CN104230935A - Anti-tumor effect and application of compound containing alicyclic structure - Google Patents

Anti-tumor effect and application of compound containing alicyclic structure Download PDF

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CN104230935A
CN104230935A CN201410163816.6A CN201410163816A CN104230935A CN 104230935 A CN104230935 A CN 104230935A CN 201410163816 A CN201410163816 A CN 201410163816A CN 104230935 A CN104230935 A CN 104230935A
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adamantane
acetamide
oxa
oxo
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徐利锋
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LIAONING LIFENG TECHNOLOGY DEVELOPMENT CO LTD
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Abstract

The invention relates to an anti-tumor effect and application of a compound containing an alicyclic structure, in order to provide a chain compound formed by adamantyl or a similar structure base of the adamantyl, stereoisomer, prodrug, pharmaceutical salt, double salt or solvated compound; and the compound containing an alicyclic structure has a structural general formula I as shown in specification, wherein S independently represents an optionally substituted cyclic structure base, P is an independent optionally substituted functional structure base which can be connected to S or/and T, and T independently represents an optionally substituted adamantyl or/and a similar structure base of the adamantyl; the compound is characterized in that any two or three of S, P and T can be independently combined. The compound disclosed by the invention has an anti-tumor pharmacological activity as well as a pharmacological activity of resisting viruses and treating nervous system diseases and diseases caused by inflammation, and can be used as an effective medicine for resisting viruses, immunizing, resisting inflammation and treating nervous system diseases. The invention also discloses a preparation method and application of the compound.

Description

Antitumor action containing alicyclic structure compound and application
Technical field
The present invention relates to, containing adamantyl or with the chain compound that diamantane similar structures base is formed, there is new activity and the new indications such as antitumor.The invention still further relates to this compounds as the antitumor application waiting disease medicament.
background of invention
Literature system retrieval shows, chain compound containing adamantyl only has two sections of anticancer patents: US7365231B2 memantine is used for cancer caused by anticol cell plastid prolotherapy glial cells hyperplasia as brain, neck glioma, the anti-tumor activity of US2006/0079463 urotropine, all the other are the application of anti-virus aspect respectively, as US4230725, US5576355; Cardiovarscular, treatment Parkinson disease US2004/0242493A1, US4,122,193, US4122193, US4,064,285; Treatment diabetes, the application US2008/0103183A1 of obesity, US2008/0312214A1, US2008/0103183A1, US2008/0096869A1, US7435833; Treat the application US2009/0081259A1 of multiple sclerosis; The application US2006/0270742A1 of nerve degenerative diseases, US6,444,702B1, US7,326,730B2, US2008/0009546A1; The application US4386105 for the treatment of measles; The application US5061703 for the treatment of cerebral ischemia; The application US6602862 for the treatment of trypanosomiasis; The patent CN1 of the application US20050222271A1 for the treatment of senile dementia and ring like structure derivative and analogue synthesis, 556,094A, US6229050B1, US RE39,744E; At our application for a patent for invention 200910146141.3 adapalene (Adapalene), 201010561132.3 Memantine hydrochlorides (Memantine), 201010561122.X tromantadine (Tromantadine) have on the basis of anti-tumor activity and cancer therapy application, further research find containing cyclic group or and the chain compound of adamantyl there is anti-tumor activity.
US Patent No. 2005/0222271 and US6384083 report that Memantine hydrochloride (Memantine) and amantadine (Amantadine) have the effect for the treatment of senile dementia respectively, and US Patent No. 20080153850 reports that adamantane derivative has anti-inflammatory action.
The compound that existing large quantifier elimination and bibliographical information have anti-tumor activity has antiviral activity, as nucleoside compound medicine simultaneously.The compound with adamantane structure enters clinical application as antiviral, also be found to have antitumor action simultaneously, as we application for a patent for invention 200910146141.3201010561132.3,201010561122.X have anti-tumor activity, also find that there is the effect for the treatment of nervous system disorders simultaneously, as treated Parkinson disease US2004/0242493A1, US4,122,193, US4122193, US4,064,285; Treatment senile dementia disease US2005/0222271 and US6384083, and anti-inflammatory action US20080153850.
Summary of the invention
The object of this invention is to provide a kind of containing adamantyl or and diamantane similar structures base formed chain compound, steric isomer, prodrug, pharmaceutical salts, double salt or and the compound of solvation there is having structure general formula I,
It is characterized in that: in S, P, T, the composition form of three kinds of structures can be three kinds of textural associations or two kinds of textural associations independently exist, form S-P-T, S-T-P, T-S-P, P-T or S-T general structure; Described S-P-T, S-T-P, T-S-P, P-T or S-T are independent S, P of replacing arbitrarily or become carbon-carbon bond with T-shaped or be connected with carbon heterodesmic, formed ether, ester, acid amides, alcohol, aldehyde, ketone, amine, acetal, ketal, oxime or and hydrazone group structure;
Wherein S the connected S that to be ring texture base, the P independently replaced arbitrarily be independently replaces arbitrarily or and the functional structure base of T, T be the adamantyl that independently replaces arbitrarily or and diamantane similar structures base; The ring texture base that described S independently replaces arbitrarily be independently replace arbitrarily or and condense, saturated or unsaturated, monocycle base, two condensed ring radical, three condensed ring radicals, four condensed ring radicals, many condensed ring radicals, condensed ring radical or bridged ring base, little cyclic group, middle cyclic group or and large cyclic group; Described cyclic group is the C independently replaced arbitrarily 3-30alicyclic radical, aromatic ring yl, alicyclic heterocyclic base or and aromatic heterocyclic; Monocycle, dicyclo has having structure general formula I, II, III, IV, and wherein A ring is the C independently replaced arbitrarily 3-18unit's alicyclic radical, fragrant cyclic group, alicyclic heterocyclic base or and assorted fragrant cyclic group; B ring is the C independently replaced arbitrarily 3-18unit's alicyclic radical, fragrant cyclic group, alicyclic heterocyclic base or and assorted fragrant cyclic group; A ring and B ring directly condense or condense with bridged ring form;
The connected T that described P independently replaces arbitrarily or and the functional structure base of S be the C independently replaced arbitrarily 0-12chain or C 0-18chain or and ring-shaped fat base, aromatic ring yl, alicyclic heterocyclic base or and aromatic heterocyclic, between S and T, become carbon-carbon bond with both sides S with T-shaped respectively or be connected with carbon heterodesmic, formed independently replace arbitrarily ether, ester, acid amides, alcohol, aldehyde, ketone, amine, acetal, ketal, oxime or and hydrazone group structure, and S and T is kept at a certain distance away, it is spaced apart C 0-12chain or C 0-18chain or ring-shaped fat base, aromatic ring yl, alicyclic heterocyclic base or and aromatic heterocyclic,
The adamantyl that described T independently replaces arbitrarily or and diamantane similar structures base be the C independently replaced arbitrarily 3-30monocycle base, bicyclic group, polycyclic base, bridged ring base, cage cyclic group, diamantane cyclic group, thick and adamantyl or and diamond cyclic group; For independently replace arbitrarily containing oxygen, sulphur, nitrogen or and single heterocyclic radical of phosphine, two heterocyclic radical, or poly-heterocyclic radical are bridge heterocyclic radical, cage heterocyclic radical, diamantane heterocyclic radical or and diamond heterocyclic radical; For independently any one replaces, two replacements three replace, four replacements or polysubstituted; For independently arbitrarily aromatic nucleus or and aromatic heterocycle replaces or the above-mentioned alicyclic ring derivative that condenses and analogue base; For independently replace arbitrarily single diamantane, Double diamantane hydrocarbons, many diamantane, open loop diamantane, poly-diamantane or and caged diamantane analogue, there is having structure general formula V, VI, VII, VIII, IX, X,
Described a kind of containing adamantyl or the chain compound with the formation of diamantane similar structures base, the S general formula in described S-P-T general formula,
Described dotted portion be independently or the double bond of any replacement of combining with solid line, singly-bound or and containing the heterocyclic radical of oxygen, sulphur, nitrogen;
Described X 1, X 2, X 3, X 4can be simultaneously polysubstituted or monosubstituted in the general formula of claim 1, can be identical definition or separate different definition substituting group, for carbon, oxygen, sulphur, nitrogen, phosphorus or and the heteroatoms such as selenium, for independently replace arbitrarily double bond, singly-bound or and containing the heterocyclic radical of oxygen, sulphur, nitrogen, n=0-6, for C=O, C=S or C=NH of independently replacing arbitrarily, C=R b-R a, CHOH, CHOR b, or and CH b, wherein R bc, N, P atom is contained, R for what independently replace arbitrarily afor H, H 2, independently replace arbitrarily straight chain, branched alkane alkyl or and the saturated fatty alkyl independently replaced arbitrarily containing substituent alkyl, a 1-10 carbon, a 1-4 double bond independently replaced arbitrarily, a 1-4 triple bond independently replaced arbitrarily, independently arbitrarily replacement saturated or and unsaturated lipid cyclic group, aromatic base or heterocycle, wherein hydroxyl, halogen radical, oxygen substituting group, nitrogen substituting group, sulphur substituting group, phosphorus substituting group;
Described A 1, A 2, A 3, A 4, A 5, A 6, A 7or and A 8be independently replace arbitrarily containing hydrogen, halogen, oxygen, sulphur, nitrogen or and phosphorus atom formed C-H bond, carbon-carbon bond or and the fatty group of carbon heterodesmic, aromatic base, alicyclic radical, heterocyclic radical, alicyclic heterocyclic base or and fragrant heterocyclic radical, independently replace arbitrarily containing one of glycosyl, hydroxyl, amino acid based, phosphorus acyloxy, acyloxy, phosphate, sulphur acyloxy, alkoxyl group, fragrant oxygen base, heterocyclic oxy group, oxygen base or and its combination; Wherein said glycosyl glycosidic bond is connected with C-C or with C-heteroatomic bond; Containing substituted oxy, oxygen, sulphur, nitrogen or and the substituting group of phosphorus; Comprise 1-8 independently replace arbitrarily glycosyl or and independently replace glycosyl arbitrarily, its glycosyl is the triose, erythrose, five-carbon sugar, the hexose that independently replace arbitrarily, seven carbon sugar, monose, disaccharides, trisaccharide or and polysaccharide-based; Described substituted oxy be independently replace arbitrarily acyloxy, a 1-4 phosphonato, alkoxyl group, aryloxy or and heterocyclic oxy group; Described substituting group is for containing aerobic, sulphur, nitrogen or and phosphorus atom, independently any unsaturated or saturated C replaced 1-10the unsaturated aliphatic hydrocarbyl moiety of alkyl, a 1-4 double bond or triple bond, saturated or unsaturated C 3-10alicyclic radical, non-alicyclic radical, aromatic base or and heterocyclic radical, and the 3-10 introducing oxygen, sulphur, nitrogen or phosphorus atom independently replace arbitrarily carbochain alkyl, aromatic ring, many rings, aliphatic heterocycle, fragrant heterocycle or and fused heterocycle one or a combination set of,
Described is a kind of containing adamantyl or the chain compound with the formation of diamantane similar structures base, it is characterized in that: when forming S-P-T, becomes the compound being listed in form 1 independently replaced arbitrarily.
Described a kind of containing adamantyl or the chain compound with the formation of diamantane similar structures base, come from: the compound of cited embodiment, isomer, steric isomer, prodrug, solvation, medicinal formula or carrier, also comprise the pharmaceutical salts of this derivative and analogue, double salt, inorganic acid salt, organic acid salt, inorganic base salts, organic alkali salt or and double salt.
Described a kind of containing adamantyl or and diamantane similar structures base formed chain compound as cancer treatment method, to cancer patient to needing the described compound reaching treatment significant quantity, comprise cited embodiment, isomer, steric isomer, prodrug, pharmaceutical salts, double salt, the compound of solvation, medicinal formula or and carrier.
Described a kind of containing adamantyl or the chain compound with the formation of diamantane similar structures base, it is characterized in that: described compound has treatment, prevent or and slow down tumour and cancer, treat by virus, bacterium or fungus-causedly to catch, treatment nervous system disorders and the application of disease caused by inflammation.
Described a kind of application containing adamantyl or the chain compound with the formation of diamantane similar structures base, it is characterized in that: be included in the antitumor pharmacologically active of preparation and the application as antitumor drug, described a kind of containing alicyclic radical or the chain compound with adamantyl formation, pharmaceutical salts or and prodrug, its separately or with known antitumor and immune drug with the use of dosage be 0.001mg/kg-250mg/kg, wherein this tumour is from lung cancer, cancer of the stomach, colorectal carcinoma, small cell lung cancer, thyroid carcinoma, the esophageal carcinoma, carcinoma of the pancreas, carcinoma of endometrium, adrenocortical carcinoma, head and neck cancer, osteogenic sarcoma, mammary cancer, ovarian cancer, wilms' tumor, tumor of cervix, carcinoma of testis, apparatus urogenitalis cancer, skin carcinoma, renal cell carcinoma, bladder cancer, primary brain cancer, prostate cancer, soft tissue sarcoma, neuroblastoma, rhabdosarcoma, Kaposi sarcoma, malignant melanoma, malignant pancreatic insulinoma, non-Hodgkin lymphoma, malignant melanoma, multiple myeloma, neuroblastoma, malignant carcinoid carcinomas, choriocarcinoma, acute and lymphocytic leukemia, primary macroglobulinaemia, chronic myelocytic leukemia, lymphocytic leukemia, acute myeloblastic leukemia, hairy cell leukemia, mycosis fungoides, malignant hypercalcemia, hyperplasia of cervix uteri or and Hodgkin's disease.
Described a kind of containing cyclic group or with the chain compound of adamantyl with in the antitumor pharmacologically active of preparation and the application as antitumor drug, it is characterized in that: wherein prepare antitumor pharmacologically active and as the application of antitumor drug and other known antitumor and immune drug with the use of, also organize the pharmacologically acceptable salt of known cancer chemotherapeutic agent, antiviral agent or this reagent with next and use with the one in prodrug or together with it combines, the compound that form 1 is listed with being at least selected from.
Described a kind of containing adamantyl or with the chain compound of diamantane similar structures base formation with in the antitumor pharmacologically active of preparation and the application as antitumor drug, it is characterized in that: wherein prepare antitumor pharmacologically active and as the application of antitumor drug and other known antitumor and immune drug with the use of, also organize known cancer chemotherapeutic agent with next with being at least selected from, the pharmacologically acceptable salt of antiviral agent or this reagent is used with the one in prodrug or together with its combination, comprising: endoxan, vincristine(VCR), busulfan, vinealeucoblastine(VLB), cis-platinum, carboplatin, ametycin, Zorubicin, colchicine, Etoposide, taxol, docetaxel, camptothecine, Hycamtin, white arsenic, 5-ammonia is mixed cytidine, 5 FU 5 fluorouracil, methotrexate, the fluoro-2-deoxidation-uridine of 5-, hydroxyurea, Tioguanine, melphalan, Chlorambucil, ifosfamide, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium acetate, fludarabine, Sostatin, vitamin A acid, tamoxifen, Doxazosin, terazosin, tamsulosin, fluorine pyridol, lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin, fourth is vertical cuts down statin, amprenavir, Abacavir, L 86-8275, ritonavir, Saquinavir, rofecoxib, alanosine, retinene, tretinointocoferil, 13CRA, RETINOIC ACID, alpha-difluoromethyl ornithine, fenretinide, N-4-carboxyl phenyl Viaminate, genistein, cloth is drawn in plug, ara-C, CB-64D, CB-184, ILX23-7553, lactacystin, MG-132, PS-341, Glcevec, ZD1839 (IRessa), SH268, Herceptin, Rituxan, Gamcitabine, ABT-378, AG1776, BMS-232,632, CEP2563, SU6668, EMD121974, R115777, SCH66336, L-778,123, BAL9611, TAN-1813, UCN-01, Roscovitine, Olonoucine or and Valecoxib.
Described a kind of containing adamantyl or and the chain compound that formed of diamantane similar structures base and the application of known drug compatibility, it is characterized in that: administering mode comprises: in oral, parenteral route, subcutaneous, intravenously, intramuscular, intraperitoneal, transdermal, cheek, sheath, in encephalic, nose or and topic route.
Accompanying drawing explanation
Accompanying drawing is that 10 kinds of compounds are to sarcoma S 180restraining effect internal anatomy (the Kun Ming mice inoculation S of growth 180administration 7 days).
Synthesis and preparation
Embodiment
The preparation of test-compound salify
The present invention has following beneficial effect: due to adamantyl or and the dissolving of chain compound in water that formed of diamantane similar structures base DEG C very little, reduce bioavailability, directly affects its antitumour activity, the present invention solves its low water solubility problem for this reason, namely contained amino and carboxyl is utilized to be prepared into corresponding salt, increase its water-soluble after make injection liquid, injection preparation technology of the present invention successfully solves intravenous administration approach, well improve water-soluble and biological utilisation DEG C, also improve anti-tumor activity simultaneously.
1. a certain amount of compound containing amino-substituent is got, quantitatively be dissolved in methyl alcohol, acetone, 4-hydrogen furans or 1, make it to become true solution as dissolved bad suitably can heating on the basis keeping stability of compounds in 4 dioxane, the hydrogen chloride gas slowly having passed into dry at this is warm DEG C under ice-water bath cooling, stirring, until after completely saturated, keep again passing into 5min, be held in reactant salt 1-2h, and by thin-layer chromatography detection reaction, until whole salify, boil off solvent under decompression, be drying to obtain under decompression.
2. a certain amount of compound containing acidic substituent is got, quantitatively be dissolved in methyl alcohol, acetone, 4-hydrogen furans or 1, in 4-dioxane, make it to become true solution as dissolved bad suitably can heating on the basis keeping stability of compounds, cool at ice-water bath, at this is warm DEG C, potassium hydroxide or the sodium hydroxide solution (2N) of equivalent is slowly passed under stirring, until react completely, adjust ph 7-8.5, be held in reactant salt 1-2h, and by thin-layer chromatography detection reaction, until whole salify, boil off solvent under decompression, be drying to obtain under decompression.
To adamantyl or and diamantane similar structures base formed chain compound synthesis and preparation will the present invention will be further described by embodiment; but following embodiment is only the present invention's example wherein; do not limit the protection domain of the claims in the present invention, the protection domain of this claim is as the criterion with claims.
Embodiment synthesis and preparation is illustrated
By following examples, the present invention is described, if do not mentioned, chemical preparation reaction is room temperature.
General formula reaction A (carboxylic esterification)
By the instillation of 6.0mmol alcohol compound containing in the mixture of carboxylic acid cpd 3.20mmol, 1-ethyl-3 (3-dimethyl propylamine) carbodiimide (EDCI) 123mg (6.40mmol), DMAP (DMAP) 0.78g (6.40mmol) and 45ml methyl alcohol, stir the mixture until thin layer detection reaction is complete, reaction mixture is poured in 100ml salt solution, with extraction into ethyl acetate three times, reclaim mixture of organic phase through column chromatography for separation (SiO 2) obtain target product.
General formula reaction B (carboxylic acyloxy amination)
Aminated compounds 1.16mmol is instilled containing carboxylic acid cpd 360mg (0.58mmol), EDCI221mg (1.16mmol), DMAP141mg (1.16mmol), N-hydroxy benzo triazole (HOBT) 78mg (0.58mmol) and 5ml N, in the mixture of N-dimethylformamide (DMF), stir the mixture until thin layer detection reaction is complete, reaction mixture is poured in 100ml salt solution, with extraction into ethyl acetate three times, the lower mixture of organic phase that reclaims of decompression is through column chromatography for separation (SiO 2) obtain target product.
General formula reaction C (nitro hydrogenation)
Add nitro-compound 5mmol, 5% palladium charcoal 1.0g, 20ml methyl alcohol is in 100ml eggplant-shape bottle, and hydrogenation 7h, reduction vaporization methyl alcohol, to 20ml, adds ether, separates out faint yellow solid product, dry target product.
