JPS61143395A - N6-bicycloadenosines - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to R6-bicycloadenosine having high anti-inflammatory and analgesic activity, a pharmaceutically acceptable acid addition salt thereof, a method for producing the same, a pharmaceutical composition thereof, and a method for using the compound.

Dutch Patent No. 2,249,396 and European Patent Publication No. 40325 disclose that R6-
Bicycloalkyladenosine fat conductors are disclosed. U.S. Pat. No. 5,840,521 discloses R6-methyl-R6-[bicyclo(2,2,1)-hebutyl- 2] Adenosine is fully disclosed.

The compounds of the present invention are adenosines that have some of the same activity as azoncin, but have a significantly longer duration of action. Unlike the other adenosines mentioned above, a distinguishing feature of the compounds of the present invention is that R6-bicycloadenosine has a favorable ratio of affinity at A1 and A2 receptors and has highly desirable analgesic and anti-inflammatory properties. is at the point where it was discovered.

The present invention therefore relates to compounds of formula (1), their individual diastereomers or mixtures thereof, or pharmaceutically acceptable acid addition salts thereof.

(wherein R1 is the formula (IIA) or (JIB) (I[A
) (JIB) [However, ~NI (- is endo or exo, = is a double bond or single bond, n is 0.1t or 2, A and B are both hydrogen) An alternative is both methyl, D and E are both hydrogen or both methyl, and C is hydrogen or methyl, but if D and E are methyl, then A and B are both hydrogen. and C is methyl, but when D and E are hydrogen, A, B and C are all hydrogen or all six are methyl, and X Itt-CCCHs)z-1- C
H2-1-CH2CH2- or -〇H=CB-], FI2II hydrogen, Hagen, SF+ (where R is hydrogen and lower alkyl), N
B1B1+ (where Bl and Bll are each independently hydrogen, lower alkyl, phenyl or substituted phenyl (the substituent of the phenyl is lower alkyl, lower alkoxy, halogen or trifluoromethyl)
), and each of R2/B, / is independently hydrogen, lower alkanoyl, benzoyl, or substituted benzoyl (the substituent of benzoyl is lower alkyl, lower alkoxy, etc.) or trifluoromethyl), or R2' and R3' together form a lower alkylidene gold such as isozolopylidene, and B6/ is a halogen, hydrogen or B5'O (where 1 : 15' is hydrogen, lower alkanoyl, benzoyl or substituted benzoyl (the substituent of the benzoyl is lower alkyl, lower alkoxy, halogen or trifluoromethyl);
And ~NH- in formula JIB is bonded to one or the other of the adjacent carbons. ) The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (1) above, together with a pharmaceutically acceptable carrier, and further relates to a pharmaceutical composition comprising a compound of formula (1) as defined above in a dosage form to a mammal. ↓Relates to methods for administering to mammalian animals.

In the compounds of formula (1), the term "lower alkyl" refers to a straight chain TFC having 1 to 6 carbon atoms.

includes branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, inbutyl, tert-butyl, amyl, inoamyl, neopentyl, hexyl, and the like.

Halogens include in particular fluorine, chlorine or bromine.

Lower alkoxy is O-alkyl (having 1 to 6 carbon atoms as defined above for "lower alkyl").

Lower alkanoyl has 1 in the alkyl chain as defined above.
0-C-alkyl having ~6 carbon atoms.

The definition "~NH- in formula (JIB) is bonded to either one or other adjacent carbon" means the following.

- The compound represented by formula (1) is effective both in the form of a free base and in the form of an acid addition salt. Both forms are within the scope of the invention. In practice, using the salt form means using the base form.

Suitable pharmaceutically acceptable salts within the scope of this invention include metal acids such as hydrochloric acid and sulfuric acid, ethanesulfonic acid, benzenesulfonic acid and! and p-)luenesulfonic acid, and are obtained as hydrochloride, sulfate, ethanesulfonate, benzenesulfonic acid), p-)luenesulfonate, etc., respectively.

Acid addition salts of the above basic compounds are prepared by dissolving the free base in an aqueous or aqueous alcoholic solution or other suitable solvent containing the appropriate acid and isolating the salt by distilling off the solvent. Alternatively, it may be prepared by reacting the free base with an acid in an organic solvent; in the latter case, the salt is obtained either by direct separation or by concentrating the solution.

The compounds of the invention may have asymmetric carbon atoms. The present invention includes single norastereomer-1, ie, pure 8-isomers, or pure 8-isomers and mixtures thereof.

