DK146220B - 2-CHLORADENE INGREDIATES OR ACID ADDITION SALTS - Google Patents

Description

in 146220

The present invention relates to novel 2-chloroadenine derivatives or acid addition salts thereof which can be used as intermediates for the preparation of novel purine derivatives which are valuable as non-adrenergic bronchodilators.

Theophylline, usually administered as the ethylenediamine salt (aminophylline) or the choline salt, is a powerful and valuable non-adrenergic bronchodilator commonly prescribed for the treatment of bronchial asthma. Since aminophylline is easily soluble, it has been accepted for many years as an effective bronchodilator for oral administration. However, aminophylline is known to have certain drawbacks, e.g. gastric irritation as well as cardiovascular and central nervous system side effects that justify a search for new non-adrenergic bronchodilators which may have more beneficial properties such as increased potency and / or reduced side effects.

In relation to the compounds of the present invention, a very large number of purine derivatives have been described in the patent literature and the scientific literature. The following references are illustrative of this: 1. J, Am. Chem. Soc., 81, 197-201 (1959) discloses the synthesis of compounds of formula N

R

wherein R is cyclohexyl or 2-cyclohexeneyl. The compounds were prepared as potential anticancer agents. U.S. Patent No. 3,917,837 discloses the use of the compound 2 146220 fz rry 0 ·. ·· “as an anti-inflammatory agent.

3. U.S. Patent No. 3,930,005 discloses compounds of formula R1 I? 05 i i> δ 2 3 1.

wherein R and R inter alia may be hydrogen and R inter alia may be (lower) alkoxy. The compounds are said to possess anti-inflammatory activity.

4. Belgian Patent Specification No. 853,086 (Farmdoc 70719Y) discloses compounds of the formula

X

jkX> Q i

Y

Wherein either X is C ^-Cg alkoxy or -NHR, E is B or (lower) alkyl, Y is C ^-Cg alkyl, C ^-C ^ cycloalkyl or hydroxycycloalkyl, phenyl, halophenyl, trifluoromethyl-phenyl, bicycloalkyl or hydroxybicycloalkyl with ind-05 to 12 carbon atoms, or -AR1, A is methylene or ethylene, R is phenyl, halophenyl, trifluoromethyl-phenyl, bicycloalkyl or hydroxybicycloalkyl of up to 12 carbon atoms, Q is H, C C ^ cycloalkyl or hydroxycycloalkyl, bicycloalkyl or hydroxybicycloalkyl of up to 12 carbon atoms, phenyl, halo phenyl, trifluoromethylphenyl or AR ^ ", or X is halogen or (lower) dialkylamino, Y is methyl, ethyl, cyclopentyl, phenyl , halophenyl, trifluoromethyl-phenyl or benzyl and Q have the meaning given above.

The compounds are said to be valuable in the treatment of psoriasis.

5. West German publicly available patent application no.

2,610,985 (Farmdoc 70863Y) discloses compounds of formula f2 3 4 20 in Ϊ> cox d k- k 2 2 wherein R and R are OH or ONOO, or together form 1 4 3 C 2 -C 6 alkylidene, aralkylidene or Cr R R is H or C ^-C7 alkyl, R5 is ORg or NR ?Rg, R ° is C1-C7 alkyl, R 4 and R er are optionally substituted C ^-Calk alkyl or C together form a C 2 -C 5 alkylene group, wherein one CH 2 group is optionally replaced by a heteroatom, R is C 1 -C 4 alkyl or alkoxy, optionally substituted phenyl or Η, X is OR 2 or NR 2 q R , -, R 9 is C 1 -C 7 alkyl, C 1 -C 2 cycloalkyl, optionally sub-xx x / J substituted phenyl or aralkyl, R and R are H, optionally substituted C 1 -C 4 alkyl, alkenyl or alkynyl, optionally substituted Cg-C ^ cycloalkyl, substituted phenyl, benzylamino, 2-methylfuryl or adamantyl, or one may be H and the other a group of formula 11¾

- (0¾) -MH-OC

g R1 R2 10 wherein n is 2-16 or R 2 and R 2 together form a C 2 -C 5 alkylene group in which one CH 2 group can be replaced by a heteroatom. The compounds are said to have circulatory, cardiac and metabolic activity.

6. Chem. Pharm. Bull., 23, (4), 759-774 (1975) discloses inter alia compounds of the formula in jC> Ηγχ

OH OH

Wherein R is (lower) alkyl. The compound is said to possess coronary vasodilating activity.

7. Japanese Publicly Available Patent Application No. 52-71492 (Farmdoc 53190Y) discloses compounds of the formula NHp Λα

05 R • -S

R 3 wherein R 1 is C 1 -C 10 alkyl or branched alkyl, C 5 -cycloalkyl, C 1 -C 4 aralkyl or piperazine ethyl of the formula -CH 2 -OK, -1 / - - wherein R is C aralkyl, mono-substituted aralkyl, cinnamyl or fluorenyl, R 3 is C 1 -C 4 straight or branched alkyl, C 1 -C 4 cycloalkyl, C 1 -C 4 aralkyl or piperazine ethyl of the above meaning, except for compounds wherein R and R are methyl, R 13 is methyl and R is ethyl and R is C 9 -C 18 cycloalkyl and R 3 is C 1 -C 4 alkyl, C 8 -C 2 cycloalkyl or C 1 -C 2 aralkyl.