The preparation (see table 1 compound 1, lower same) of embodiment 1
7-hydroxyl-5-[4-(trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-formonitrile HCN (4.00g, 14.98mmol) is added in 100ml flask, phosphorus oxychloride 13ml, back flow reaction 1h, pours into reaction solution in frozen water, filters and obtains chloro thing; By chloro thing (1.60g, 4.93mmol), amantadine (1.04g, 6.90mmol) with salt of wormwood (2.04g, 14.78mmol) 6ml dimethyl sulfoxide (DMSO) (DMSO) is dissolved, and 60 DEG C of reaction 3h, pour into reaction solution in frozen water, filter, obtain white solid, obtain target product with methylene dichloride recrystallization, Mp282 ~ 284 DEG C, IR (KBr, cm -1): 3460,2918,2854,1623,1593,1455,1266,1161,1066; 1h-NMR (300MHz, DMSO-d 6): δ 8.69 (s, 1H), 8.43 (d, J=8.4Hz, 2H), 7.89 (d, J=8.4Hz, 2H), 7.11 (s, 1H), 7.02 (s, 1H), 2.18 (s, 9H), 1.80 (d, J=12Hz, 3H), 1.70 (d, J=12Hz, 3H).
The preparation of embodiment 2
To 100ml eggplant-shape bottle, add 2-(5-nitro-1,3-dioxoisoindole-2-base) acetic acid 7.72g, DMF60ml, Padil 3.30g, 150 DEG C are stirred 5h, are poured into water by reaction mixture, separate out solid target compound; IR (KBr, cm -1): 3248,2918,2836,1773,1691,1638,1623,1560,1515,1430,1412,1354,1281,1251,1233,1155,1114,958,777.
The preparation of embodiment 3
With N-(diamantane-1-base)-2-(5-nitro-1,3-dioxoisoindole-2-base) ethanamide be raw material adopt general formula reaction C obtain target product; IR (KBr.cm -1): 3443,3239,2908,1766,1688,1642,1619,1505,1420,1291,1268,1243,1160,1104; 1h-NMR (300MHz, DMSO-d 6): δ 7.65 (s, 1H), 7.47 (d, J=7.8Hz, 1H), 6.90 (d, J=1.8Hz, 1H), 6.79 (dd, J=1.8Hz, J=8.4Hz, 1H), 6.47 (s,, J=7.8Hz, 2H), 4.01 (s, 2H), 1.98 (s, 3H), 1.88 (br, 6H), 1.58 (m, 6H).
The preparation of embodiment 4
N-(diamantane-1-base)-2-aminopropan acid amides 0.5g (1.5mmo1) is added in 50ml round-bottomed flask, six hydrogen-4,7-epoxyisobenzofuran-1,3-diketone 0.25g (1.5mmo1), triethylamine 0.3g (3.0mmol), toluene 12ml, backflow 2h, obtains target product through column chromatography for separation; IR (KBr, cm -1): 3396,2908,2852,1776,1709,1666; 1h-NMR (300Hz, DMSO): δ 6.68 (s, 1H), 4.68 (s, 2H), 4.39 (q, J=3.6Hz, 1H), 3.01 (s, 2H), 1.97 (s, 3H), 1.85 (s, 6H), 1.63 (s, 4H), 1.58 (s, 6H), 1.32 (d, J=3.6Hz, 3H).
The preparation of embodiment 5
N-(1-azaadamantane-4-base)-2-(2 is added successively in 50ml round-bottomed flask, 2,2-trifluoroacetyl group) propionic acid amide 0.48g (1.5mmol), six hydrogen-4,7-epoxy isoindole-1,3-diketone 0.25g (1.5mmo1), triethylamine 0.3g (3.0mmo1), toluene 12ml, backflow 2h, concentration of reaction solution, obtains target product through column chromatography for separation; IR (KBr, cm -1): 3342,2968,2885,1786,1719,1662; 1h-NMR (300Hz, DMSO): δ 6.78 (s, 1H), 4.54 (s, 2H), 4.32 (q, J=3.6Hz, 1H), 3.03 (s, 2H), 2.25 (m, 6H), 1.94 (s, 2H), 1.62 (s, 4H), 1.46 (s, 6H), 1.21 (d, J=3.6Hz, 3H).
The preparation of embodiment 6
1-azaadamantane-3-amine 0.23g (1.5mmo1) is added successively in 125ml round-bottomed flask, 3a, 4,7,7a-tetrahydrochysene-4,7-epoxyisobenzofuran-1,3-diketone 0.25g (1.5mmol), glycine 0.13g (1.5mmol), DMF12ml, backflow 2h, concentration of reaction solution, obtains target product through column chromatography for separation; IR (KBr, cm -1): 3432,2978,2896,1795,1721,1656.
The preparation of embodiment 7
In 125ml round-bottomed flask, add N-(1-azaadamantane-3-base)-2-(1,3-dioxo-3a, 4,7,7a-tetrahydrochysene-1H-4,7-epoxy isoindole-2 (3H)-Ji) ethanamide 3.57g (10mmo1), trifluoroacetic acid 10ml ether 20ml, potassium hydroxide solution 10ml (40%), stirred at ambient temperature 3h, add saturated anhydrous sodium bicarbonate solution and separate out solid, obtain product through column chromatography for separation; IR (KBr, cm -1): 3452,2905,2886,1772,1735,1622,1534,1452,1366; 1h-NMR (300Hz, DMSO): δ 6.66 (s, 1H), 4.45 (s, 2H), 4.44 (q, J=3.6Hz, 1H), 3.58 (br, 1H), 3.23 (s, 2H), 2.32 (m, 6H), 1.84 (s, 2H), 1.80 (m, 4H), 1.45 (s, 6H).
The preparation of embodiment 8
With 2-(5-nitro-1,3-dioxoisoindole-2-base) acetic acid and diamantane-1-amine for raw material, general formula reaction B is adopted to obtain target product; IR (KBr, cm -1): 3288,2928,1768,1699,1648,1622,1555,1432,1359,1289,1234.
The preparation of embodiment 9
With N-(1-azaadamantane-3-base)-2-(5-nitro-1,3-dioxoisoindole-2-base) ethanamide be raw material adopt general formula reaction C obtain target product, IR (KBr.cm -1) 3433,3269,2928,1769,1698,1644,1620,1543,1420,1287,1233,1150,1103; 1h-NMR (300MHz, DMSO-d 6) δ 8.03 (s, 1H), 7.97 (d, J=7.8Hz, 1H), 7.27 (s, 1H), 6.79 (d, J=7.8,1H), 6.59 (s, 2H), 4.81 (m, 3H), 2.33 (m, 2H), 2.20 (br, 4H), 2.03 (m, 2H), 1.56 (m, 2H), 1.41 (m, 1H), 1.18 (m, 2H).
The preparation of embodiment 10
3-(2,4 dichloro benzene base)-2-methyl-6-phenylpyrazole also [1,5-a] pyrimidine-5 is added in eggplant-shape bottle, 7-diphenol (1.00g, 2.59mmo1), phosphorus oxychloride 4ml, backflow 8h, pours into reaction solution in 50m1 frozen water, obtains white solid; IR (KBr, cm -1): 3426,2961,1615,1551,1384,198,1133,1103,1070; Above-mentioned product (0.50g is added successively in 25ml eggplant-shape bottle, 1.18mmol), amantadine (2.15g, 1.41mmol), salt of wormwood (0.50g, 3.54mmol) and 10M1DMSO, 60 DEG C are stirred 15h, concentration of reaction solution, separate out solid, be separated through silica gel column chromatography and obtain target product, mp164-166 DEG C; IR (KBr, cm -1): 3435,3302,2910,1615,1517,1456,1406,1357,1300,1261,1186,1125,1072; 1h-NMR (300MHz, DMSO-d 6): δ 7.52 (d, J=2.4Hz, 1H), 7.49 (t, J=7.2Hz, 2H), 7.45 (t, J=7.2Hz, 1H), 7.39 (dd, J=7.2Hz, J=1.2Hz, 2H), 7.36 (d, J=8.4Hz, 1H), 7.32 (dd, J=7.2Hz, 2.4Hz, 1H), 5.61 (s, 1H), 2.40 (s, 3H), 1.97 (s, 3H), 1.76 (s, 6H), 1.56 (d, J=12Hz, 3H), 1.49 (d, J=12Hz, 3H).
The preparation of embodiment 11
By 4,5-phenylbenzene-1H-imidazoles (2) (0.30g, 1.36mmol), N-diamantane-2-chlor(o)acetamide (0.30g, 1.36mmol), is dissolved in 3mlDMF, add Anhydrous potassium carbonate (0.56g, 4.09mmol), KI (0.23g, 1.36mmol), 50 DEG C are stirred 10h, reaction solution is poured in frozen water, filter to obtain desired product as white solid, mp211-214 DEG C; IR (KBr, cm -1): 3435,2909,1672,1553,1507; 1h-NMR (300MHz, DMSO-d 6): δ 7.71 (s, 1H), 7.46 (s, 1H), 7.45 (s, 3H), 7.35 (d, 2H), 7.26 (m, 2H), 7.17 (t, 2H), 7.10 (t, 1H), 4.37 (s, 2H), 1.97 (s, 3H), 1.81 (s, 6H), 1.58 (q, 6H).
The preparation of embodiment 12
With 2-(2-(4,5-phenylbenzene-1H-imidazoles-1-base))-N-(dihydroxy ethyl) ethanamide and diamantane-1-formic acid be raw material adopt general formula reaction A obtain target product, mp200-202 DEG C; IR (KBr.cm -1): 3449,2920,1712,1660,1542,1490; 1h-NMR (300MHz, DMSO-d 6): δ 8.05 (br, 1H), 7.74 (s, 1H), 7.44 (t, J=3Hz, 3H), 7.35 (d, J=7.8Hz, 2H), 7.26 (m, 2H), 7.17 (t, J=7.8Hz, 2H), 7.10 (t, J=7.2Hz, 1H), 4,45 (s, 2H), 3.90 (t, J=5.4Hz, 2H), 3.23 (q, J=5.4Hz, 2H), 1.93 (s, 3H), 1.76 (s, 6H), 1.62 (dd, J=12Hz, J=24Hz, 6H).
The preparation of embodiment 13
With 4,5-phenylbenzene-1H-imidazoles-2-base amine and diamantane-1-formic acid be raw material adopt general formula reaction A obtain target product, mp203-206 DEG C; IR (KBr.cm -1): 2905,1654,1384; 1h-NMR (300MHz, DMSO-d 6): δ 11.67 (s, 1H), 10.59 (s, 1H), 7.45 (d, J=7.2Hz, 2H), 7.40 (d, J=7.2Hz, 2H), 7.36 (t, J=7.8Hz, 2H), 7.28 (d, J=7.2Hz, 1H), 7.25 (t, J=7.8Hz, 2H), 7.18 (t, J=7.8Hz, 1H), 2.00 (s, 3H), 2.19 (s, 6H), 1.69 (s, 6H).
The preparation of embodiment 14
With 3-(2,4 dichloro benzene base)-2,7-dimethyl pyrazoles [1,5-a] pyrimidine-6-carboxylic acid and diamantane-1-amine be raw material adopt general formula reaction B obtain target product, IR (KBr, cm -1): 3447,3079,2908,2847,1633,1593,1511,1529,1497,1455,1383; 1h-NMR (300MHz, DMSO-d 6): δ 8.39 (s, 1H), 8.06 (s, 1H), 7.77 (d, J=2.4Hz, 1H), 7.52 (dd, J=7.8Hz, J=2.4Hz, 1H), 7.46 (d, J=7.8Hz, 1H), 2.80 (s, 3H), 2.36 (s, 3H), 2.06 (s, 10H), 1.65 (s, 6H).
The preparation of embodiment 15
With 7-amino-3-(2,4 dichloro benzene base)-2-methylpyrazole, also [1,5-a] pyrimidine-6-first cyanogen and diamantane-1-acid obtain target product for raw material adopts general formula to react B; IR (KBr.cm -1): 3326,2980,2851,2220,1735,1618,1596,1532,1492,1463,1380,1364,1298,1207,1173,1100,1064,996; 1h-NMR (300MHz, DMSO-d 6): δ 10.91 (s, 1H), 8.71 (s, 1H), 7.80 (d, J=1.2Hz, 1H), 7.55 (m, 1H), 7.51 (m, 1H), 2.34 (s, 3H), 2.07 (br, 3H), 2.02 (br, 6H), 1.73 (br, 6H).
The preparation of embodiment 16
With 5-(2-amine ethylamino)-8H-phthalazines, also [1,2-b] quinazoline-8-ketone and diamantane-1-acid obtain target product for raw material adopts general formula to react B; IR (KBr.cm -1): 3329,3068,2901,2849,1675,1630,1530,1485,1467,1449,1384,1342,1316,1278,1237,1178,1139,1126,1036; 1h-NMR (DMSO-d 6, 300MHz): δ 8.89 (dd, 1H, J=1.2Hz, J=7.8Hz), 8.25 (dd, J=1.2Hz, J=7.8Hz, 1H), 8.20 (d, J=8.4Hz, 1H), 7.97 (m, 2H), 7.84 (m, 1H), 7.81 (d, J=7.80Hz, 1H), 7.64 (m, 2H), 7.51 (m, 1H), 3.57 (m, 2H), 3.45 (m, 2H), 1.87 (br, 3H), 1.73 (br, 6H), 1.58 (m, 6H).
The preparation of embodiment 17
By chloro-for 7-3-(2,4 dichloro benzene base)-2,6-dimethyl-5-(4-trifluoromethyl) pyrazolo [1,5-a] pyrimidine (1.41g, 3.00mmol), amantadine (0.54g, 3.60mmol) and salt of wormwood (0.83g, 6.00mmol), be dissolved in THF20ml, 65 DEG C of reaction 20h, pour into reaction solution in frozen water, filter, obtain target product; IR (KBr, cm -1): 3315,2912,1616,1527,1493,1459,1404,1376,1356,1321,1272,1259,1186,1166,1126,1102,1081,1065,1010; 1h-NMR (300MHz, DMSO-d 6): δ 7.72 (d, J=8.4Hz, 2H), 7.68 (d, J=8.4Hz, 2H), 7.52 (d, J=2.4Hz, 1H), 7.36 (d, J=7.8Hz, 1H), 7.28 (dd, J=1.8Hz, J=7.8Hz, 1H), 5.45 (s, 1H), 2.42 (s, 3H), 2.32 (s, 3H), 2.19 (br, 3H), 2.10 (br, 6H), 1.72 (br, 6H).
The preparation of embodiment 18
Eggplant-shape bottle to 100ml adds sodium hydride 0.42g (60%), THF10ml, 0.81g dimethylethanolamine is added under cryosel bath, the THF solution 40ml of N-1-adamantyl-2-chlor(o)acetamide 1.60g (7.00mmol), backflow 3h, reaction solution is poured in frozen water, filter, obtain target product; IR (KBr.cm -1): 3414,3214,3026,2908,2851,1671,1535,1513,1454,1384,1360,1344,1297,1251,1224,1129,1116,1098,1051.996,970,859,815; 1h-NMR (300MHz, DMSO-d 6): δ 10.74 (br, 1H), 7.33 (s, 1H), 3.83 (s, 2H), 3.72 (m, 2H), 3.24 (m, 2H), 2.76 (s, 6H), 1.95 (m, 9H), 1.59 (br, 6H).
The preparation of embodiment 19
With 4-((3,4,5-triacetoxyl group-6-(acetyl-o-methyl)-tetrahydrochysene-2H-pyrans-2-base) oxygen base) phenylformic acid and diamantane-1-amine be raw material adopt general formula reaction B and D obtain target product, IR (KBr, cm -1): 3429,2914,2850,1637,1608,1541,1500; 1h NMR (300Hz, DMSO): δ 7.76 (d, J=8.7Hz, 2H), 7.44 (s, 1H), 7.01 (d, J=8.7Hz, 2H), 5.75 (s, 1H), 4.98 (d, J=3.6Hz, 1H), 4.67 (d, J=7.5Hz, 1H), 4.50 (t, J=5.4Hz, 1H), 3.93 (d, J=3.0Hz, 1H), 3.68 (m, 2H), 2.06 (s, 9H), 1.65 (s, 6H), 1.05-1.06 (br, 4H).
The preparation of embodiment 20
Adamantanamine hydrochloride 12.4g (21mmol) is added in 500ml round-bottomed flask, Boc-L-L-Ala 6.3g (33mmol), EDCI9.5g (49mmol), DMAP4g (32mmol), HOBT4.4g (32mmol), DMF solvent 120ml, stirring at room temperature 3h, poured into by reaction solution in frozen water, filter, silica gel column chromatography is separated and obtains product; In 100ml round-bottomed flask, add upper step synthetic compound 2.5g, trifluoroacetic acid and methylene dichloride mixed solution 11ml (4: 1), stirring at room temperature 10h, pour into reaction solution in frozen water, filters, obtain target product; IR (KBr, cm -1): 3445,3100,2915,2855,1670.
The preparation of embodiment 21
N-(diamantane-1-base)-2-aminopropan acid amides 0.5g (1.5mmo1) is added successively in 50ml round-bottomed flask, six hydrogen-4,7-epoxy isoindole-1,3-diketone 0.25g (1.5mmol), triethylamine 0.3g (3.0mmol), toluene 12ml, backflow 2h, concentration of reaction solution, obtains target product through column chromatography for separation; IR (KBr, cm -1): 3396,2908,2852,1776,1709,1666; 1h NMR (300Hz, DMSO): δ 6.68 (s, 1H), 4.68 (s, 2H), 4.39 (q, J=3.6Hz, 1H), 3.01 (s, 2H), 1.97 (s, 3H), 1.85 (s, 6H), 1.63 (s, 4H), 1.58 (s, 6H), 1.32 (d, J=3.6Hz, 3H).
The preparation of embodiment 22
N-(diamantane-1-base)-2-aminopropan acid amides 0.5g (1.5mmol) is added successively in 50ml round-bottomed flask, 5,6-dibromo six hydrogen-4,7-epoxy isoindole-1,3-diketone 0.48g (1.5mmo1), triethylamine 0.3g (3.0mmol), toluene 10ml, backflow 3h, concentration of reaction solution, carries out column chromatography for separation and obtains target product; IR (KBr, cm -1): 3406,2996,2909,2850,1782,1709,1678; 1h-NMR (300Hz, DMSO): δ 5.32 (s, 1H), 4.99 (t, J=5.4Hz, 1H), 4.92 (d, J=10.5Hz, 1H), 4.62 (q, J=7.2Hz, 1H), 4.39 (m, 1H), 3.99 (t, J=3.0Hz, 1H), 3.82 (t, J=7.5Hz, 1H), 3.12 (t, J=6.6Hz, 1H), 2.07 (s, 3H), 1.95 (m, 6H), 1.70-1.66 (m, 8H), 1.52 (d, J=7.2Hz, 3H).
The preparation of embodiment 23
N-(diamantane-1-base)-2-aminopropan acid amides 0.27g (0.8mmol) is added successively in 50ml round-bottomed flask, Tetra hydro Phthalic anhydride 0.12g (0.8mmol), triethylamine 0.16g (1.6mmo1), toluene 10ml, backflow 3h, concentration of reaction solution, column chromatography for separation obtains target product; IR (KBr, cm -1): 3304,3082,2907,2859,1779,1714,1656,1613,1555; 1h-NMR (300Hz, DMSO): δ 7.84 (m, 4H), 7.32 (s, 1H), 4.64 (q, J=3.6Hz, 1H), 1.97 (s, 3H), 1.89 (s, 6H), 1.56 (s, 6H), 1.54 (d, J=3.9Hz, 3H).
