CN1626088A - Hydrolase inhibitor of adenosine homeotypic cysteamine acid and usage - Google Patents

Abstract

An adenosine homotype of cysteine hydrolase depressant, 9-[(1'R, 2', S, 3'R)-2',3'-dihydroxycyclopentyl] adenine (DHCaA), 9-(trans-2', trans-3'-dihydroxycyclopentyl-4'-enylester) adenine (DHCeA) and its 3-site nitrogen analog is disclosed. It can be used to treat lupus erythematosus and allergic dermatitis.

Description

Adenyhomotype aminothiopropionic acid hydrolase inhibitor and uses thereof

Technical field

The present invention relates to a kind of adenyhomotype aminothiopropionic acid hydrolase inhibitor that contains, be fit to reagent combination of external application and uses thereof, this reagent combination is to lupus erythematosus with because the other diseases that the epithelial cell hyper-proliferative causes has therapeutical effect, external application comprises adenyhomotype aminothiopropionic acid hydrolase inhibitor DHCaA or DHCeA, and 3-position nitrogen analog.

Background technology

Lupus erythematosus is benign human skin disease, and general features covers on the speckle of thickening for thin scurf.Cause this sick reason to be because the epidermal cell proliferation that not clear reason increases.For common skin, cell moves to the time that granular layer approximately needed for 5 week from basic unit.For the skin of lupus erythematosus, only need 6 to 9 days time, reason is because the growth of proliferative cell quantity and the growth (G.Grove, Int.J.Dermatol.18:111,1979) of somatoblast ratio.The population of the U.S. about 2% has lupus erythematosus, and it is American 3% to account for white race, and it is American 1% to account for non-descendants, and the native country American almost do not have.

With the epidermal hyperplasia of inflammation-related be the lupus erythematosus skin characteristic.The skin tissue biopsy of affected area shows as the hyperkeratosis that nuclear fragmentation is stagnated, the outgrowth increase of keratinization, the infiltration of chronic inflammatory disease.(E.A.Bauer，M.Tabas?and?J.B.Goslen，in?Textbook?of?Internal?Medicine，W.N.Kelly(ed.)，1989，pp?1042-1045)。Along with ever-increasing cell increment, in impaired tissue, the DNA aggregate velocity increases, and so becomes the effective ways of assessment LJP394 agent effect.

The animal model that does not have real lupus erythematosus is though precious primates has the clinical and histopathologic feature of lupus erythematosus to be reported (N.J.Lowe, Drug Dev.Res.13:147-155,1988).Therefore, the research of LJP394 agent is to rely on experiment to impel the animal hypertrophy, or suffers from the mouse (J.P.Sundberg et al., J.Invest.Dermatol.92:414,1989) of natural mutation character (fsn).It is to suffer from the nude mice of essential fatty acid deficiency (EFAD) that another kind has the mouse models of epidermal hyperplasia.

With experiment method bring out animal model, also comprise to the immunodeficiency type nude mouse and transplant ill human skin.

The present invention uses to comprise and successfully reduces quick cell increment and reduce inflammation and treat.These treatments comprise the topical application of topical agent, the general application or both, binding radioactivity treatment simultaneously.Topical therapeutic comprise the external application of the external application of steroid ointment and coal tar ointment follow ultra violet radiation (UV B, 290-320nm).The external application of 5-fluorouracil has obtained some successes, but treatment is in the zone of having handled and can not be caused that serious erythema, edema, bubble form and ulcer (C.J.McDonald by the skin area of patient's good absorption, Pharmac.Ther.14:1-24,1981).TRIAZURE.TM (three acetoxy group 6-azauridines) did local test suffering from the patient skin of lupus erythematosus, but did not have effect (William Drell, personalcommunication, May, 1993)

Anti-proliferative drug comprises methotrexate, 6-azauridine and triazure, has also passed through the general application.The treatment of a large amount of lupus erythematosus is oral 8-methoxypsoralen, photosensitizer, follows taking of ultraviolet light,long wave (320nm) radiation or biostearin, Etretinate for example, follow ultraviolet light,long wave radiation (C.J.McDonald, Pharmac.Ther.14:1-24,1981; E.A.Bauer, M.Tabas, and J.B.Goslen, inTextbook of Internal Medicine, W.N.Kelly (ed.), 1989, pp 1042-1045).

Other are because the dermatosis that the epithelial cell hyper-proliferative causes comprises atopic dermatitis, lichen planus, actinic keratosis, matrix cells cancer, squamous cell carcinoma.At present also not to using adenyhomotype aminothiopropionic acid hydrolase inhibitor DHCaA or DHCeA, and 3-position nitrogen analog, treatment lupus erythematosus or other are because the excessive relevant report of the dermatosis that cause of increment of epithelial cell.

U.S. Patent application (Ser.No.08/060,258, hereby incorporated by reference) reveals the herpes nucleotide phosphate, acyclovir for example, to being effective by the variant character animal of viral infection, because sudden change influences activating enzymes, thymidine kinase, so acyclovir wherein can not be transformed into acyclovir phosphate

Summary of the invention

Invention provides a kind of reagent combination of suitable external application, it is characterized in that containing the 9-[(1 ' R of effective quantity with opposing epithelial cell hyper-proliferative, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA), and 3-position nitrogen analog or its esters.

Reagent combination according to invention, 9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] effective ingredient concentration in adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their the 3-position nitrogen analog at 0.001gm% between the 100gm%.In preferred agents, 9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] the effective ingredient concentration of adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog is between 0.01gm%to10gm%.In special preferred medicament, 9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] concentration of adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog is between 0.1gm%to5gm%.

According to the one side of invention, medicament every day of external application one to ten time, each consumption 0.001gm% is to 100gm%.Also can select, every day, each consumption 0.01gm% was to 10gm% with one to ten time.In preferred agents, the ointment every day that is used for the skin damage zone, each consumption 0.1gm% was to 5gm% with one to ten time.

Another aspect according to invention, the pharmacy 9-[(1 ' that comprises effective ingredient is provided R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] method of adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog.In preferred agents, 9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog further comprise propylene glycol, polyoxyethylene 400 and polyoxyethylene 3350.In special preferred agents, 9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog further be included in the composition that strengthens dermal osmosis in the external application process.

Specific embodiments

Adenyhomotype aminothiopropionic acid hydrolase inhibitor DHCaA or the DHCeA of the present invention with immunosuppressant effectiveness, treat lupus erythematosus and allergic dermatitis as the main component of external application, this class inhibitor is by to the inhibition of adenyhomotype aminothiopropionic acid hydrolytic enzyme, effectively stops the generation of TNF-α and other cytokines and reached the immunosuppressant function.

9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) salt in adenine (DHCeA) and their the 3-position nitrogen analog is easy to refine, and such salt just shows very high dissolubility at water solublity Emulsion in Emulsion, gel or other water dispersants.9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] representational effective salt comprises sodium, potassium, lithium, ammonium or hydrogen salt in adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their the 3-position nitrogen analog.The acceptable cation of mentioning in those documents of well-known any physiology also can be used.In addition, this salt favorable mucosa is provided or influence propylene glycol Emulsion that skin scatters and liquid in be available and effective.

9-[(1 ' R, 2 ' S, 3 ' R are used in external application)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog

Another aspect according to invention, the method of topical therapeutic lupus erythematosus, be that a kind of comprising the effective adenyhomotype aminothiopropionic acid of the lupus erythematosus infringement hydrolase inhibitor 9-[(1 ' R on the patient skin used in external application, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog.

Base fluid is the important component part of some external application medical ointments, because it can be used for improving penetrating power, in order to prolong activity periods, or reaches the requirement of application.For example, be applied in the prescription of the callous part of health, as palm or sole, comprising strengthening for example dimethyl sulfoxine of infiltration medicament, propylene glycol or ketone .TM. select the powder composition that the position of mill is used on the other hand, for example stride portion, between interior elbow or finger, the toe.9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog also can be made into the chemical compound that comprises that different organic polymers or other are known in the literature, for the release that allows effective anti-lupus erythematosus derivant slowly continue.

The chemical compound of most of suitable topical application can both find in the pharmacopeia known to all pharmacy pharmacists: Blaug, S., Ch.87 is (15th Ed., 1975, Mack PublishingCompany in the pharmaceutical science of Lei Mingdun, Easton, Pa.18042).These chemical compounds comprise, Powdered, pulpous state, Emulsion, glue, wax shape, oily attitude, oils and fats, water not absorption base, water medium oil or W/O drip type breast attitude, organic Emulsion (Polyethylene Glycol of various molecular weights), semi-solid glue and comprise the organic lubricant semi-solid mixtures.

9-[(1 ' the R that external application is in the present invention used, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) in adenine (DHCeA) and their the 3-position nitrogen analog, the concentration of effective ingredient can be from 0.001gm% to 100gm%; Concentration preferably is approximately from 0.01gm% to 10gm%; Optimum concentration from about 0.1gm% to about 5gm%.9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog can further comprise, the valid density that other help to improve dermal osmosis and the rehabilitative action medicament is arranged, as described in the above-mentioned reference drug standard and those documents in known common skill.

9-[(1 ' the R of external application, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) effect of adenine (DHCeA) and their 3-position nitrogen analog, comprising among the present invention the nucleoside analog phosphate as effective ingredient can assess with the test program of routine, as technical ability known in those documents.Comprise simulated animal model (hypertrophy of epidermis just) and other application of in the reality chemical examination, predicting (N.J.Lowe, Drug Dev.Res.13:147-155,1988).

9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog can be repeated the extraterrestrial lupus erythematosus infringement part that spreads on influenced skin; As: once a day, twice or several times, also can prolong several days till rehabilitation.The toxicity and the sex risk that stimulates are reduced to Min..

Topical application anaesthetic assessment chemical examination

1. suppress the synthetic chemical examination of epidermis DNA.Because strengthening DNA synthetic is the outgrowth typical characteristic of lupus erythematosus epiderm skin, the synthetic of radioactivity DNA precursor enters the skin histology of crossing with the pharmacy chemicals treatment, has been used to assess this materia medica medicament to the synthetic inhibition degree of DNA.Briefly, a kind of LJP394 agent in external application medical ointment is used in the athymism Mus zone of the lupus erythematosus human skin of having used technology transplant very well-known in the document and epidermis.Similarly, in order to measure the effect of anti-hypertrophy anaesthetic, the nude mouse model of suffering from essential fatty acid deficiency can be used in this assay.After treatment about six hours, for internal labeling pulse in 0.1-5 hour, the tissue of having handled is exsomatized, put into tissue culturing medium, comprise .sup.3H-thymidine ribodesose or .sup.3H-bromodeoxyribouridine.With the program of standard DNA is separated from tissue then, the conjugate of .sup.3H-thymidine ribodesose or .sup.3H-bromodeoxyribouridine enters DNA, measures by measuring radiant (cpm/.mu.g of DNA) in separated DNA.The LJP394 agent is to the mensuration of hypertrophy inhibition effect, be by relatively entering the radiant chemical compound of DNA from untreated tissue, the tissue (percent of increase effective ingredient) oneself handled of DNA wherein with different LJP394 immunomodulator compounds.