The compounds are said to exhibit an inhibitory effect on platelet aggregation as well as having coronary dilating activity.

8. Chem. Pharm. Bull., 25 (7), 1811-1821 (1977) discloses the preparation of 2-thioadenosine derivatives including inter alia a compound of formula 6, 146220 NR, [> ΛΛ |> 0

The above compound is said to be a bit effective as a plate aggregation inhibitor. The authors note that the corresponding compound with a ribose sugar moiety 05 at the 9-position was far more effective and concludes that the ribosyl moiety of 2-thioadenosine derivatives is essential for effective inhibition of plate aggregation and cannot be replaced by other substituents.

No prior art has been found dealing with 2,9-disubstituted adenine derivatives having an alkoxy substituent at the 2-position and a cycloalkyl or cycloalkenyl group at the 9-position.

The novel purine derivatives prepared by means of the MSII CT products of the present invention effectively inhibit fire restriction. is induced by histamine or other bronchi al-con tricks. The compounds belong to the non-adrenergic class of bronchodilators and are valuable for administration to mammals and humans for the treatment of asthma, including bronchial asthma, allergic asthma, bronchitis, pulmonary emphysema and other chronic respiratory diseases involving bronchospasm. The preferred compounds prepared by the intermediates of the invention have been shown by standard pharmacological testing methods to have higher bronchodilatory activity than aminophylline with reduced cardiovascular and central nervous system side effects.

The valuable end products have the general formula: I, R1 and pharmaceutically acceptable acid addition salts thereof, wherein R represents C, C, alkyl and R 1. _ _

Ό owner O

The term "pharmaceutically acceptable acid addition salts" as used herein includes those salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, hydrogen iodide acid, nitric acid, sulfuric acid, phosphoric acid and the like. as well as organic acids such as acetic acid, citric acid, pivalic acid, lactic acid, tartaric acid, oxalic acid, succinic acid, malic acid and the like. Any non-toxic acid which forms a salt with the present compounds is suitable. The salts are prepared by conventional methods known per se.

The above-mentioned C ^-Cg alkyl groups include those with either straight or branched hydrocarbon chains. Particularly preferred alkyl groups are those having from 1-4 carbon atoms. Examples of suitable C ^-Cg alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl and the like.

The most preferred compounds encompassed by Formula I are those wherein R is C 2 H 2 -, n-C 8 H 2 - e- ^ is n-C 2 H 8 -. Such compounds showed, by standard in vitro and in vivo tests for bronchodilatory activity, enhanced potency relative to aminophylline. They also exhibited reduced cardiovascular and central nervous system side effects compared to aminophylline as a reference agent.

The novel intermediate products of the invention have the formula: 146220 8 ΝΕ, I 7 g g / 03 ci \ A / "0 0 II" and can be readily converted by the methods described below to the compounds of formula I. The following general reaction-05 scheme illustrates these processes as well as the preparation of the intermediates.

146220

Cl 9 I I M = Na, K, TI, Ag or HgCl o- / o

/ \ X = Cl, Br, I

Cl Cl

/ r \ catalytic '' {'^ S'A

J ^ AV hydrogenation ^ Λ / 6 'o' NH, BE, »V 3 HP, NHg

Vrs I I v / catalytic -> ArMJk / hydrogenation ^ Cl Jl

Cl

0 “Oh

RO-alfc RO-alk

1 V

% ^ v -M.

I Μ catalytic_ \ I || R (X ^N ^N / hydrogenation 0 ’· 0 Ifa 146220 ίο

The compounds of formula I wherein is 2-cyclohexenyl can be prepared from 2,6-dichloropurine, a known compound, by the following steps in sequence: 1) react 2,6-dichloropurine with ca. an equivalent HgCl_ + + + + * 05 or a source of Na, K, TI or Ag (i.e., a salt which dissociates to form the desired ion) in an inert solvent to prepare a metal derivative of the formula

Cl.

ir ^ S ^ N

k LI

III

Wherein M is HgCl, Na, K, TI or Ag, 2) condensing metal derivative III in a substantially anhydrous inert organic solvent with a 3-halo-cyclohexene of the formula

ISLAND

IV

Wherein X represents chlorine, bromine or iodine to prepare an intermediate of the formula

3) submits the intermediate V amination with NH 3 in an inert solvent to prepare an intermediate of the formula NHg

n ^ 'N-'A

i Γ)

Cl

II

and and 4) heats the intermediate II with an alkali metal alkoxide of the formula RO-alk, wherein alk means sodium or potassium and R is as defined above in an inert solvent to prepare the desired free base compound of formula I and, if desired , transforms the compound in a manner known per se into a pharmaceutically acceptable acid addition salt thereof.