Single noastereomers are prepared or isolated by methods within the art.

Under certain conditions, it is necessary to protect either the N or 0 of the intermediate in the above-mentioned preparation method with a known suitable protecting group. The introduction and removal of such suitable oxygen and nitrogen protecting groups is well known in the art of organic chemistry.

For example (1) J, F, W, McOmie's r Pr
otective Groups inOrganic
Chemistry J pp 45ff, 95f
f (1973), (21J, F, W, McOm
ie's r Advances in Organic
ChemistryJ, Vol. 3, pp. 191-281 (1
963), (5) LA.

Borssonas r Advance in Or
Ganic Chemistry J, Volume 3, 159
~190 pages (1963), and (4) J, F.

W. McOmie's Chem, & Ind.
See J 605 (1979).

Examples of suitable oxygen protecting groups include benzyl, t-butyldimethylsilyl, methyl, isoglupyr, ethyl, tertiary
Examples include butyl and ethoxyethyl. Protection of N--H containing moieties is necessary for some of the methods described for the preparation of the compounds of the present invention. Suitable nitrogen protecting groups include benzyl, triphenylmethyl, trialkylsilyl, trichloroethyl carbamate, trichloroethoxycarzenyl, vinyloxycarbamate, and the like.

It is necessary to protect two different oxygens with dissimilar protecting groups such that under certain conditions one of the two oxygens can be totally selectively removed while leaving one intact. Benzyl and t-butyldimethylsilyl groups are used as follows. That is, if one is present, the other is removed; the benzyl group is removed by catalytic hydrogenolysis, and t-butyldimethylsilyl is removed, for example, by reaction with tetra-n-butylammonium fluoride. removed.

The need for protecting groups in the method of preparing compound sounds of the present invention is generally well known to those skilled in the art of organic chemistry, and therefore the use of appropriate protecting groups is specifically discussed herein. Although not illustrated, they are included in the steps of the present invention as necessary.

The reaction products described herein are extracted.

Isolated by conventional methods such as distillation, chromatography, etc.

A preferred embodiment of the present invention is a compound of formula (1), in which FlI is represented by formula (I[A), and ~NH
- is either endo or exo; A.

B, C, D and E are all hydrogen, B2 is hydrogen, R6/ is chlorine and R2/ and B, / are as defined above.

In particular, as a preferred embodiment, R6-nindobicyclo (
2,2,1) hebutyladenosine, R6-nyxobicyclo(2,2,1)hebutyladenosine and R6-
Nindobiccyclo(2,2,1)butyl-5'-chloroadenosine is rejected. This R6-nindopicyclo(2,2,1)hebutyl-5'-chloroadenosine is the most preferred embodiment.

The compound represented by formula (1) includes 6-herogly/riboside t represented by formula (2), bicycloamine (fcdashi A) represented by formula (IVA) or formula αB) shown later,
B, C, D, E and X are as previously defined) in an inert solvent such as an aprotic solvent such as alcohol or dimethylformamide,
=9 can be conveniently synthesized by reacting for 1 to 48 hours under conditions between about 160<0>C. Bicycloamines of formula (IVAJ or (MB)) above are commercially available and may be produced by methods known in the art;
It is generated by a method similar to that. It may be beneficial to add a base such as triethylamine or calcium carbonate to neutralize the hydrogen chloride formed as a by-product of the reaction, but this requires the use of an extra equivalent of alkylamine. It can also be achieved by: Although not necessary, the bofuranose hydroxyl group as an acetate or benzoate ester can be removed by ammonium hydroxide or sodium methoxide following the synthesis of the R6-substituted adenosine? It is also convenient to protect. The reaction is as shown below.

UM) (IVA) (lvB) [wherein Hal is halogen, preferably chlorine or bromine, and A%B, C, D, B, R2, B2/
B3/ and R51 are as defined in formula (1)].

Furthermore, a compound represented by formula (1) in which llN6' is a halogen also has a compound represented by formula (1) in which current' is B5'0 and B
11, B51 and Rb2 are all hydrogen, so they may be prepared in a stepwise manner as shown below from compounds of the formula A compound represented by formula (1) containing a protecting group by reacting the compound in acetone to form a protecting group for the #L element of 0E12' and 0EIs' (for example, dimethoxy 10) and then chlorination of the 5'-hydroxymethyl with thionyl chloride in tetrahydrofuran followed by removal of the protecting group using an acid such as hydrochloric acid, acetic acid, sulfuric acid, etc. under aqueous acidic conditions. .