2. the polyamine biosynthesis suppresses chemical examination.This chemical examination is existing in epidermis cell ODC Ornithine decarboxylase (ODC) based on some.ODC is the rate-limiting enzyme in the formation of polyamine, improves in hypertrophy usually, comprises the epidermal hyperplasia relevant with lupus erythematosus.Improve the ODC radioactivity and also can remove the peel (Lesiewicz, et al., inModels in Dermatology, vol.2, pp.112-116 (H.I.Maibach ﹠amp by horny layer; N.J.Lowe, eds.), 1985) or the application (12-O-tetradecanoylphorbol-13-acetate or TPA) of phorbol ester realize.

3. skin histology section.Transplanting nude mouse, recessive mutation dna murine or the athymism Mus of the trouble essential fatty acid deficiency of lupus erythematosus human skin was handled with the LJP394 thing, skin examination lupus erythematosus overall performane (skin biopsy, inflammation erythema or the like) for handling within 1-15 days, analyze by tissue biopsy then, so that can calculate with the normal structure program in the quantity of the cuticular cellulose of microscopically.The quantity of cuticular cellulose is compared with similar normal inspection and untreated lupus erythematosus skin, measures the therapeutic effect with the LJP394 thing.Equally, inflammation relative extent in the tissue, quantity (just, neutral ball and/or monocyte) that can be by being determined at capillary of skin Diplopterygium glaucum (Thunb ex Houtt) Nakai cell and measure with respect to the telangiectasis of be untreated lupus erythematosus skin and normal control skin.

Similarly, the human clinical trial finishes with Skin biopsy and microscope close examination, adopts ambilateral paired inspection to contrast, and is applied to the about 3cm of skin diameter zone (for example, forearm or lower limb) with a small amount of LJP394 agent.Paired on both side comparing is particular preferred a kind of mode to avoiding entering the risk that the untreated control zone penetrates influence from processing region.

4. the application of recessive mutation dna rat.The born mouse that recessive mutation gene (fsn/fsn) arranged, after ablactation, the white lupus erythematosus skin of its growth promoter thickening day by day with age, this is similar hypertrophy dermatosis in special lupus erythematosus.When growing 42 days, mouse shows as the epidermal hyperplasia of multilamellar Ranvier's membrane and inflammation, as the measurement by leukocyte increasing and capillary of skin, meets all features of human lupus erythematosus.These mouse can be as the human skin disease model, for measuring the therapeutic efficiency service of topical application nucleotide phosphate.Comprise 9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog, be to be used in fsn/fsn mouse back or skin of abdomen 1-5mm part, from 12 hours to 15 days, skin is observed roughly and microscopic examination, up to measure the epidermal hyperplasia degree and above other lupus erythematosus skin symptoms of proposing with standard Dermatology and Histological method.Relevant comparing is the similar part of not handling to mouse, to another fsn/fsn Mus of not handling, to only being ingredient fsn/fsn Mus of handling and the mouse that suddenlys change with not having of handling similarly of fsn with what do not contain nucleotide phosphate.

5. keratinocyte sign.The variation of protein expression is that the hypertrophy relevant with lupus erythematosus skin changes unanimity.To two useful molecules of anomalous condition in the detection of skin is keratin and silk polymeric protein.Mouse special keratic in the epidermis on the base portion gathers, K6, is that the representational molecule that is associated with hypertrophy changes.In the nude mouse or recessive mutation gene (fsn/fsn) mice of suffering from essential fatty acid deficiency, antibody based on the method for surveying K6 is useful to existence and the quantity that is determined at molecule in the base portion upper epidermis, thereby can be as the 9-[(1 ' R of anti-lupus erythematosus, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] indicator of adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog effect uses.

The silk polymeric protein is a kind of albumen in epidermis, usually with in granular layer and transition cell, rather than disappears in the keratinocyte of top, and the keratohyalin granule is associated.Yet in the fsn/fsn Mus, silk polymeric protein remnants are presented on and are in the transition cell superficial cell layer of imitated phase.Thereby the existence of the silk polymeric protein in the keratinocyte of top, as by anti-silk polymeric protein antibody and (or) micro detects, be the feature of lupus erythematosus sexual cell, can be used for the effect of the LJP394 thing preparation of evaluate application on fsn/fsn Corium Mus skin.

(1) DHCaA and 3-position nitrogen analog thereof is synthetic

2,3-(Cyclohexylidenedioxy)-4-hydroxy-4-(2-propyloxy)-butanoic AcidLactone (5) .L-erythruronolactone ¹⁷4 (1.0g, 4.7mmol) be dissolved in 50mL comprised catalytic action some pyridine P-toluene fulfonates (10mol%, 0.12g, in dry 2-propanol 0.47mmol), fractional distillation 1.5 hours.Then mixture is concentrated into slurry, be dissolved in 50mL Et2O, (2x is 50mL) with the saline extraction, by the Na2SO4 drying with H2O, filter, filter liquor concentrates, and mixes slurry and is dissolved in a spot of normal hexane/Et2O (5: 1) mixed liquor, by a small amount of silica gel (5g), produce 1.15g chemical compound 5 (97% output) with normal hexane/Et2O (5: 1) elution: [α] D+45.18 ° (c1.55, MeOH); IR (neat) 1799cm-1; 1HNMR (CDCl3) δ 5.54 (s, 1H, H-4), 4.81 (d, 1H, H-2, J=6Hz), 4.51 (d, 1H, H-3, J=6Hz), 4.02 (heptet, 1H, (CH3) 2CHO, J=7Hz), 1.58 (br s, 10H, cyclohexyl), 1.24and 1.18 (2s, 6H, 2CH3); MS (D-El, CH2Cl2), m/e256 (M+), 213 (Me2CH), 81 (cyclohexyl) .Anal. (C13H2005) C, H.

(-)-2,3-(Cyclohexylidenedioxy)-4-cyclopentenone (1). in the 500-mL three-necked bottle (making) of oven dry, add and contain dimethyl methyl based phosphates (3.98g with interval and the additional funnel of 125-mL, 31.4mmol) the 200mL dry THF, be dissolved in lactone 5 (8.07g, 31.4mmol) the additional funnel of injection among the 25mL THF.Phosphate solution is cooled to-78 ℃ with acetone/the dry ice bath, and (1.6M is normal hexane, and 19.6mL is 31.4mmol) through 8-10 minute dropwise to add n-bu-tyllithium from syringe then.When additive reaction was finished, solution stirred down at-78 ℃ and removed the dry ice bath in 2.5 hours subsequently.When solution is reduced to room temperature (～30 minutes), mixture is injected the 500mL Et2O that comprises 100mL H2O, shake, so organic layer separates.With extra 100mL Et2O extraction water, organic layer chemical combination.The Et2O layer cleans with saline, by the Na2SO4 drying, filters, and concentrates (＜50 ℃) to oil (coarse, 6g, 90%).Oil is dissolved among the Et2O, adds in the silicagel column (10g), uses the Et2O elution, provides 4.85g (80%) colourless liquid (solidifying, with Et2O/ normal hexane recrystallize) in refrigerating plant: mp65 ℃; [α] D-74 ° (c3.0, MeOH); IR (neat) 1734cm-1; 1H NMR (CDCl3) δ 7.60 (dd, 1H, H-4, J=7Hz), 6.19 (d, 1H, H-5, J=7Hz), 5.26 (dd, 1H, H-3, J=6Hz), 4.41 (d, 1H, H-2, J=6Hz), 1.58 (m, 10H); MS (D-El, CH2Cl2), m/e 194 (M+) .Anal. (C11H1403) C, H.

2,3:5,6-O-Dicyclohexylidene-D-mannonolactone (7a). (53g, (33.5g 335mmol), at room temperature stirred 1.5 hours then to add a part of CrO3 in the solution of 500mL CH2Cl2 670mmol) to containing pyrimidine.2,3:5, (19g 56mmol) is dissolved among the 50mL CH2Cl2 6-di-O-cyclohexylidene-D-mannose (18), adds rapidly in pyrimidine/CrO3 mixture.1.5 hour remove solution later on, (2X 200mL) thoroughly pulverizes tar with Et2O.Bonded organic layer filters and fills Celite by adding, and filter liquor concentrates.Residue is absorbed by 250mL Et2O, and (2x, 200mL) (3x 200mL) with the saline solution extraction, by the Na2SO4 drying, filters .H2O with the HCL that dilutes.Filter liquor is concentrated into drying, and the solid that obtains is dissolved among a small amount of Et2O, uses silicagel column (30g), with Et2O/hexane (1: 1) elution to obtain required chemical compound 7a (15.9g, 84% output): mp 108-109 ℃ (lit.18mp108-110 ℃).

2,3-O-Cyclohexylidene-D-mannonolactone (7b). (4g 12mmol) is dissolved among 100mL EtOH and the 100mL H2O lactone 7, adds 2g Dowex 50W (H+).Mixture stirred 16 hours down at 40 ℃, removed resin by filtration subsequently, concentrating filtrate.The oil that obtains is dissolved in a small amount of EtOAc/ normal hexane (1: 1), and the solid of formation (D-mannonolactone) removes by filtration.Filter liquor is used silicagel column (10g), remaining raw material (＜200mg) by separating with 75mL EtOAc/ normal hexane (1: 1) elution, required chemical compound provides 2.6g required compound mucilage (85% output) by the EtOAc elution: [α] D+42 ℃ of (c1.1, CHCL3). chemical compound (mp, NMR, IR) with 2,3-O-cyclohexylidene-L-erythruronolactone is identical, be previous Beer et al.17 reported (lit.17[α] D-39.8 ℃ (c1.65 is CHCL3) for the enantiomer of correspondence)

(-)-2,3-(Cyclohexylidenedioxy)-4-hydroxy-4-(2-propyloxy) butanoicAcid Lactone (9). (1.0g 4.7mmol) is transformed into 9 according to the method that obtains chemical compound 5 to chemical compound 8.9: obtain 1.17g (98%); [α] D-45.5 ℃ (c5.57, MeOH). the data of material (bp, NMR, IR) identical with corresponding enantiomer 5.