Conveniently, a compound of the formula is prepared:. Wherein R is C ^-Cg alkyl or a pharmaceutically acceptable acid addition salt thereof by heating the intermediate II with an alkali metal alkoxide of the formula RO-alk, wherein alk represents sodium or potassium and R has it The above-mentioned meaning in an inert solvent until the desired free base is formed and, if desired, transforms this compound in a manner known per se into a pharmaceutically acceptable acid addition salt thereof.

Compounds of formula I wherein R "1" is cyclohexyl can be prepared by catalytic hydrogenation of the corresponding compounds where R 1 = cyclohexenyl. As an example of a suitable process, a compound of formula I can be dissolved in a suitable non-reducing inert solvent (e.g., methanol, ethanol, water, aqueous methanol, aqueous ethanol) and then hydrogenated using a conventional hydrogenation reaction. catalyst. Examples of suitable catalysts include palladium "black", Pd-BaSO ^, Pd-C, PtC₂, Ru-C, Rh-C, Raney nickel,

CuCrO, RhCl [P (CgH2) 3 and RuCl [P (CgH2) 3 · A preferred catalyst is palladium-on-carbon. Although temperature and pressure are not critical to the hydrogenation step, beneficial results are obtained under conditions of room temperature and atmospheric pressure.

An alternative process for the preparation of compounds of formula I, wherein cyclohexyl represents the following 20 steps in sequence: 1) reacting 2,6-dichloropurine with ca. an equivalent HgCl 2 or a source of Na +, K +, T1 + or AG + in an inert solvent to prepare the metal derivative III, 2) condenses the metal derivative III in a substantially anhydrous inert organic solvent with a cyclohexyl halide of the formula

ISLAND

IV '13 146220 wherein X means chlorine, bromine or iodine to prepare an intermediate of formula rY>

: Q

3) subject the intermediate V to amination with NH4 in a 05 inert solvent to prepare an intermediate of formula 11¾

Cl IX '/ and 4) heats intermediate II' with an alkali metal alkoxide of the formula RO-alk, wherein a] k means sodium or potassium and R has the meaning given above in an inert solvent to prepare the desired free base compound of formula I and, if desired, convert the compound in a manner known per se into a pharmaceutically acceptable acid addition salt thereof.

Conveniently, a compound of the formula is prepared:.

wherein R is C ^-C ^ alkyl or a pharmaceutically acceptable acid addition salt thereof by heating the intermediate IX 'with an alkali metal alkoxide of the formula RO-alk, wherein alk represents sodium or potassium and R is as defined above , in an inert solvent until the desired free base is formed and, if desired, transforms this compound in a manner known per se into a pharmaceutically acceptable acid addition salt thereof.

10

As can be seen from the general reaction scheme shown above, the process for preparing Compounds 11 from 2,6-dichloropurine may include all possible variants, wherein both intermediates V or II 'are prepared via catalytic hydrogenation of the corresponding cyclohexenyl intermediate. Thus, the method e.g. include preparing intermediate III, preparing intermediates V and II, catalytically hydrogenating II to II 'and then producing Ifa from II'. An alternative pathway would be III- * V- * V '(by catalytic hydrogenation) - "* II The above-described reaction conditions for catalytic hydrogenation of I < 1 > can also be used for the conversions V-> V * or II -> 11 '.

The preparation of the 2,6-dichloropurine metal derivatives of formula III can be accomplished by methods previously described in the literature.

The silver derivative of 2,6-dichloropurine can be prepared according to the general procedure of J. Am. Chem.

Soc., 73, 1650 (1951), i.e. the 2,6-dichloropurine is dissolved in boiling water, the solution is made basic (e.g. with aqueous 05 ammonia) and an aqueous solution of approx. an equivalent of a silver salt (e.g., AgNO4) is added to form the desired 2,6-dichloropurine silver salt.

The sodium salt of 2,6-dichloropurine can be prepared according to the general method described in Chem. Pharm. Bull., 25, 1811 (1977), i.e. suspending the 2,6-dichloropurine in an inert solvent such as dimethylformamide and ca. an equivalent of a sodium salt such as NaOH or NaOCH 2 is added to form the desired salt in situ.

The potassium salt of 2,6-dichloropurine can be prepared according to the 15 general procedure described in J. Org. Chem ..

Soc., 81, 197 (1959) and J. Org. Chem., 81, 2310 (1963), i.e. dissolving 2,6-dichloropurine in an inert solvent such as dimethylsulfoxide or dimethylformamide and an equimolar amount of a potassium slate such as K2CO3 is added to form the desired metal salt in situ.

The thallium (I) salt of 2,6-dichloropurine can be prepared according to the general procedure of J. Org.

Chem., 34, 1170 (1969), i.e. by adding a thallium (I) salt such as thallium (I) ethoxide to a solution of 2.6-25 dichloropurine in an inert solvent such as ethanol.