Furthermore, the compound represented by the formula (11) in which B2 is neither hydrogen nor halogen, is a compound represented by the formula (2 represented by
It can also be prepared from 6-cyclopurine by the stepwise method shown below.

First, a compound represented by the formula (■) is reacted with a bicycloamine represented by the formula (5) a) and (IVb) to form a compound represented by the formula (■), and then the chlorine atom at 02 of the B2 group is is substituted using all nucleophilic substitution conditions to remove all acetate protecting groups.

(■A) A compound represented by formula (I) in which R6/ is hydrogen is prepared according to the following reaction scheme.

Generally, the conditions for the above reaction scheme are similar to those known in the art.

It has been discovered that compounds of formula (1) have varying affinities χ for adenosine receptors (designated for convenience as A1 and A2 receptors).

These compounds have shown activity in animal studies, including as having analgesic properties, and are effective in treating pain and inflammation.

Pharmacological evaluation adenosine receptor binding-A1 receptor affinity (RBAl)
Preparation of membrane Whole brain of male Long Evans rat (150-20C1) with cerebellum and brainstem removed f Br1nlana
Homogenize in 50 volumes of ice-cold α05 M Tris-HCL buffer (pH 7,7) using a Polytron FT-10i for 20 s (set to number 6) and for 10 min at 2 CJ, 000 x t (8, orvallRC).
-2), and centrifuged at 4°C. The supernatant was discarded and the pellet was resuspended and centrifuged as before. This pellet) t-2 international units/M (7) adenosine deaminase (sigma type ■ from repaired intestinal mucosa) t-containing 2
Resuspend in 0-Tris-HC1 buffer and incubate at 67°C.
The cells were incubated at 0° C. for 30 minutes and then at 0° C. for 10 minutes. The homogenate was centrifuged again and the final pellet was placed in ice-cold 0.05M Tri
It was resuspended in s-HC2 buffer (p! (7,7) to a concentration of 20 η/1 as the original wet tissue weight and used immediately.

Assay Conditions Tissue homogenate (10 v/d) with or without test substance, 1.0 BM (3B)-N6-cyclopentyladenosine ((3n)-cnA)? (105 M Tris-ECt buffer (PH7,
7) for 1 hour at 25°C (6 sets).

The incubation volume was 2-. Unbonded [5H]
-CHA' was separated by passing it through a glass fiber (GF/B) filter and treating it in a fast reactor under reduced pressure. All 5 of those filters are ice-cold α05MTris-H
Rinsed three times with CL@ buffer (-17). The radiolabeled ligands retained on the filters were measured by liquid scintillation spectrophotometry after shaking the filters for 1 hour or more on a mechanical shaker in 10 d of Beckman Reddysolp EP scintillation cocktail.

Calculated non-specific binding f 1 was defined as the binding that occurs in the presence of mM theophylline. specific binding of son (ICsa
) t - the concentration of the test substance that inhibits the non-! Measured by type I computer curve fit. Skatste Yard (5ca
tchard) Plot the radiation binding radiation binding content (mol/f kumishi) k (free radiation Q,!y
Free radioligand was calculated by linear regression of the fc line obtained by plotting against F''. Since the amount of bound radioligand is a small fraction of the total amount added, free radioligand is the concentration of radioligand added to the incubation mixture. (
nM) defined as 9. The H111 coefficient was calculated by linear regression of the line obtained by deleting the logarithm of bound radioligand against the logarithm of bound radioligand [-unit radiation, yF]. The maximum number of binding sites (BXnax) was calculated from the t-scattered glot.

Adenosine receptor binding - A2 receptor affinity (EBA2)
Tissue specimens 200-5009, male and female 8prague-Dawl
ey rat brain f Pel - Purchased from Freez. Long-gvans type with hood-shaped crown hairs (
hooded) male rat (Blue Spruce
Fresh brains (purchased from Farms) gave essentially the same results. The brain was brought out of the frozen state and then kept on ice to dissociate the striatum. Ice-cold 50mM of striatal t-10 volume
Tris-HCA (pH 7.7 at 25°C.

Po1 for 30 seconds in F'a26) (Tris) at 5°C.
ytronPT-10 (Brinkmann)It
(set to 5). The suspension k 5QOO
Centrifuge for 10 minutes at OX$', discard the supernatant, resuspend the pellet in 10 volumes of ice-cold Tris as described above, centrifuge again, resuspend at a rate of 1 t15mj, and store at -70°C. (stable for at least 6 months) in plastic vials. If necessary, tissues were brought back to room temperature from the frozen state, disrupted with a Polytron, and kept on ice until use.

