LU82694A1 - NOVEL PURINE COMPOUNDS, PROCESS FOR PRODUCING THE SAME, AND PHARMACEUTICAL COMPOSITION CONTAINING THEM - Google Patents

Description

1.

The present invention relates as a whole to heterocyclic carbon compounds which have the property of being drugs and of affecting biological processes. The invention relates more particularly to new bronchodilators which are endowed with non-adrenergic smooth muscle relaxation properties, which make them particularly useful for combating acute bronchospasm and as auxiliary substances for controlling the symptoms of chronic obstructive pulmonary diseases (for example example asthma, bronchitis, emphysema). The invention also relates to methods and therapeutic compositions using one or more of the new compounds as active ingredients.

With regard to the types of non-adrenergic bronchodilators, xanthine derivatives of the theophylline group are particularly remarkable. For example, aminophylline, which is the ethylenediamine salt of theophylline, is an effective bronchodilator which can be administered parenterally, orally or rectally and which is useful in patients who require direct relaxation bronchial muscle. Despite their widespread use, non-adrenergic xanthine class bronchodilators have major drawbacks relating to gastric irritation and side effects on the cardiovascular and central nervous systems. Consequently, it is essential to find new and effective bronchodilators which have increased potency and / or which produce fewer or less pronounced adverse effects. Conventional pharmacological tests have demonstrated that representative examples of compounds of the present invention exhibit greater bronchodilator activity compared to: aminophylline, with fewer side effects on the cardiovascular system and the central nervous system. The basic purine ring comprises a hexagonal pyrimidine ring condensed to a pentagonal imi-dazole ring as represented by the following formula which shows the numbering system adopted in this specification.

2.

* »6 7

3 hrs

Various types of purine derivatives are known in which the basic substance, namely purine, is substituted in one or more of the positions 2, 6 and 9.

Adenine is 6-aminopurine. The following references illustrate these compounds.

1. R.K. Robins et al. Describe in J. Am.

15 Chem. Soc., 83, 2574 (1961), the synthesis of the compound of formula: 20 '"ό 30 as a potential antitumor agent, starting from' 6-chloro-9- (tetrahydro-2-pyranyl) -purine .

2. U.S. Patent No. 3,228,937 describes 6-benzylamino-9-tetrahydropyran-2-yl-9H-purine: "μ 3.

^ »W ^ f

Vv ^ j, CO: ΓΛ

10 W

* · - Λ as an inhibitor of wilting and dieback of leafy green plants.

3. R. Marumoto et al., Chem. Pharm. Bull., 23 (4), 759-774 (1975) describe inter alia compounds of formula s 20 Ψΐ

CO

RO

25 t

OH OH

In which R is a lower alkyl radical. Coronary vasodilator activity is attributed to these compounds.

4.

4. H. J. Schaeffer et al. Describe in J. Am. Chem. Soc., 81, 197-201 (1959) synthesis of the compound of formula: 5 T2 i ixy

R

Wherein R is cyclohexyl or 2-cyclohexyl, as potential anticancer agents.

5. U.S. Patent No. 3,917,837 describes the use of the compound of formula: 15 m '

CO

20 (i “as an anti-inflammatory agent.

6. United States Patent No. 3,862,189 relates to compounds of the formula: ♦ 4.

30

ÜQ

; * 2 in which, inter alia, is amino, alkylamino, aralkylamino, etc. ; and R £ is a phenylalkyl group, a substituted phenylalkyl group, a * "5.

tetrahydroquinoylalkyle group, etc., useful as antianginal agents and bronchodilators.

7. United States patent No. 3,930,005 describes compounds of the formula: 5% h ’. '* 1 .1 1, Γ2 ό' 20 in which and R ^ may represent, inter alia, hydrogen and may represent, inter alia, a lower alkoxy group, as agents endowed with anti-inflammatory activity.

, 8. K. Kikugawa et al. Describe in Chem.