The chlorine mercury salt of 2,6-dichloropurine can be prepared by methods previously used for other purines, see e.g. J. Org. Chem., 22, 954-959 (1957). The 2,6-dichloropurine is added to ca. a weight equivalent of HgCl 2 in an inert aqueous or aqueous orange solvent, e.g. an aqueous C ^-Cg alkanol such as 50% ethanol. A base such as an aqueous solution of an alkali metal hydroxide (e.g., NaOH, KOH) is then added with stirring. A sufficient amount of base is used to produce a permanent light yellow color (due to HgO formation) indicating the completion of the reaction step. The chlorxneric curly salt is the preferred metal derivative for use in the methods of the present invention.

The metal derivative III is condensed with a 3-halo cyclohexene, preferably 3-bromo-cyclohexene, or a cyclohexyl halide to produce intermediate V or V, respectively. The reaction conditions may be substantially the same as used in the conventional nucleoside synthesis [see e.g.

J. Am. Chem. Soc., 81, 197-201 (1959)]. In a preferred embodiment, the 3-halo cyclohexene or cyclohexyl halide, preferably in excess, is added to Compound III in an inert substantially anhydrous organic solvent such as an aromatic hydrocarbon (e.g., benzene, xylene, toluene) and the reaction mixture is heated to reflux. of the intermediate V or V.

Amination of the intermediate thus formed to replace the 6-chloro substituent with a 6-amino group can be carried out by conventional methods [see e.g. Chem. Phar. Bull., ~ 202_3, 759-774 (1975)]. In a preferred embodiment, their intermediate V or V is suspended in an inert solvent (e.g., water, methanol, ethanol), the suspension is saturated with gaseous ammonia (preferably at a reduced temperature such as / w0 ° C) and the saturated reaction mixture is then heated. to a temperature from just above room temperature to the boiling point of the reaction mixture. A most preferred amination method comprises heating a solution of the appropriate methanolic ammonia intermediate product in a sealed tube at ca. As noted above, compounds II and II are intermediates for the preparation of 2-alkoxy compounds of formula I.

Intermediate II or II 'can then be subjected to a nucleophile substitution reaction conversion of the 2-chloro substituent to a 2-alkoxy group. This step can be carried out by the 35 general procedure disclosed in West German published patent application No. 14582078. In a preferred embodiment, the intermediate II or II 'is heated with a solution of an alkali metal (lower) alkoxide (RONa or ROK where R is C ^-Cg alkyl) in an inert solvent (e.g., benzene, dimethylformamide or C ^ -Cgalkanol). If a (lower) alkanol is used as a solvent, both the alkanol and the alkoxide used in this step should contain the same "R" substituent. Although the temperature of the reaction is not critical, it is preferable to perform the substitution at reflux temperature to maximize yield and minimize reaction time. At the end of the reaction, any excess base in the reaction mixture is neutralized with acid and the desired free base is recovered, such as by evaporation to dryness.

Free bases of formula I, II or II 'can be converted to 15 acid addition salts by conventional methods. Thus, the free base can e.g. dissolved in an inert solvent, reacted with ca. an equivalent weight of a suitable organic or inorganic acid to form the desired salt and the salt is recovered such as by solution precipitation 20 or lyophilization.

To reduce bronchial constriction in a human or mammal suffering from this condition, an effective bronchodilatory amount of a compound of general formula I or a pharmaceutically acceptable acid addition salt thereof is administered to the subject.

The compounds can be used in a unit dosage formulation pharmaceutical. Such composition comprises as active ingredient an effective bronchodilating amount of a compound of formula I above or a pharmaceutically acceptable acid addition salt thereof, in admixture with a pharmaceutically acceptable carrier or diluent.

146220 18

The subject pharmacologically active compounds can be administered either as individual therapeutic agents or as mixtures with other therapeutic agents. They can be administered alone, but are generally administered in the form of pharmaceutical preparations. Examples of such compositions include tablets, cough pills, capsules, powders, aerosol sprays, aqueous or oily suspensions, syrups, elixirs and aqueous solutions. The compounds are preferably administered orally, but may also be administered by inhalation or injection.

The nature of the pharmaceutical composition and pharmaceutical carrier or diluent will, of course, depend on the desired route of administration. For example. oral preparations may be in the form of tablets or capsules and may contain conventional excipients such as binders (e.g., syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g., lactose, sugar, corn starch, calcium phosphate, sorbitol or sorbitol). glycine), lubricants (e.g., magnesium stearate, talc, polyethylene glycol or silica), solvents (e.g., starch), or wetting agents (e.g., sodium lauryl sulfate). Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc. and may be presented before use as a dry product for reconstitution with water or another suitable carrier. Such liquid compositions may contain conventional additives such as suspending agents, flavoring agents, diluents or emulsifying agents. For parenteral administration or inhalation, solutions or suspensions of a compound of formula I with conventional pharmaceutical carriers, e.g. as an aerosol spray for inhalation, as an aqueous solution for intravenous injection or as an oily suspension for intramuscular injection.