(+)-4,5-(Cyclohexylidenedioxy)-2-cyclopentenone (2). (0.5g 2.0mmol) obtains by the identical method described in the chemical compound 1 chemical compound 2 from 9.2: obtain 0.30g (77%); [α] D+74 ℃ (c1.0, MeOH). the data of material (mp, NMR, IR) identical with corresponding enantiomer 1.

(-)-2,3-(Cyclohexylidenedioxy)-4-cyclopentenone-1-ol (10). cyclopentenone 1 (2.04g, 10.5mmol) and CeCL3-7H2O (3.91g, 10.5mmol) add among the 60mL MeOH and be cooled to 0 ℃, add NaBH4 (0.48g, 12.6mmol) (foaming), mixture allows to stir 20 minutes.With 1N HCL pH value is adjusted to 7.0 then, adds 200mL Et2O, a small amount of washed with saline solution of organic layer.The Et2O layer filters by the Na2SO4 drying, is condensed into yellow liquid liquid is dissolved among a small amount of CH2CL2, adds in the silicagel column (5g), obtains 1.7g (83%) colourless liquid by elution: and [α] D-23.59 ℃ (c4.45, MeOH); 1H NMR (CDCl3) δ 5.84 (s, 2H, H-4and H-5), 4.96 (d, 1H, H-1, J=6Hz), 4.69 (t, 1H, H-3, J=6Hz), 4.53 (dd, 1H, H-2, J=6Hz) 1.55 (m, 10H, cyclohexyl); MS (D-El, CH2Cl2), m/e196 (M+), 8l (cyclohexyl) .Anal. (C11H1603) C, H.

(-)-2,3-(Cyclohexylidenedioxy)-1-[p-tolylsulfonyl) oxy]-cyclopent-4-ene (11). cyclopentenol 10 (0.22g, 1.12mmol) and chlorination p-tosyl (0.41g, 2.14mmol) be dissolved among the 10mL CH2Cl2, add then Et3N (0.46g, 4.48mmol).Mixture at room temperature stirred 24 hours, subsequently with H2O and saline solution extraction mixture.Organic layer filters by the Na2SO4 drying, is concentrated into drying.Then solid is dissolved in a small amount of CH2Cl2/ normal hexane (1: 1), is contained on 2-mm chromatograph (Model7429T) photographic plate (silica gel), with CH2Cl2/ normal hexane (1: 1) elution to obtain coarse product: mp110-111 ℃ of 0.31g (80%); [α] D-62.26 ℃ (c2.65, CHCL3); 1H NMR (CDCl3) δ 7.85 (d, 2H, aromatic J=8Hz), 7.27 (d, 2H, aromatic J=8Hz), 5.87 (m, 2H, H-4and H-5), 5.3 (d, 1H, H-1, J=5Hz), 4.87 (d, 1H, H-3, J=5Hz); 4.53 (t, 1H, H-2, J=5Hz), 2.42 (s, 3H, CH3), 1.50 (m, 10H); MS (D-El, CH2Cl2), m/e350 (M+), 155 (tosylate), 81 (cyclohexyl) .Anal. (C18H2205S) C, H.

(-)-9-[2 ', 3 '-(Cyclohexylidenedioxy) cyclopent-4 '-enyl]-adenine (12). tosyl 11 (1.45g, 4.1mmol) be dissolved among the 3mL DMF, join in the 10mL DMF solution that contains adenine sodium [by with NaH (80%, 0.35g, 12.3mmol) join contain adenine slurry (1.66g, preparation adenine sodium among 10mL DMF 12.3mmol)].Mixture stirred 1-2 days down at 50 ℃, removed DMF by distillation then.Adenine is dissolved among the CH2Cl2 (50mL), for dissolved substances is come out by isolated by filtration.Filter liquor is concentrated into drying, and solid is dissolved among a small amount of CH2Cl2/EtOH (9: 1), is contained on 4-mm chromatograph (Model 7429T) photographic plate, collects 12:mp87 ℃ of 0.56g (45%) chemical compound; [α] D-23.59 ° (c4.45, MeOH); 1H NMR (CDCl3) δ 8.36 (s, 1H, H-2), 7.68 (d, 1H, H-8), (6.58 brs, 2H, NH2, exchanged D2O), 6.33 (dd, 1H, H-4 ', J=6Hz, J=2Hz), 5.93 (dd, 1H, H-5 ', J=6Hz, J=2Hz), 5.63 (d, 1H, H-1 ', J=1Hz), 5.49 (d, 1H, H-3 ', J=6Hz), 4.71 (d, 1H, H-2 ', J=6Hz), 1.60 (m, 10H); MS (D-El, MeOH), m/e313 (M+), 135 (base, adenine), 81 (cyclohexyl) .Anal. (C16H19N5023/4H2O) C, H, N.

(-)-9-[2 ', 3 '-(Cyclohexylidenedioxy) cyclopent-4 '-enyl]-3-deazaadenine (13). chemical compound 13 prepares as 12 mode, by from 11 (170mg, 0.5mmol) beginning, (100mg 0.75mmol) replaces: obtain 100mg (67%) by 3-denitrogenation adenosine (25) except adenine; Mp156-158 ℃; [α] D-164 ° (c0.5, MeOH); UVmax263nm, 267nm (sh); 1HNMR (CDCl3+D2O) δ 7.87 (d, 1H, H-6, J=6Hz), 7.65 (s, 1H, H-2), 6.79 (d, 1H, H-7, J=6Hz), 6.38 (d, 1H, H-4 ', J=5Hz), 6.10 (d, 1H, H-5 ', J=5Hz), 5.36 (m, 1H, H-1 ' and H-3 ' J=6Hz) 4.58 (d, H-2 ', J=6Hz), 1.62 (m, 10H); MS (D-El, CH2Cl2), m/e312 (M+), 134 (3-deazaadenine), 81 (cyclohexyl) .Anal. (C17H20N4021/2H2O) C, H, N.

The conventional method of chemical compound 12 and 13 deprotection bases.Chemical compound 12 or 13 usefulness 20mL H2O are mixed, add 1mL 6N HCL, mixture at room temperature stirs and showed there is not the raw material residue up to TLC (CH2Cl2/EtOH 9: 1) in 3-6 hour.Solution concentration is dissolved in solid among the 1-2mL H2O to dry (forming azeotropic mixture with EtOH), uses Dowex 1x8-50 (H+) post.Product is concentrated into drying with the aqua ammonia elution of dilution.Chemical compound and ethanol azeotropic drying.

(-)-9-(trans-2 ', trans-3 '-Dihydroxycyclopent-4 '-enyl)-and adenine (14): obtain 230mg (98%); Mp175-176 ℃; [α] D-170 ° (c1.0, H2O); 1HNMR (DMSO-d6+D2O) δ 8.47 (s, 2H, H-2, H-8), 6.09 (m, 2H, H-4 ' andH-5 '), 5.45 (d, 1H, H-1 ', J=6Hz), 4.55 (d, 1H, H-3 ', J=6Hz), 4.25 (dd, 1H, H-2 ', J=6Hz); MS (QP-El-Probe), m/e 233 (M+1), 216 (HO), 135 (base, adenine) .Anal. (C10H11N502H2O) C, H, N.

(-)-9-(trans-2 ', trans-3 '-Dihydroxycyclopent-4 '-enyl)-and 3-deazaadenine (15): obtain 305mg (98%); Mp140 ℃; [α] D-210 ° (c1.1, MeOH); UVmax263nm, and 267nm (sh) .1H NMR (DMSO-d6+D2O) δ 8.03 (s, 1H, H-2), 7.64 (d, 1H, H-6, J=6Hz), 6.76 (d, 1H, H-7, J=6Hz), 6.13 (m, 2H, H-4 ' and H-5 '), 5.29 (d, 1H, H-1 ', J=5Hz), 4.49 (d, 1H, H-3 ', J=5Hz), 4.05 (dd, 1H, H-2 ', J=5Hz); MS (D-El, MeOH), m/e 232 (M+) peak match Δ=0.0007,215 (HO), 134 (base, 3-deazaadenine) .Anal. (C11H12N402EtOH) C, H, N.

(2) DHCeA and 3-position nitrogen analog thereof is synthetic

(2R，3R，4S)-2，3-(Cyclohexylidenedioxy)-4-methylcyclopentanone(4c)。Right-40 ℃ of suspension Copper diiodide (I) (Aldrich Gold Label in the 50ml ether, 3.43g, 18mmol) dropwise add lithium methide (1.2M is in ether), in 45 minutes processes, up to the yellow mercury oxide that begins to form dissolved (25mL, 30mmol).Reactant mixture is warming up to 0 ℃ then, then in 10mL THF/ ether (3: 2), dropwise add solution 3 (650mg, 3.6mmol), 5-10 minute.Reactant mixture allows to be warming up to ambient temperature then.(comprise the heating-up time) after one hour, mixture is cooled to 0 ℃ again, adds 25mL15% acetic acid (at first lentamente).This mixture cleans with the saturated NH4Cl solution of 50mL then, the NH4OH solution of 2 * 75mL dilution, 50mL H2O.Organic facies is carried out drying by Na2SO4, filters, and concentrates in a vacuum, and filtering residue passes through silica gel (15g, ether/normal hexane, 1: 1) to obtain 470mg (67%) 4c white crystal: mp30-32 ℃; 1H-NMR (300MHZ, CDCL3) δ 1.03 (d, J=7Hz, 3H), 1.20-1.80 (m, 10H), 1.96 (d, J=18Hz, 1H), 2.55 (d, J=7Hz, 1H), 2.82 (dd, J=18,8Hz, 1H), 4.23 (d, J=5Hz, 1H), 4.49 (d, J=5Hz 1H); 13C-NMR (75MHz, CDCL3) δ 19.1,23.6, and 23.8,24.9,31.1,34.2,36.5,41.4,77.7,82.6,112.8,214.4; IR (neat) 2920,2850,1750,1445,1400,1380,1365,1330,1275,1245,1230,1160,1140,1110,1085,1070,1035,960,940,925,905,845,825cm-1; MS (EI) m/e 211 (M+1), 210 (M+), 181,167,140,125,99,95,81,69,55,42; [α] D=-20 ° of (c=0.705, CHCL3) .Anal. (C12H1803) C, H.