The preparation of embodiment 24
N-(diamantane-1-base)-2-aminopropan acid amides 0.5g (1.5mmol) is added successively in 50ml round-bottomed flask, 4-nitrophthalic acid acid anhydride 0.3g (1.5mmol), triethylamine 0.3g (3.0mmol), toluene 10ml, backflow 3h, concentration of reaction solution, column chromatography for separation obtains target product; IR (KBr, cm -1): 3318,3080,2908,2849,1781,1722,1641,1530,1452,1346; 1h-NMR (300Hz, DMSO): δ 8.62 (dd, J=7.2Hz, 1H), 8.49 (d, J=1.8Hz, 1H), 8.12 (d, J=8.4Hz, 1H), 4.68 (q, J=7.2Hz, 1H), 1.97 (s, 3H), 1.89 (s, 6H), 1.60 (s, 6H), 1.54 (d, J=7.2Hz, 3H).
The preparation of embodiment 25
In 100ml round-bottomed flask, add nitro-compound 0.6g (1.9mmol) successively, palladium carbon 0.6g, tetrahydrofuran (THF) 20ml, passes into H 2, 30 DEG C of reaction 4h, concentration of reaction solution, carries out column chromatography for separation and obtains target product; IR (KBr, cm -1): 3440,3345,2907,2857,1755,1698,1595,1505; 1h-NMR (300Hz, DMSO): δ 7.58 (d, J=7.8Hz, 1H), 7.00 (s, 1H), 6.82 (d, J=7.8Hz, 1H), 5.68 (s, 1H), 4.75 (t, J=6.6Hz, 1H), 4.49 (s, 2H), 2.06 (s, 3H), 1.99 (s, 6H), 1.63 (m, 9H).
The preparation of embodiment 26
1,3-dibromodiamantane 5.0g (17mmol) is added successively, acetone: water=1: 1, mixed solution 50ml, backflow 3h in 250ml round-bottomed flask, suction filtration while hot, filtrate placement is spent the night, and separates out white crystal, obtains target product; IR (KBr, cm -1): 3220,2934,2851,1028.
The preparation of embodiment 27
Compound diamantane glycol 0.5g (3.0mmol) is added successively in 50ml round-bottomed flask, 5-chloro-4-nitrobenzoic acid 1.5g (7.5mmol), EDCI2.3g (12.0mmol), DMAP0.7g (5.7mmol), stirring at room temperature 2h, concentration of reaction solution, carries out column chromatography for separation and obtains target product; IR (KBr, cm -1): 3559,3272,3056,2920,2851,1731,1714,1600,1528; 1h-NMR (300Hz, DMSO): δ 8.57 (d, J=2.4Hz, 1H), 8.23 (q, J=2.4Hz, 1H), 2.42-1.55 (m, 15H).
The preparation of embodiment 28
At 0 DEG C, by containing hydrogenated aluminium lithium (0.02mol/d cm -1) tetrahydrofuran solution, be added drop-wise in the tetrahydrofuran solution containing 1-azaadamantane-4-ketone (0.4mmol), stir 30min, in reaction solution, add frozen water, organic layer separated, obtain target product; 1h-NMR (300Hz, DMSO): δ 3.15 (m, 1H), 2.23 (m, 6H), 1.75 (m, 3H), 1.49 (m, 2H), 124 (m, 2H).
The preparation of embodiment 29
The tetrahydrofuran solution 8ml of bromine triphenyl phosphorus 2.00g (5.6mM) is added drop-wise to butyllithium (3ml, 2.5M, 7.5mM), room temperature reaction, 15min, be added drop-wise in the 15ml tetrahydrofuran solution containing 1-azaadamantane-4-ketone 500mg (3.3mM), room temperature reaction 2h, add water 0.5ml, filters, drying, obtains colourless liquid target product; 1h-NMR (CDCl 3): δ 4.49 (s, 2H), 3.00-3.21 (m, 4H), 3.12 (s, 2H), 2.27 (s, 2H), 1.85-2.04 (m, 4H), 1.63 (s, lH).
The preparation of embodiment 30
1-azaadamantane-4-ketone 3.76g (24.9mmol) is added in 500ml flask, to Methyl benzenesulfonyl methyl isocyanide (6.38g, 32.3mmol) 1，2-ethandiol dme 87ml and ethanol 3.2ml, is cooled to-78 DEG C, drip potassium tert.-butoxide 6.70g (59.7mmol), 40 DEG C are stirred 0.5h, and reaction solution cools, and filter, be separated through Silica hydrogel chromatography after concentrated, obtain target product; 1h-NMR (300MHz, methanol-d 4): δ 2.05-2.46 (m, 6H), 1.21-1.72 (m, 7H).
The preparation of embodiment 31
Under room temperature condition, compound 1-azaadamantane-4-acetonitrile 136mg (0.84mmo1) is added successively in the round-bottomed flask of 50ml, concentrated hydrochloric acid and Glacial acetic acid mixed solution 4ml (1: 1), reaction stirs 14h at 110 DEG C in sealed tube, reaction solution cool to room temperature, concentrated, obtain target product hydrochloride; IR (KBr, cm -1): 3347,2989,2961,2850,1679,1560,1433,1249,1035; 1h-NMR (300MHz, DMSO-d 6): δ 10.32 (s, 1H), 1.22-2.36 (m, 14H).
The preparation of embodiment 32
In the tetrahydrofuran solution 3.8ml of lithium aluminum hydride (3.80mmol), add the 1-azaadamantane-4-acetonitrile (1.231g of 0.41g (2.53mmol), 7.60mmol) tetrahydrofuran solution 6ml, back flow reaction 2h, after cooling, add water 144ml, sodium hydroxide 144ml (15%) removed by filtration aluminium salt precipitates, and obtains pale yellowish oil target product by concentrated for filtrate; IR (KBr, cm -1): 3421,2926,2884,1524,1431,1340; 1h-NMR (300MHz, DMSO-d 6): δ 5.31 (br, 2H), 2.64 (d, J=3.6Hz, 2H), 2.205-2.36 (m, 6H), 1.05-1.62 (m, 8H).
The preparation of embodiment 33
1-azaadamantane formic acid (181mg is added successively in the round-bottomed flask of 50ml, lmmol), ethanol 3ml, the dicyclohexylcarbodiimide 230mg (1.2mmol) of 2 equivalents and DMAP147mg (1.2mmol),) stirring at room temperature 3h, obtain target compound; IR (KBr, cm -1): 3386,2988,1734,1438,1356,1229,1059; 1h-NMR (300MHz, DMSO-d 6): δ 3.86 (q, J=3.6Hz, 2H), 1.13-2.43 (m, 17H).
The preparation of embodiment 34
The tetrahydrofuran solution of compound 1-azaadamantane-ethyl formate 209mg (1mmol) is dripped in the tetrahydrofuran (THF) suspension of lithium aluminum hydride (1mmol), stirring at room temperature 1h, water is added in reaction solution, and the aqueous sodium hydroxide solution of 5%, insolubles is removed by diatomite filtration, with ethyl acetate washing, concentrating under reduced pressure obtains target product; IR (KBr, cm -1): 3434,2938,2868,1434,1268,1135; 1h-NMR (300MHz, DMSO-d 6): δ 3.49 (d, J=3.6Hz, 2H), 2.05-2.36 (m, 7H), 1.35-1.66 (m, 8H).
The preparation of embodiment 35
Sodium borohydride 9.08g (240mmol) aqueous solution 45ml is made solution A; By 2,4,6-trinitrophenol 12.0g (52mmol) sodium hydroxide adds solution 300ml (1.5%) and makes solution B, under room temperature, solution A is added drop-wise in solution B, stir 20min, drip concentrated phosphoric acid and adjust pH value 5.0, filtering-depositing obtains 1, and 3,5-trinitro--1,3,5-methylol hexanaphthene (positive trans isomer), adds 400ml water and stirs 1h, the ammonia soln of 10% of 8.3ml is dripped in suspension, room temperature places 2 days, and throw out obtains target product by distillation, Mp:267.5-268.0 DEG C; IR (KBr, cm -1): 1540,1345; 1h-NMR (300MHz, DMSO-d 6): δ 3.42 (s, 6H), 3.00 (d, J=13Hz, 3H) 2.80 (d, J=13Hz, 3H).
The preparation of embodiment 36
Compound 3 is added successively in 250ml round-bottomed flask, 5,7-triamino-1-azaadamantane 5.0g (27.4mmo1), Virahol 100ml, auspicious mud nickel 0.1g, every 4 h add 1 time, after completion of the reaction, the auspicious mud nickel of filtering, residue re crystallization from toluene obtains target product Mp:87.0-88.0 DEG C; IR (KBr, cm -1): 3350-3010; 1h-NMR (300MHz, DMSO-d 6): δ 2.65 (s, 6H), 1.59 (s, 6H), 2.24ppm (s, 2H).
The preparation of embodiment 37
Compound 3 is added successively in the round-bottomed flask of 50ml, 5,7-tri-bromo-1-azaadamantane 0.55g (3mmol), diacetyl oxide 5.0ml, backflow 3h, add ethanol 5ml, continue backflow 15min, be spin-dried for reaction solution, residue toluene (3 × 3ml) is washed, obtain target product, mp233.0 DEG C; IR (KBr, cm -1): 3240,3040,1740,1640; 1h-NMR (300MHz, DMSO-d 6): δ 2.54-2.81 (m, 6H), 2.12-2.40 (m, 6H).
The preparation of embodiment 38
To the round-bottomed flask of 125ml, add urotropine 1.40g (10mmol) successively, Phloroglucinol compound 2.46g (10mmol), methyl alcohol 30m1, backflow 15h, concentration of reaction solution obtains white solid crude product, and ethyl alcohol recrystallization obtains target product; IR (KBr, cm -1): 3421,2908,1656,1632,1508,1321; 1h-NMR (300MHz, DMSO-d 6): δ 5.32-5.65 (m, 9H), 2.88 (s, 6H), 2.52 (s, 6H).
The preparation of embodiment 39
To the round-bottomed flask of 100ml, add 2,4,6-3-methyl cyclohexanol-1,3-diketone 1.54g (10mmol), urotropine 1.40g (10mmol), methyl alcohol 30ml, backflow 5h, concentration of reaction solution, ethyl alcohol recrystallization obtains white object product; IR (KBr, cm -1): 2970,1720,1685,1455,1375,1330,1205,1125; 1h-NMR (300Hz, CDCl 3): δ 3.45-2.75 (m, 6H), 1.70 (s, 2H), 1.16 (s, 3H), 1.05 (s, 6H).
The preparation of embodiment 40
3-allyl group-7-(methoxymethyl)-3-boron dicyclo [3.3.1]-6-in ninth of the ten Heavenly Stems alkene 2.86g (14.8mmol) is added to 50ml flask; Tetrahydrofuran (THF) (14.80ml, the 14.8mmol) solution of borane, backflow 1h, concentration of reaction solution obtains white crude, and vacuum (0.100mmHg, 70 DEG C) distils, and obtains water white transparency solid target compound, mp89-91 DEG C; 1h-NMR (300Hz, CDCl 3): δ 3.34 (t, J) 6.8,4H), 2.74 (br s, 3H), 2.00 (m, 6H), 1.01 (m, 10H).
The preparation of embodiment 41
To 100ml flask, add 1-azaadamantane-4-ketone 1.51g (10mmol), potassium tert.-butoxide 0.56g (5mmol) tetrahydrofuran (THF) 20ml solution, hydrazine (0.32g, 10mmol) tetrahydrofuran (THF) 10ml solution, stirring at room temperature 1.5h, concentrating under reduced pressure reaction solution, dilutes with water 30ml, extracts by ethyl acetate (3 × 30ml), concentrated organic phase, obtains product; IR (KBr, cm -1): 2986,1642,1358,1264; 1h-NMR (300MHz, DMSO-d 6): δ 2.12-2.56 (m, 6H), 1.32-1.58 (m, 7H).
To 100ml flask, add 1-azaadamantane 1.37g (10mmo1), methyl alcohol 30ml, 35% hydrogen peroxide 10ml, stirring at room temperature 6h, concentrating under reduced pressure reaction solution, dilutes with water 30ml, extracts by ethyl acetate (3 × 30ml), merge organic phase, concentrated, obtain target product; IR (KBr, cm -1): 2988,1686,1324,1258,1105; 1h-NMR (300MHz, DMSO-d 6): δ 3.58 (t, J=3.6Hz, 1H), 2.82 (m, 1H), 1.21-2.3 (m, 10H).
The preparation of embodiment 42
To the round-bottomed flask of 25ml, add 1-azaadamantane-1-oxide compound 30mg (0.2mmol), pyridine 1ml, sulphur phosphide P 4s 1014mg (0.03mmo1), backflow 14h, by reaction solution underpressure distillation to doing to obtain solid crude product, then by solid crude product distillation (55 DEG C), condensation, obtains orange solids target product; HMS (EI/hexanes): obsd167.0759, calcd167.0769; 1h-NMR (300Hz, CDCl 3): δ 1.84 (bs, 1H), 2.16-2.35 (m, 4H), 2.58 (s, 2H), 3.25-3.56 (m, 6H).
The preparation of embodiment 43
To the round-bottomed flask of 250ml, add 2-oxa-diamantane-4-alcohol 4.0g (25.9mmol), acetone 50ml, dripping vitriolated chromic acid solution (8N) presents orange to reaction solution, after continuing to stir 2h, and underpressure distillation, add water 50ml, with ether (2 × 75ml) extraction, evaporate to dryness organic phase obtains solid crude product, and solid crude product distillation obtains target product; 1h NMR (300Hz, CDCl 3): δ 4.10-3.99 (m, 2H), 2.75-1.74 (m, 10H).
The preparation of embodiment 44
To the round-bottomed flask of 250ml, the diethyl ether solution 100ml of plus hydrogenated lithium aluminium 1.0g (26mmol), two rings [3.3.1]-6-in ninth of the ten Heavenly Stems alkene-3-ketone 5g (36.7mmol) again, backflow 8h, in reaction solution, drip 10% aqueous sodium hydroxide solution, filter cake dry ether washs, the concentrated filtrate merged, concentrated cleaning solution, distillation condensation obtains target product, mp157-159 DEG C; IR (KBr, cm -1): 3369,2980,2887,1631,1356,1294; 1h-NMR (300MHz, DMSO-d 6): δ 3.58 (m, 1H), 2.78 (m, 1H), 2.30 (m, 1H), 2.0 (m, 2H), 1.42-1.75 (m, 7H).
The preparation of embodiment 45
Dicyclo [3.3.1] nonane-3 that spent glycol protects is added successively in the round-bottomed flask of 100ml, 7,9-triketone 210mg (1mmo1), methanol solution 30ml, sodium borohydride 38mg (1mmo1), stirs 3h, adds 1 containing 1ml HCl (6N), 4-dioxane solution, stirred at ambient temperature 1h obtains target product; IR (KBr, cm -1): 3431,2988,1664,1356,1201; 1h-NMR (300MHz, DMSO-d 6): δ 3.21 (m, 1H), 1.54-2.36 (m, 11H).
The preparation of embodiment 46
In the round-bottomed flask of 100ml, add compound 1-hydroxyl-2-oxa-diamantane-6-ketone 1M successively, ammonia methanol solution 7N, 5% palladium carbon, after reacting liquid filtering revolves steaming after stirring 12h, obtain target product; IR (KBr, cm -1): 3432,3421,3358,2864,1357; 1h-NMR (300MHz, DMSO-d 6): δ 5.11 (s, 2H), 3.52 (s, 1H), 2.58 (t, J=2.1Hz, 1H), 1.36-2.02 (m, 11H).
The preparation of embodiment 47
Under room temperature condition, in the round-bottomed flask of 100m1, add compound dicyclo [3.3.1] nonane-3,7-diketone 132mg (1.0mmo1) successively, sodium borohydride 42mg (1.1mmo1), methanol solution 50ml, backflow 3h, obtain target product IR (KBr, cm -1): 3345,2986,1432,1350,1114; 1h-NMR (300MHz, DMSO-d 6): δ 3.45 (s, 1H), 2.21 (br, 1H), 1.12-1.64 (m, 12H).
The preparation of embodiment 48
To the eggplant-shape bottle of 500m1, add TRIMETHYL PHLOROGLUCINOL 168mg (1mmo1), urotropine 155mg (1.1mmo1), methyl alcohol 200ml, backflow 48h, cool to room temperature, filters, and washing is separated out solid and obtained target product, mp270-271 DEG C; IR (KBr.cm- 1): 2987,2975,2934,1736,1688; 1h-NMR (300MHz, CDCl 3): δ 1H1.25 (m, 9H), 3.41 (s, 6H).
The preparation of embodiment 49
To m-chloro-benzoic acid peroxide 4.04g (0.02mo1) the dichloromethane solution 40ml of 85%, add N-(dicyclo [3,3,1] ninth of the ten Heavenly Stems-6-alkene-3-base) the dichloromethane solution 40ml of benzamide 4.8g (0.02mo1), stirring at room temperature 18h, adjust in neutral with saturated sodium bicarbonate solution, solution drying concentrates to obtain colourless oil liquid afterwards, ethanol solidifies, and recrystallization obtains target product, mp143-145 DEG C; IR (CHCl 3.cm -1): 3320,2930,2850,1590,1570,1445,1375,1080,1025,970,920,790,735,700; 1h-NMR (CDCl 3): δ 1.18-2.54 (m, 10H), 3.45 (s, lH), 3.80 (m, 2H), 4.75 (m, 1H), 7.34 (s, 5H).
The preparation of embodiment 50
Benzoyl replaces-2-nitrogen adamantanol 2.57g (10mmol) and is dissolved in 25ml THF, add diboron hexahydride THF solution 20ml (1M), backflow 3h, add 6N hydrochloric acid 10ml under cryosel bath cooling, evaporation removing THF, crosses and filters boric acid precipitation, extracted with diethyl ether, ether obtains white crystals after concentrating mutually, is target product, mp94.5-96 DEG C; IR (gm -1): 3340,2930,2850,1500,1455,1360,1150,1080,1035,1000,740,700; 1h-NMR (CDCl 3): δ 1.18-2.33 (m, 11H), 2.67 (m, 2H), 3.81 (s, 2H), 4.00 (m, 1H), 7.24 (br, s, 5H).
The preparation of embodiment 51
Benzyl replaces adamantanol 0.73g (0.003mo1) and is dissolved in 50ml ethanol, add the 5% palladium carbon catalysis of 100mg, pass into hydrogen, filter after completion of the reaction, the unhindered amina of gained is dissolved in ethanol, adds the ethanol of the oxalic acid of equivalent, add ether and separate out oxalate precipitation, pure target product is obtained, mp172-175 DEG C (decomposition) with Virahol-Diethyl ether recrystallization; IR (cm -1): 3500-3100,2900,2850,1640,1580,1460,1060,1025.
The preparation of embodiment 52
By 4-hydroxyl-2-aza-adamantane-2-base) benzophenone 2.57g (0.01mo1) is dissolved in 20ml pyridine, add valency benzene sulfonyl chloride 1.91g (0.01mol), room temperature reaction 14 days, adding after hydrochloric acid makes pyridine salify pours in frozen water, dichloromethane extraction, organic phase drying concentrates to obtain colorless oil afterwards, obtains solid target compound, mp100.5-102.5 DEG C through recrystallization; IR (cm -1): 3010,2940,2880,1640,1595,1460,1420,1375,1360,1290,1185,1170,980,960,860,810,720,700; 1h-NMR (CDCl 3): δ 1.40-2.40 (m, 10H), 2.47 (s, 3H), 3.90 (m, 1H), 4.68 (m, 2H), 710-800 (m, 9H).