The compounds of formula I or pharmaceutical compositions thereof may be administered to mammals (including, in particular, human patients) at oral doses ranging from ca. 0.1 to 20 mg / kg / day 35 active ingredient. For intravenous administration to humans, single doses of approx. 0.02-5 mg / kg / dose of active ingredient. Suitable human doses for aerosol administration 19 are in the range of ca. 0.1-20 mg / dose of active ingredient.

However, these values are illustrative only, and it is of course the physician who will ultimately determine the appropriate dose for a particular patient on the basis of factors such as age, weight, severity of the symptoms, and nature of the agent to be administered.

Representative compounds of general formula (I) were subjected to comparative tests with aminophylline to determine btonchodilatory activity in vitro and 10 in vivo and hypotensive activity in vivo (a measure of cardiovascular side effects).

Bronchodilatory activity in vitro

Guinea pig trachea chains were prepared according to the method described by A. Akcasu in Arch. Int. Pharmacodyn. Ther., 122, 201 (1959).

The reaction to each test compound was recorded by the Magnus method and expressed as a percentage of the maximum reaction obtained with 0.1 mcg./ml of isoproterenol before each experiment. The bronchodilatory activity (in vitro) of aminophylline and the test compounds is expressed in Table I below as an EC5q value (concentration in mcg / ml which produces a relaxation which is 50% of the maximum reaction to 0.1 mcg./ml isoproterenol ).

Bronchodilatory and Hypotenaic Activity in Vivo The bronchodilatory activity of aminophylline and test conditions in vivo was assessed due to an increase in detintra-tracheal pressure (ITP) in guinea pigs through a modification of the method described by James in J. Pharm. Pharmac., 21, 379 (1969).

Cannules were brought to trachea in anesthetized guinea pigs and ITP recorded on a polygraph by artificial ventilation. The arterial blood pressure (ABP, measure of hypotensive activity) was also measured by the experiment. Data were obtained for both intravenous and intraduodenal administration. Table I shows the in vivo bronchodilatory activity (ITP) for each compound as EDgQ value (dose mg / kg resulting in a 50% decrease in intratracheal pressure) and hypotensive activity (ABP) as ED2Q value (dose in mg / kg, which reduces arterial blood pressure by 20%).

Separation of bronchodilatory and cardiovascular effects

For the separation of the desired bronchodilatory activity and the undesirable cardiovascular (hypotensive) effect of the test compounds, the ratio of hypothetical ED2Q / bronchodilatory ED1Q was calculated as shown in Table I. The compounds with the highest ABP / ITP ratio showed the greatest separation of cardiovascular side effects from bronchodilator activity.

21 146220 tu tr * σ \ ο -PH ·. Φ X in ιλ σ \ cvi

+ J (1, Η Η VO

J Μ · Η Μ Η Ό (1> «· ΙίτΙ ά> &« ί Q) -Ρ Si 0)

1¾¾ OH

+> 8β c χ ^ - +. * 0 S U? -S ϋΓ «0 Η OT Sc] '<Λ α) ιϋ Λ! ο PQ ε W C -g cd Η -Η ^ Ο +3 • Η · Η rH g -ΡΧ ^

Hii'd «ώ • g -g · γη 3 5

j! + J ί} - ^ CVI +> S CM

® ® η I ^ Η Η ΟΗ «η II ιι ιι> ββ &> Η S S β Η tu εη οο σ \ οο Η ·

\ VO CM Ν- CM ΙΑ =? CM

Dh i — I VO III H and I

., m n- A

H <$ H

<u • p _.

(β S'T

jj jn

Zj b bC

ω «> ^ -t oo ^. ^ h

2 mja c w ΙΛ ΙΛ 1Λ - + CM ΙΛ CM IA CM H

§K -¾ Λ A Λ λ Λ

-p S

tn s CL) ίΰ o --— H -P jj in · o

HQ) fjjS 5 t'- t · - O tA ^ -tn CO

Λ in U> ^ n o R S

rO-H & c O O O rA ^ IA O O O ΓΑ fA fA O

^ S 'K-S λΛλ ΛΛΛ

• 3 OH

^ o n g e vom g c * - in β -Η N COCMCMH- 5 S 1 d S vrt P> ·. · Η O O ΓΑ CO · + O O O - = f ΙΑ M3 ty β in O O O O O r-ι H O O O O O (A vo

”HH e Λ H

Oj '' · "0 ......

HJ

\ J '3 S

S- (-H o OH

Λ <N I σ \ O O „CT \ O O >>

° ν ° «O C K H fA O O SI H iA -C

K fe I f— CJVp-HH t ^ -CTiJ-HH P.

o tu tu o tu tu o tu tu o κ ru o in ία 4 · i in va in, -a = r i invo c κ o o o o ru ru o o o α h

cm I i w i · CM I I W I I S

cjcchcc: o ββ-πββ cj

IZ

146220 22

The following examples illustrate the preparation of the intermediates of the invention and their conversion into valuable end products.