25 Pharm. Bull., 25, (7), 1811-1821 (1977) the synthesis of various 2-thioadenine derivatives of formula: nh2 30 A, X> SS N '* 1 in which, inter alia, R and Rj are alkyl, cycloalkyl, etc. groups as platelet aggregation inhibitors. Representative examples of these 35 6.

* compounds include those in which R is a propyl or n-hexyl group and R, j is an n-hexyl group; R and R-j are cyclopentyl groups. The authors conclude from this study that the ribosyl portion of the 2-5 thio-adenosine derivatives is essential for the effective inhibition of platelet aggregation and cannot be replaced by other substituents.

9. The Japanese patent application filed with the Public Inspection under the number 52-71 492 (Farmdoc 53190Y) describes 10 compounds of formula ï f 2 15 Γ] Γ>. * 3 in which R, j is a straight chain or branched C-j to C-jq alkyl group, a C-j cycloalkyl group, jq, a C? Aralkyl group? to or a piperazino-ethyl group of formula: 25 / "Λ

-CH - CH-N S-R

2 2W 2 30 a wherein R £ is a Cy aralkyl group to a monosubstituted aralkyl group, a cinnamyl group or a fluorenyl group; R ^ is a C1 to C1Q straight or branched chain alkyl group, a C5 * C10 cycloalkyl group, a C 1-6 aralkyl group or a piperazino-ethyl group as defined above, excluding 4 # 7.

compounds in which and are methyl groups, is a methyl group and R3 is an ethyl group and R ^ is a C 1-6 cycloalkyl group and R3 is a C1 to C4 alkyl group, C5 to C1Q cycloalkyl group or 5 aralkyl at to Cjj. The compounds are said to exert an inhibitory effect on the aggregation of platelets and on the dilation activity of the coronary vessels.

10. British Patent No. 1,493,684 describes substituted 2-thioadenosines on the sulfur atom, considered to be platelet inhibitors and coronary vasodilators, and having the formula: nh2 - 15 f F /

HrS

/

OH OH

In which, inter alia, R is a straight chain or branched C 1 -C 4 alkyl group.

11. J.A. Montgomery et al. Describe in J. Am. Chem. Soc., 8 £, 409-411 (1958) of adenine derivatives of formula: 30 NH2 03 N "

R

i 8.

in which R is an n-butyl, cyclopentyl or cyclohexyl group, as potential anticancer agents.

12. Belgian patent no. 853 086 (Farmdoc 70719Y) describes compounds of formula: 5 x rV>.

10

Y

in which either X is a C1-C5 alkoxy group or -NHR; R is a hydrogen atom or a lower alkyl group; Y is C1-C6 alkyl, cyclo-alkyl or hydroxycycloalkyl, phenyl, halogenophenyl, trifluoromethylphenyl, bicycloalkyl or hydroxybicycloalkyl having up to 12 carbon atoms, or an -AR group; A is a methylene group or

AT

ethylene; R is a phenyl, halophenyl, trifluoromethyl-phenyl, bicycloalkyl or hydroxybicycloalkyl group having up to 12 carbon atoms; Q represents H, a C1-C6 alkyl group, a C3-C1Q cycloalkyl group or a hydroxycycloalkyl, bicycloalkyl or hydroxybicycloalkyl group having up to 12 carbon atoms, phenyl, halophenyl, <1 trifluoromethylphenyl or AR; or X is a halogen or a di- (lower alkyl) -amino group; Y 30 is methyl, ethyl, cyclopentyl, phenyl, “halophenyl, trifluoromethylphenyl or benzyl and Q has the definition given above. These compounds are believed to be useful in the treatment of psoriasis.

The present invention relates to new purines of formula: * · 9.

NH,

Jw ‘\ /

R “A N

Hx t in which A is an NH group, a sulfur atom or an oxygen atom, R is a C1-C4 alkyl or lower alkoxy group or a cyclohexyl group; R <j is a cyclohexyl, 2-cyclohexenyl group or a pyran residue; with the proviso that when A is an NH group, R is a lower alkyl group in C1 to R and j is a cyclohexyl group or 2-cyclo-20 hexenyl; and that when A is an oxygen atom, R is an alkoxy group at and R-j is a pyran residue, or a pharmaceutically acceptable acid addition salt of these compounds. The latter effectively inhibit histamine-induced bronchial constriction by acting directly on the trachea muscle to relax the spasms with minimal cardiovascular side effects. Thus, the compounds belong to the non-adrenergic class of bronchodilators.