Incubation conditions All incubations consisted of 5 wq original tissue weight of rat striatal membrane, 4 nM (3H)-s-ethyladenosine-5'-calzexamide ((3)i)NECA),
0 nM N6-cyclopentyladenosine (to eliminate A1 receptor binding), 10 mM MgC22,0,
It was carried out for 60 minutes at 25°C in 11 Tris t-containing glass tubes (12X75IIC) with 1 unit/- of adenosine deaminase and 1 tidimethyl sulfoxide. N6-cyclobentyadenosine 70.02 NH
Dissolved in O2 to a concentration of 10mM and diluted in Tris. Stock solutions and diluted solutions of N6 one-day pentyladenosine could be stored for several months at -20°C.

The test compound was added to dimethyl sulfoxide on the day of the above experiment.
Dissolved in mM concentration and dimethyl sulfoxide at 1
The final incubation concentration was diluted 1:00.

An equal volume (10 μL) of dimethyl sulfoxide was used for control incubations, and the resulting 9-dimethyl sulfosite concentration did not affect binding. (5H)NgCA
'g diluted to 40 nM in Tris.

Membrane suspensions (5μ/Q, 79m) were prepared at final incubation concentrations of 10mM gold and α1 units/Q, respectively.
It contained sufficient MgCl2 and adenosine deaminase to produce a For test compounds with IC5Q values lower than 1 μM, the order of addition is as follows:
μ/, ), N6-cyclopentyladenosine (100μ
t), (!H) NECA (100 μL), and membrane (
(1L79m). For test compounds with ICSo values greater than 1 layer and limited good wood solubility, the order of addition (same volumes) was test compound, membrane, N6-7 clopentyla fnosine, and (5H)NECA. After all additions were completed, the tube rack was vortexed and the tubes were then incubated for 60 minutes at 25° C. in a shaking water bath.

In the middle of the incubation, the tube rack was further vortexed for a certain period of time.

Incubation was performed at 2.4 ex GF/B under reduced pressure.
It was terminated by passing it through a filter. Each pipe was treated as follows. That is, pour the contents of the tube into the filter, add it to the water-cooled Trist tube of 4-, pour the contents into the filter, and pour the contents into the filter
Washed twice with water-cooled Tris-41117. Ffi is completed in about 12 seconds.

Place the filter in a scintillation vial and
ORMULA 947 scintillation fluid was added and the vials were allowed to stand overnight, shaken, and counted in a liquid scintillation counter at 401 efficiency.

Data Analysis Non-specific binding was defined as binding in the presence of 100 μM N6-cyclopentyladenosine, and specific binding was defined as total binding minus total non-specific binding. IC5o was calculated by weighted nonlinear least squares curve fitting to the following mass action equation:

Y=T-8″D+ where Y is the bond cpm; T is the total combined cpm in the absence of drug; S is the specific binding cpm in the absence of drug; D is the concentration of the drug; And K is the IC5o of the drug.

The weighting factor was calculated under the assumption that the standard deviation is proportional to the predicted value of Y. In this computer analysis, non-specific binding was treated as an extremely high (infinite) concentration of drug.

IC5 for adenosine A1 and A2 receptor affinity
The o value (nM) is as shown in the table. ◎Evaluation of analgesic effect Anti-agonizing (abbreviated as AW)
The study provides a preliminary evaluation of compounds containing potential analgesic activity. The test is performed on male 5wlss-Webster mice. Compounds are administered subcutaneously in an amount of 101 Ll/klI in aqueous 12% methylcellulose or other suitable vehicle. Dosage represents the active portion.

Twenty minutes after administering the adenosine apnist, acetic acid (α6%, 9 to 10 rILt/t) is injected intraperitoneally. Seven minutes after acetic acid injection, the number of writhing movements is counted for 5 minutes. Writhing is defined as stretching of the trunk and hind limbs with abdominal contraction and concave arching of the back. The data is gD
It is expressed as the so value. Here, ED5G is the dose required to suppress agony by 50% compared to the control case.

The ED50 value is calculated using non-linear regression analysis.