The preparation of embodiment 53
Pyridine 1.9g (0.024mo1) is dissolved in 30ml methylene dichloride, add chromium trioxide 1.2g (0.012mol), stir 15min, tosic acid (N-benzoyl-2-aza-adamantane-4-alcohol radical) ester 0.514g (0.002mo1) dichloromethane solution 10ml is added in above-mentioned solution, separate out black precipitate, add extracted with diethyl ether, organic phase is concentrated obtains lark oily target product; IR (cm -1): 3050,2925,2860,1730,1620,1575,1450,1410,1345,1310,1245,1095,1075,1055,1030,975,790,720,700; 1h-NMR (CDCl 3): δ 1.77-2.50 (m, 10H), 2.75 (m, 1H), 4.50 (br, 1H), 7.40 (s, 5H).
The preparation of embodiment 54
Take 1,4-dioxa volution [4,5] certain herbaceous plants with big flowers-8-base methylamine 8.55g (0.05mol), is dissolved in 20ml ethanol, is slowly added drop-wise in the sulfuric acid 1L solution of micro-paraformaldehyde 7.0g and 2% boiled, backflow 24h, cooling, alkalizes with 10N sodium hydroxide solution 80ml, with dichloromethane extraction twice, merge organic phase, pillar layer separation obtains white crystal target product; IR (KBr, cm -1): 3332,2977,1657,1408,1321,1174; 1h-NMR (300MHz, DMSO-d 6): δ 2.38-2.52 (m, 5H), 1.72-2.33 (m, 8H).
The preparation of embodiment 55
1-nitrogen diamantane ketone 17.1g (0.113mol) ethanolic soln 280ml is added pyridine 9.17ml (0.113mol) and oxammonium hydrochloride 11.0g, backflow 17h, concentrated reaction solution, with chloroform extraction, after concentrated, recrystallization obtains target product; IR (KBr.cm -1): 3190,3065,1662,1447,932; 1h-NMR (300MHz, CDCl 3): δ 9.32 (s, 1H), 3.47 (s, 1H), 3.36-.3.11 (m, 6H), 2.47 (s, 1H), 2.16 (m, 2H), 2.04 (m, 2H), 1.79 (s, 1H).
The preparation of embodiment 56
The THF solution 300ml of Z-1-nitrogen heterocyclic diamantane-4-ketone azanol 17.7g (0.107mol) is dripped in the THF solution 128ml (0.128mol) of lithium aluminium hydride, backflow 15h, cool to room temperature, drip, 20ml water, filter, merging filtrate, reduction vaporization goes out desolventizing and obtains lark target product; IR (KBr, cm -1): 3445,3432,2986,1432,1345,1125; 1h-NMR (300MHz, DMSO-d 6): δ 5.12 (br, 2H), 2.55 (t, J=2.7Hz, 1H), 2.30 (d, J=3.0Hz, 6H), 1.36-1.64 (m, 7H).
The preparation of embodiment 57
By dicyclo [3.3.1] nonane-3,7-diketone 3.0g (20mmol) and ammonium acetate 15.4g (0.199mol) is dissolved in 90ml methyl alcohol, add boron sodium cyanide 0.868g (13.8mol), stirring at room temperature 2 days, drip 12N hydrochloric acid and be adjusted to acidity, solvent removed by evaporation at reduced pressure, dichloromethane extraction, solvent removed by evaporation at reduced pressure must obtain target product through recrystallization; Mp254-257 DEG C; IR (KBr, cm -1): 3345,3209,2920,1432,1230,1120; 1h-NMR (300MHz, DMSO-d 6): δ 3.78 (br, 1H), 2.57 (m, 1H), 1.75 (m, 4H), 1.55 (m, 5H), 1.36 (m, 3H).
The preparation of embodiment 58
Thionyl chloride 12.5ml is added to 1-hydroxyl-2-nitrogen diamantane 1.159g (7.575mmol), backflow 1h, the thionyl chloride that decompression removing is excessive, adds methylene dichloride 65ml, water 130ml, 50% aqueous sodium hydroxide solution regulator solution is strong basicity, decompression removing organic phase solvent obtains target product 1.20g, productive rate 93%, mp90-94 DEG C (1it.mp97-98 DEG C), IR (KBr, cm -1): 3329,2923,2845,1440,1342,1201,1105; 1h-NMR (300MHz, DMSO-d 6): δ 2.53 (m, 1H), 1.85 (m, 2H), 60 (m, 4H), 1.49 (m, 3H), 1.36 (m, 3H).
The preparation of embodiment 59
Glycol dimethyl ether to 1-chloro-2-nitrogen diamantane 1.495g (8.717mmol) adds the ethylene glycol dimethyl ether solution of containing hydrogenated lithium aluminium 0.536g (14.1mol), reflux 2 days, decompression removing glycol dimethyl ether, ether 0.54ml is added in mixture, water 1.6ml15% aqueous sodium hydroxide solution 0.54ml, decompression removing extraction liquid obtains brown solid, dissolution of solid is in 50ml methylene dichloride, 2N hydrochloric acid, dichloromethane extraction, removal of solvent under reduced pressure obtains desired product as white solid, mp224-227 DEG C; 1h-NMR (300MHz, CDCl 3): δ 1.5-2.2 (m, 12H), 2.45-2.75 (br, 1H), 2.90-3.25 (br, 2H).
The preparation of embodiment 60
The methanol solution of 2-nitrogen diamantane 0.551g (4.02mmol), drip oxyethane 0.200g (4.5mmo1) at 0 DEG C, stirring at room temperature 24h, obtains brown oil after removal of solvent under reduced pressure, add ether and separate out solid target compound, mp45-48 DEG C; IR (KBr.cm -1): 3370,2998,1060; 1h-NMR (300MHz, CDCl 3): δ 1.35-2.30 (m, 12H), 2.65-3.05 (m, 4H), 3.45 (t, J=5Hz, 2H).
The preparation of embodiment 61
At 0 DEG C, thionyl chloride 5:187g (43.6mmol) is added drop-wise in 350mg (1.90mol) 2-(azaadamantane-2-base) ethanol, backflow 2.5h, the thionyl chloride that decompression removing is excessive, obtain brown crude product, target product hydrochloride is obtained, mp232-233 DEG C (decomposition) through recrystallization; IR (KBr.cm -1): 2560,2485,1100; 1h-NMR (300MHz, CDCl 3): δ 1.50-3.15 (m, 13H), 3.35-3.82 (m, 4H), 4.19 (t, J=5.5Hz, 2H).
The preparation of embodiment 62
To 1,3-bis-(3,4,5-trimethoxyphenyl) acetone (1.9g, 0.005mol) adds paraformaldehyde (0.94g, 0.025mol), ammonium acetate (0.77g, 0.01mo1), anhydrous alcohol solution 5ml, backflow 5h, reaction mixture is placed into refrigerator and cooled but spend the night, crystallize out, obtains target product, mp:231-232 DEG C; IR (KBr, cm -1): 2960,2860,1710,1624,1543,1456,1384,1286,1211,1102; 1h-NMR (300MHz, CDCl 3): δ 6.50 (s, 4H), 3.83 (s, 18H), 3.43 (s, 2H), 2.84 (m, 8H).
The preparation of embodiment 63
To 1, two (4-nitro-3-hydroxy phenyl) third-2-ketone (1.66g of 3-, 0.005mol) add paraformaldehyde (0.94g, 0.025mol), ammonium acetate (0.77g, 0.01mol), dehydrated alcohol 5ml, backflow 5h, is placed into refrigerator and cooled by reaction mixture and but spends the night, crystallize out, obtains target product; 1h-NMR (300MHz, CDCl 3): δ 8.02 (s, 2H), 7.52 (d, J=7.5Hz, 2H), 7.13 (d, J=7.5Hz, 4H), 4.73 (m, 2H), 2.87 (m, 8H).
The preparation of embodiment 64
To 1, two (4-(4-hydroxyl-3-nitro-phenoxy) phenyl) third-2-ketone (2.58g of 3-, 0.005mole) add paraformaldehyde (0.94g, 0.025mole), ammonium acetate (0.77g, 0.01mole), dehydrated alcohol 5ml, backflow 5h, is placed into refrigerator and cooled by reaction mixture and but spends the night, crystallize out, obtains target product; 1h-NMR (300MHz, CDCl 3): δ 8.05 (d, J=7.5Hz, 2H), 7.32 (d, J=7.5Hz, 4H), 7.26 (d, J=7.5Hz, 4H), 6.95 (s, 2H), 6.77 (d, J=7.5Hz, 2H), 4.73 (m, 2H), 2.87 (m, 8H).
The preparation of embodiment 65
To 1, two (4-nitro-3-hydroxy phenyl) third-2-ketone (1.66g of 3-, 0.005mole) add paraformaldehyde (0.94g, 0.025mole), ammonium acetate (0.77g, 0.01mole), dehydrated alcohol 5ml, backflow 5h, is placed into refrigerator and cooled by reaction mixture and but spends the night, crystallize out, obtains target product; 1h-NMR (300MHz, CDCl 3): δ 8.02 (s, 2H), 7.52 (d, J=7.5Hz, 2H), 7.13 (d, J=7.5Hz, 4H), 4.73 (m, 2H), 2.87 (m, 8H).
The preparation of embodiment 66
Ammonium acetate (129g, 1.67mol) ethanol 200ml is added, Nitromethane 99Min. (33.3g to 500ml flask, 0.544mol), paraformaldehyde (111g, 3.70mol), backflow 1h, obtains target product, mp305-310 DEG C by cold for the white crystal of generation washing with alcohol; 1h-NMR (300MHz, DMSO-d 6): δ 2.74-2.91 (br, 6H), 3.44 (m, 6H).
The preparation of embodiment 67
Ethanol 175ml is added to 7-nitro-1,3,5-tri-nitrogen diamantane (46.1g, 0.25mol), add 5% palladium carbon 8.0g, logical hydrogen reducing reaction 13h under 12-25 normal atmosphere, reduction vaporization filtrate obtains target product, m.p.216-219 DEG C, IR (KBr, cm -1): 2920,1519,1453,1370,1336,1306,1237,1078,997 1h-NMR (300MHz, DMSO-d 6): δ 5.11 (br, 2H), 3.44 (m, 6H), 2.67 (m, 3H), 2.42 (m, 3H).
The preparation of embodiment 68
Valeraldehyde (17.2g is added to amino-1,3, the 5-tri-nitrogen diamantane (30.8g, 0.2mol) of 7-, 0.2mol), ethanol 150ml, platinum oxide 0.7g, hydrogen reducing 1h under 25 normal atmosphere, filter, filtrate evaporated under reduced pressure is done, and obtains target product, m.p119-120 DEG C; IR (KBr.cm -1): 3300; 1h-NMR (300MHz, CDCl 3): δ 4.44,4.08 (J=12Hz, 6H), 3.29 (s, 6H), 2.56 (m, 2H), 1.33 (m, 7H), 0.90 (m, 3H).
The preparation of embodiment 69
DMAP (0.61g is added to 2-(5-nitro-1,3-dioxoisoindole-2-base) acetic acid (1.38g, 5.53mmol), 4.90mmol), EDCI (1.92g, 10.00mmol), HOBT (0.68g, 5.00mmol), 1,3,5 triazaadamantane-7-amine (0.785g, 5.10mmol), THF25ml, 45 DEG C are stirred 5h, add in 100ml water, extraction into ethyl acetate, crude product, this product is directly used in the next step; To the eggplant-shape bottle of 100ml, add above-mentioned product 1.20g, add methylene dichloride 30ml, palladium carbon 1.0g, logical hydrogen, reaction 4h, filters to obtain target product; IR (KBr.cm -1): 3443,3239,2908,1766,1688,1642,1547,1402,1268,1160,1104,951; 1hNMR (300MHz, DMSO-d 6): δ 8.0 (b, 1H), 5.12 (d, J=7.8Hz, 2H), 4.69 (d, J=1.8Hz, 1H), 4.09 (dd, J=1.8Hz, J=8.4Hz, 2H), 3.43 (m, J=7.8Hz, 6H), 3.01 (m, 1H), 2.89 (m, 1H), 2.67 (m, 1H), 2.54 (m, 4H), 2.42 (m, 1H), 1.92 (m, 1H), 1.67 (m, 1H).
The preparation of embodiment 70
To 7-amino-1,3,5-tri-nitrogen diamantane (1.54g, 0.01mol) adds 25% glutaraldehyde water solution (4.0g, 0.01mol), ethanol 200ml, platinum oxide 0.2g, hydrogen reducing 3h under 25 DEG C of 25 normal atmosphere, filter, filtrate evaporated under reduced pressure is done, and normal hexane recrystallization is dry obtains target product, m.p166-172 DEG C; 1h-NMR (300MHz, CDCl 3): δ 4.44,4.06 (J=12Hz, 6H), 3.44 (s, 6H), 2.60 (m, 4H), 1.49 (m, 6H), δ 4.44,4.08 (J=12Hz, 6H), 3.29 (s, 6H).
The preparation of embodiment 71
To volution [dicyclo [3,3,1] nonane-3,2-Oxyranyle]-7-ketone (1.01g, 6.1mmol) add water 25ml, 70% perchloric acid (0.25ml), stirring at room temperature 3h, drips saturated solution of sodium bicarbonate neutralization, then chloroform extraction (3x20ml) is used, merge organic phase, concentrate and obtain colorless microcrystalline powder target product, mp114-116 DEG C; IR (KBr.cm -1): 3350 (s), 3220,2930,2910,2870,1370,1340,1140,1075,1045,1015; 1h-NMR (300MHz, CDCl 3): δ 1-38 (d, J=12.3Hz, 2H), 1.72-1.81 (m, 8H), 2.36 (br s, 2H), 2.89 (br, 1H), 3.41 (s, 2H), 3.89 (br, 1H).
The preparation of embodiment 72
To Cerous chloride heptahydrate (27.4g, 73.5mmol) add tetrahydrofuran (THF) 365ml, stirring at room temperature 2h, be cooled to-78 DEG C, adding methyl-magnesium-bromide 19.5ml (58.5mmol). mixture drips volution [dicyclo [3 after-78 DEG C of reaction 1h, 3,1] nonane-3,7,9-triketone (5.00g, 23.8mmol) THF solution 100ml, is raised to room temperature reaction 12h by reaction mixture, add the ammonium chloride solution 190ml of protection, isolate organic phase, concentrating under reduced pressure, white crude obtains desired product as white solid through recrystallization, mp143-144 DEG C; 1h-NMR (300MHz, CDCl 3): δ 1.21 (s, 3H), 1.61 (b, d, J ≈ 12.8Hz, 2H), 1.66 (d, J=12.2Hz, 2H), 1.83 (d, J=12.8Hz, 2H), 2.07 (s, 2H), 2.13 (d, J=12.2Hz, 2H), 3.82 (s, 1H), 3.96-3.99 (m, 4H);
The preparation of embodiment 73
To ketal oxo adamantane compound (5.12g, dioxane solution 500ml 22.7mmol), add 2N HCl145ml, backflow is spent the night, concentrating under reduced pressure, 100ml water is added in resistates, dichloromethane extraction (5 × 200ml), merge organic phase, removal of solvent under reduced pressure obtains brown solid crude product, silica gel column chromatography is separated to obtain white product, mp156-158 DEG C; 1h-NMR (300M Hz, CDCl 3): δ 1.32 (s, 3H), 1.95 (d, J=13.2Hz, 2H), 2.01 (d, J=13.2Hz, 2H), 2.05 (d, J=12.4Hz, 2H), 2.22 (d, J=12.4Hz, 2H), 2.73 (b, 2H), 4.28 (s, 1H).
The preparation of embodiment 74
Oxammonium hydrochloride (5.04g is added in flask, 72.5mmo1), sodium carbonate 61.8mmol, salt of wormwood 47.5mmol, diamantane ketone (2.58g, 14.2mmol) with Isosorbide-5-Nitrae-dioxane solution 85ml, backflow is spent the night, filter, decompression removing filtrate, obtains white solid target, mp225-226 DEG C; IR (KBr.cm -1): 3364,1664; 1h-NMR (300MHz, CDCl 3): δ 1.19 (s, 3H), 1.64 (ddd, J=13.0Hz, J=3.5Hz, J=1.0Hz, 1H), 1.67 (ddd, J=13.0Hz, J=3.5Hz, J=1.5Hz, 1H), 1.74 (ddd, J=13.0Hz, J=J=3.0Hz, 1H), 1.76-1.84 (m, 4H), 1.87 (dddd, J=12.0Hz, J=J=3.0Hz, J=1.0Hz, 1H), 2.78 (m, 1H), 3.80 (m, 1H), 4.84 (s, 1H).
The preparation of embodiment 75
Methanol solution 40ml to six hydration Nickel Chlorides (494mg, 2.08mmol) adds sodium borohydride (236mg, 6.24mmo1), oxo diamantane oxime (820mg, methanol solution 10ml 4.16mmol), then add sodium borohydride (552mg, 14.6mmo1), stirring at room temperature 1h, diatomite filtration, filtrate decompression is except desolventizing, and the green solid obtained obtains the mixture of two kinds of isomer through recrystallization, be target product, mp164-166 DEG C; IR (KBr.cm -1): 3600-2400; 1h-NMR (300MHz, CDCl 3): δ 2.61-2.92 (m, 1H), 1.64-1.72 (m, 2H), 1.50-1.64 (m, 3H), 1.30 (s, 3H), 1.10-1.35 (m, 5H).
The preparation of embodiment 76
Concentrated nitric acid 2.5ml is added to 100ml flask, 2-oxo diamantane (270mg, 2mmole), 60 DEG C of reaction 1.5h, reduction vaporization removing nitric acid, add water (1ml) and the vitriol oil (96%, 0.4ml), be heated to 100 DEG C and stir 1h, 30% sodium hydroxide solution neutralizes this solution, chloroform extraction, organic phase obtains crude product through removal of solvent under reduced pressure after merging, and aluminium sesquioxide column chromatography for separation obtains target product; IR (KBr.cm -1): 3220-35,1075,1020; 1h-NMR (300MHz, CDCl 3): δ 3.32-3.68 (m, 2H), 1.06-1.85 (m, 11H).
The preparation of embodiment 77
To 100ml flask ice acetic acid 4.2ml, 2-oxo diamantane 300mg (2.2mmol) and lead tetraacetate 1.3g (2.9mmol), backflow 20h, extracted with diethyl ether, oily crude product is obtained after solvent removed by evaporation at reduced pressure, aluminium sesquioxide column chromatography (chloroform-normal hexane, 1: 1) is separated and obtains target product, mp153-156 DEG C; IR (KBr.cm -1): 1745,1250,1075,1020; 1h-NMR (300MHz, CDCl 3): δ 3.35-3.62 (m, 2H), 2.21 (s, 6H), 1.12-1.80 (m, 10H).
The preparation of embodiment 78
Take diacetyl oxo diamantane 130mg, be dissolved in 10ml ethanol, add potassium hydroxide 60% aqueous solution of 6 times amount, back flow reaction 2h obtains product, mp313-315 °; IR (KBr.cm -1): 3200-3500,1075,1020; 1h-NMR (300MHz, CDCl 3): δ 4.40-5.22 (br, 2H), 3.32-3.64 (m, 2H), 1.12-1.80 (m, 10H).
The preparation of embodiment 79
Bromine 3ml is added, 2-oxo diamantane 200mg (1.5mmol) and alchlor 300mg, 60 DEG C of reaction 80h to 100ml flask, reaction mixture cool to room temperature, adds tetracol phenixin 5ml, crosses and filters precipitation, concentrated filtrate obtains target product through column chromatography for separation, mp113 DEG C; IR (KBr.cm -1): 1050,1020; 1h-NMR (300MHz, CDCl 3): δ 6.02 (m, 1H), 3.32-3.64 (m, 2H), 1.10-1.70 (m, 10H).