It should be noted that the term "lower alkyl" covers straight chain and branched chain * groups having 1 to 4 carbon atoms. Examples of these groups are methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl and tert-butyl. The term "halogen" refers to chlorine, bromine, fluorine and iodine.

For the purposes of this specification, the term "pharmaceutically acceptable acid addition salt" means the salt form of a compound of formula (I) obtained i -, 10.

by association with a non-toxic inorganic or organic acid which is relatively free of toxicity in the anionic form. Examples of non-toxic pharmaceutically acceptable acid addition salts of the compounds of formula (I) are the salts formed with sulfuric, hydrochloric, phosphoric, hydrobromic, hydroiodic, sulfamic, methanesulfonic, benzenesulfonic acids , paratoluenesulfonic, acetic, lactic, succinic, malic, maleic, mucic, tartaric, citric, gluconic, benzoic, cinnamic, isethionic, fumaric, levulinic and related acids.

The transformation of compounds of formula (I) into a pharmaceutically acceptable non-toxic acid addition salt is carried out in a conventional manner by mixing the base with at least one molecular equivalent of an acid chosen from a inert organic solvent such as ethanol, benzene, ethyl acetate, ether, a halogenated hydrocarbon, etc. The isolation of the salt is carried out by known techniques, for example by initiating precipitation with a non-polar solvent (such as ether) in which the salt has limited solubility.

According to the present invention, certain compounds of formula (I) can be prepared by a process consisting in reacting a 2-halo-9- (tetrahydropyran-2-yl) -9H-adenine of formula (II): NH- 30 N j (H), s <d_) ° in which X is bromine, fluorine, iodine or preferably chlorine, with an alkali metal alcoholate of fa 11.

formula ROM in which R has the definition given above and M represents sodium or potassium, in an inert solvent, preferably a lower alkanol of formula ROH in which R has the definition given above, to produce the compound of formula (I) in the form of the free base. High temperatures ranging from about 50 to 200 ° C are used in the reaction process, preferably at the reflux temperature of the inert solvent or in a sealed tube.

The 2-halo-9- (tetrahydropyran-2-yl) -9H- intermediate adenines of formula (II) are obtained in accordance with the following reaction scheme valid for 2-chloro-9- (tetrahydropyran-2-yl) -9H -adenine (lia) preferred: ιΥΛ 'ΓΎ> ci * 3 s, ^ ΤΓ ο O; (III) (IIa) 25

In general, the starting 2,6-dichloro-9- (tetrahydropyran-yl) -9H-adenine (III) is suspended in an inert solvent (for example water, lower alkanols such as methanol, ethanol), the suspension is saturated with gaseous ammonia and the saturated reaction mixture is heated from about 30 to about 150 ° C in a sealed tube to complete the reaction.

Compounds of formula (I) can also be prepared by methods illustrated according to the following reaction scheme: "" 12.

NH,

i2 X

hydrogenation ^ ’\ 5 XX / oam7tique 1 x, x /

Cl | Cl s I

0 o (II) (ΙΠ) 10 HNH2 ra2 4 »v NH„

15 fa jX

w 'jp ^ hydrogenation |

„AA /“ ““ n— „AA

O 0 /

Cia) “”> 25

Compounds of formula (I) in which A is an NH group can be obtained by condensation of 2-chloro-9- (2-cyclohexenyl) -9H-adenine (II) or 2-chloro-9-cyclohexyl- 9H-adenine (III) with a compound RNH2 in a solvent inert to the reaction, preferably a lower alkanol such as methanol or ethanol, to produce the desired free base of formula (la) or (Ib). The reaction is preferably carried out in a closed reactor such as a sealed tube at elevated temperatures ranging from about 50 to 200 ° C.