Example 1 9- (2-cyclohexenyl) -2-n-propoxy-9H-adenine NH

'I'v

05

N-C ^ hyo

Aa. HgCl salt of 2/6-dichloropurine

Cl mT \

A solution of 7.38 g (27.2 mmol) of HgCl 2 in 100 ml of 50% ethanol was stirred and 5.15 g (27.2 mmol) of 2,6-dichloro-purine was added. After 5 minutes, 10% NaOH (~ 10 ml) was added to the solution until the color reaction stopped (yellow due to HgO).

The mixture was stirred for 30 min and the precipitate was filtered off, washed in this order with water, ethanol and diethyl ether and dried to give 6.91 g (64% yield) of the title salt.

B. 9- (2-cyclohexenyl) -9H-2,6-dichloropurine

Cl i Γ .0

A mixture of 6.91 g (16.3 mmol) of the product of Step A and 6.91 g of "Celite" (diatomaceous earth) in benzene was azeotropically evaporated to remove moisture. To the resulting mixture 05 was added 100 ml of dry xylene and 4 ml (339 mmol) of 3-bromocyclohexene. The mixture was refluxed for 2.5 hours with stirring, cooled and filtered. The filtrate was washed with a small amount of CHCl 3. The filtrate and wash were evaporated to dryness. The residue was dissolved in 50 ml of benzene and solution 10 was washed with 20% KI solution (3 times) and aqueous NaCl (once) and dried over Na 2 SO 4 · The filtrate was evaporated and the residue was purified by chromatography on silica gel to give 3.87 g (88%) of the title intermediate, ...

mp. 133-135 ° C. IR (KBr): 2930, 1590, 1565, 1405, 1355, 1315, 1210, 875, 835 cm "1. UV: x ^ ^0h 276 nm (ε 9500).

IDclX

NMR (CDCl3): 62.00 (6H, m), 5.60 (1H, m), 6.00 (2H, m), 8.11 (1H, s).

Anal. ber. for chhioN4CL2: C '49'09' H '3.75, N, 20.82, Cl, 26.35.

Found: C, 48.54; H, 3.48; N, 20.34; Cl, 25.54.

C. 2-Chloro-9- (2-cyclohexenyl) -9H-adenine 11¾ 'ιΤ \ ο

Ammonia gas was bubbled to a mixture of 2.8 g (10.3 mmol) of 9- (2-cyclohexenyl) -9H-2,6-dichloropurine in 50 ml of CH 2 OH at 0 ° C until gas absorption stopped. The mixture was heated at 0500 ° C for 4 hours in a sealed tube, then cooled and concentrated to deposit crystals which were filtered off to give 2.39 g of the title compound.

A further yield (112 mg) was obtained from the filtrate by chromatographic separation on silica gel. Total yield = 2.50 g (96%), m.p. 195-197 ° C. IR (KBr): 3120, 1640, 1590, 1320,

1300, 1225, 1190, 920 cm-1. UV: 266 nm (ε14600), NMR

XuclX

(CDCl3): 0.89 (1H, m), 1.26 (1H, m), 2.00 (4H, m), 5.30 (1H, m), 6.00 (2H, m), 8.11 (1H, s).

D. 9- (2-cyclohexenyl) -2-n-propoxy-9H-adenine A solution of 2.4 g (9.2 mmol) of 2-chloro-9- (2-cyclohexenyl) -9H-adenine in 60 ml of 1N sodium n-propoxide in n-propanol was heated at reflux overnight under a nitrogen atmosphere. The reaction mixture was poured into ice-water containing a sufficient amount of acetic acid to neutralize the excess alkoxide. The mixture was evaporated in vacuo.

The residue was dissolved in CHCl3 with stirring. The CHCl ^ extracts were washed with water, dried over Na 2 SO 4 and evaporated to give 2.35 g (90%) of the title product, m.p. 157-159 ° C. IR (KBr): 3450, 3110, 1630, 1585, 1470, 1390, 1335 cm "UV. UV: λ * ° Η 266 nm (ε13200). NMR (CDCl ^): IQaX δ δ 1.03 (3H , t, 7Hz), 1.80 (8H, m), 4.15 (2H, t, J = 7Hz), 5.03 (2H, m), 5.88 (1H, m), 6.56 ( 2H, m), 7.4 (1H, s).

25 146220

Example 2 9-Cyclohexyl-2-n-propoxy-9H-adenine NHg

A solution of 2.21 g (7.8 mmol) of 9- (2-cyclohexenyl) -2-n-05 propoxy-9H-adenine in 30 ml of 90% ethanol was hydrogenated overnight with 250 mg 10% in Pd-C and then filtered.