Anti-inflammatory activity assay Evaluation of immunoinflammatory or anti-inflammatory activity is obtained by the carrageenan pleuritis assay. Carrageenin pleuritis was developed by previously reported methods (Carter, G.
W, et al. J, Pharm, Pharmacol
, J34:66-67.1982). Carrageenin (310 μf/rat) in 12,517 volumes of saline that is incompatible with chloride! Intramembrane injection. After 4 hours, the rats are sacrificed and 21 Ej of phenol red solution (525 wIg of phenol red in 1 J of L05M phosphate buffered saline) is added to each pleural cavity. The contents of the pleural cavity are mixed and transferred to a glass test tube. A 50 μt aliquot was removed from the main tube and (ZapOglOk) iDeCoulter B
After dissolving the red blood cells (using 1 electronics*'H1aleah FL f), the exudate cells are counted using a Coulter model ZBI counter. Centrifuge the residual exudate-phenol red mixture for 15 minutes at '1750Xj'.

100 μt supernatant t-5, 9 tnl phosphate buffer (0,072 M tribasic sodium phosphate Na3P
(O4.12H20 aqueous solution) and the absorbance was adjusted to 5.
Measure at 60 nm.

The exudate solution volume is calculated as follows: (where v1 = unknown volume of exudate, V2 = volume of dye added into the cavity (2111/), AI = absorbance of exudate (assumed to be zero), etc. = Absorbance of phenol red solution, As
= absorbance of exudate and phenol red solution) The inhibition of exudate or formation is calculated by the following formula:

Inhibition rate (exudate) = Inhibition rate (function (, number of cells) = IDso values are calculated by probit analysis.

The compound of Example 1 was administered 1 hour before carrageenan injection.

Summarize the biological data in a table. The present invention therefore also encompasses a pharmaceutical composition for treating pain and inflammation comprising an effective amount of a compound of formula I as defined above and a pharmaceutically acceptable carrier on the corresponding pain and inflammation effects. do.

Receptor binding examples RBA-1 (nM) RBA-2 (nM
)2 1.4 14005
α69 50951 α03 Carrageenin Pleuritis Assay Details for the various administrations il are given below.

1 0.1 49,3 74.10,
2 60.0 71100.4
81.3 9α0 α8 42.7 6&4 2 0.3 24.3 2S, 71.0
22.9 52.9 5 0.1 11.7 1 & 40.6
16.84Q,0 The present invention further provides for the administration of a corresponding pharmaceutical composition comprising a compound of formula I according to the above definition in a suitable unit dosage form to a mammal suffering from pain and inflammation, either orally or parenterally. Also included are methods of treating pain and inflammation in such mammals comprising orally administering.

Inert, pharmaceutically acceptable carriers for preparing pharmaceutical compositions from the compounds of this invention can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances that can also act as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, or tablet disintegrant. It may also be an encapsulating material. In the case of powders, the carrier is a finely divided solid in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier containing the necessary binding properties in suitable proportions and compacted to the desired shape and size. Preferably, powders and tablets contain from 5 or 10% to about 70% active ingredient. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, textolino, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa milk fat.

The term "formulation" refers to the active ingredient (with or without other carriers) in which the active ingredient is surrounded by the carrier and thus the carrier together with the active ingredient to give a capsule containing the active compound and the encapsulating material as a carrier. This includes formulations with. Similarly, cachet is also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

For the manufacture of suppositories, first a low-melting wax such as a mixture of fatty acid glycerides or cocoa milk fat is melted in a whole bath and the active ingredient is dispersed homogeneously therein, for example by stirring. The molten homogeneous mixture is then poured into conveniently sized molds and allowed to cool and thereby solidify.

Liquid formulations include solutions, suspensions and emulsions. - By way of example, water or water-propylene glycol solutions may be mentioned for parenteral injection. Liquid preparations can also be formulated as solutions in aqueous ethylene glycol baths. Aqueous solutions suitable for oral use include the active component dissolved in water and, optionally, suitable colorants and flavoring agents.
It can be prepared by adding stabilizers and thickeners. Suspensions suitable for oral use consist of finely divided active ingredient dispersed in water together with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium calgesylmethylcellulose and other well-known suspending agents. It can be prepared by

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid preparations for oral or parenteral administration. Such liquid dosage forms include solutions, suspensions and emulsions. These particular solid formulations are most conveniently presented in unit dosage form and are used by themselves to form a single liquid dosage unit. Alternatively, after conversion to a liquid dosage form, a given volume of the liquid dosage form preparation can be measured over a number of times, such as with a syringe, teaspoon or other volumetric container. , even give enough solid gold. It is preferred to maintain unused portions of the liquid dosage at low temperatures (i.e., below refrigeration) in order to retard the degradation that may be expected when multiple liquid dosages are so prepared. Solid preparations intended to be converted into liquid dosage forms contain, in addition to the active substance, flavoring agents, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickening agents, It may also contain an emulsifying agent and the like. The liquid used to prepare liquid formulations may be water, isotonic water, ethanol, glycerin, propylene glycol, etc., and mixtures thereof. Naturally, the liquid used will be selected in consideration of the route of administration, and liquid preparations containing large amounts of ethanol are not suitable for parenteral use.

