m，1H)，4.01(d，J＝1.2Hz，2H)，7.52-7.54(m，3H)，7.95-7.97(m，2H)。
Embodiment 13: plaque minimum inhibition concentration is tested
12 orifice plates are used to support mdck cell in advance to about 90% density.By WSN viral dilution to 50PFU concentration, add embodiment compound 93 respectively mix and use amantadine and Tamiflu medicine in contrast, add respectively in mdck cell with different concentration hatch 30 minutes by gradient (100 μMs, 50 μMs, 25 μMs, 10 μMs, 5 μMs, 2.5 μMs, 1 μM, 0.5 μM, 0.25 μM and 0.1 μM), the virus liquid sucking-off after hatching is mixed with agar and 2 × DMEM.Then mixed solution is added in orifice plate, cultivate about 48 hours.Add the fixing dyeing of Viola crystallina.Choose in experiment Cmin in the concentration gradient suppressing plaque to occur and, as plaque assay minimum inhibition concentration, suppress virus effectiveness for quantitative assay compound.Result shows that the inhibition of the compounds of this invention 93 pairs of virus infectiones is far better than amantadine, and any cytotoxic effect that compound 93, Tamiflu and amantadine all do not manifest at 100 μMs.
Claims (13)
1. formula (I) compound or its salt:
Wherein:
R
1be selected from H, OH, substituted or unsubstituted alkoxyl group or amino;
R
2be selected from H, OH, halogen, C
1-8alkyl, C
3-8cycloalkyl, alkoxyl group, N-C
1-4alkyl; Or optionally by C
1-4alkyl, C
3-45-6 unit's aromatic ring that cycloalkyl, alkoxyl group, halogen replace further or heterocycle;
A is 5-6 unit's aromatic ring or heterocycle, and it comprises the heteroatoms that 1-3 is selected from N, O, S;
N1, n2 and n3 are selected from 0,1,2,3 or 4 independently of one another.
2. formula (I) compound as claimed in claim 1,
Wherein:
R
1be selected from H, OH, substituted or unsubstituted alkoxyl group;
R
2be selected from H, C
1-6alkyl, C
3-6cycloalkyl or by C
1-4alkyl, C
3-4cycloalkyl, alkoxyl group or the 5-6 unit's aromatic ring replaced further by halogen or heterocycle;
A is 5 yuan of heterocycles, and it comprises the heteroatoms that 1-3 is selected from N, O, S;
N1, n2 and n3 are selected from 1,2,3 or 4 independently of one another.
3. formula (I) compound as claimed in claim 1,
Wherein:
R
1be selected from H or OH;
R
2be selected from the 6 yuan of aromatic rings replaced further by halogen;
A is 5 yuan of heterocycles, and it comprises the heteroatoms that 1-3 is selected from N, O, S;
N1, n2 and n3 are selected from 1,2,3 or 4 independently of one another.
4. formula (I) compound as described in any one of claim 1-3, wherein said substituting group is selected from: halogeno-group, hydroxyl, amino, amide group ,-SH, cyano group, nitro, sulfanyl, carboxylic acid ,-NH-C (=NH)-NH
2, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, cycloalkyl or Heterocyclylalkyl.
5. formula (I) compound as claimed in claim 1, it is selected from:
2-[(5-cyclopropyl-3-methylisoxazole)-amino]-diamantane-2}-methyl alcohol;
2-[(5-phenyl-3-methylisoxazole)-amino]-diamantane-methyl alcohol;
2-[(2-methyl-4-picoline)-amino]-diamantane-methyl alcohol;
2-[(2-methyl-5-picoline)-amino]-diamantane-methyl alcohol;
(2-{ [(5-phenyl-isoxzzole-3-methyl)-amino]-methyl-diamantane-2)-methyl alcohol;
(2-{ [(2-picoline-4-methyl)-amino]-methyl diamantane-2)-methyl alcohol;
(2-{ [(2-picoline-5-methyl)-amino]-methyl diamantane-2)-methyl alcohol;
(2-{ [(5-cyclopropyl-3-methylisoxazole)-amino]-methyl diamantane-2)-methyl alcohol;
(2-methyl adamantane-2-methyl)-(5-phenyl isoxzzole-3-methyl) ammonia;
(2-methyl adamantane-2-methyl)-(5-phenyl-1,3,4-thiadiazoles-3-methyl) ammonia;
(2-methyl adamantane-2-)-(5-phenyl isoxzzole-3-methyl) ammonia; Or
(2-methyl adamantane-2-)-(5-phenyl-1,3,4-thiadiazoles-3-methyl) ammonia.
6. prepare the method for formula (I) compound described in any one of claim 1-5, comprise the steps:
2-diamantane ketone is converted into cyanamide compound, and then cyan-hydrolysis is become acid, then esterification is amino ester compound, then forms Bu Tong amino formula (I) compound replaced by alkylation or acylations with last reduction.
7. prepare the method for formula (I) compound described in any one of claim 1-5, comprise the steps:
2-diamantane ketone being converted into cyano group compound by second cyaniding, then connecting formic acid ester group, is then amine methyl by cyano reduction, then forms Bu Tong amino formula (I) compound replaced by alkylation or acylations with last reduction.
8. prepare the method for formula (I) compound described in any one of claim 1-5, comprise the steps:
2-diamantane ketone being converted into cyano group compound by second cyaniding, then carrying out alkylated reaction, is then amine methyl by cyano reduction, then forms Bu Tong amino formula (I) compound replaced by alkylation or acylations with last reduction.
9. prepare the method for formula (I) compound described in any one of claim 1-5, comprise the steps:
2-diamantane ketone is converted into tertiary alcohol, is then amino by conversion of hydroxyl, then forms Bu Tong amino formula (I) compound replaced by alkylation or acylations with last reduction.
10. a pharmaceutical composition, it comprises formula (I) compound described in any one of claim 1-5 and its pharmaceutically acceptable carrier for the treatment of significant quantity.
11. compositions as claimed in claim 10, it comprises other activeconstituentss further.
12. compositions as claimed in claim 11; other activeconstituentss described are selected from amantadine, Rimantadine or Oseltamivir, (3R; 4R; 5S)-4-ethanamide-5-amino-3 (1-ethylpropoxy)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester), zanamivir or N-ethanoyl-2,3-bis-deoxidation-4-guanidine radicals sialic acid.
The purposes of formula (I) compound described in 13. any one of claim 1-5 in preparation antiviral.
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| KR102657677B1 (en) * | 2023-10-26 | 2024-04-16 | 국방과학연구소 | Process for preparing isoxazoles using flow reaction in deep eutectic solvent |
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