The filtrate was evaporated in vacuo to give a residue which was crystallized from ethyl acetate-n-hexane. Yield 1.85 g (76%), m.p. 148-150 ° C. IR (KBr): 3510, 2930, 1670, 1640, 1595, 1405 cm -1. UV: 252 nm (ε8360), 269 nm fe

ItlaX

13200). NMR (CDCl3): Si, 03 (3H, t, J = 7Hz), 1.80 (12H, m), 4.20 (2H, t, J = 7Hz), 4.35 (1H, m), δ , 02 (2H, s), 7.55 (1H, s).

Anal ·, calc. for C, 61.07, H, 7.69, N, 25.43.

Found: C, 61.07, H, 7.89, N, 25.48.

Example 3 9- (2-Cyclohexenyl) 2-ethoxy-9H-adenine N & p S | T '

A mixture of 2-chloro-9- (2-cyclohexenyl) -9H-adenine (310 mg, 1.24 mmol) and a solution of sodium ethoxide in ethanol (0.25-1N, 10 ml) was refluxed overnight for a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate 05 (20 ml). The extracts were washed with water, dried over Na 2 SO 4 and filtered. The filtrate was evaporated and the residue was then subjected to silica gel chromatography (7 g silica gel, eluted with 1% CH 3 OH-CHCl 3) to give the title product by 93%. yield, m.p. 67-72 ° C. IR 10 (KBr): 3320, 2940, 1640, 1595, 1465, 1410, 1385, 1340 cm_1..

UV: XEtOH 243 nm (ε8400), 269 nm (ε12600). NMR (CDCl1): 1.44 max δ (3H, t, J = 7Hz), 2.00 (6H, m), 4.45 (2H, q, J = 7Hz), 5.20 (1H, m ), 5.95 (2H, m), 6.16 (2H, s), 7.62 (1H, s).

Example 4 9- (2-Cyclohexenyl) -2-n-butoxy-9H-adenine 19¾

n-CjlHgO

island

The procedure of Example 3 was repeated except that the sodium ethoxide in ethanol solution was replaced with an equivalent amount of sodium n-butoxide in n-butanol. The title product (as hygroscopic powder) was prepared in 40% yield.

IR (KBr): 3310, 3160, 2930, 1640, 1595, 1410, 1345 cm -1. UV: λ 254 nm (ε8300), 270 nm (ε11500). NMR (CDCl 3: 1.80 max δ (13H, m), 4.23 (2H, t, J = 7Hz), 5.02 (1H, m), 5.84 (2H, m), 6.06 ( 2H, s), 7.58 (1H, s).

EXAMPLE 5 9- (2-Cyclohexenyl) -2-n-pentyloxy-9H-adenine

The procedure of Example 3 was repeated except that the sodium ethoxide in ethanol solution was replaced by an equivalent amount of sodium n-pentyloxide in n-pentanol. The title product 05 (as a hygroscopic powder) was prepared in 48% yield. IR (neat): 3500/3320, 2970, 1635, 1590, 1500, 1465, 1400, 1335 cm "UV. UV: λEtOH 253 nm (ε8400), 269 nm (ε12500).

ITlclX

NMR (CDCl3): 1.80 (15H, m), 4.25 (2H, t, J = 6.5 Hz), 5.07 (1H, m), 5.89 (2H, m), δ, 08 (2H, s), 7.56 (1H, s).

Example 6 9- (2-Cyclohexenyl) -2-n-hexoxyloxy-9H-adenine 11¾RY;

The procedure of Example 3 was repeated except that the sodium ethoxide in ethanol solution was replaced with an equivalent amount of sodium n-hexyl oxide in n-hexanol. The title product (as a hygroscopic powder) was prepared in 26% yield.

IR (pure): 3500, 3320, 1635, 1590, 1460, 1395, 1340 cm -1.

UV: XEtOH 252 nm (ε6900), 268 nm (ε10200). NMR (CDCl): 1.50 max 3 (17H, m), 4.25 (2H, t, J = 6Hz), 5.08 (1H, m), 5.86 (2H, m), δ , 01 (2H, s), 7.60 (1H, s).

Example 7 9- (2-Cyclohexenyl) -2-isobutoxy-9H-adenine NH

iso-ChHoO

05 4 9 · 6

The procedure of Example 3 was repeated except that the sodium ethoxide in ethanol solution was replaced with an equivalent amount of sodium isobutoxide in isobutanol. The title product was prepared with 66% yield, m.p. 132-135 ° C. IR (neat): 3025, 1630, 1590, 1460, 1395, 1375, 1350 cm -1. UV: λΕΕ Η 253 ΙΏαΧ nm (ε8600), 269 nm (ε13000). NMR (CDCl3): 0.98 (δ, d, J = 6.5 Hz). 1.90 (7H, m), 3.96 (2H, d, J = 6.5 Hz), 5.02 (1H, m), 5.83 (2H, m), 6.18 (2H, s) ), 7.50 (1H, s).