(1S, 2S, 3R, 4S)-2,3-(Cyclohexylidenedioxy)-4-methylcyclopentanol (7c). the 1M that right-78 ℃ of 681mg (3.24mmol) 4c solution in 60mL CH2CL2 (store surpass 3 ° of A molecular sieves) add 4.85mL in CH2CL2 (4.85mmol) diisobutylaluminium hydride above 2 minutes.3.5 after hour, add MeOH (8mL) (beginning dropwise adds), reactant mixture is warming up to ambient temperature.Add entry (15mL) then, after a few minutes, colloidal suspension is inhaled into filtration, cleans with a large amount of CH2CL2 and H2O.After the CH2CL2 layer is removed, with the extra CH2CL2 aqueous phase extracted of 2 * 150mL.Bonded organic facies is cleaned with 200mL H2O, by the Na2SO4 drying, filters vacuum concentration.Filtering residue passes through silica gel (35g, Et2O/hexane, 1: 1) to obtain the 7c colorless transparent oil of 655mg (95%): 1H-NMR (500MHz, CDCL3) δ 0.93 (dd, J=3,8Hz, 3H), 1.30-1.75 (m, 11H), 2.15 (m, 1H), 2.50 (d, J=9Hz, 1H, OH), 4.10 (m, 1H), 4.25 (d, J=6Hz, 1H), 4.50 (dd, J=6,6Hz, 1H); 13C-NMR (125MHz, CDCL3) δ 17.6,23.5, and 23.9,25.1,33.7,35.4,35.8,38.2,71.3,78.5,85.6,111.9; IR (neat) 3480,2930,2860,1450,1405,1370,1285,1165,1145,1105,1035,960,950,925,910,850cm-1; MS (EI) m/e 212 (M+), 183,169,97,81,69,55,41; [α] D=-23 ° of (c=0.340, CHCL3) .Anal. (C12H2003) C, H.

(1’R，2’S，3’R，4’S)9-[2’，3’-(Cyclohexylidenedioxy)-4’-methylcyclopentan-1’-yl]adenine(8c)。(498mg, 2.35mmol) ((0.395mL, 663mg 2.35mmol), dropwise add above 8 minutes 2.58mmol) to add Trifluoromethanesulfonic anhydride for 0.210mL, 204mg for solution and pyrimidine to 0 ℃ of 7c in 15mLCH2CL2.After 40 minutes, use the cold H2O of 7mL will react quenching.Mixture injects separatory funnel with additional 15mL of CH2CL2.Use the cold H2O of 2 * 25mL to clean organic facies then, by the Na2SO4 drying, filter, vacuum concentration is to obtain the natural triflate of 880mg.(954mg, 7.05mmol), (7.0mmol), (308mg 1.17mmol) is heated to 70 ℃ and continues 4 hours the 18-hat-6 among the 20mL DMF NaH adenine suspension, is cooled to room temperature then for 60%dispersion in mineraloil, 280mg.This suspension is added triflate in 5mL DMF, reactant mixture is stirred all night.Mixture (is inhaled in 2 * 25mL) and filters and extraction at CH2CL2 (75mL) and NaCL saturated solution.After the Na2SO4 drying, organic facies is filtered and concentrates in a vacuum.Residue is developed in preliminary TLC plate (20cm * 20cm * 200 μ m, EtOAc/ normal hexane 2: 1, develop separately) to obtain 8c:mp80-83 ℃ of 135mg (17%) of by silica gel (50g, CH2CL2/EtOH, 9: 1) then; 1H-NMR (300MHz, CDCL3) δ 1.25 (d, J=6Hz, 3H), 1.35-1.85 (m, 10H), 2.15-2.60 (m, 3H), 4.45 (dd, J=5,7Hz, 1H), 4.70 (m, 1H), 5.10 (dd, J=5,7Hz, 1H), 6.00 (s, 2H, NH2), 7.85 (s, 1H), 8.35 (s, 1H); 13C-NMR (75MHz, CDCL3) δ 18.0,23.4, and 24.0,25.0,34.6,37.4,38.8,38.9,62.1,83.3,85.4,114.5,120.5,139.9,150.0,152.7,155.6; IR (KBr) 3320,3160,2925,2860,1640,1595,1570,1470,1415,1370,1330,1300,1250,1160,1090,1070,1055,940,925,910,850,795,725,645cm-1; MS (EI) m/e330 (M+1), 300,286,231,216,162,136,108,79,67,55,41; [α] D=-50 ° of (c=0.402, CHCL3) .Anal. (C17H23N502) C, H, N.

(1’R，2’S，3’R，4’S)-9-(2’，3’-Dihydroxy-4’-methylcyclopentan-1’-yl)adenine(1c)。128mg (0.39mmol) 8c is dissolved among 20mL 0.3 NHCL.After 18 hours, solvent is under reduced pressure removed, and residue is by Dowex 50W (H+), at first water elution, then with the NH4OH that dilutes to obtain 92mg (95%) 1c white solid: mp172-174 ℃; 1H-NMR (300MHz, DMSO-d6+D2O) δ 1.10 (d, J=7Hz, 3H), 1.60 (m, 1H), 1.95 (m, 1H), 2.25 (m, 1H), 3.60 (dd, J=5,6Hz, 1H), 4.35 (dd, J=6,8Hz, 1H), 4.65 (m, 1H), 8.15 (s, 1H), 8.25 (s, 1H); 13C-NMR (75MHz, DMSO-d6+D2O) δ 19.4,34.7, and 37.8,60.7,74.7,76.5,119.4,140.9,149.9,152.6,156.1; IR (KBr) 3330,3180,2900,1660,1605,1570,1485,1450,1430,1335,1315,1260,1220,1135,1110,1080,830,795,720,660,630cm-1; MS (EI) m/e calcd for C11H15N502249.1226, found 249.1220; 250 (M+1), 249 (M+), 190,178,162,136,135,108,55,41; [α] D=-36 ° of (c=0.994,0.3NHCL) .Anal. (C11H15N502) C, H, N.

(2R，3R，4R)-2，3-(Cyclohexylidenedioxy)-4-vinylcyclopentanone(4e)。Right-5 ℃, (785mg, 4.15mmol) suspension added the 1M ethylene magnesium bromide in THF (8.25mmol) of 8.25mL to Copper diiodide among the 25mL THF (I), through 1.5-2.0 minute.Suspension is stored in-5 ℃, comprises the addition time, and is cooled to-78 ℃ then in lasting 3 minutes.(500g 2.60mmol) dropwise joins reactant mixture with enone3 among the 10mL THF.After 1 hour, dry ice/acetone batch is replaced by ice bath, and reactant mixture is allowed to 0 ℃.In this temperature, reaction is quenched with 50mL 15% acetic acid (degassing) after 15 minutes.Program is the same with 4c, with obtain the 4e colorless transparent oil of 560mg (98%): 1H-NMR (500MHz, CDCL3) δ 1.30-1.70 (m, 10H), 2.30 (d, J=18Hz, 1H), 2.85 (dd, J=18,9Hz, 1H), 3.15 (m, 1H), 4.20 (d, J=5Hz, 1H), 4.60 (d, J=5Hz, 1H), 5.10 (m, 2H), 5.85 (m, 1H); 13C-NMR (125MHz, CDCL3) δ 23.6,23.8, and 24.9,34.3,36.5,38.5,39.7,77.4,80.9,113.0,116.3,137.2,213.4; IR (neat) 2930,2850,1755,1640,1445,1430,1400,1365,1335,1290,1270,1250,1230,1160,1105,1070,1035,995,960,925,845,830,775cm-1; MS (EI) m/e222 (M+), 193,179,140,107,97,81,67,55,41; [α] D=-192 ° of (c=0.391, CHCL3) .Anal. (C13H1803) C, H.

(1S; 2S, 3R, 4R)-2,3-(Cyclohexylidenedioxy)-4-vinylcyclopentanol (7e) .y with 633mg (2.85mmol) 4e be used in 7c and go up identical experimental arrangement, and silica gel chromatography, with obtain the clear, colorless oil of 567mg (89%) 7e: 1H-NMR (300MHz, CDCl3) δ 1.30-1.75 (m, 10H), 1.90 (m, 2H), 2.50 (d, J=7.5Hz, 1H, 0H), 2.75 (m, 1H), 4.05 (m, 1H), 4.50 (m, 2H), 5.10 (m, 2H), 5.75 (m.1H); 13C-NMR (75MHz, CDCl3) δ 23.7,24.1, and 25.2,33.8,35.9,36.0,44.5,71.0,78.5,83.8,112.2,115.2,138.1; IR (neat) 3500 (br), 2930,2850,1640,1450,1370,1285,1165,1090,1035,995,950,930,915,850,835cm-1; MS (EI) m/e 224 (M+), 195,181,109,91,81,67,55; [α] D=-9 ° of (c=0.450, CHCL3) .Anal. (C13H2003) C, H.

(1 ' R, 2 ' S, 3 ' R, 4 ' R)-9-[2 ', 3 '-(Cyclohexylidenedioxy)-4 '-vinylcyclopentan-1 '-yl] adenosine (8e). use the synthetic identical experimental arrangement with 8c, synthesize 8e. acquisition chemical compound 8e (200mg with 470mg (2.10mmol) 7e; 28%) white crystals body: mp80-82 ° C; 1H-NMR (300MHz, CDCl3) δ 1.30-1.85 (m, 10H), 2.45 (m, 2H), 2.80 (m, 1H), 4.65 (dd, J=7,7Hz, 1H), 4.80 (m, 1H), 5.20 (m, 3H), 5.95 (m, 1H), 6.25 (br s, 2H, NH2), 7.85 (s, 1H), 8.35 (s, 1H); 13C-NMR (75MHz, CDCl3) δ 23.4,23.9, and 25.0,34.5,36.5,37.4,48.1,61.7,82.9,83.4,114.6,115.9,120.4,137.7,139.8,149.9,152.7,155.7; IR (KBr) 3320,3160,2925,2855,1640,1595,1570,1470,1415,1370,1330,1300,1250,1160,1110,1090,1070,1055,920,850,800,725,650cm-1; MS (EI) m/e342 (M+1), 341 (M+), 312,298,243,228,190,162,136,135,108,91,77,65,55,41; [α] D=-4 ° of (c=0.220, CHCL3) .Anal. (C18H23N502) C, H, N.

(1 ' R, 2 ' S, 3 ' R, 4 ' R)-9-[2 ', 3 '-Dihydroxy-4 '-vinylcyclopentan-1 '-yl] adenine (1e). use and the identical program of acquisition 1c, obtain 140mg (90%) 1e white powder with 204mg (0.60mmol) 8e: mp210 ℃ of dec; 1H-NMR (300MHz, DMSO-d6+D2O) δ 1.92 (m, 1H), 2.58 (m, 1H), 3.84 (dd, J=6,6Hz, 1H), 4.33 (dd, J=6,6Hz, 1H), 4.69 (m, 1H), 5.10 (m, 2H), 6.00 (m, 1H), 8.15 (s, 1H), 8.23 (s, 1H); 13C-NMR (75MHz, DMSO-d6+D2O) δ 31.6,47.1, and 60.0,74.3,74.7,114.5,119.3,140.2,140.3,149.5,152.1,156.0; MS (EI) m/e calcd for C12H15N502 261.226, found261.1221; 261 (M+1), 244,232,202,190,162,149,136,108,78,63,41; [α] D=+8 ° (c=0.982,0.3NHCl); HPLC method A, Rf=13.18min; Method B, Rf=14.18min.