The preparation of embodiment 80
Add dicyclo [3.3.1] nonane-3,7-diketone (6.00g, 39.4mmol) anhydrous THF200ml to 100ml flask, benzylamine (4.29g, 40.0mmo1), backflow 30min, under cryosel bath cooling, drip LiAlH 4the diethyl ether solution 80ml of (3.00g, 79.0mmol), room temperature reaction 6h, drip the sodium hydroxide solution (19ml) of 1N, diatomite filtration removing precipitation, filtrate is through decompression removing, obtain oily crude product, recrystallization obtains target product, mp257-259 DEG C; IR (KBr cm -1): 2927,2712,2408,2377,1569,1323,1206,1194,1126,1093,1008; 1h-NMR (300MHz, CD 3oD): δ 1.78 (d, J=12.5Hz, 2H), 1.90 (dquint, J=14.0Hz, J=2.5.Hz, 1H), 1.97 (dtt, J=14.0Hz, J=2.5Hz, J00=1.5Hz, 1H), 2.01-2.06 (m, 4H), 2.14 (d, J=11.5Hz, 2H), 2.40 (b, 2H), 4.26 (s, 2H), 4.39 (b, 1H), 4.86 (1H), 7.42-7.49 (m, 3H) 7.50 (m, 2H).
The preparation of embodiment 81
Add dicyclo [3.3.1] nonane-3,7-diketone (3.00g, 19.7mmol) THF100ml to 500ml flask, phenylethylamine (2.55g, 21.1mmo1), backflow 30min, under cryosel bath cooling, drip LiAlH 4(3.00g, diethyl ether solution (80ml) 79.0mmol), 40 DEG C of stirring reaction 6h, cryosel bath is lower drips sodium hydroxide solution 19ml (1N), diatomite filtration removing precipitation, filtrate evaporated under reduced pressure obtains oily crude product except desolventizing, obtains target product, mp256-259 DEG C through recrystallization; IR (KBr.cm -1): 2934,2855,2721,2674,2617,2419,1604,1467,1455,1324,1209,1192,1093,1018,1001,784,725,698; 1h-NMR (300MHz, CD 3oD): δ 1.74 (d, J=14.0Hz, 2H), 1.87 (d, J=13.0Hz, J=2.5Hz, 1H), 1.95 (overlapped d, 1H), 1.96-2.03 (m, 4H), 2.06 (d, J=11.0Hz, 2H), 2.38 (b, 2H), 2.99 (m, 2H), 3.28 (m, 2H), 4.33 (b, 1H), 4.86 (b, active-H), 7.27 (t, J=7.5Hz, 1H), 7.29 (d, J=7.5Hz, 2H), 7.35 (t, J=7.5Hz, 2H).
The preparation of embodiment 82
1-benzyl-2-oxo adamantane hydrochloride (838mg is added to 100ml flask, 3.00mmol) acetonitrile 20ml, 37% formalin (2.36ml, 30mmol) and sodium cyanoborohydride (595mg, 9.00mmol), stirring at room temperature 30min, adds 0.6ml glacial acetic acid, stirring at room temperature 2h, concentrated reaction mixture, add 2N aqueous sodium hydroxide solution 30ml, dichloromethane extraction (3 × 45ml), concentrating under reduced pressure obtains desired product as white solid; IR (KBr.cm -1): 2929,2897,2838,1456,1442,1381,1323,1190,994,972,957,856,747; 1h-NMR (300MHz, CD 3oD): δ 1.55 (d, J=13.5Hz, 2H), 1.67 (b, J=12.0Hz, 2H), 1.78 (d, J=13.5Hz, 1H), 1.82 (d, J=13.5Hz, 1H), 1.90 (d, J=13.5Hz, 2H), 2.16 (d, J=12.0Hz, 2H), 2.26 (b, 2H), 2.29 (s, 3H), 3.81 (s, 2H), 4.17 (br, 1H), 4.86 (br, 1H), 7.19 (t, J=7.5Hz1H), 7.28 (t, J=7.5Hz, 2H), 7.32 (d, J=7.5Hz, 2H).
The preparation of embodiment 83
1-ethyl-2-oxo diamantane (257mg, 1.00mmol) acetonitrile 10ml is added, 37% formalin (0.78ml to 100ml flask, 10mmol) with sodium cyanoborohydride (188mg, 3.00mmol), stirring at room temperature 30min, adds glacial acetic acid 0.3ml, continue stirring at room temperature reaction 2h, reaction mixture is concentrated dry, adds 2N aqueous sodium hydroxide solution 10ml, dichloromethane extraction (3 × 15ml, concentrating under reduced pressure obtains desired product as white solid, IR (KBr.cm -1): 2956,2596,1481,1467,1411,1210,1027,996, 1h-NMR (300MHz, CD 3oD): (free alkali) δ 1.54 (d, J=13.0Hz, 2H), 1.59 (d, J=12.0Hz, 2H), 1.74 (d, J=13.0Hz, J=2.0Hz, 2H), 1.80 (d, J=13.0Hz, J=2.0Hz, 2H), 1.88 (d, J=13.0Hz, 2H), 2.07 (d, J=12.0Hz, 2H), 2.23 (br, 2H), 2-47 (s, 3H), 2.79 (m, 2H), 2.89 (m, 2H), 4.14 (br, 1H), 4.86 (br, mobile H), 7.18 (t, J=7.5Hz, 1H), 7.20 (d, J=7.5Hz, 2H), 7.27 (t, J=7.5Hz, 2H).
The preparation of embodiment 84
Benzyl methyl oxo diamantane (765mg is added to 250ml flask, 2.97mmol), 10% palladium carbon (200mg), dehydrated alcohol 80ml, at 38 normal atmosphere, 100 DEG C of hydrogenolysis 24h., reaction mixture filters, merge ethanol phase, evaporating ethanol, recrystallization obtains target product hydrochloride, mp226-230 DEG C; IR (KBr.cm -1): 2928,2856,2750,2694,2416,2372,1467,1209,1157,1097,1078,1023,998; 1h-NMR (300MHz, CD 3oD): δ 1.75 (d, J=12.5Hz, 2H), 1.88 (d, J=13.0Hz, J=2.5Hz, 1H), 1.95 (m, 1H), 1.97 (m, 4H), 1.99 (m, 2H), 2.39 (b, 2H), 2.64 (s, 3H), 4.33 (b, 1H), 4.86 (br, active-H).
The preparation of embodiment 85
Benzyl-2-oxo adamantane hydrochloride (2.20g is added to 500ml flask, 7.87mmol), 10% palladium carbon (100mg) and dehydrated alcohol 300ml, at 38 normal atmosphere, 100 DEG C of hydrogenolysis 24h., reaction mixture filters, merge ethanol phase, solvent removed by evaporation at reduced pressure, obtains free alkali, and after free alkali adds saturated hydrogen chloride methanol solution, evaporation is dry, then recrystallization obtains target product hydrochloride, mp>218 DEG C (dec.); IR (KBr.cm -1): 3034,2945,2851,2789,2744,2697,2631,2563,1578,1502,1384,1359,1329,1304,1211,1156,1016,996; 1h-NMR (300MHz; CD 3oD): δ 1.74 (d, J=13.0Hz, 2H), 1.86 (d, J=13.5Hz, J=2.5Hz, 1H), 1.95 (m, 1H), 1.96 (s, 4H), 1.98 (m, 2H), 2.35 (br, 2H), 4.28 (br, 1H), 4.86 (br, active-H).
The preparation of embodiment 86
Benzyl-2-oxo adamantane hydrochloride (280mg, 1.00mmol) is added, salt of wormwood (690mg to 100ml flask, 5.00mmol), benzyl chlorine (0.14ml, 1.25mmol), sodium iodide (50mg, 0.33mmol) and acetonitrile 10ml, backflow 18h, cool to room temperature, add methylene dichloride 20m1, filter, concentrating under reduced pressure, crude product re-crystallizing in ethyl acetate obtains target product, mp155-157 DEG C; IR (KBr.cm -1): 2932,2922,2851,1600,1493,1449,1382,1321,1198,1158,1122,986; 1h-NMR (300MHz, CD 3oD): δ 1.54 (d, J=12.5Hz, 2H), 1.59 (d, J=12.0Hz, 2H), 1.72 (d, J=12.5Hz, 1H), 1.76 (br, J=12.5Hz, 1H), 1.90 (d, J=12.5Hz, 2H), 2.14 (d, J=12.0Hz, 2H), 2.18 (br, 2H), 4.01 (s, 4H), 4.21 (br, 1H), 4.86 (br, active-H), 7.12 (t, J=7.5Hz, 2H), 7.20 (t, J=7.5Hz, 4H), 7.30 (d, J=7.5Hz, 4H).
The preparation of embodiment 87
Hydroxyl oxygen is added for diamantane (10.5g to 100ml flask, 62.5mmol), anhydrous hydrazine (68.5ml, 98%aq solution, 1.38mol), concentrated hydrochloric acid (2.2ml), backflow 18h, reaction mixture cryosel bath cooling, produce precipitation, filter, methanol/ether recrystallization obtains target product hydrochloride, mp181-183 DEG C; IR (KBr.cm -1): 3180,2923,2681,1690,1611,1528,1509,1497,1383,1106,1077,943,839; 1h-NMR (300MHz, CD 3oD): δ 1.16 (s, 3H), 1.60 (d, J=13.5Hz, 2H), 1.63 (m, 2H), 1.66 (m, J=12.5Hz, 2H), 1.74 (d, J=12.5Hz, 2H), 1.79 (m, 2H), 2.31 (m, 2H), 4.86 (s, active-H).
The preparation of embodiment 88
To 500ml flask oxygenation for diamantane hydrazine hydrochloride (6.70g, 30.6mmol), platinum dioxide (20mg) and dehydrated alcohol 200ml, room temperature hydrogenolysis 4 days, concentrating under reduced pressure solvent, recrystallizing methanol obtains product hydrochloride salt, mp268-269 DEG C; IR (KBr.cm -1): 2966,2924,2852,1582,1516,1379,1235,1060,1038,1005; 1h-NMR (300MHz, CD 3oD): δ 1.18 (s, 3H), 1.66 (d, J=14.0Hz, 2H), 1.70 (d, J=14.0Hz, 2H), 1.81 (m, 2H), 1.85 (d, J=11.5Hz, 2H), 1.90 (dd, J=11.5Hz, J=2.5Hz, 2H), 2.38 (b, 2H), 4.86 (s, active-H).
The preparation of embodiment 89
To 100ml flask methylate oxo amantadine (410mg, 2.45mmol) with ether 8ml, be cooled to 0 DEG C, drip 37% formalin (4.85ml, 61mmol) and formic acid (3.8ml, mixed solution 98mmol), 80 DEG C of reaction 10h, drip 5N aqueous sodium hydroxide solution 5ml, after organic phase concentrating under reduced pressure, methanol-diethyl ether recrystallization obtains target product hydrochloride, mp174-175 DEG C; IR (KBr.cm -1): 2963,2856,2556,2458,1488,1450,1410,1240,1033,102l, 916; 1h-NMR (300MHz, CD 3oD): δ 1.22 (s, 3H), 1.69 (m, 2H), 1.71 (m, 2H), 1.82 (m, 2H), 1.85 (d, J=11.0Hz, 2H), 2.05 (dd, J=11.0Hz, J=2.0Hz, 2H), 2.46 (m, 2H), 2.83 (s, 6H).
The preparation of embodiment 90
Amino oxo adamantane hydrochloride (350mg is added to 100ml flask, 1.60mmol), methyl alcohol 20ml, sodium cyanoborohydride (95%, 200mg, 3.20mmol), glacial acetic acid (0.6ml), acetaldehyde (0.56ml, 9.6mmol) stirring at room temperature 16h, solvent removed by evaporation at reduced pressure, add water 30ml, saturated solution of sodium bicarbonate alkalization extraction into ethyl acetate (3 × 15ml), the organic phase of merging, concentrating under reduced pressure, recrystallization obtains target product hydrochloride; IR (KBr.cm -1): 2972,2933,2855,2645,2579,2484,1458,1446,1377,1033,1014,975,949; 1h-NMR (300MHz, CD 3oD): δ 0.93 (t, J=7.5Hz, 3H), 1.38 (t, J=7.5Hz, 6H), 1.53 (q, J=7.5Hz, 2H), 1.64 (d, J=13.0Hz, 2H), 1.75 (d, J=13.0Hz, 2H), 1.82 (m, 1H), 1.85 (m, 1H), 1.94 (d, J=12.5Hz, 2H), 2.09 (d, J=12.5Hz, 2H), 2.47 (t, J=2.5Hz, 2H), 3.06 (b, 2H), 3.59 (b, 2H).
The preparation of embodiment 91
Amino oxo adamantane hydrochloride (400mg is added to 100ml flask, 1.84mmol), methyl alcohol 10ml, sodium cyanoborohydride (95%, 393mg, 5.93mmo1), acetic acid (0.3ml), phenyl aldehyde (0.42ml, 4.12mmol), mixture stirring at room temperature 16h, solvent removed by evaporation at reduced pressure, add water 30ml, mixture 1N sodium hydroxide alkalization, extraction into ethyl acetate (4 × 15ml), the organic phase merged, concentrating under reduced pressure, recrystallization obtains target product hydrochloride, mp213-214 DEG C; IR (KBr.cm -1): 2922,2851,2725,2656,2619,2414,1566,1463,1056,1042,1007,988,749,690; 1h-NMR (300MHz, CD 3oD): δ 0.96 (t, J=7.5Hz, 3H), 1.56 (q, J=7.5Hz, 2H), 1.67 (d, J=12.5Hz, 2H), 1.77 (d, J=12.5Hz, 2H), 1.87 (b, 2H), 1.98 (d, J=11.5Hz, 2H), 2.04 (d, J=11.5Hz, 2H), 2.46 (m, 2H), 4.25 (s, 2H), 4.86 (s, active-H), 7.42-7.50 (m, 5H).
The preparation of embodiment 92
Benzyl oxo amantadine (90mg is added to 100ml flask, 0.29mmol), acetonitrile 10ml, 37% formalin (0.23ml, 0.29mmol) with sodium cyanoborohydride (95%, 55mg, 0.83mmo1), glacial acetic acid 0.2ml, mixture stirring at room temperature 16h, solvent removed by evaporation at reduced pressure, adds 1N NaOH (15ml), dichloromethane extraction (5 × 10ml), organic phase washing twice (2 × 10ml) merged, concentrating under reduced pressure removes desolventizing and obtains product amine, and recrystallization obtains target product hydrochloride, mp165-166 DEG C; IR (KBr.cm -1): 2969,2921,2853,2472,235 3,1458,1033,1024,972,938,750,702; 1h-NMR (300MHz, CD 3oD): δ 0.99 (t, J=7.5Hz, 3H), 1.60 (q, J=7.5Hz, 2H), 1.69 (d, J=12.5Hz, 2H), 1.77-1.84 (b, 2H), 1.87 (m, 1H), 1.89 (m, 1H), 1.94-2.08 (b, 2H), 2.14-2.25 (b, 2H), 2.53 (b, 2H), 2.71 (s, 3H), (3.93 b, 1H, J=8.0Hz), 4.85 (m, 1H), 4.86 (s, active-H), 7.50 (m, 5H).
The preparation of embodiment 93
Benzyl methyl oxo amantadine (390mg is added to 250ml flask, 1.21mmol) with 10%Pd/C (10mg), dehydrated alcohol 80ml, 100 DEG C of reaction 24h under 38 normal atmosphere, reaction mixture is filtered, merges ethanol phase, removal of solvent under reduced pressure, recrystallization obtains target product hydrochloride, mp155-156 DEG C; IR (KBr.cm -1): 2968,2931,2848,2706,2592,1561,1474,1118,1068,1057,1028,991,972; 1h-NMR (300MHz, CD 3oD): δ 0.92 (t, J=7.5Hz, 3H), 1.50 (q, J=7.5Hz, 2H), 1.63 (d, J=12.5Hz, 2H), 1.72 (d, J=12.5Hz, 2H), 1.84 (s, 2H), 1.87 (d, J=13.0Hz, 2H), 1.91 (d, J=13.0Hz, 2H), 2.43 (br, 2H), 2.63 (s, 3H).
The preparation of embodiment 94
By 2-(3,5-two [(special fourth dimethyl is silica-based) oxygen base)] cyclohexyl) acetaldehyde is dissolved in the hydrochloric acid 14ml of 0.5N, stirring at room temperature reaction 2.5h, react complete, with Skellysolve A extraction (3 × 40ml), solvent removed by evaporation at reduced pressure after anhydrous magnesium sulfate drying, silica gel column chromatography is separated to obtain target product, mp210-212 DEG C; IR (CCl 4.cm -1): 3020,2900; 1h-NMR (300MHz CDCl 3): δ 1.40-2.70 (m, 9H), 4.19 (m, 2H), 5.11 (m, 1H).
The preparation of embodiment 95
Inositol 10.80g (60mmol) is added, ethyl orthoformate 15ml, tosic acid 1g in round-bottomed flask, 100 DEG C of reaction 1h, by reaction mixture cool to room temperature, add triethylamine 4ml, concentrating under reduced pressure obtains syrupy liq, is dissolved in pyridine 60ml, drips benzyl chlorine (18.8g, 133mmo1), stirring at room temperature 18h, reduction vaporization removing pyridine, residuum is dissolved in chloroform, concentrating under reduced pressure obtains target product through recrystallization, mp164-165 DEG C; IR (KBr, cm -1): 3318,2921,2841,1642,1586,1498,1450,1265,1216,1154.
The preparation of embodiment 96
Flask in 125ml adds racemic three oxygen diamantane (1.000g, 2.008mmol), DMAP (0.050g), (1S)-(K)-camphane acyl chlorides (0.566g, 2.614mmol) with pyridine 10ml, 80 DEG C of reaction 10h, reaction mixture cool to room temperature, reduction vaporization removing pyridine, crude product is dissolved in methylene dichloride and obtains product A and B through column chromatography for separation, compd A, IR (KBr, cm -1): 1788,1768, 1h-NMR (300MHz, CDCl 3): δ 7.83 (d, J=10.0Hz, 2H), 7.78 (d, J=10.0Hz, 2H), 7.43 (d, J=10.0Hz, 2H), 7.39 (d, J=10.0Hz, 2H), 5.50 (s, 1H), 5.48-5.45 (m, 1H), 5.10-5.05 (m, 1H), 4.74 (d, J=2.0Hz, 1H), 4.52-4.48 (m, 1H), 4.23-4.20 (m, 1H), 4.07-4.03 (m, 1H), 2.48 (s, 3H), 2.45 (s, 3H), 2.45-2.40 (m, 1H), 2.05-1.90 (m, 2H), 1.73-1.65 (m, 1H), 1.15 (s, 3H), 1.07 (s, 3H), 0.95 (s, 3H).
Compd B, IR (KBr, cm -1): 1776, 1h-NMR (300MHz, CDCl 3): δ 7.83 (d, J=10.0Hz, 2H), 7.73 (d, J=10.0Hz, 2H), 7.50-7.40 (m, 4H), 5.65-5.55 (m, 1H), 5.48 (d, J=5.0Hz, 1H), 5.00-4.93 (m, 1H), 4.90-4.85 (m, 1H), 4.40-4.30 (m, 2H), 4.15-4.05 (m, 1H), 2.48 (s, 6H), 2.55-2.40 (m, 1H), 2.12-2.05 (m, 1H), 2.05-1.90 (m, 1H), 1.80-1.70 (m, 1H), 1.15 (s, 3H), 1.10 (s, 3H), 0.98 (s, 3H),
The preparation of embodiment 97
Pyridoxal hydrochloride 20.81g (102.2mmol) is added in 250ml flask, Phloroglucinol 12.89g (102.2mmol) and 90% ethanol 9ml, backflow 10min, adds sodium bicarbonate 8.59g (102.2mmo1), glassy yellow crystallization is produced after backflow 10min, mixture continues stirring and refluxing 5min, slowly cool to room temperature ,-18 DEG C of insulation 4h, filter, filter cake 65ml water washing, dry yellow powder product, for the next step.