Preferably, the pharmaceutical formulation is in unit dosage form. In such dosage forms, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of pharmaceutical preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Unit dosage form is nine capsules,
It may be a cachet or tablet itself, or it may be packaged in any number of suitable packages.

The amount of active compound in a unit dosage formulation may vary from 1 to 5 ooq, preferably from 5 to 100 tft, depending on the individual application and the effectiveness of the active ingredient. The compositions can also optionally include other compatible therapeutic agents.

In therapeutic applications as described above, the mammalian dosage range for a 70 kg treated subject is (L1-150 capes/body weight 7 days or preferably 1-50 q/# body weight 7 days. Variations may vary depending on the patient's requirements, the severity of the condition being treated, and the compound used. Determination of the appropriate dosage for a particular condition is within the skill of those skilled in the art. In general. , treatment is initiated with a small dose that is less than the optimum dose of the compound, followed by increasing the dose in small increments until the optimum effect under the conditions is achieved. As desired,
The total daily dose may be divided and administered in several portions during the day.

The present invention will be explained by the following examples, but the present invention is not limited thereto.

Example 1 N6-nindopicyclo(2,2,1) to butyladenosine 4.0t of 6-chloropurinori 2 sites, 2.571 of endo-2-aminonorzernan hydrochloride and 5
．． A mixture of 53t of triethylamine is refluxed in t-100+j of ethanol under a nitrogen atmosphere for 20 hours. The solvent is distilled off and dried. Minimum amount of 2-
Dissolve in lononol and dilute with excess cold water. Remove the clear aqueous solution by decantation. The remaining solid material is dissolved in ethanol and the volatile components are distilled off. Repeat this one more time and get 58t (75%) of 111-6.
-endobicyclo(2,2,1)butyladenosine,
Gold was obtained with a melting point of 128-150°C.

Elemental analysis (C1yH2skJsOa) Calculated value: C=56.49. H=6.41. N=19.
37 Actual measurements: c = 5 & 44, H = & 81,
N=1 &78.

Example 2 N6-nikin-bicyclo(2,2,13 hebutyladenosine 402 6-chloropurine lyseside, 1.82 exo-2-aminonorzernan and Z1f in a mixture of triethylamine t-100 m ethanol The mixture was refluxed for 20 hours under nitrogen atmosphere.

The solvent was distilled off and dried. The remaining solids were treated with 50 g of cold water. Decant off the clear aqueous solution and dissolve the solid in ethanol. The volatile gold components are distilled off under vacuum. This was repeated twice to obtain a solid material. This solid was crystallized from a total ethanol-ethyl acetate-hexane solvent to give 1r (s1%) of N6-N6-N6-(2,2,1) butyladenosine, melting point 110-11.
2°C was obtained.

Elemental analysis (C17H2gNso4) Calculated value: C=5&49. H=&41. N=19.57
Actual value 20 = 55.88. E=489. N=1a59 Example 6 N6-2-(endo)-norzelnyru 2', 5'-
0-isopropylideneadenosine N6゛-2-(endo)norzernyladenosine (IZ
7i35mmol), 2,2-dimethoxyde Qz4-(551117) hydroxide p-dithophenylphosphoric acid hydrate (12,8?, 38mmol) f0 reaction mixture stirred at room temperature for 18 hours in acetone (150d) k (LI N NaECOs (10011114)
? and stirred for 1 hour. The acetone was distilled off under vacuum and the aqueous solution was dissolved in methylene chloride (20011
7).

The organic phase was dried over magnesium sulfate and distilled under vacuum to form an off-white foam. The foam is methanol/'(1oo
Dowex 1 x 8 (Na800
Type g) was poured into a resin filling. The resin is mixed with methanol (
Washed with 5[)OjE/) and distilled 9F1[ under vacuum, 1cL6f (75%) of white solid, melting point 90-98℃
I got it.