(1 ' R, 2 ' S, 3 ' R, 4 ' S) 9-[2 ', 3 '-Dihydroxy-4 '-ethylcyclopentan-1 '-yl] adenine (1g). with the 1e (100mg among the 60ml MeOH, 0.38mmol) solution adds 10mg PtO2, suspension was placed under the hydrogen environment (24psi) 15 hours. filtering suspension liquid then, and filter liquor concentrates in a vacuum to obtain 101mg (100%) 1g ecru solid: mp191-192 ℃; 1H-NMR (300MHz, DMSO-d6+D2O) δ 0.92 (t, J=7Hz, 3H), 1.40 (m, 1H), 1.50-1.85 (m, 3H), 2.25 (m, 1H), 3.70 (dd, J=5,5Hz, 1H), 4.35 (dd, J=9,6Hz, 1H), 4.65 (dd, J=9,18,1H), 8.10 (s, 1H), 8.20 (s, 1H); 13C-NMR (75MHz, DMSO-d6+D2O) δ 12.5,27.2, and 32.4,44.9,60.1,74.4,74.5,119.4,140.1,149.9,152.4,156.0; IR (KBr) 3330,3180,2960,2920,1655,1605,1570,1485,1450,1420,1335,1315,1255,1215,1120,1105,1080,720,655cm-1; MS (EI) m/e calcd for C12H17N502263.1382, found263.1388; 263 (M+), 234,216,190,178,162,136,78,63,45.Anal. (C12H17N502.1/10H20) C, H, N.

(2R, 3R, 4R)-2,3-(Cyclohexylidenedioxy)-4-phenylcyclopentanone (4f). method A. is with Copper diiodide (the I) (2.95g in the well-beaten 75ml absolute ether, 15.5mmol, AldrichGold Label) and suspension is cooled to-35 ℃, dropwise adds phenyl lithium (15.5ml, 2.0M in cyclohexylamine/ether (2: 1), 31.0mmol) through 10 minutes.After 30 minutes, reaction is allowed to be warming up to 0 ℃, and (1.0g, 5.15mmol) solution is through several clocks to add 3 among the 10ml THF therein.0 ℃ of situation is after following 1 hour, and reaction is quenched with 25ml 15% acetic acid.Mixture is handled with the method that 4c describes.The oily filtering residue obtains 972mg (69%) 10 pale yellow oil by silica gel (50g, normal hexane/ether, 2: 1).

(74mg, 0.39mmol) suspension added phenyl-magnesium-bromide (3M is in ether for 260 μ l, 0.78mmol) through 1.5 minutes to method B. with the Copper diiodide (I) among-5 ℃ of 5ml THF.Reactant mixture is cooled to-78 ℃, and (100mg, 0.52mmol) solution was through 5 minutes dropwise to add 3 among the 2mL THF.At-78 ℃ mixture was stirred one hour, be warming up to 0 ℃ then.After 20 minutes, mixture quenches with 10mL 20% acetic acid, extracts between 75mL ether and 50mL 6% oxyammonia.With 2 * 50mL extracted with diethyl ether water layer, bonded organic facies is cleaned with 25mL ammonium chloride saturated solution, by the Na2SO4 drying, filters, and concentrates in a vacuum.Oily filtering residue moment is by silica gel (35g, normal hexane/ether, 4: 1), to obtain 111mg (79%) 10 pale yellow oil:

1H-NMR(300MHz，CDCl3)δ1.35-1.75(m，10H)，2.55(d，J＝20Hz，1H)，3.10(dd，J＝9，19Hz，1H)，3.70(d，J＝8Hz，1H)，4.35(d，J＝5Hz，1H)，4.70(d，J＝5Hz，1H)，7.10-7.40(m，5H)；13C-NMR(75MHz，CDCl3)δ23.6，23.9，24.9，34.3，36.7，40.5，42.7，77.8，83.1，113.2，126.9，127.2，129.1，141.3，214.0；IR(neat)3060，3030，2930，2850，1755，1500，1450，1370，1290，1270，1235，1160，1110，1035，985，945，930，910，850，830，770，700cm-1；MS(EI)m/e272(M+)，243，229，157，145，140，131，115，104，97，91，77，69，55，41；[α]D＝-148°(c＝0.194，CHCl3).Anal.(C17H2003)C，H。

(1S, 2S, 3R, 4R)-2, and 3-(Cyclohexylidenedioxy)-4-phenylcyclopentanol (7f). the synthetic described same quadrat method of reaction with 7c, use 900mg (3.31mmol) 4f.Unprocessed product purifies by silicagel column (normal hexane/ether, 4: 1 according to 1: 1), and 7f is provided (670mg; 74%) water white transparency oily: 1H-NMR (500MHz, CDC13) δ 1.35-1.85 (m, 10H), 2.05 (m, 1H), 2.23 (m, 1H), 2.67 (d, J=6Hz, 1H, exchanges withD2O), 3.43 (m, 1H), 4.20 (m, 1H), 4.60 (dd, J=6,6Hz, 1H), 4.70 (dd, J=3,6Hz, 1H), 7.15-7.40 (m, 5H); 13C-NMR (125MHz, CDCl3) δ 23.5,24.0, and 25.1,34.0,36.0,38.5,47.1,70.6,79.4,85.8,113.3,126.4,127.2,128.5,141.9; IR (neat) 3500,3050,3020,2930,2850,1495,1445,1370,1285,1165,1100,1040,945,930,755,700cm-1;

MS(EI)m/e274(M+)，245，231，159，141，131，117，104，99，91，81，77，69，55，41；[α]D＝+26°(c＝0.239，CHCl3).Anal.(C17H2203)C，H。

(1 ' R, 2 ' S, 3 ' R, 4 ' R)-9-[2 ', 3 '-(Cyclohexylidenedioxy)-4 '-phenylcyclopentan-1-yl] adenine (8f). reaction is used 516mg (1.88mmol) 7f with synthesizing identical method with 8c.Separate white crystalline solid: mp235-237 ℃ of chemical compound 8f (396mg, 54%);

1H-NMR(500MHz，CDCl3)δ1.35-1.85(m，10H)，2.70(m，1H)，2.90(dd，J＝12，25Hz，1H)，3.35(m，1H)，4.85(m，2H)，5.20(dd，J＝5，7Hz，1H)，5.60(brs，2H)，7.27(m，2H)，7.37(m，3H)，7.87(s，1H)，8.36(s，1H)；13C-NMR(125MHz，CDCl3)δ23.4，24.0，25.0，34.6，37.5，37.7，49.5，62.0，83.0，85.2，114.8，120.4，126.9，127.1，128.7，140.0，141.0，150.0，152.8，155.7；IR(KBr)3290，3140，2920，1665，1635，1600，1565，1470，1425，1365，1330，1300，1240，1160，1115，1095，930，700cm-1；

MS(EI)m/e392(M+1)，362，348，293，278，162，158，141，136，128，115，108，91，84，55；[α]D＝+16°(c＝0.376，CHCl3).Anal.(C22H25N502)C，H，N。

(1 ' R, 2 ' S, 3 ' R, 4 ' R)-9-[2 ', 3 '-Dihydroxy-4 '-phenylcyclopentan-1-yl] adenine (1f). the hydrolysis ketal is done, and produces 200mg (84%) 1f white powder with the synthetic described the same method of 1c with 300mg (0.77mmol) 8f: mp194-195 ℃;

1H-NMR(300MHz，DMSO-d6+D2O)δ2.25(dd，J＝12，24Hz，1H)，2.45(m，1H)，3.10(m，1H)，4.10(dd，J＝6，6Hz，1H)，4.47(dd，J＝6，6Hz，1H)，4.80(m，1H)，7.25-7.45(m，5H)，8.20(s，1H)，8.35(s，1H)；13C-NMR(75MHz，DMSO-d6+D2O)δ34.1，49.6，61.0，74.8，76.2，119.5，126.8，127.9，128.9，141.0，143.4，149.9，152.7，156.1；IR(KBr)3400，3320，3140，3020，2925，1660，1605，1570，1480，1415，1335，1325，1250，1105，1050，760，700，645cm-1；MS(EI)m/e?calcd?forC16H17N5O2311.1382，found?311.1377；312(M+1)，178，162，136，135，115，108，91，77，44；[α]D＝+14°(c＝0.20，H2O).Anal.(C16H17N502)C，H，N。

(1 ' R, 2 ' S, 3 ' R)-9-[2 ', 3 '-Dihydroxycyclopentan-1 '-yl] adenine (1b). with the 2b17 (100mg among the 100ml MeOH, 0.425mmol) solution adding 10mg PtO2, suspension is placed in following 6 hours of hydrogen (25psi) environment.Catalyst separation is removed, and chemical compound concentrates in a vacuum and obtains 101mg (100%) 2 ecru solid: mp218 ℃ dec;

1H-NMR(300MHz，DMSO-d?6+D2O)δ1.6-2.25(m，4H)，3.95(m，1H)，4.25(dd，1H)，4.45(m，1H)，8.40(s，1H)，8.55(s，1H)；13C-NMR(75MHz，DMSO-d6)δ25.7，28.8，59.5，70.5，76.2，119.5，140.5，149.7，152.0，156.0；MS(EI)m/e?calcdfor?C10H13N5O2235.1069，found?235.1071；235(M+)，162，136；[α]D＝-50°(c＝0.80，H2O).Anal.(C10H13N502)C，H，N。

2,3-O-cyclohexylidene-5-O-methylsulfonyl-D-ribonic Acid γ-Lactone (12). in the time of will-5 ℃ among the 200ml CH2Cl2 2,3-O-cyclohexylidene-D-ribonicAcid γ-Lactone (35) T (15.77g, 69.1mmol) and triethylamine (6.99g, 69.1mmol) solution dropwise adds and contain chlorination sulfonyl methane (7.92g, 50ml CH2Cl2 69.1mmol).Sluggish is to room temperature, and stirs 4 hours. and mixture is cooled to 0 ℃ then, slowly adds the cold H2O of 50ml.Stir after a few minutes, layer is separated, cleans organic facies with 2 * 100ml H2O, by the Na2SO4 drying.After filtering and concentrating, obtain orange and solidify with interior room temperature 3 hours.This solid from CH2Cl2/ normal hexane recrystallize to obtain 19.1g (90%) 12 ecru solid.The analysis pure sample is separated, by from a spot of this material of ethyl acetate/normal hexane recrystallize: mp110 ℃;