The compounds of formula (I) in which A is a sulfur atom can be obtained by reaction of 2-chloro-9- (2-cyclohexenyl) -9H-adenine (II) or of 2-chloro-9- * 4 13 .

cyclohexenyl-9H-adenine (III) with an alkali metal mercaptide of formula RS-alk, in which alk represents sodium, potassium or lithium and R has the definition given above, in an inert solvent until that the desired free base of the product of formula (I) has been formed, and optionally transformation of the product into one of its pharmaceutically acceptable acid addition salts by conventional methods illustrated herein . The desired alkali metal mercaptides "RS-alk" are normally obtained by treating the mercaptan with alkali metal hydroxides (e.g. sodium or potassium hydroxide), or preferably alkali metal hydrides (e.g. sodium or potassium hydride) in an inert solvent. The term "inert solvent" used herein means any solvent (eg dimethylformamide) chemically inert with respect to the starting 2-chloradenines (II) and (III) or the RS-alk mercaptides. High temperatures ranging from about 50 to 150 ° C are preferably used in the reaction which is carried out for a period ranging from 0.5 to 24 hours.

The compounds of formula (I) in which R ^ is a cyclohexyl group (ie (Ib)) are also prepared correctly by catalytic hydrogenation of the corresponding products (la). For example, a satisfactory procedure consists in hydrogenating a compound of formula (la) in an inert non-reducible solvent (for example methanol, ethanol, water or aqueous methanol, aqueous ethanol) in the presence of a conventional hydrogenation catalyst. Examples of suitable catalyzers include palladium black, Pd-

BaSO4, PtC ^, Ru-C, Rh-C, Raney nickel, CuCrO, RhCl (P (CgH5) 3J3 and RuCl (P (CgH5) 3 J3.) Palladium attached to carbon is a valued catalyst. advantageous have been obtained at room temperature and at atmospheric pressure, although the temperature and pressure are not critical for the hydrogenation step.

i 14.

Compounds of formula (I), and their pharmaceutically acceptable salts, according to the invention are useful in a process for producing a bronchodilator effect in a mammal requiring such an effect, by systemic administration to said mammal of an effective dose of about 0.1 to 20 mg / kg of body weight of the compound of formula (I). Compounds particularly appreciated for the implementation of the process are 2-n-propoxy-9- (tetrahydropyran-2-yl) -9H-adenine, 2-n-propylamino-9-10 cyclohexyl-9H-adenine and 9- (2-cyclohexyl) -2-n-propylthio-9H-adenine. The term “systemic administration” is intended to denote both the oral and parenteral routes, for example an intramuscular, intravenous, intraperitoneal and subcutaneous administration. Likewise, the active ingredient can be administered by inhalation using a suitable aerosol preparation. Oral administration is appreciated.

In another of its aspects, the present invention provides a pharmaceutical composition in unit dosage form useful for the relief of bronchoconstriction in mammals. This composition comprises, as active ingredient, an amount with bronchodilator effect of a compound of formula (I) or of a pharmaceutically acceptable acid addition salt of this compound, in mixture with a vehicle or pharmaceutically acceptable diluent.

The pharmacologically active compounds of the present invention can be administered as individual therapeutic agents or in admixture with other therapeutic agents. They can be administered alone, but are generally administered in the form of pharmaceutical compositions. Examples of these compositions include tablets, cachets, capsules, powders, aerosol spray compositions, water or oil suspensions, syrups, elixirs and aqueous solutions.

The nature of the pharmaceutical composition and of the pharmaceutical carrier or diluent naturally depends on the ί 15.

desired route of administration. For example, oral compositions can be in the form of tablets or capsules and can contain conventional excipients such as binders (for example syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (for example e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g. starch) or wetting agents (e.g. example sodium lauryl sulfate). Oral liquid preparations can be in the form of aqueous or oily suspensions, solutions and emulsions, syrups, elixirs, etc., or can be presented in the form of a dry product intended to be reconstituted with water or other suitable vehicle before use. These liquid preparations can contain conventional additives such as suspending agents, perfumes, diluents or emulsifiers. For parenteral administration or inhalation, solutions or suspensions of a compound of formula (I) can be used with conventional pharmaceutical vehicles, for example in the form of a sprayable aerosol composition for inhalation , in the form of an aqueous solution for intravenous injection or in the form of an oil suspension for intramuscular injection.