Example 8 2-Ethoxy-9-cyclohexyl-9H-adenine NHβ

cpH5 ° I

ό 29 146220

A mixture of 9- (2-cyclohexenyl) -2-ethoxy-9H-adenine (0.5 mmol) and 10% palladium-on-charcoal (35 mg) in ethanol (6 mL) was hydrogenated at room temperature and under atmospheric pressure. The reaction mixture was filtered and the filtrate was evaporated. The re-05 residue was lyophilized to give the title product in 40% yield, m.p. 134-136 ° C. IR (KBr): 3280, 2995, 1705, 1615, 1525, 1415, 1310, 1010 cm "1. UV: 253 nm (ε6800), 269

IQaX

nm (ε, 10200). NMR (CDCl3): 1.44 (3H, t, J = 7Hz), 2.00 (10H, m), 4.45 (2H, q, J = 7Hz), 4.50 (1H / m), δ , 07 (1H, s), 8.60 (2H, s).

Example 9 2-n-butoxy-9-cyclohexyl-9H-adenine for O

The procedure of Example 8 was repeated except that the 9- (2-cyclohexenyl) -2-ethoxy-9H-adenine was replaced by an equivalent amount of 9- (2-cyclohexenyl) -2-n-butoxy-9H-adenine.

The title product was prepared in 47% yield, m.p. 138-141 ° C. IR (KBr): 3300, 2930, 1660, 1640, 1590, 1405, 1345 cm -1.

UV: 253 nm (ε7600), 269 nm (ε11500). NMR (CDCl1): 1.50

IuciX J

20 (17H, m), 4.30 (1H, m), 4.31 (2H, t, J = 6Hz), 6.40 (2H, s), 7.67 (1H, s).

Example 10 2-n-pentyloxy-9-cyclohexyl-9H-adenine 30

1Λ 6 2 2 O

Γ2 χχ> n ”C5HH °

ISLAND

The procedure of Example 8 was repeated except that the 9- (2-cyclohexenyl) -2-ethoxy-9H-adenine was replaced by an equivalent amount of 9- (2-cyclohexenyl) β-n-pentyloxy-gH-OS adenine. The title product was prepared in 90% yield, m.p.

64-68 ° C. IR (pure): 3500, 3320, 1635, 1590, 1460, 1395, 1340, 1325, 1265 cm -1. UV: XEt H 253 nm (ε10900), 269 nm (ε16800).

ItlclX

NMR (CDCl 3) δ 1.50 (19H, m), 4.20 (1H, m), 4.26 (2H, t, J = 6.5 Hz), 6.25 (2H, s), 7, 56 (1H, s).

Example 11 2-n-Hexyloxy-9-cyclohexyl-9H-adenine NHg rV> n-c6Hi3 °

The procedure of Example 8 was repeated except that the 9- (2-cyclohexenyl) -2-ethoxy-9H-adenine was replaced with a 15 equivalent weight of 9- (2-cyclohexenyl) -2-n-hexoxy-9H-adenine. The title product was prepared in 90% yield, m.p. 57-60 ° C.

IR (neat): 3500, 1635, 1595, 1500, 1465, 1420, 1400 cm "UV. UV: λΕΕ ° Η 253 11111 (ε7200), 270 nm (ε10900). NMR (CDCl1): 1.5 (21H,

JuaX O

M), 4.25 (2H, t, J = 6.5Hz), 4.40 (1H, m), 6.07 (2H, s), 7.54 (1H, s).

Example 12 2-Isobutoxy-9-cyclohexyl-9H-adenine NHg II) Ί

The procedure of Example 8 was repeated except that 9- (2-cyclohexenyl) -2-ethoxy-9H-adenine was replaced by an equivalent weight of 9- (2-cyclohexenyl) -2-isobutoxy-9H-adenine. The title product was prepared in 60% yield, m.p. 123-134 ° C.

IR (pure): 3320, 3160, 2940, 1635, 1590, 1395, 1375 cm -1. UV: λ ^ ° Η 253 nm (ε7000), 269 nm (εΙΙΟΟΟ). NMR (CDCl1): 1.05 (6H, d, J = 6.5 Hz), 1.90 (11H, m), 4.05 (2H, d, J = 6.5 Hz), 4.24 (1H, m), 6.14 (2H, s), 7.55 (1H, s).

Example 13 2-n-hutoxy-9-cyclohexyl-9H-adenine A 2-chloro-9-cyclohexyl-9H-adenine A mixture of 2-chloro-9- (2-cyclohexenyl) -9H-adenine-1 · ( 252 mg, 1.0 mmol) in ethanol was hydrogenated with 10% palladium-on-charcoal (93 mg) at room temperature and under atmospheric pressure. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel chromatography to give 0 139 mg (55%) of the title compound, m.p. 206-209 ° C. IR (KBr):

3360, 3150, 2905, 1645, 1595, 1570, 1540 cm -1. UV: \ C2H5 ° U

max 267 nm (ε15,300). NMR (CDCl3): δ 1.80 (10H, m), 4.47 (1H, m), 6.23 (2H, s), 7.82 (1H, s).