Pyridine Phloroglucinol product 28.1g (102.1mmol) is suspended in (500mmolHC1) in the 5M hydrochloric acid of 100ml, back flow reaction 15min, be warmed up to 170-180 DEG C, but room temperature 12h is arrived, the dark yellow solid of separating out is filtered, 400ml water washing, dry brownish black target product; IR (KBr, cm -1): 3350,2900,2825,1590,1520,1430,1395,1270,1210,1110,1065,1020,900,820,740; 1h-NMR (300MHz, CDCl 3): δ 2.50 (s, 3H), 3.32 (s, 6H), 4.85 (m, 2H), 5.90 (m, 1H), 8.11 (s, lH).
The preparation of embodiment 98
2-benzoyl-1,3-propylene dichloride (1.085g is added in 250ml flask; 5mmol), acetonitrile 10ml, 4-(piperidin-1-yl)-1-p-toluenesulfonyl-1,2,3,6-tetrahydropyridine (1.53g, 5mmo1), triethylamine (0.606g, 6mmol) and acetonitrile 20ml, 10ml water is added after reaction 2h, stir 1h, solvent removed by evaporation at reduced pressure, chloroform extraction, target product is obtained, m.p. (EtOAc/cyclohexane) 183-185 DEG C after evaporation of solvent; IR (CHCl 3.cm -1): 1725,1685,1360,1170; 1h-NMR (100MHz, CDCl 3): δ 7.73 (d, J=7.5Hz, 2H), 7.43 (d, J=7.5Hz, 2H), 7.50-7.98 (m, 5H), 3.30-3.45 (m, 5H), 2.34 (s, 3H), 1.72-2.45 (m, 6H).
The preparation of embodiment 99
7-benzoyl-3-p-toluenesulfonyl-3-azabicyclo [3.3.1]-9-in ninth of the ten Heavenly Stems ketone (795m is added in 250ml flask, 2mmo1), tetrahydrofuran (THF) 20ml, the tetrahydrofuran solution of lithium aluminium hydride (152mg, 4mmol), 50 DEG C are stirred 4h, drip ethyl acetate and metabisulfite solution, filter, concentrating under reduced pressure evaporation of solvent, reduction vaporization removing dissolves to obtain target product, (two kinds of isomer mixture=60:40); IR (CHCl 3.cm -1): 3500,1360,1160; 1h-NMR (100MHz, CDCl 3): δ 4.32 (J=8Hz, 0.6H), 4.20 (J=7Hz, 0.4H), 3.70 (b, 0.4H), 3.65 (4a, 1.2H), 3.45 (4a, 0.6H), 3.40 (4b, 0.8H).
The preparation of embodiment 100
Mixture (the 460mg of 7-(hydroxyl (phenyl) methyl)-3-p-toluenesulfonyl-3-azabicyclo [3.3.1]-9-in ninth of the ten Heavenly Stems Alkanol isomer is added in 250ml flask, 1.14mmol), the mixed solution of concentrated hydrochloric acid 20ml and glacial acetic acid 20ml, backflow 5h, removal of solvent under reduced pressure, chloroform extraction, removal of solvent under reduced pressure obtains oily target product; IR (CHCl 3.cm -1): 3400,1600; 1h-NMR (100MHz, CDCl 3): δ 4.10 (s, 80%, H 25a), 4.00 (t, 80%, H 65a), 3.30 (AB, H 9), 3.00 (AB, H 8): silver carbonate/diatomite (3g, 5mmol) be suspended in the dimethylbenzene of 50ml, add above-mentioned oxy-compound (70mg, 0.3mmol) heating reflux reaction 10min, solution becomes black, filter, filtrate evaporated under reduced pressure is dry obtains target product, m.p. (cyclohexane) 114-115 DEG C; IR (CHCl 3.cm -1): 1700; 1h-NMR (100MHz, CDCl 3): δ 7.45 (5H, C 6h 5), 4.30 (s, H 2), 3.50 (m, 3H); 2.90 (m, 1H).
The preparation of embodiment 101
4-(piperidin-1-yl)-1-p-toluenesulfonyl-1,2,3 is added in 250ml flask, 6-tetrahydropyridine 24.5g (0.08mo1), acetonitrile 200ml, reflux, drip the ethanol 200ml solution of brooethyl ethyl propenoate 15.4g (0.08mole), backflow 5h, solvent removed by evaporation at reduced pressure, adds water and each 50ml of ethanol, solution stirring 1h, reduction vaporization removing ethanol obtains 30.2g crude product, and re-crystallizing in ethyl acetate obtains target product, mp.156-159 DEG C; IR (KBr.cm -1): 1710,1720,1160,1340; 1h-NMR (100MHz, CDCl 3): δ 7.74 (d, J=7.5Hz, 2H), 7.40 (d, J=7.5Hz, 2H), 4.13 (q, J=8Hz, 2H), 3.45 (d, J=7Hz, 4H), 2.63 (t, J=7Hz, 1H), 2.34 (s, 3H), 1.95-2.48 (m, 6H), 1.29 (t, J=8Hz, 3H).
The preparation of embodiment 102
Add in 500ml flask and get ketone-ester 58.4g (0.16mo1), dithioglycol 20ml and chloroform 200ml, boron trifluoride ether solution 15ml, mixture is at stirring at room temperature 1h, reaction mixture is successively with cold 1NNaOH solution and saturated nacl aqueous solution washing, solvent removed by evaporation at reduced pressure, re-crystallizing in ethyl acetate obtains target product, m.p.:190-192 DEG C; IR (cm -1, CDCl 3): 1715,2900,2970,1160,1350; 1h-NMR (100MHz, CDCl 3): δ 7.74 (d, J=7.5Hz, 2H), 7.40 (d, J=7.5Hz, 2H), 4.13 (q, J=8Hz, 2H), 4.04 (t, J=7.1Hz, 4H), 3.58 (d, J=7Hz, 4H), 2.27 (t, J=7Hz, 1H), 2.34 (s, 3H), 1.65-2.35 (m, 6H), 1.29 (t, J=8Hz, 3H).
The preparation of embodiment 103
In 500ml flask, add thioether-one 2.207g (5mmol), auspicious mud Ni22ml, ethanol 200ml reflux 18h, and filter, solvent removed by evaporation at reduced pressure obtains product and obtains target product through recrystallization, m.p.:133-134 DEG C, IR (KBr, cm -1): 1720,2870,2929,1160,1340; 1h-NMR (100MHz, CDCl 3): δ 7.72 (d, J=7.5Hz, 2H), 7.38 (d, J=7.5Hz, 2H), 4.13 (q, J=8Hz, 2H), 3.56 (d, J=7Hz, 4H), 2.27 (t, J=7Hz, 1H), 2.34 (s, 3H), 1.35-1.80 (m, 8H), 1.29 (t, J=8Hz, 3H).
The preparation of embodiment 104
3-p-toluenesulfonyl-3-azabicyclo [3 is added in 250ml flask, 3,1] nonane-7-carboxylic acid, ethyl ester 12.01g (34.2mmol), the tetrahydrofuran (THF) 20ml of tetrahydrofuran (THF) 100ml, lithium aluminium hydride 2.21g (68.4mmol), 70-75 DEG C of reaction 3h, add ethyl acetate after cooling, filter, solvent removed by evaporation at reduced pressure also obtains target product with Virahol-isopropyl ether recrystallization, m.p.140.143 DEG C; IR (KBr, cm -1): 3600,2880,2950,1160,1340; 1h-NMR (100MHz, CDCl 3): δ 7.74 (d, J=7.5Hz, 2H), 7.40 (d, J=7.5Hz, 2H), 3.46-3.58 (m, 6H), 1.52 (m, J=7Hz, 1H), 2.34 (s, 3H), 1.24-2.67 (m, 8H).
The preparation of embodiment 105
Thiovanic acid 53.25g (699.6mmo1) is added, methylene dichloride 300ml and zinc chloride 19.49g (143.0mmol), backflow 24h in round-bottomed bottle, mixture is poured in frozen water, adding methyl alcohol makes pale solid separate out, washing, and vacuum-drying obtains target product; Mp220-3 DEG C; IR (KBr, cm -1): 2966.4,2910.2,2846.9,2713.3,1433.6,1363.3,1342.2,1089.1,1025.8,716.4. 1h-NMR (100MHz, CDCl 3): δ 2.18 (s).
The preparation of embodiment 106
Bicycloheptadiene 453g (2.18M) is added in three-necked bottle, benzene 600ml and triphenylphosphine cobaltous bromide 15g, boron trifluoride diethyl etherate liquid 4ml, backflow 12h, the mixture of cooling dilutes with methylene dichloride 650ml, extract crude product distills to obtain white solid, m.p.59-63 DEG C, for the next step at 106-107 DEG C (1.5mm);
Above-mentioned product 219.0g (0.73M) is dissolved in (containing 8.7ml concentrated hydrochloric acid) in 800ml Glacial acetic acid, adds 15g platinum oxide, hydrogenation, 70 DEG C, 3h, and crude product obtains colourless liquid target product through distillation b.p.105-110 DEG C (1.5mm). 1H-NMR(100MHz，CDCl 3)：δ3.68(s，12H)，3.54(m，2H)，2.67(m，2H)，1.41-1.75(m，10H).
The preparation of embodiment 107
Aluminum bromide 28g (0.1M) is added in three-necked bottle, hexanaphthene 100ml and above-claimed cpd 159g (0.53M), backflow 3h, reclaim hexanaphthene, dichloromethane extraction, obtains crude product, obtains white crystal and be target product through Structural Identification with Skellysolve A recrystallization, mp244.0-245.4 DEG C 1h-NMR (100MHz, CDCl 3): δ 3.68 (s, 6H), 2.26 (s, 6H), 2.22-2.58 (m, 6H), 1.35-1.59 (m, 7H).
Embodiment 108-249 is in table 1
Table 1 embodiment 1-249
Embodiment 250 anti-tumor agent
Take 8.0g compound 2 (referring to the compound prepared by embodiment 2, in table 1 compound 2), add dimethyl sulfoxide (DMSO) 50ml, be stirred to dissolve, after dissolving, add 500ml1,2-propylene glycol and 100ml tween 80, be uniformly mixed, inject water to cumulative volume 5000ml, with 0.22 μm of membrane filtration, packing, 100 DEG C of pressure sterilizing 30min, leak detection, Quan Jian, packaging, obtains 8mg/5ml (ammonia bottle), totally 1000.
Embodiment 251 anticancer experiment in vitro example
1 materials and methods
(1) clone
Select human pancreatic cancer cell Panc-1, Human Large Intestine Carcinoma Cells system HT-29, human lung cancer cell line NCI-H460 and breast cancer cell MCF7; Its substratum is DMEM (Gibco BRL), containing 10% foetal calf serum (Gibco BRL) and 2mM L-glutaminate (Gibco BRL).
(2) sample is tested: compound 37, compound 43, compound 47, compound 62 and compound 68 (see table 1 embodiment compound)
Get above-mentioned sample dissolution in dimethyl sulfoxide (DMSO) (DMSO, Sigma Co., USA's product), then substratum doubling dilution is used, dense DEG C of DMSO end is in the medium 0.5%, this dense DEG C is proved no cytotoxicity, positive control drug be cis-platinum (CDDP, Kunming Institute of Precious Metals provides, pure DEG C of >96%), use substratum doubling dilution.
(3) method
Cell is after tryptic digestion, be dispersed into individual cells, and make in its above-mentioned substratum be suspended in containing penicillin (25U/ml) and Streptomycin sulphate (25 μ g/ml), cell is inoculated in 96 well culture plates (Corning Incorporated), at 37 DEG C, containing 5%C0 2air, after cultivating 24h under relatively wet DEG C 100% condition, discard nutrient solution, add the nutrient solution containing a series of dense DEG C of tested material, establish parallel hole for each dense DEG C, after cultivating 48h, discard the nutrient solution containing tested material, replace and to gurgle indigo plant (MTT containing thiophene, Sigma Co., USA's product) nutrient solution, whole dense DEG C of MTT is 0.5g/L, HCl dropwise Virahol lysate after continuation incubation 4h, after 1h, purple crystal dissolves completely, close DEG C of the light (OD) of 570nm/630nm is detected in SK601 type microplate reader (Japan Seikagaku Products), be calculated as follows cell survival rate:
(experimental group OD/ control group OD) × 100%;
Positive control drug CDDP processes with above-mentioned tested material is synchronously same.
2 results and conclusion
To colorectal cancer cells restraining effect: compound 68 suppresses dense DEG C of (IC with the half of compound 62 couples of HT-29 50) and 95% fiducial limit be respectively 1.03 (0.93-2.38) μ g/ml and 3.62 (3.23-4.89) μ g/ml, the IC of these 2 kinds of tested materials 50stronger than the proliferation function of CDDP, and be less than the IC of 5-FU significantly 50(P<0.05), compound 37, compound 47 are then relatively weak with the antiproliferative effect of compound 43, IC 50and 95% fiducial limit be respectively 35.62 (27.24-54.62) μ g/ml, 38.33 (21.52-46.39) μ g/ml and 54.12 (50.17-66.8) μ g/ml, the IC of CDDP 50and 95% is crediblely limited to 3.69 (3.22-5.96) μ g/ml, the IC of 5-fluor-uracil (5-FU) 50and be crediblely limited to 14.36 (13.08-15.96) μ g/ml.
To breast cancer cell restraining effect: the IC of 5 kinds of tested material compounds 68, compound 62, compound 37, compound 47 and compound 43 pairs of mammary cancer MCF7 cells 50and 95% fiducial limit be respectively 2.28 (2.01-2.59), 6.94 (5.02-8.82), 19.26 (16.98-21.54), 56.32 (45.28-67.42) and 44.23 (40.20-48.22), the IC of positive control drug CDDP 50and 95% is crediblely limited to 3.92 (3.05-4.79) μ g/ml, NCI-H460 cell is responsive to compound 68, the IC of this tested material 50(P<0.05).
To pancreatic cancer cell restraining effect: the antiproliferative effect of 5 kinds of tested materials to Panc-1 is different, the half of compound 68, compound 62, compound 37, compound 47 and compound 43 couples of Panc-1 suppresses dense DEG C of (IC 50) and 95% fiducial limit be respectively 3.4 (2.03-4.77) μ g/ml, 3.26 (2.08-4.48) μ g/ml, 5.23 (4.28-6.18) μ g/ml, 17.6 (12.42-22.75) μ g/ml and 26.8 (17.63-35.97) μ g/ml, as can be seen from the above results, the antiproliferative effect of compound 62 is comparatively strong, its IC 50be equivalent to the IC of 5-FU 50, but slightly more weak than the proliferation function of CDDP, the IC of CDDP 50and 95% is crediblely limited to 2.17 (1.91-2.44) μ g/ml; The IC of 5-FU 50and 95% is crediblely limited to 3.33 (2.2-4.46) μ g/ml,
To lung carcinoma cell restraining effect: 5 kinds of tested materials are comparatively strong to the antiproliferative effect of HT-29, the IC of positive control drug CDDP 50and 95% is crediblely limited to 5.40 (4.04-6.76) μ g/ml, the IC of tested material compound 68, compound 62, compound 37, compound 47 and compound 43 pairs of NCI-H460 cells 50and 95% fiducial limit be respectively 3.38 (2.80-3.96), 4.89 (4.20-5.58), 7.73 (5.95-9.51), 17.25 (10.58-23.92) and 13.65 (10.12-17.18) μ g/ml, NCI-H460 cell is more responsive to compound 9, compound 22
This test test-compound is compound 37, compound 43, compound 47, compound 62 and compound 68, screening cell strain is large bowel cancer HT-29, carcinoma of the pancreas Panc-1, lung cancer NCI-H460, breast cancer cell MCF7, through twice test, very well, test-results shows result repeatability, and large bowel cancer, breast cancer cell are good to this compound responsive, wherein compound 68 and compound 62 activity are the highest, IC 50similar to positive drug cis-platinum, to large intestine activity more than 5-FU, also show certain activity to carcinoma of the pancreas Paac-1, wherein the activity of compound 62 is better than 5-FU,
In Vitro Anti cancer cells result is see table 2
Table 25 kind of compound is to the restraining effect (IC of four kinds of cancer cells 50, μ g/ml)
Embodiment 252. anti-tumor in vivo experiment embodiment
1. material
Test sample: compound 1, compound 7, compound 8, compound 9, compound 10, compound 11, compound 15, compound 16, compound 27, compound 29, compound 30, compound 32, compound 34, compound 35, compound 36, compound 37, compound 38, compound 41, compound 42, compound 43, compound 44, compound 47, compound 49, compound 50, compound 51, compound 53, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, compound 60, compound 61, compound 62, compound 64, compound 65, compound 66, compound 67, compound 68, compound 69, compound 70, compound 71, compound 73, compound 74, compound 75, compound 76, compound 78, compound 87, compound 88, compound 91, compound 93, compound 94, compound 97, compound 98, compound 100, compound 105 and compound 107 (see embodiment table 1 compound).
Experimental animal: Kunming kind healthy mice, body weight 19 ~ 21g, male and female half and half are divided into groups, and often organize 10, are provided by institute of materia medica of Military Medical Science Institute, Beijing animal center.
Knurl strain: murine sarcoma S 180for ascitic type goes down to posterity, derive from institute of materia medica of Military Medical Science Institute, Beijing.
2. method
The preparation of animal model for tumour: the aseptic absorption sarcoma S of raw 7 days 180go down to posterity mouse ascites, and being diluted to close DEG C respectively with physiological saline is 4 × 10 7cellml -1tumor cell suspension, it is subcutaneous that every mouse 0.2ml is inoculated in right fore armpit, inoculate latter 7 days, the more consistent tumour of size is grown in the right oxter of modeling mouse, be modeling success, for ensureing the vigor of inoculating cell, in experimentation, cell suspension is placed in the beaker containing ice, whole modeling process completes in 230min.
By the mouse random packet of 24h after inoculation, model control group, positive drug endoxan (CTX) control group 25mg/kg, 5-Fluorouracil (5-FU) 15mg/kg; Each compound dosage is in table 3, and each treated animal daily 1 time, successive administration 7 days, next day is put to death knurl mouse in drug withdrawal, strips knurl block, weighs mouse and knurl block weight, calculates tumour inhibiting rate and body weight change situation.
3. result: compare with blank group when p<0.05 is for there being significant difference, compound 7, compound 8 and compound 9, compound 11, compound 16, compound 68 and compound 107 have significant difference, and test-results is in table 3 and accompanying drawing.
Table 311 kind of compound is to sarcoma S 180the restraining effect of growth
Blank ? - 2.02±0.37 -
CTX 15 iv 1.21±0.88 44.5
Compound 1 10 ip 1.24±0.31 41.34
Compound 7 10 iv 0.75±0.51 53.33＊＊
Compound 8 20 iv 0.59±0.35 52.98＊＊
[0306]?