1H-NMR(300MHz，CDCl3)δ1.35-1.71(m，10H)，3.06(s，3H)，4.47(m，2H)，4.78(d，J＝6Hz，1H)，4.80(m，1H)，4.83(d，J＝6Hz，1H)；13C-NMR(75MHz，CDCl3)δ23.7，23.8，24.7，34.9，36.3，37.6，68.3，74.7，76.9，79.4，114.8，173.4；IR(KBr)2943，1778，1363，1178，1113，1068，1008，988，963，928，883，853，808，783，723cm-1；MS(EI)m/e306(M+)，277，263，79，55；[α]D＝-40°(c＝0.430，CHCl3).Anal.(C12H1807S)C，H。

2,3-O-cyclohexylidene-5-deoxy-5-iodo-D-ribonic Acid γ-Lactone (13). sodium iodide (607mg, 4.05mmol) and 12 (497mg 1.62mmol) is dissolved in the 20ml butanone, and reaction vessels clogs with dried stopper.This mixture stirred 30 minutes down at 50 ℃, and the end adds 20ml H2O.After layer is separated, with 2 * 20ml ether aqueous phase extracted.Bonded organic layer cleans with 30ml H2O, by the Na2SO4 drying, filters, and concentrates to obtain the viscosity butter in a vacuum.This butter is by silica gel (22g, normal hexane/EtOAc; 4: 1) to produce (90%) 13 colorless transparent oil.This clean oil finally is frozen into and remains specpure light brown solid, and acceptable elementary analysis is provided:

mp61-63?℃；1H-NMR(300MHz，CDCl3)δ1.35-1.72(m，10H)，3.43(m，2H)，4.60(d，J＝6Hz，1H)，4.64(dd，J＝4，4Hz，1H)，4.95(d，J＝6Hz，1H)；13C-NMR(75MHz，CDCl3)δ5.8，23.7，23.8，24.7，34.9，36.1，74.9，80.0，81.0，114.8，173.2；IR(KBr)2945，2925，1790，1447，1418，1375，1350，1285，1252，1232，1215，1176，1158，1108，1050，1023cm-1；MS(EI)m/e338(M+)，309，295，98，69，55；[α]D＝-21°(c＝2.87，CHCl3).Anal.(C11H15IO4)C，H。

2,3-O-cyclohexylidene-5-deoxy-4,5-didehydro-D-ribonic Acid γ-Lactone (14). contain 13 (810mg, 2.40mmol) and diazabicylo (DBU, 400mg, 15mL benzole soln 2.64mmol) clogs with dried stopper, at room temperature allows to stir all night.Reactant is filtered then, cleans white precipitate with dried benzene, and filtrate is condensed into the glassy yelloe oily in a vacuum.This oil moment, the silica gel (5g in sintered glass funnel, EtOAc/ normal hexane, 1: 1) by sealing was to obtain 410mg (82%) 14 water white transparency oily, purity about 95% by 1H-and 13C-NMR.Because the unstability of this chemical compound, it is impossible further purifying:

1H-NMR(300MHz，CDCl3)δ1.34-1.71(m，10H)，4.83(d，J＝3Hz，1H)，4.87(d，J＝6Hz，1H)，5.03(d，J＝3Hz，1H)，5.09(d，J＝6Hz，1H)；13C-NMR(75MHz，CDCl3)δ23.7，23.8，24.7，35.3，36.2，74.9，75.0，95.1，115.5，152.9，171.5；IR(neat)2927，2852，1818，1684，1449，1369，1334，1280，1229，1160，1109，991，929，877，853cm-1；MS(EI)m/e210(M+)，181，167，153，97，81，69，55。

(2R, 3R)-2,3-(cyclohexylidenedioxy)-4-methyl-4-cyclopentenone (6c) .Method A. contains dimethyl methyl based phosphates (0.46mL, 520mg under-78 ℃, 4.2mmol) 25mL THF solution in dropwise add the n-butyl lithium (2.90mL, 4.20mmol).After 1 hour, (442mg, 10mL THF 2.10mmol) is slowly dropwise added to contain 14.Mixture little by little is warming up to-10 ℃, adds during this period and contains glacial acetic acid (0.12mL, 126mg, 5mL THF 2.10mmol).Gradually mixture is warming up to room temperature then, the additional stirring 1 hour quenched with 100mL pH7 phosphate buffer.With 5 * 50mL extracted with diethyl ether, bonded extract cleans with 2 * 100mL H2O, by the Na2SO4 drying, filters, and concentrates in a vacuum.Thus obtained dark oil produces 222mg (51%) 6c white solid by silica gel (17g, normal hexane/EtOAc, 4: 1).

Method B. dimethyl copper is formed picture described in 4c synthetic, utilize contain 513mg Copper diiodide (I) (2.7mmol) the 25mL absolute ether and the 3.84mL lithium methide (1.4M is in ether, 5.4mmol).(174mg 0.9mmol) is dissolved in 5mL THF to chemical compound 3, dropwise adds 0 ℃ of dimethyl copper solution.After 3 hours, reactant mixture is transferred to-78 ℃ and contains chlorination sulfonyl methane 36 (0.430mL, 590mg is in 40mL diethyl ether solution 7.2mmol).Reactant mixture was warming up to 0 ℃ through 0.5 hour, during add 10mL 10% water acetic acid.Solution waters down with the 100mL ether, contains 5%NH4OH with 2 * 150mL NH4CL saturated solution, cleans with 100mL H2O.Use the own bonded water of 6 * 100mL CH2CL2 extraction then.The CH2CL2 stratification is closed, concentrate in a vacuum, by silica gel (17g, CH2CL2/EtOH, 19: 1) to obtain the mixture of 145mg β-four kinds of diastereomers of ketone sulfoxide 5c.These need not further purify, but 134mg uses 46mg CaCO3 fractional distillation through 18 hours in 40mL toluene.After filtration and the silica gel chromatography (26g, ether/cyclohexylamine, 1: 1), obtain 100mg (46%overall from 1) 6c white solid:

mp80℃；1H-NMR(300MHz，CDCl3)δ1.32-2.21(m，10H)，2.22(s，3H)，4.47(d，J＝5Hz，1H)，5.01(d，J＝5Hz，1H)，5.89(s，1H)；13C-NMR(75MHz，CDCl3)δ17.0，23.7，23.9，24.9，35.9，37.3，77.6，80.7，116.0，130.0，174.7，202.6；IR(KBr)2940，2920，2830，1697，1621，1375，1196，1162，1100，921，834cm-1；MS(EI)m/e208(M+)，179，165，111，82，55；[α]D＝-24°(c＝2.33，CHCl3).Anal.(C12H16O3)C，H。

(1S, 2S, 3R)-2,3-(Cyclohexylidenedioxy)-4-methyl-4-cyclopenten-1-ol (9c). contain 6c (5.00g with-78 ℃, 24.0mmol) 250mL CH2Cl2 solution in dropwise add diisobutyl aluminium hydride (1.0M in CH2Cl2,36.0mL 36.0mmol).After 6 hours, reaction is warming up to room temperature then by dropwise 25mL MeOH quenching in this temperature.After adding 100mL H2O, vigorous stirring 15 minutes, mixture is inhaled into and filters and stratum disjunctum.Separate out water with 3 * 50mL CH2Cl2, clean bonded organic layer with 150mL H2O then,, filter, concentrate in a vacuum by the Na2SO4 drying.The oily residue passes through silicagel column (225g, normal hexane/EtOAc, 9: 1) to obtain 4.80g (95%) 9c colorless transparent oil:

1H-NMR(300MHz，CDCl3)δ1.30-1.70(m，10H)，1.79(s，3H)，2.73(d，J＝9Hz，1H，exchanged?with?D2O)，4.49(m，1H)，4.70(dd，J＝6，6Hz?1H)，4.78(d，J＝6Hz，1H)，5.46(s，1H)；13C-NMR(78MHz，CDCl3)δ13.5，23.7，24.0，24.9，36.4，37.4，73.4，77.5，85.3，112.8，130.1，141.9；IR(neat)3538，2933，2855，1658，1445，1365，1280，1171，1105，1054，999，963，932，896cm-1；MS(EI)m/e210(M+)，181，167，95，56，42；[α]D＝+3°(c＝1.86，CHCl3).Anal.(C12H1803)C，H。

(1S, 2R, 3R)-2,3-(Cyclohexylidenedioxy)-4-methyl-4-cyclopenten-1-olMethanesulfonate (16). will contain 7 (356mg under-5 ℃, 1.69mmol) and triethylamine (188mg, 1.86mmol) 10mL CH2Cl2 add rapidly and contain chlorination sulfonyl methane (213mg, CH2Cl2 1.86mmol).After 1 hour, add 15mL ice H2O, solution is by vigorous stirring a few minutes.After the stratum disjunctum, organic facies is cleaned with 15mL ice H2O, by the Na2SO4 drying, filters, and concentrates to obtain 487mg (100%) spectroscopic pure 16 clean oils in a vacuum.Because the unstability of this methylsulfonyl does not obtain analyzing pure sample so do not reattempt:

1H-NMR(300MHz，CDCl3)δ1.30-1.70(m，10H)，1.88(s，3H)，3.15(s，3H)，4.79(d，J＝5Hz，1H)，4.87(dd，J＝5Hz，1H)，5.38(m，1H)；5.48(s，1H)13C-NMR(75MHz，CDCl3)δ13.9，23.9，23.9，24.9，36.5，37.1，39.0，76.7，81.?5，85.2，113.8，124.2，146.6；IR(neat)2928，2858，1661，1354，1173，1445，1281，1124，1096，1054，1014，952，905，860，819，755cm-1；MS(EI)m/e288(M+)，259，245，193，95，55。