Elemental analysis<c2as2yk;2sOa) Calculated value: C=5
9.84. Yo;&78. N=17.45 Actual value: C=
59.48. H=&71. N=17.24 Example 4 N6-2-(endo)-nordaranyl-5'-chloro-
5'-deoxy-2',5'-0-isopropylideneadenosine Isopropylidene analog prepared in Example 6 above (6
,3L, 1a7mmol) 1TI (FC100m)
Stir in thionyl chloride l' (2,8f, 2
5'5 mmol). The reaction mixture was stirred at room temperature overnight.

Vacuum distill the solvent and convert the residue into methylene chloride (100mj)
and washed with water (IQQd twice).

The entire organic phase was dried over magnesium sulfate and vacuum distilled. The residue was dissolved in ethyl acetate (25 m) and pretz f (p
rep) 500A chromatography (silica gel, 1
Column, 10Q, m77 min).

The slow running fraction was isolated by evaporation of the solvent and yielded a white foam of 4,49 (67%), mp 61-7.
Obtained 0°C.

Elemental analysis (C20H26clRsos) calculated value: C
=57.20. E-424, N=1&68゜0A=a4
4 Actual measurement value: C=56.97. E=6.13. N=1&5
9゜CA=&62 Example 5 N6-2-enr-norzernyru-5'-chloro-5'
-deoxy-adenosine 5I-chloroisoglopylidene analog prepared in Example 4 above (4,3f, 1 (L2 mmol)'t
The mixture was stirred in 50 g of formic acid (10 gm) at 50° C. for 4 hours. The acid was removed in vacuo and the residue was distilled twice with methanol (50 μm) to give an off-white foam. The foam was dissolved in acetone (251 LJ) and precipitated. (prop) Purified by 500A chromatography (silica gel, 1 column, 100 m/min) K. The fraction active at the main refractive index was isolated by distilling off the gold solvent, 2.49 (62%) +7) white. Solid, melting point 96-99°C.

Elemental analysis (017H22cnqsos) calculated value: c=
=s A75, H=5.84, N=1 a44
Actual value: C=5A89. H=405. N=1a23 Example 6 H6-(endo)nor-luer-5'-deoxyadenosine 6-chloroglin (2,!ir, 15 mmol), triethylamine (55t #55 mmol) and 2-endoaminonorzernan hydrochloride ( 2,
5M, 17 mmol)'t 100- of ethanol and mixed under reflux for 72 hours. The solution was cooled to room temperature and the ethanol was removed in vacuo. The residue was dissolved in chloroform and washed with water (100114). The organic phase was dried over magnesium sulfate and the solvent was distilled off in vacuo. The residue was dried overnight under vacuum at −65 °C to 2.1 f (6
29G) was obtained as a light green solid, melting point 217-219°C.

Adenocomplete book<4.4f, 19.1mmol) and 5'
Deoxyly/-x (6uf, 23mmol) f
Melt mixing was carried out at 200°C. Fine droplets of concentrated sulfuric acid were added for melting, and the acetic acid formed was removed by a gentle flow of nitrogen. The solution was stirred for 4 hours and then cooled to room temperature. The glassy residue was ground into 0100 Mt ethyl acetate in an ultrasonic bath. The solution was then purified by chromatography and evaporated to give an off-white foam of 1.6 f. This was identified in Example 7 below.

The foam (f, 4t, i3mmol) is then 100d
Methanolic ammonia (saturated at 0℃)
and the solution was stirred at room temperature for 6 hours.

The solution was distilled in vacuo and purified by chromatography on the residue to give, after evaporation of the solvent, (L9f (181k)), a hygroscopic white solid, mp 96-101<0>C.

Example 7 H6-endonorzenyl-5/-deoxyadenosine-21,31-2-〇-acetyl Compound 7 of Example 6
As a result of analysis, the product N6-(2-endorzernyl)-5/-deoxy-2/, sl-diacetyladenosine 1.6 t(19,596), melting point 68-7
A temperature of 7°C was obtained.