Compound 9 8 ip 0.96±0.60 58＊＊
Compound 10 50 iv 1.53±0.34 42.11
Compound 11 80 ip 1.11±0.33 54＊＊
Compound 15 25 iv 0.86±0.47 32.08
Compound 16 10 iv 0.55±0.44 52.9＊＊
Compound 27 16 ip 1.43±0.72 10.75
Compound 29 50 ip 1.66±0.13 32
Compound 30 100 ip 1.76±1.11 37.61
Compound 32 100 iv 1.18±0.30 33.03
Compound 34 12.5 iv 1.54±0.47 41.69
Compound 35 100 ip 1.47±0.26 40.56
Compound 36 50 ip 1.63±0.86 32
Compound 37 100 iv 1.54±0.35 44.75
Compound 38 100 ip 1.63±0.69 32
Compound 41 400 ip 1.98±0.11 26.1
Compound 42 50 iv 1.56±0.47 32.12
Compound 43 25 iv 1.96±0.40 24.19
Compound 44 2 iv 1.48±0.77 35
Compound 47 10 iv 1.51±0.32 34.72
Compound 49 50 iv 1.54±.033 34.35
Compound 50 150 ip 1.54±0.42 47
Compound 51 100 ip 1.44±0.39 44.81＊
Compound 53 40 iv 1.46±0.50 40.46
Compound 54 100 iv 1.95±0.33 24.87
Compound 55 100 ip 1.57±0.49 32
Compound 56 10 ip 1.43±0.76 41
Compound 57 40 ip 1.84±0.45 30.46
Compound 58 400 ip 2.55±0.37 28.2
Compound 59 60 ip 1.99±0.70 23
Compound 60 60 ip 2.74±0.27 25
Compound 61 100 ip 1.83±0.58 34
Compound 62 10 ip 0.32±0.24 49.71＊
Compound 64 8 ip 0.42±0.24 42.92
Compound 65 45 iv 0.43±0.24 41.61
Compound 66 120 ip 2.65±0.59 36
Compound 67 50 ip 1.31±0.31 51.67＊
Compound 68 70 iv 1.24±0.73 54＊＊
Compound 69 200 ip 1.69±0.63 28
Compound 70 10 iv 1.36±0.75 40
Compound 71 200 iv 2.48±0.37 11.47
Compound 73 25 ip 0.69±0.60 33.28
Compound 74 100 ip 2.08±0.63 20
Compound 75 200 ip 1.74±0.59 30
Compound 76 30 iv 0.86±0.48 34.35
Compound 78 60 ip 1.25±0.33 38.68
[0307]?
Compound 87 120 ip 1.07±0.71 35.15
Compound 88 20 iv 1.04±0.70 38.79
Compound 91 80 ip 0.97±0.51 41.12
Compound 93 80 ip 0.70±0.32 35.19
Compound 94 15 iv 1.34±0.48 25.56
Compound 97 15 iv 0.95±0.25 32.02
Compound 98 100 ip 0.64±0.19 40.74
Compound 100 30 iv 1.26±0.56 38.11
Compound 105 8 iv 0.82±0.32 40.25
Compound 107 60 ip 0.45±0.19 49.33＊
* p<0.05, compares significant difference with Control group; * p<0.01, compares significant differences with Control group
As shown in table 3 and accompanying drawing, each compound experimental group and blank group, endoxan positive controls tumour contrast photo after dissecting (Kun Ming mice inoculate S 180administration 7 days), experimental group is in mouse oxter inoculation S180 tumour cell, administration also observes 7 days, by measuring the way of mouse swelling of the axilla tumor weight, comparative sample group and positive controls (endoxan) tumour inhibiting rate, wherein to more than 40%, inhibitory rate all can think that sample has restraining effect to tumour cell, compare with positive controls (endoxan), tumour inhibiting rate is significantly better than positive controls, test-results shows: compound 1, 7, 8, 9, 10, 11, 16, 34, 35, 37, 50, 51, 53, 56, 62, 64, 65, 67, 68, 70, 91, 98, 105 and 107 tumour inhibiting rates are all more than 40%, compound 7, 8, 9, 11, 16, 37, 50, 67, 68 and 107 tumour inhibiting rates are all better than positive controls.

Claims (9)

1. the object of this invention is to provide a kind of containing adamantyl or and diamantane similar structures base formed chain compound, steric isomer, prodrug, pharmaceutical salts, double salt or and the compound of solvation there is having structure general formula I,
It is characterized in that: in S, P, T, the composition form of three kinds of structures can be three kinds of textural associations or two kinds of textural associations independently exist, form S-P-T, S-T-P, T-S-P, P-T or S-T general structure; Described S-P-T, S-T-P, T-S-P, P-T or S-T are independent S, P of replacing arbitrarily or become carbon-carbon bond with T-shaped or be connected with carbon heterodesmic, formed ether, ester, acid amides, alcohol, aldehyde, ketone, amine, acetal, ketal, oxime or and hydrazone group structure;
Wherein S the connected S that to be ring texture base, the P independently replaced arbitrarily be independently replaces arbitrarily or and the functional structure base of T, T be the adamantyl that independently replaces arbitrarily or and diamantane similar structures base;
The ring texture base that described S independently replaces arbitrarily be independently replace arbitrarily or and condense, saturated or unsaturated, monocycle base, two condensed ring radical, three condensed ring radicals, four condensed ring radicals, many condensed ring radicals, condensed ring radical or bridged ring base, little cyclic group, middle cyclic group or and large cyclic group; Described cyclic group is the C independently replaced arbitrarily 3-30alicyclic radical, aromatic ring yl, alicyclic heterocyclic base or and aromatic heterocyclic; Monocycle, dicyclo has having structure general formula I, II, III, IV, and wherein A ring is the C independently replaced arbitrarily 3-18unit's alicyclic radical, fragrant cyclic group, alicyclic heterocyclic base or and assorted fragrant cyclic group; B ring is the C independently replaced arbitrarily 3-18unit's alicyclic radical, fragrant cyclic group, alicyclic heterocyclic base or and assorted fragrant cyclic group; A ring and B ring directly condense or condense with bridged ring form;
The connected T that described P independently replaces arbitrarily or and the functional structure base of S be the C independently replaced arbitrarily 0-12chain or C 0-18chain or and ring-shaped fat base, aromatic ring yl, alicyclic heterocyclic base or and aromatic heterocyclic, between S and T, become carbon-carbon bond with both sides S with T-shaped respectively or be connected with carbon heterodesmic, formed independently replace arbitrarily ether, ester, acid amides, alcohol, aldehyde, ketone, amine, acetal, ketal, oxime or and hydrazone group structure, and S and T is kept at a certain distance away, it is spaced apart C 0-12chain or C 0-18chain or ring-shaped fat base, aromatic ring yl, alicyclic heterocyclic base or and aromatic heterocyclic,
The adamantyl that described T independently replaces arbitrarily or and diamantane similar structures base be the C independently replaced arbitrarily 3-30monocycle base, bicyclic group, polycyclic base, bridged ring base, cage cyclic group, diamantane cyclic group, thick and adamantyl or and diamond cyclic group; For independently replace arbitrarily containing oxygen, sulphur, nitrogen or and single heterocyclic radical of phosphine, two heterocyclic radical, or poly-heterocyclic radical are bridge heterocyclic radical, cage heterocyclic radical, diamantane heterocyclic radical or and diamond heterocyclic radical; For independently any one replaces, two replacements, three replace, four replacements or polysubstituted; For independently arbitrarily aromatic nucleus or and aromatic heterocycle replaces or the above-mentioned alicyclic ring derivative that condenses and analogue base; For independently replace arbitrarily single diamantane, Double diamantane hydrocarbons, many diamantane, open loop diamantane, poly-diamantane or and caged diamantane analogue, there is having structure general formula V, VI, VII, VIII, IX, X,
。
2. a kind of containing adamantyl or the chain compound with the formation of diamantane similar structures base according to claim 1, the S general formula in described S-P-T general formula,
Described dotted portion be independently or the double bond of any replacement of combining with solid line, singly-bound or and containing the heterocyclic radical of oxygen, sulphur, nitrogen;
Described X 1, X 2, X 3, X 4can be simultaneously polysubstituted or monosubstituted in the general formula of claim 1, can be identical definition or separate different definition substituting group, for carbon, oxygen, sulphur, nitrogen, phosphorus or and the heteroatoms such as selenium, for independently replace arbitrarily double bond, singly-bound or and containing the heterocyclic radical of oxygen, sulphur, nitrogen, n=0-6, for C=O, C=S or C=NH of independently replacing arbitrarily, C=R b-R a, CHOH, CHOR b, or and CH b, wherein R bc, N, P atom is contained, R for what independently replace arbitrarily afor H, H 2, independently replace arbitrarily straight chain, branched alkane alkyl or and the saturated fatty alkyl independently replaced arbitrarily containing substituent alkyl, a 1-10 carbon, a 1-4 double bond independently replaced arbitrarily, a 1-4 triple bond independently replaced arbitrarily, independently arbitrarily replacement saturated or and unsaturated lipid cyclic group, aromatic base or heterocycle, wherein hydroxyl, halogen radical, oxygen substituting group, nitrogen substituting group, sulphur substituting group, phosphorus substituting group;
Described A 1, A 2, A 3, A 4, A 5, A 6, A 7or and A 8be independently replace arbitrarily containing hydrogen, halogen, oxygen, sulphur, nitrogen or and phosphorus atom formed C-H bond, carbon-carbon bond or and the fatty group of carbon heterodesmic, aromatic base, alicyclic radical, heterocyclic radical, alicyclic heterocyclic base or and fragrant heterocyclic radical, independently replace arbitrarily containing one of glycosyl, hydroxyl, amino acid based, phosphorus acyloxy, acyloxy, phosphate, sulphur acyloxy, alkoxyl group, fragrant oxygen base, heterocyclic oxy group, oxygen base or and its combination; Wherein said glycosyl glycosidic bond is connected with C-C or with C-heteroatomic bond; Containing substituted oxy, oxygen, sulphur, nitrogen or and the substituting group of phosphorus; Comprise 1-8 independently replace arbitrarily glycosyl or and independently replace glycosyl arbitrarily, its glycosyl is the triose, erythrose, five-carbon sugar, the hexose that independently replace arbitrarily, seven carbon sugar, monose, disaccharides, trisaccharide or and polysaccharide-based; Described substituted oxy be independently replace arbitrarily acyloxy, a 1-4 phosphonato, alkoxyl group, aryloxy or and heterocyclic oxy group; Described substituting group is for containing aerobic, sulphur, nitrogen or and phosphorus atom, independently any unsaturated or saturated C replaced 1-10the unsaturated aliphatic hydrocarbyl moiety of alkyl, a 1-4 double bond or triple bond, saturated or unsaturated C 3-10alicyclic radical, non-alicyclic radical, aromatic base or and heterocyclic radical, and carbochain alkyl, aromatic ring, many rings, aliphatic heterocycle, fragrant heterocycle or and fused heterocycle one or a combination set of that the 3-10 introducing oxygen, sulphur, nitrogen or phosphorus atom independently replaces arbitrarily.
3. according to claim 1 a kind of containing adamantyl or the chain compound with the formation of adamantane similar structures base, it is characterized in that: when forming S-P-T, become the compound independently replaced arbitrarily: 7-(1-adamantane-1-base amido)-5-[4-(trifluoromethyl) phenyl] pyrazolo [1, 5-a] pyrimidine-3-formonitrile HCN, N-(adamantane-1-base)-2-(5-nitro-1, 3-dioxoisoindole-2-base) acetamide, N-(adamantane-1-base)-2-(5-amino-1, 3-dioxoisoindole-2-base) acetamide, N-(adamantane-1-base)-2-(1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) propionamide, N-(1-azaadamantane-3-base)-2-(1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) propionamide, N-(1-azaadamantane-3-base)-2-(1, 3-dioxo-3a, 4, 7, 7a-hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-y1) acetamide, N-(1-azaadamantane-3-base)-2-(5-hydroxyl-1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2-(3H) base) acetamide, N-(1-azaadamantane-3-base)-2-(5-nitro-1, 3-dioxoisoindole-2-base) acetamide, N-(1-azepine-3-base)-2-(5-amino-1, 3-dioxoisoindole-2-base) acetamide, the chloro-3-(2 of N-(adamantane-1-base)-5-, 4-dichlorophenyl)-2-methyl-6-Phenylpyrazole also [1, 5-a] pyrimidine-7-amine, N-(adamantane-1-base)-2-(4, 5-diphenyl-1H-imidazoles-1-base) acetamide, adamantane-1-formic acid 2-(2-(4, 5-diphenyl-1H-imidazoles-1-base)) acetamido ethyl ester, N-(4, 5-diphenyl-1H-imidazoles-2-base) adamantane-1-formamide, N-1-adamantyl-3-(2, 4-dichlorophenyl)-2, 7-dimethyl pyrazole [1, 5-a] pyrimidine-6-acid amides, N-(6-cyano group-3-(2, 4-dichlorophenyl)-2-methylpyrazole also [1, 5-a] pyrimidin-7-yl) adamantane-1-acid amides, N-(2-((8-oxo-8H-phthalazines also [1, 2-b] quinoline-5-base) amino) ethyl) adamantane-1-acid amides, N-(adamantane-1-base)-3-(2, 4-dichlorophenyl)-2, 6-dimethyl-5-(4-(trifluoromethyl) phenyl) pyrazolo [1, 5-a] pyrimidine-7-amine, N-(adamantane-1-base)-2-(2-(dimethylamino) ethyoxyl) acetamide, N-(adamantane-1-base)-4-((3, 4, 5-tri-hydrogen-6-(methylol) tetrahydrochysene-2H-pyrans-2-base) oxygen base) benzamide, the amino propylamine trifluoro-acetate of N-(adamantane-1-base)-2-, N-(adamantane-1-base)-2-(1,3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) propionamide, N-(adamantane-1-base)-2-(5, 6-bis-bromo-1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) propionamide, N-(adamantane-1-base)-2-(1, 3-dioxoisoindole-2-base) propionamide, N-(adamantane-1-base)-2-(5-nitro-1, 3-dioxoisoindole-2-base) propionamide, N-(adamantane-1-base)-2-(5-amino-1, 3-dioxoisoindole-2-base) propionamide, Buddha's warrior attendant-1, 3-glycol, 3-hydroxyadamantane-1-base 2-chloro-5-nitrobenzoic acid, 1-azepine-4-hydroxyadamantane, 1-azepine-4-methylene adamantane, 1-azaadamantane-4-acetonitrile, 1-azaadamantane-4-formic acid, 1-azaadamantane-4-ethamine, 1-azaadamantane-2-Ethyl formate, 1-azaadamantane-4-base ethanol, 3, 5, 7-trinitro--1-azaadamantane, 3, 5, 7-triamido-1-azaadamantane, 3, 5, the bromo-1-azaadamantane of 7-tri-, 3, 5, 7-triallyl-1-azaadamantane-4, 6, 10-triketone, 3, 5, 7-trimethyl-1-azaadamantane-4, 6-diketone, 1-boron is mixed adamantane oxolane, 1-azaadamantane-1-oxide, 1-azaadamantane-4-thioketones, 2-oxa-adamantane-4-ketone, 2-oxa-adamantane-4-alcohol, 1-hydroxyl-2-oxa-Buddha's warrior attendant-6-ketone, 6-amino-2-oxa-adamantane-1-alcohol, 2-oxa-adamantane-1-alcohol, 3, 5, 7-trimethyl-1-azaadamantane-4, 6, 10-triketone, N-benzoyl-4-hydroxyl-2-aza-adamantane, 2-benzyl-2-aza-adamantane-4-alcohol, 2-aza-adamantane-4-alcohol, p-methyl benzenesulfonic acid (N-benzoyl-2-aza-adamantane-4-alcohol radical) ester, 2-benzoyl-2-azepine Buddha's warrior attendant-4-ketone, 1-azaadamantane 4-ketone, 1-azaadamantane-4-ketoxime, 1-azaadamantane-4-amine, 2-aza-adamantane-1-alcohol, the chloro-2-aza-adamantane of 1-, 2-aza-adamantane, 2-(azaadamantane-2-base) ethanol, 2-(2-chloroethyl)-2-aza-adamantane, 5, 7-two (3, 4, 5-2,4,5-trimethoxyphenyl)-1, 3-diaza adamantane-6-ketone, 5, two (the 4-hydroxyl-3-nitrobenzophenone)-1 of 7-, 3-azaadamantane-6-ketone, 5, two (4-(3-hydroxyl-4-nitrophenoxy) phenyl)-1 of 7-, 3-diaza adamantane-6-ketone, 5, two (the 3-hydroxyl-4-nitrophenoxy)-1 of 7-, 3-diaza adamantane-6-ketone, 7-nitro-1, 3, 5-triazaadamantane, 1, 3, 5-triazaadamantane-7-amine, N-amyl group-1, 3, 5-triazaadamantane-7-amine, N-((1s, 3s, 5s)-1, 3,5-triazaadamantane-7-base)-2-(5-amino-3-hydroxyl-1-oxa-six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, 7-(piperidin-1-yl)-1, 3, 5-tri-nitrogen adamantane, 3-(methylol)-2-oxa-adamantane-1-alcohol, 3-methyl-2-oxa-volution [adamantane-6, 2 '-[1, 3] dioxolanyl]-1-alcohol, 1-hydroxy-3-methyl-2-oxa-adamantane-6-ketone, Z-1-hydroxy-3-methyl-2-oxa-adamantane-6-ketoxime, 5-amino-3-methyl-2-oxa-adamantane-1-alcohol, 2-oxa-adamantane-5-alcohol, 5, 7-diacetoxy-2-oxa-adamantane, 2-oxa-adamantane-5, 7-glycol, 1-bromo-2-oxa-adamantane, N-benzyl (2-oxa-adamantane-1-base) amine, N-(2-phenethyl) (2-oxa-adamantane-1-base) amine, N-Benzyl-N-methyl-2-oxa-adamantane-1-amine, N-methyl-N-(2-phenethyl) (2-oxa-adamantane-1-base) amine, N-methyl (2-oxa-adamantane-1-base) amine, (2-oxa-adamantane-1-base) amine, N, N-dibenzyl-2-oxa-adamantane-1-amine, (3-methyl-2-oxa-adamantane-1-base) hydrazine, (3-Methyl-2-oxa-adamantane-1-base) amine, N, N-dimethyl (3-methyl-2-oxa-adamantane-1-base) amine, N, N-diethyl (3-ethyl-2-oxa-adamantane-1-base) amine, N-benzyl (3-ethyl-2-oxa-adamantane-1-base) amine, N-Benzyl-N-methyl (3-ethyl-2-oxa-adamantane-1-base) amine, N-methyl (3-ethyl-2-oxa-adamantane-1-base) amine, 2, 4-dioxa adamantane, 9-hydroxyl-2, 4, 10-trioxaadamantane-6, 8-propylene glycol dibenzoate, D-and L-4, 7, 7-trimethyl-3-oxo-2-oxabicyclo [2, 2, 1] heptane-1-formic acid [-8, two (the p-methyl benzenesulfonic acid base)-2 of 9-, 4, 10-trioxaadamantane-6-base] alcohol ester, L-2, 4-bis--O-p-methyl benzenesulfonic acid base-6-O-[1S]-camphane acid chloride group-inositol base-1, 3, 5-triethyl orthoformate, 3, 5-dihydroxy-4-((3-hydroxyl-5-(methylol)-2-picoline-4-base) methylene) cyclohexyl-2, 5-dienone, 3-(3-hydroxyl-5-(methylol)-2-picoline-4-base)-2, 4, 10-trioxaadamantane-1, 5, 7-triol, 7-benzoyl-3-p-toluenesulfonyl-3-azabicyclo [3.3.1]-9-in ninth of the ten Heavenly Stems ketone, 7-(hydroxyl (phenyl) methyl)-3-p-toluenesulfonyl-3-azabicyclo [3.3.1]-9-in ninth of the ten Heavenly Stems alcohol, 8-methyl-8-phenyl-1-azaadamantane-4-ketone, 9-oxo-3-p-toluenesulfonyl-3-azabicyclo [3.3.1]-7-in ninth of the ten Heavenly Stems carboxylic acid, ethyl ester,3-p-toluenesulfonyl-3-azaspiro [dicyclo [3.3.1] ninth of the ten Heavenly