(1R, 2S, 3R)-9-[2 ', 3 '-(Cyclohexylidenedioxy)-4 '-methyl-cyclopenten-4-enyl] adenine (10c). will contain adenine (2.96g, 21.9mmol) 50mL DMF suspension add sodium hydride (80% be dispersed in the mineral oil, 660mg, 21.9mmol) and 18-hat-6 (5.79g, 21.9mmol).Mixture was heated to 80 ℃ in 1.5 hours, allow to cool back ambient temperature then, and this moment, part adding contained 16 (2.1g, 10mL DMF 7.3mmol).After stirring all night, reactant mixture concentrates in a vacuum.Residue is added 100mL H2O, and aqueous solution is adjusted to pH11 with 3M NaOH.With 4 * 50mL CH2Cl2 extraction, bonded precipitate cleans with 50mL 0.5M NaOH, by the K2CO3 drying, filters, and concentrates in a vacuum.Synthetic filtering residue is by silica gel (100g, CH2Cl2/EtOH, 9: 1); Finish final purification by preliminary TLC (four 20 * 20cm * 250mm plates, CH2Cl2/EtOH, 13: 1), to obtain 830mg (35%) 10c white solid:

mp186℃；1H-NMR(30MHz，CDCl3)δ1.34-1.70(m，10H)，1.99(s，3H)，4.66(d，J＝6Hz，1H)，5.23(d，J＝6Hz，1H)，5.50-5.60(br，4H，2H?after?D2Oexchange)，7.66(s，1H)，8.39(s，1H)；13C-NMR(75MHz，CDCl3)δ14.5，23.9，24.3，25.3，36.1，37.6，64.9，84.2，86.4，113.4，120.4，122.5，138.8，149.2，150.0，153.4，154.0；IR(KBr)3310，3160，2935，1675，1600，1512，1475，1415，1369，1332，1303，1250，1207，1164，1052，1014，cm-1；

MS(EI)m/e328(M+1)，327(M+)，284，230，229，200，136，135，95，55，41；[α]D＝-153(c＝14.53，CHCl3).Anal.(C17H21N502)C，H，N。

(1R, 2S, 3R)-9-(2 ', 3 '-Dihydroxy-4 '-adenine (2c) of methyl-4 '-cyclopentenyl). (532mg 1.63mmol) is dissolved among the 0.3N HCl chemical compound 10c, and reactant mixture is stirred all night.Mixture is concentrated into below the 1ml in a vacuum, adds 20mL ice EtOH.Form white crystals immediately, mixture is 20 ℃ of storages overnight.Filtering for crystallizing continues to clean with EtOH ambient temperature ether then, and is dry to obtain 388mg (84%) 2c-HCl:

mp205℃；1H-NMR(300MHz，DMSO-d6+D2O)δ1.83(s，3H)，4.28(m，1H)，4.37(d，J＝6Hz，1H)，4.45-5.35(br?s，2H，exchangedwith?D2O)，5.43(m，1H)，5.60(s，1H)，8.51(s，1H)，8.55(s，1H)，9.00(br?s，1H，exchanged?with?D2O)，9.60(br?s，1H，exchanged?with?D2O)；

13C-NMR(75MHz，DMSO-d6)δ14.9，65.8，75.2，76.8，118.3，123.8，142.8，144.6，146.5，148.6，150.3；IR(Nujol)3500-3000，1713，1685，1105cm-1；MS(EI)m/e?calcd?forC11H13N5O2247.1069，found?247.1081；248(M+1)，136，135，108，94；[α]D＝-151°(c＝2.95，H2O)；HPLC?method?A，Rf＝10.73min；method?B，Rf＝13.44min。

(1S, 2S, 3R, 4R)-2, and 3-(Cyclohexylidenedioxy)-4-methyl-cyclopentanol (15). (768mg, 250mL methanol solution 3.66mmol) and 80mg PtO2 one reinstate hydrogen (25psi) and handled 16 hours to contain 9c.Suspension is filtered, and concentrates in a vacuum, and residue passes through silica gel (35g, ether/normal hexane, 1: 1) to obtain 728mg (94%) 15 colorless transparent oil:

1H-NMR(300MHz，CDCl3)δ1.05(d，J＝7Hz，3H)，1.25-1.70(m，12H)，1.85(m，1H)，2.50(d，J＝10Hz，1H，OH)，3.85(m，1H)，4.40(m，2H)；

13C-NMR(75MHz，CDCl3)δ12.8，23.6，24.0，25.2，33.1，33.7，35.4，37.7，72.3，78.6，81.2，110.8；IR(neat)3450，2920，2850，1450，1400，1370，1285，1250，1230，1165，1140，1110，1090，1060，1030，1000，970，950，930，910，820，670，635cm-1；

MS(EI)m/e212(M+)，169，97，79，69，55，42；[α]D＝+4°(c＝0.810，CHCl3?).Anal.(C12H20O3)C，H。

(1 ' R, 2 ' S, 3 ' R, 4 ' R)-9-[2 ', 3 '-(Cyclohexylidenedioxy)-4 '-methylcyclopentan-1 '-yl] adenine (8d) .triflation and adenine displacement reaction be synthetic as 8c's described above, with 675mg (3.18mmol) 15 to obtain 1.16g (quantitative output) coarse triflate and 648mg (62%) 8d white solid:

mp148-150℃；1H-NMR(300MHz，CDCl3)δ1.15(d，J＝7Hz，3H)，1.30-1.80(m，10H)，1.95(m，1H)，2.20(m，1H)，2.50(m，1H)，4.75(dd，J＝5，5Hz，1H)，4.85(d，J＝7Hz，1H)，5.00(dd，J＝5Hz，1H)，6.35(s，2H.NH2)，7.70(s，1H)，8.35(s，1H)；13C-NMR(75MHz，CDCl3)δ13.2，23.6，24.0，25.1，33.6，36.1，36.9，37.2，61.7，82.2，85.2，111.4，119.8，138.9，149.9，152.9，155.7；IR(KBr)3300，3140，2925，1665，1645，1600，1570，1475，1450，1415，1370，1335，1300，1250，1165，1100，1075，1055，995，950cm-1；

MS(CI)m/e330(M+1)，286，231，216，136，108，81，79，55；[α]D＝-20°(c＝0.680，CHCl3).Anal.(C17H23N502)C，H，N。

(1 ' R, 2 ' S, 3 ' R, 4 ' R) 9-(2 ', the adenine (1d) of 3 '-Dihydroxy-4 '-methylcyclopentan-1 '-yl). (648mg 1.97mmol) is dissolved among the 75mL 0.3N HCl, stirs all night under the room temperature with chemical compound 8d, with the same method described in the 1c, to obtain 359mg (73%) 1d white powder:

mp238-240℃；1H-NMR(300MHz，DMSO-d6+D2O)δ0.95(d，J＝7Hz，3H)，1.75-2.10(m，2H)，2.45(m，1H)，3.75(dd，J＝4，4Hz，1H)，4.40(dd，J＝4，9Hz，1H)，4.70(m，1H)，8.10(s，1H)，8.15(s，1H)；13C-NMR(75MHz，DMSO-d6+D2O)δ15.3，33.8，35.4，60.6，74.9，78.2，119.7，141.6，149.9，152.8，156.2；IR(KBr)3360，3320，3110，2970，2930，2890，1660，1605，1565，1480，1415，1410，1330，1310，1245，1145，1115，990，880，795，690，645cm-1；[α]D＝-46°(c＝0.668，H2O)；

MS(EI)m/e?calcd?for?C11H15N502?249.1226，found?249.1215；249(M+)；HPLCmethod?A，Rf＝12.25min；method?B，Rf＝12.45min。

(2R, 3R)-2,3-(Cyclohexylidenedioxy)-4-ethyl-4-cyclopentenone (6g). (1.57g, 50mL THF suspension adding 8.20mmol) contained the ether (16.5mmol) of 5.50mL 3M ethylene magnesium bromide through 1.5-2.0 minute to contain Copper diiodide (I) under right-5 ℃.Suspension is preserved down at-5 ℃ and was comprised the addition time in 3 minutes, is cooled to-78 ℃ then.(1.00g, 10mL THF 5.20mmol) dropwise joins in the reactant mixture will to contain 3.After 1 hour, dry ice/acetone batch replaces with ice bath, and reactant mixture is warming up to 0 ℃.In this temperature after 15 minutes, reaction is cooled to-78 ℃ again, is transferred to-78 ℃ by pipe and contains the chlorination sulfonyl methane (2.20mL is in 400mL THF solution 3.00g.3.10mmol).Reactant mixture was warming up to 0 ℃ through 30 minutes, at this moment, as the method processing reaction described in the 6c to obtain the coarse sulfoxide diastereomer of 1.15g.Then, (1.00g, 1.00mmol) middle fractional distillation is 17 hours at the CaCO3 that contains toluene (200mL) for the sulfoxide mixture.Concentrate in a vacuum, residue moment is by silica gel (CH2Cl2/EtOH; 99: 1), to obtain the pale yellow oil of 495mg (43% all from 3) pure 6g:

1H-NMR(500MHz，CDCl3)δ1.25(t，J＝7Hz，3H)，1.30-1.80(m，10H)，2.45(m，1H)，2.65(m，1H)，4.45(d，J＝6Hz，1H)，5.05(d，J＝6Hz，1H)，5.90(s，1H)；

13C-NMR(75MHz，CDCl3)δ10.9，23.6，23.8，24.3，24.9，35.8，37.3，77.5，79.8，115.8，127.8，180.1，202.3；IR(neat)2930，2855，1720，1615，1450，1415，1370，1345，1335，1290，1255，1230，1195，1165，1145，1110，1075，1055，995，965，940，910，870，850，835cm-1；

MS(EI)222(M+)，193，179，125，96，81，67，55，41；[α]D＝-32.5°(c＝0.962，CHCl3).Anal.(C13H1803)C，H。

(1S, 2S, 3R)-2,3-(Cyclohexylidenedioxy)-4-ethyl-4-cyclopenten-1-ol (9g). use the experimentation identical with 7c, with 815mg (3.67mmol) 6g, by silica gel chromatography, to obtain 634mg (77%) 9g colorless transparent oil:

1H-NMR(300MHz，CDCl3)δ1.10(t，J＝7Hz，3H)，1.30-1.75(m，10H)，2.10(m，1H)，2.25(m，1H)，2.75(d，J＝10Hz，1H，exchanges?with?D2O)，4.50(m，1H)，4.70(dd，J＝5，5Hz，1H)，4.85(d，J＝5，1H)，5.45(s，1H)；13C-NMR(75MHz，CDCl3)δ11.7，21.0，23.8，24.0，25.0，36.5，37.4，73.4，77.4，84.4，112.8，128.0，148.0；IR(neat)3540(br)，2930，2850，1645，1445，1430，1390，1360，1330，1275，1245，1225，1160，1110，1065，1040，980，945，930，900，870，845cm-1；

MS(EI)224(M+)，195，181，126，109，95，81，69，55，41；[α]D＝+1°(c＝0.962，CHCl3).Anal.(C13H2003)C，H。