Elemental analysis (C21H27N505) Calculated values: C=5a54, H=6.60, N=
=14.79 Actual value: C=5a32. )1=6.48
．． N=14.86 Patent applicants: 2 people other than Werner-Lampert Kompany

Claims (1)

[Claims] 1) A compound represented by formula (I), its individual diastereomers or mixtures thereof, or a pharmaceutically acceptable acid addition salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) {In the formula, R_1 is the formula (IIA) or (IIB)▲There are mathematical formulas, chemical formulas, tables, etc.▼(IIA) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IIB) [However, ~NH- is endo or exo, ■ is a double bond or a single bond, n is 0, 1 or 2, and A and B are both hydrogen or both are methyl, D and E are both hydrogen or both methyl, and C is hydrogen or methyl, provided that when D and E are methyl, A and B are both hydrogen and C is methyl, but when D and E are hydrogen, A, B and C are all hydrogen or all three are methyl, and X is -C(CH_3)_2-, -CH_2- ,−
CH_2CH_2- or -CH=CH], where R_2 is hydrogen, halogen, SR (where R is hydrogen or lower alkyl), NR^iR^i^i
(where R^i and R^i^i are each independently hydrogen, lower alkyl, phenyl, or substituted phenyl (the substituent of the phenyl is lower alkyl, lower alkoxy, halogen, or trifluoromethyl); ), and R_2' and R_3' are each independently hydrogen, lower alkanoyl, benzoyl, or substituted benzoyl, where the substituents on benzoyl are lower alkyl, lower alkoxy, halogen, or trifluoromethyl. or R_2' and R_3' together form a lower alkylidene, and R_6' is halogen, hydrogen or R_5'O
(where R_5' is hydrogen, lower alkanoyl, benzoyl, or substituted benzoyl, where the substituents on benzoyl are lower alkyl, lower alkoxy, halogen, or trifluoromethyl), and ~NH
- is bonded to one or the other of the adjacent carbons. } 2) The compound according to claim 1, wherein R_2 is hydrogen. 3) The compound according to claim 1, wherein R_1 is a group represented by formula (IIA). 4) The compound according to claim 1, wherein R_1 is a group represented by formula (IIB). 5) A compound according to claim 6, which is N^
A compound that is 6-endo-bicyclo[2.2.1]heptyladenosine. 6) A compound according to claim 3, which is N^
A compound that is 6-exo-bicyclo[2.2.1]heptyladenosine. 7) A compound according to claim 6, wherein N
^6-endo-bicyclo[2.2.1]heptyl-5'
- A compound that is chloro-5'-deoxyadenosine. 8) A compound according to claim 3, wherein N
A compound that is ^6-(endo)-norbornyl-5'-deoxyadenosine. 9) A compound according to claim 3, wherein N
A compound that is ^6-(2-endo-norbornyl)-5'-deoxy-2',3'-diacetyladenosine. 10) A compound according to claim 3,
A compound that is N^6-norbornyl-2',3'-0-isopropylideneadenosine. 11) A compound according to claim 3, comprising:
A compound that is N^6-2-(endo)-norbornyl-5'-chloro-5'-deoxy-2',3'-0-isopropylideneadenosine. 12) Formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) 6-halopurine riboxide [in the formula, Hal is a halogen] is expressed as formula (IVA) or formula (IVB). ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IVA) or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IVB).
React at 0°C for 1-48 hours, if desired, add R_5'O
A process for preparing a compound according to claim 1, which comprises converting the resulting free base into a pharmaceutically acceptable acid addition salt by known methods. 15) Formula (c) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(c) A compound represented by (in the formula, Ac is acetyl) is reacted with a nucleophile corresponding to R_2 to form ammonium hydroxide. R_2 as defined in claim 1 by removing the acetyl group and, if desired, converting the resulting free base into a pharmaceutically acceptable acid addition salt by known methods. is SR or NR^iR^i
A method for preparing a compound in which ^i and R_2', R_3' and R_5' are hydrogen. 14) Formula (d) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(d) A compound represented by formula (d) (wherein R_1 is as defined above, and with the additional condition that R_3' and R_2' are both not hydrogen) (based on the above definition),
R_3' and R_2 by reaction with thionyl chloride and, if desired, further treatment with aqueous acid.
A process for preparing a compound in which R_6' is chlorine as claimed in claim 1, by replacing each of ' with hydrogen. 15) Formula (e) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (e) The compound represented by (in the formula, R_1 and R_2 are as defined above) is expressed as formula (f) ▲ Numerical formulas, chemical formulas, tables, etc. ▼(f) A method for preparing a compound in which R_6 is hydrogen as set forth in claim 1, which comprises reacting with a compound represented by (in the formula, R' is a protecting group). 16) A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 together with a pharmaceutically acceptable carrier. 17) A method for alleviating pain in a mammal, which comprises administering to the mammal a compound according to claim 1 in unit dosage form. 18) A method for suppressing inflammation in a mammal, which comprises administering to the mammal a compound according to claim 1 in a unit dosage form.