Stems-9, 2 '-[1, 3] dithia cyclopenta]-7-carboxylic acid, ethyl ester, 3-p-toluenesulfonyl-3-azabicyclo [3.3.1]-7-in ninth of the ten Heavenly Stems carboxylic acid, ethyl ester, (3-p-toluenesulfonyl-3-azabicyclo [3.3.1]-7-in ninth of the ten Heavenly Stems base) methyl alcohol, 1, 3, 5, 7-tetramethyl-2, 4, 6, 8, 9, 10-six thia adamantane, decahydro-2, 8, 4, 6-(ring fourth [1, 2, 3, 4] dimethyl) naphthalene-2, 4, 4a, 6-tetracarboxylic acid methyl esters, decahydro-2, 8, 4, 6-(ring fourth [1, 2, 3, 4] dimethyl) naphthalene-1, 11-dicarboxylic acid methyl ester, N-(1-azaadamantane-3-base)-2-(5-hydroxyl-1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(1-azaadamantane-3-base)-2-(5-amino-1, 3-dioxoisoindole woods-2-base) acetamide, 7-(adamantane-1-base is amino)-2-methyl-5-(4-(trifluoromethyl) phenyl) pyrazolo [1, 5-a] pyridine-3-formonitrile HCN, adamantane-1-formic acid 2-(2-(4, 5-diphenyl-1H-imidazoles-1-base) acetamido) ethyl adamantane-1-carboxylate, N-(adamantane-1-base)-2-(1, 3-dioxo-1H-4, the different benzindole-2 (3H) of 7-epoxy-Ji) propylamine, N-(adamantane-1-base)-2-(5, 6-bis-bromo-1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) propylamine, N-(adamantane-1-base)-2-(1, 3-dioxoisoindole-2-base) propionamide, N-(adamantane-1-base)-2-(5-nitro-1, 3-dioxoisoindole-2-base) propionamide, 3, 5, 7-trimethyl-1-azaadamantane-4, 6-glycol, 3, 5, 7-trimethyl-1-azaadamantane-4, 6-diketone, 3, 5, 7-trimethyl-1-azaadamantane-4, 6-glycol, 1-azaadamantane, 1-oxa-adamantane-4-alcohol, two rings [3.3.1]-6-in ninth of the ten Heavenly Stems alkene-3-alcohol, 1-[3-hydroxyl-5-(methylol)-2-methyl-4-pyridine radicals]-2, 8, 9-trioxaadamantane-3, 5, 7-triol, N-(adamantane-1-base)-2-(N-formoxyl formamido group) acetamide, N-(adamantane-1-base)-2-(2-hydroxyl-5-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(adamantane-1-base)-2-(2-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(adamantane-1-base)-2-(2, 5-dioxo pyrrolidin-1-base) acetamide, N-(adamantane-1-base)-2-(2-hydroxyl-5-oxo-pyrrolidine-1-base) acetamide, N-(adamantane-1-base)-2-(2-oxo-pyrrolidine-1-base) acetamide,N-(adamantane-1-base)-2-(5-amino-3-hydroxyl-1-oxo isoindole woods-2-base) acetamide, N-(adamantane-1-base)-2-(5-amino-1-oxo isoindole woods-2-base) acetamide, N-(adamantane-1-base)-2-(5-amino-1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(adamantane-1-base)-2-(5-amino-3-hydroxyl-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(adamantane-1-base)-2-(5-amino-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, (4-hydroxyl-2-aza-adamantane-2-base) (phenyl) ketone, 1-azaadamantane-4-ketone, 1-azaadamantane-4-amine, 2-(2-aza-adamantane-2-base) ethanol, 2-aza-adamantane-1-alcohol, the chloro-2-aza-adamantane of 1-, 2-(2-aza-adamantane-2-base) ethanol, 2-(2-chloroethyl)-2-aza-adamantane, N-(1-azaadamantane-3-base)-2-(N-formoxyl formamido) acetamide, N-(1-azaadamantane-3-base)-2-(2-hydroxyl-5-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(1-azaadamantane-3-base)-2-(2-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(1-azaadamantane-3-base)-2-(2, 5-dioxo pyrrolidin-1-base) acetamide, N-(1-azaadamantane-3-base)-2-(2-hydroxyl-5-oxo pyrroles-1-base) acetamide, N-(1-azaadamantane-3-base)-2-(2-oxo pyrroles-1-base) acetamide, N-(2-aza-adamantane-1-base)-2-(2, 5-dioxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2-aza-adamantane-1-base)-2-(2-hydroxyl-5-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2-aza-adamantane-1-base)-2-(2-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2-aza-adamantane-1-base)-2-(2, 5-dioxo pyrrolidin-1-base) acetamide, N-(2-aza-adamantane-1-base)-2-(2-hydroxyl-5-oxo pyrroles-1-base) acetamide, N-(2-aza-adamantane-1-base)-2-(2-oxo pyrroles-1-base) acetamide, N-(1-azaadamantane-3-base)-2-(5-amino-1, 3-dioxoisoindole woods-2-base) acetamide, N-(1-azaadamantane-3-base)-2-(5-amino-3-hydroxyl-1-oxo isoindole woods-2-base) acetamide, N-(1-azaadamantane-3-base)-2-(5-amino-1-oxo isoindole woods-2-base) acetamide,N-(1-azaadamantane-3-base)-2-(5-amino-1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(1-azaadamantane-3-base)-2-(5-amino-3-hydroxyl-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(1-azaadamantane-3-base)-2-(5-amino-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(2-aza-adamantane-1-base)-2-(5-amino-1, 3-dioxoisoindole woods-2-base) acetamide, N-(2-aza-adamantane-1-base)-2-(5-amino-3-hydroxyl-1-oxo isoindole woods-2-base) acetamide, N-(2-aza-adamantane-1-base)-2-(5-amino-1-oxo isoindole woods-2-base) acetamide, N-(2-aza-adamantane-1-base)-2-(5-amino-1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(2-aza-adamantane-1-base)-2-(5-amino-3-hydroxyl-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(2-aza-adamantane-1-base)-2-(5-amino-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, 5, 5 '-(1-azaadamantane-4, 4-bis-couples (oxygen base)) two (2-nitrophenol), two 2-hydroxyl-4-((4-(3-hydroxyl-4-nitrophenoxy)-1-azaadamantane-4-base) oxygen base) benzene first cyanogen, 5, 5 '-(1-azaadamantane-4, 4-bis-couples (4, 1-benzylidene) two (oxygen base)) two (2-nitrophenol), 5, 5 '-(1-azaadamantane)-4, 4-bis-couples (4, 1-benzylidene) two (oxygen base) two (2-cyanophenol), 5, 5 '-(1-azaadamantane-3, 5-bis-couples (oxygen base) two (2-nitro) phenol, 5, 5 '-(1-azaadamantane-3, 5-bis-couples (oxygen base)) two (2-cyano group) phenol, 5, 5 '-(1-azaadamantane-3, 5-bis-couples (4, 1-phenylene) two (oxygen base)) two (2-nitro) phenol, 5, 5 '-(1, 3-diaza adamantane-6, 6-bis-couples (oxygen base)) two (2-nitro) phenol, 5, 5 '-(1, 3-diaza adamantane-6, 6-bis-couples (oxygen base)) two (2-cyano group) phenol, 5, 5 '-(1, 3-diaza adamantane-6, 6-bis-couples (4, 1-phenylene) two (oxygen base)) two (2-nitro) phenol 5, 5 '-(1, 3-diaza adamantane-6, 6-bis-couples (4, 1-phenylene) two (oxygen base)) two (2-cyano group) phenol, 5, 5 '-(1, 3-diaza adamantane-5, 7-bis-couples (oxygen base)) two (2-nitro) phenol, 5, 5 '-(1, 3-diaza adamantane-5,7-bis-couples (oxygen base)) two (2-cyano group) phenol, 5, 5 '-(1, 3-diaza adamantane-5, 7-bis-couples (4, 1-phenylene) two (oxygen base)) two (2-nitro) phenol, 5, 5 '-(1, 3-diaza adamantane-5, 7-bis-couples (4, 1-phenylene) two (oxygen base)) two (2-cyano group) phenol, 5, 5 '-(1, 3, 5-triazaadamantane-6, 6-bis-couples (oxygen base)) two (2-nitro) phenol, 5, 5 '-(1, 3, 5-triazaadamantane-6, 6-bis-couples (oxygen base)) two (2-cyano group) phenol, 5, 5 '-(1, 3, 5-triazaadamantane-6, 6-bis-couples (4, 1-phenylene) two (oxygen base)) two (2-nitro) phenol, 5, 5 '-(1, 3, 5-triazaadamantane-6, 6-bis-couples (4, 1-phenylene) two (oxygen base)) two (2-cyano group) phenol, N-(1, 3, 5-triazaadamantane-7-base)-2-(5-amino-1, 3-dioxoisoindole woods-2-base) acetamide, N-(1, 3, 5-triazaadamantane-7-base)-2-(5-amino-3-hydroxyl-1-oxo isoindole woods-2-base) acetamide, N-(1, 3, 5-triazaadamantane-7-base)-2-(5-amino-1-oxo isoindole woods-2-base) acetamide, N-(1, 3, 5-triazaadamantane-7-base)-2-(5-amino-1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(1, 3, 5-triazaadamantane-7-base)-2-(5-amino-3-hydroxyl-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(1, 3, 5-triazaadamantane-7-base)-2-(5-amino-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(1, 3, 5-triazaadamantane-7-base)-2-(2, 5-dioxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(1, 3, 5-triazaadamantane-7-base)-2-(2-hydroxyl-5-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-((, 3, 5-triazaadamantane-7-base)-2-(2-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(1, 3, 5-triazaadamantane-7-base)-2-(2, 5-dioxo pyrrolidin-1-base) acetamide, N-(1, 3, 5-triazaadamantane-7-base)-2-(2-hydroxyl-5-oxo-pyrrolidine-1-base) acetamide, N-(1, 3, 5-triazaadamantane-7-base)-2-(2-oxo-pyrrolidine-1-base) acetamide, 1-hydroxyl-2-oxa-adamantane-6-ketone, 3-(methylol)-2-oxa-adamantane-1-alcohol, 5-amino-2-oxa-adamantane-1-alcohol, 2-oxa-adamantane-5, 7-glycol, 3, 5,7-trimethyl-1-azaadamantane-4, 6, 10-triketone, N, N-dibenzyl phenyl-2-oxa-adamantane-1-amine, 1-hydroxy-3-methyl-2-oxa-adamantane-6-ketone, 3-(methylol)-2-oxa-adamantane .1-alcohol, 2-oxa-adamantane-5, 7-glycol, 1-bromo-2-oxa-adamantane, 2-oxa-adamantane-5-alcohol, 5, 5 '-(2-oxa-adamantane-5, 7-glycol two (4, 1-phenylene) two (oxygen base)) two (2-nitro) phenol, 5, 5 '-(2-oxa-adamantane-5, 7-glycol two (4, 1-phenylene) two (oxygen base)) two (2-cyanophenol), 5, 5 '-(2-oxa-adamantane-5, 7-glycol two (oxygen base)) two (2-nitro) phenol 5, 5 '-(2-oxa-adamantane-5, 7-glycol two (oxygen base)) two (2-cyano group) phenol, N-(2-oxa-adamantane-1-base)-2-(5-amino-1, 3-dioxoisoindole woods-2-base) acetamide, N-(2-oxa-adamantane-1-base)-2-(5-amino-3-hydroxyl-1-oxo isoindole woods-2-base) acetamide, N-(2-oxa-adamantane-1-base)-2-(5-amino-1-oxo isoindole woods-2-base) acetamide N-(2-oxa-adamantane-1-base)-2-(5-amino-1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(2-oxa-adamantane-1-base)-2-(5-amino-3-hydroxyl-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide N-(2-oxa-adamantane-1-base)-2-(5-amino-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(2-oxa-adamantane-1-base)-2-(2, 5-dioxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2-oxa-adamantane-1-base)-2-(2-hydroxyl-5-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2-oxa-adamantane,-1-base)-2-(2-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2-oxa-adamantane-1-base)-2-(2, 5-dioxo pyrrolidin-1-base) acetamide, N-(2-oxa-adamantane-1-base)-2-(2-hydroxyl-5-oxo-pyrrolidine-1-base) acetamide, N-(2-oxa-adamantane-1-base)-2-(2-oxo-pyrrolidine-1-base) acetamide, 5, 5 '-(2, 4-dioxa adamantane-1, 7-bis-couples (4, 1-phenylene) two (oxygen base)) two (2-nitro) phenol, 5, 5 '-(2, 4-dioxa adamantane-1, 7-bis-couples (4, 1-phenylene) two (oxygen base)) two (2-cyano group) phenol, 5, 5 '-(2, 4-dioxa adamantane-1, 7-bis-couples (oxygen base)) two (2-nitro) phenol, 5, 5 '-(2,4-dioxa adamantane-1, 7-bis-couples (oxygen base)) two (2-cyano group) phenol N-(2, 4-dioxa adamantane-3-base)-2-(2, 5-dioxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2, 4-dioxa adamantane-3-base)-2-(2-hydroxyl-5-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2, 4-dioxa adamantane-3-base)-2-(2-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2, 4-dioxa adamantane-3-base)-2-(2, 5-dioxo pyrrolidin-1-base) acetamide, N-(2, 4-dioxa adamantane-3-base)-2-(2-hydroxyl-5-oxo-pyrrolidine-Ji) acetamide, N-(2, 4-dioxa adamantane-3-base)-2-(2-oxo-pyrrolidine-1-base) acetamide, 5, 5 '-(2, 4, 10-trioxaadamantane-1, 5-bis-couples (4, 1-phenylene) two (oxygen base)) two (2-nitro) phenol, 5, 5 '-(2, 4, 10-trioxaadamantane-1, 5-bis-couples (4, 1-phenylene) two (oxygen base)) two (2-cyano group) phenol, 5, 5 '-(2, 4, 10-trioxaadamantane-1, 5-bis-couples (oxygen base)) two (2-nitro) phenol, 5, 5 '-(2, 4, 10-trioxaadamantane-1, 5-bis-couples (oxygen base)) two (2-cyano group) phenol, N-(2, 4, 10-trioxaadamantane-3-base)-2-(5-amino-1, 3-dioxoisoindole woods-2-base) acetamide, N-(2, 4, 10-trioxaadamantane-3-base)-2-(5-amino-3-hydroxyl-1-oxa-isoindoline-2-base) acetamide, N-(2, 4, 10-dioxygen is mixed adamantane-3-base)-2-(5-amino-1-oxo isoindole woods-2-base) acetamide, N-(2, 4, 10-trioxaadamantane-3-base)-2-(5-amino-1, 3-dioxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(2, 4, 10-trioxaadamantane-3-base)-2-(5-amino-3-hydroxyl-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(2, 4, 10-trioxaadamantane-3-base)-2-(5-amino-1-oxo six hydrogen-1H-4, 7-epoxy iso-indoles-2 (3H)-Ji) acetamide, N-(2, 4, 10-trioxaadamantane-3-base)-2-(2, 5-dioxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2, 4, 10-trioxaadamantane-3-base)-2-(2-hydroxyl-5-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2, 4, 10-trioxaadamantane-3-base)-2-(2-oxo-2, 5-dihydro-1H-pyrroles-1-base) acetamide, N-(2, 4,10-trioxaadamantane-3-base)-2-(2,5-dioxo pyrrolidin-1-base) acetamide, N-(2,4,10-trioxaadamantane-3-base)-2-(2-hydroxyl-5-oxo-pyrrolidine-1-base) acetamide, N-(2,4,10-trioxaadamantane-3-base)-2-(2-oxo-pyrrolidine-1-base) acetamide.
4. one kind according to claim 1 a kind of containing adamantyl or and diamantane similar structures base formed chain compound, come from: the compound of cited embodiment, isomer, steric isomer, prodrug, solvation, medicinal formula or carrier, also comprise the pharmaceutical salts of this derivative and analogue, double salt, inorganic acid salt, organic acid salt, inorganic base salts, organic alkali salt or and double salt.
5. one kind according to general structure I a kind of containing adamantyl or and diamantane similar structures base formed chain compound as cancer treatment method, to cancer patient to needing the described compound reaching treatment significant quantity, comprise cited embodiment, isomer, steric isomer, prodrug, pharmaceutical salts, double salt, the compound of solvation, medicinal formula or and carrier.
6. a kind of containing adamantyl or the chain compound with the formation of diamantane similar structures base according to claim 1, it is characterized in that: described compound has treatment, prevent or and slow down tumour and cancer, treat by virus, bacterium or fungus-causedly to catch, treatment nervous system disorders and the application of disease caused by inflammation.
7. a kind of application containing adamantyl or the chain compound with the formation of diamantane similar structures base according to claim 1, it is characterized in that: be included in the antitumor pharmacologically active of preparation and the application as antitumor drug, described a kind of containing alicyclic radical or the chain compound with adamantyl formation, pharmaceutical salts or and prodrug, its separately or with known antitumor and immune drug with the use of dosage be 0.001mg/kg-250mg/kg, wherein this tumour is from lung cancer, cancer of the stomach, colorectal carcinoma, small cell lung cancer, thyroid carcinoma, the esophageal carcinoma, carcinoma of the pancreas, carcinoma of endometrium, adrenocortical carcinoma, head and neck cancer, osteogenic sarcoma, mammary cancer, ovarian cancer, wilms' tumor, tumor of cervix, carcinoma of testis, apparatus urogenitalis cancer, skin carcinoma, renal cell carcinoma, bladder cancer, primary brain cancer, prostate cancer, soft tissue sarcoma, neuroblastoma, rhabdosarcoma, Kaposi sarcoma, malignant melanoma, malignant pancreatic insulinoma, non-Hodgkin lymphoma, malignant melanoma, multiple myeloma, neuroblastoma, malignant carcinoid carcinomas, choriocarcinoma, acute and lymphocytic leukemia, primary macroglobulinaemia, chronic myelocytic leukemia, lymphocytic leukemia, acute myeloblastic leukemia, hairy cell leukemia, mycosis fungoides, malignant hypercalcemia, hyperplasia of cervix uteri or and Hodgkin's disease.
8. a kind of containing adamantyl or with the chain compound of diamantane similar structures base formation with in the antitumor pharmacologically active of preparation and the application as antitumor drug according to claim 7, it is characterized in that: wherein prepare antitumor pharmacologically active and as the application of antitumor drug and other known antitumor and immune drug with the use of, also organize known cancer chemotherapeutic agent with next with being at least selected from, the pharmacologically acceptable salt of antiviral agent or this reagent is used with the one in prodrug or together with its combination, comprising: endoxan, vincristine(VCR), busulfan, vinealeucoblastine(VLB), cis-platinum, carboplatin, ametycin, Zorubicin, colchicine, Etoposide, taxol, docetaxel, camptothecine, Hycamtin, white arsenic, 5-ammonia is mixed cytidine, 5 FU 5 fluorouracil, methotrexate, the fluoro-2-deoxidation-uridine of 5-, hydroxyurea, Tioguanine, melphalan, Chlorambucil, ifosfamide, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium acetate, fludarabine, Sostatin, vitamin A acid, tamoxifen, Doxazosin, terazosin, tamsulosin, fluorine pyridol, lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin, fourth is vertical cuts down statin, amprenavir, Abacavir, L 86-8275, ritonavir, Saquinavir, rofecoxib, alanosine, retinene, tretinointocoferil, 13CRA, RETINOIC ACID, alpha-difluoromethyl ornithine, fenretinide, N-4-carboxyl phenyl Viaminate, genistein, cloth is drawn in plug, ara-C, CB-64D, CB-184, ILX23-7553, lactacystin, MG-132, PS-341, Glcevec, ZD1839 (IRessa), SH268, Herceptin, Rituxan, Gamcitabine, ABT-378, AG1776, BMS-232,632, CEP2563, SU6668, EMD121974, R115777, SCH66336, L-778,123, BAL9611, TAN-1813, UCN-01, Roscovitine, Olonoucine or and Valecoxib.
9. according to described in claim 1 and 8 a kind of containing adamantyl or and the chain compound that formed of diamantane similar structures base and the application of known drug compatibility, it is characterized in that: administering mode comprises: in oral, parenteral route, subcutaneous, intravenously, intramuscular, intraperitoneal, transdermal, cheek, sheath, in encephalic, nose or and topic route.
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