(1S, 2R, 3R)-2,3-(Cyclohexylidenedioxy)-4-ethyl-4-cyclopenten-1-olMethanesulfonate (17). with forming 16 identical experimental arrangement to obtain quantitative 17 water white transparency oilies:

1H-NMR(300MHz，CDCl3)δ1.15(t，J＝7Hz，3H)，1.30-1.70(m，10H)，2.15(m，1H)，2.30(m，1H)，3.15(s，3H)，4.85(m，2H)，5.40(m，1H)，5.50(d，J＝2Hz，1H)；

13C-NMR(75MHz；CDCl3)δ11.4，21.4，23.9(two?superimposedpeaks)，24.9，36.5，37.1，39.0，76.6，81.4，84.3，113.8，122.3，152.4；IR(neat)2960，2850，1645，1445，1430，1360，1280，1250，1225，1170，1120，1090，1050，1000，960，940，900，880，860，840，825cm-1；

MS(EI)302(M+)，273，259，206，187，109，97，92，81，79，69，55，41。

(1 ' R, 2 ' S, 3 ' R)-9-[2 ', 3 '-(Cyclohexylidenedioxy)-4 '-ethyl-cyclopent-4-enyl] adenine (10g). chemical compound 9g handles to obtain 10g:mp207-208 ℃ as 6g; 1H-NMR (300MHz; CDCl3) δ 1.20 (t, J=7Hz, 3H), 1.30-1.80 (m, 10H), 2.35 (m, 2H), 4.65 (d, J=5,1H), 5.30 (d, J=5,1H), 5.50 (s, 1H), 5.55 (s, 1H), 6.15 (br s, 2H, NH2), 7.65 (s, 1H), 8.40 (s, 1H); 13C-NMR (75MHz; CDCl3) δ 11.6,21.8, and 23.7,24.0,25.0,35.8,37.4,64.5,83.9,85.3,113.1,120.1,120.4,138.5,149.8,153.1,154.7,155.6; IR (KBr) 3280,3130,2930,1680,1640,1605,1570,1465,1410,1360,1325,1300,1205,1160,1105,1040,730cm-1; MS (EI) 341 (M+), 298,243,134,109,55; [α] D=-124 ° (c=1.08, CHCl3).

(1 ' R, 2 ' S, 3 ' R)-9-(2 ', 3 '-Dihydroxy-4 '-adenine (2g) of ethyl-4 '-cyclopenyl). as the hydrolysis ketal 10g described in 1c synthetic:

mp212-214℃；1H-NMR(500MHz，DMSO-d6+D2O)δ1.05(t，J＝7Hz，3H)，2.15(m，2H)，4.25(dd，J＝5，5，1H)，4.40(d，J＝5，1H)，5.30(s，1H)，5.55(s，1H)，8.05(s，1H)，8.10(s，1H)；13C-NMR(125MHz，DMSO-d?6+D20)δ11.6，22.2，64.9，74.6，76.8，119.3，123.1，140.1，149.9，151.6，152.8，156.1；IR(KBr)3360，3320，3140(br)，2960，1650，，1605，1570，1480，1410，1325，1305，1245，1115，1050，860，800，690cm-1；MS(EI)m/e?calcd?for(M+1)of?C12H15N502262.1304，found?262.1300；261(M+)，233，214，186，149，136，108.Anal.(C12H15N502)C，H，N。

Embodiment 1

The application of adenyhomotype aminothiopropionic acid hydrolase inhibitor on the EFAD mouse model with anti-proliferative effect

The adenyhomotype aminothiopropionic acid hydrolase inhibitor of anti-hypertrophy nucleoside analog is by method for preparing.9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog are by the discrete external application polyethylene ointment of making, picture is described above, comprises the effective ingredient in propylene glycol solid, PEG400 and the Polyethylene Glycol 3350 from 0.001gm% to 10gm%, in order to make ointment mixture.The similar prescription that comprises the composition (for example, dimethyl sulfoxide or AZONE.TM.) that improves the skin penetration ability also can be made.

9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) ointment of adenine (DHCeA) and their 3-position nitrogen analog is by the back of external application at the EFAD nude mouse, every part of 10.mu.1,6 hours is an interval, the cycle was from 6 hours to 5 days.Finish an interval at every turn, killing a Mus, cutting off and handle tissue, putting into the tissue culture medium (TCM) that comprises .sup.3H-thymidine ribodesose, carrying out pulse labeling, continuing 2 hours, measure single, two and the effect used in skin cell proliferation of triguaiacyl phosphate.Isolate DNA with standardization program from tissue then, the combination that .sup.3H-thymidine deoxyribose enters DNA is measured by determine radiant (cpm/.mu.g of DNA) in DNA individuality independently.

The inhibiting anti-lupus erythematosus 9-[(1 ' R of hypertrophy is arranged, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog single, two and the effect of triguaiacyl phosphate, knit from untreated fish group by radiant relatively and to enter measuring of DNA, be used for the DNA of the tissue that personal different LJP394 agent prescription handled in conjunction with situation.

The total quantity of the effective ingredient of each skin slicer test is determined by use effective ingredient gm% in the medical ointment prescription medicament, is given the application of some before chemically examining at the Corium Mus skin.To each test period point, the time point that is untreated is accordingly chemically examined with the skin of same Mus abdominal part..sup.3H-the thymidine ribodesose enters the bonded different of DNA from skin of back with abdominal part contrast skin, is used to calculate the percent of total that suppresses cell proliferation, as the sum of effective every kind of phosphate ester.

The bonded result of 3H-also is used to determine and suppresses percent (the relatively combination of skin of back and skin of abdomen), as each independent 9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] time of adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog test.

.sup.3H-in conjunction with entering the time of corresponding D NA on the skin of back of handling with phosphate ester and the total quantity of effective effective ingredient, significantly be less than the .sup.3H-combination and enter corresponding D NA on untreated skin of abdomen.

Embodiment 2

DHCaA and DHCeA with anti-proliferative effect, the application on the mouse of transplanting the lupus erythematosus human skin

With the anti-proliferative effect of skin slicer detection floxuridine triphosphate and 5-fluorouridine triphosphate salt, when the athymism mouse of transplanting human lupus erythematosus skin is carried out external application.With known technology in the document, the human lupus erythematosus skin transplantation of about 1-10mm diameter is arrived the back of athymism Mus.After fully transplanting,, handle the lupus erythematosus human skin with comprising as the DHCaA of effective ingredient or the LJP394 thing of DHCeA.Method described in these chemical compound use-cases 1 is synthesized.With the medicine manufacturing of the external application polyethylene ointment that comprises effective ingredient, by the previous described method effective ingredient of concentration 0.1gm% to 10gm%.The ointment that comprises effective ingredient was being transplanted the part of skin with every part of 20.mu.1 external application, and per 6 hours is an interval between 1-15 days.Every processing was checked processed skin after 24 hours, whole indexs (erythema of skin biopsy and inflammation) of record lupus erythematosus.After 15 days, skin removes on one's body from mouse, learns a skill with normal structure, by the microscopic examination slicer, with the relative extent of capillary dilation in the quantity of determining cuticular cellulose and the skin.

Relatively be transplanted to the quantity of the checked normal and untreated human lupus erythematosus epiderm skin cellular layer of nude mouse on one's body, to determine to comprise 9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] therapeutic effect of adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog.By determining under suitable dyeing situation, neutrophil cell and monocytic quantity in the capillary of skin are measured the quantity of tissue inflammation relative extent.Write down the expansible relative extent contrast of the capillary tube situation of be untreated lupus erythematosus skin and normal regulating skin.

The quantity of cuticular cellulose, the natural law of degree of inflammation and capillary dilation degree and treatment and the quantity of effective ingredient have relation, as 9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and the concentration of their 3-position nitrogen analog and determining of medication quantity.9-[(1 ' R, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA) and their 3-position nitrogen analog all have the obvious treatment effect to the lupus erythematosus symptom with respect to the lupus erythematosus skin that is untreated.

Claims (15)

1. the reagent combination of a suitable external application, it is characterized in that containing the 9-[(1 ' R of effective quantity with opposing epithelial cell hyper-proliferative, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA), and 3-position nitrogen analog or its esters.

2. reagent combination according to claim 1 is characterized in that DHCaA or DHCeA, and the concentration of 3-position nitrogen analog or its esters is that 0.001gm% is to 100gm%.

3. reagent combination according to claim 2 is characterized in that DHCaA or DHCeA, and the concentration of 3-position nitrogen analog or its esters is approximately from 0.01gm% to 10.0gm%.

4. reagent combination according to claim 3 is characterized in that DHCaA or DHCeA, and the concentration of 3-position nitrogen analog or its esters is approximately from 0.1gm% to 1.0gm%.

5. according to the described reagent combination of any one claim of claim 1 to 4, it is characterized in that comprising water solublity Emulsion.

6. according to the described reagent combination of any one claim of claim 1 to 4, it is characterized in that further comprising propylene glycol, propylene glycol 400 or propylene glycol 3350.

7. according to the described reagent combination of any one claim of claim 1 to 4, it is characterized in that further comprising the saturating enhancer of skin.

8. the reagent combination of a suitable external application, it is characterized in that, the certain effectively 9-[(1 ' R of quantity that comprises the opposing lupus erythematosus, 2 ' S, 3 ' R)-2 ', 3 '-dihydroxy cyclopenta] adenine (DHCaA), 9-(trans-2 ', trans-3 '-dihydroxy basic ring penta-4 '-alkenyl esters) adenine (DHCeA), and 3-position nitrogen analog or its esters.

9. reagent combination according to claim 8 is characterized in that DHCaA or DHCeA, and the concentration of 3-position nitrogen analog or its esters is approximately from 0.001gm% to 50gm%.

10. reagent combination according to claim 9 is characterized in that DHCaA or DHCeA, and the concentration of 3-position nitrogen analog or its esters is approximately from 0.01gm% to 10.0gm%.

11. reagent combination according to claim 10 is characterized in that DHCaA or DHCeA, and the concentration of 3-position nitrogen analog or its esters is approximately from 0.1gm% to 1.0gm%.

12. to the described reagent combination of 11 any one claim, it is characterized in that comprising water solublity Emulsion according to Claim 8.

13. to the described reagent combination of 11 any one claim, it is characterized in that further comprising propylene glycol, propylene glycol 400 or propylene glycol 3350 according to Claim 8.

14., it is characterized in that further comprising the saturating enhancer of skin according to Claim 8 to the described reagent combination of 11 any one claim.

15. reagent combination according to claim 1 wherein comprises opposing epithelial cell hyper-proliferative: atopic dermatitis, lichen planus, actinic keratosis, matrix cells cancer, squamous cell carcinoma.