The following examples illustrate in detail the compounds and pharmaceutical compositions of the invention and their applications to bronchodilation.

EXAMPLE 1 2-chloro-9- (tetrahydropyran-2-yl) -9H-adenine Γ2

CD

Cl w

O

f 16.

(a) 2,6-dichloro-9- (tetrahydropyran-2-yl) -9H- purine

The pH of a solution of 2.0 g (10.6 mmol) of 2,6-dichloropurine and 2 ml of 3,4-5 dihydro-2H-pyran in 20 ml of acetate is adjusted to 2. ethyl by addition of anhydrous p-toluenesulfonic acid. The reaction mixture is heated at 60 ° C for 1 hour, neutralized with concentrated ammonium hydroxide, washed with water, dried over sodium sulfate and evaporated in vacuo . By crystallizing the residual material from a mixture of ethyl acetate and n-hexane, 2.6 g (96%) of 2,6-dichloro-9- (tetrahydropyran-2-yl) -9H- are obtained. purine melting at 119-121 ° C.

-1

Infrared spectrum (KBr) î 3100, 1600, 1560 cm 15 Ultraviolet spectrum xMe0H 273 nm (£ 9900). Max nuclear magnetic resonance (CDClg): δ 1.6-2.4 (6H, m), 3.5-4.4 (2H, m), 5.6-5.9 (1H, m), 8, 28 (1H, s).

Analysis: C,% H,% N,% Cl,% calculated for C10H10N4 ° 20 43.98 3.69 20.51 25.96 found 44.12 3.45 20.57 25.44.

(b) 2-chloro-9- (tetrahydropyran-2-yl) -9H-adenine A suspension of 2.0 g (7.3 mmol) of 2,6-dichloro-9- (tetrahydropyran-2-yl) - 9H-purine in 50 ml of methanol is saturated with ammonia at 0 ° C and a solution is formed during this time. The solution is heated at 100 ° C for 4 hours in a sealed tube and cooled. Concentration of the cooled reaction mixture gives 1.55 g (84%) of 2-chloro-9- (tetrahydropyran-2-yl) -9H-adenine melting at 204-210 ° C (decomposition).

Infrared spectrum (KBr): 3350, 3180, 1670, 1605 cm-1. Ultraviolet spectrum Ύ ^ χΗ 263 nm (£ 14,300). Nuclear magnetic resonance (DMSO-dg): δ 1.4-2.2 (6H, m), 3.5-4.2 (2H, m), 5.13 (1H, dd, J = 11 and 3 Hz ), 7.73 (2H, 35 wide, s), 8.28 (1H, s).

Analysis: C,% H,% N,% Cl,% calculated for C10H12C1N5 ° 47.34 4.77 27.61 13.97 found 46.84 4.71 27.17 14.10.

17.

* * EXAMPLE 2 2-methoxy-9 (tetrahydropyran-2-yl) -9H-adenine 5 Γ2

10 - CHjOF

o 15

A solution of 253 mg (1 mmol) of 2-chloro-9- (tetrahydropyran-2-yl) -9H-adenine in 10 ml of 1N sodium methylate in methanol, heated to 100 ° C in a sealed tube for a period of 16 hours, cooled and filtered, gives 154 mg of product. A second harvest (49 mg) obtained from the filtrate gives a total yield of 203 mg (87%) of 2-methoxy-9- (tetrahydropyran-2-yl) -9H- adenine melting at 199 ° C (decomposition) .

Infrared spectrum (KBr): 3300, 1640, 1600 cm “1.

i ΜύΠΗ

Ultraviolet spectrum s X “ax 267 nm (8-12100). NMR spectrum (DMS0-d6): <5 1.4-2.2 (6H, m), 3.80 (3H, s), 3.2-4.2 (2H, m), 4.47 (1H , dd, J = 12 and 3 Hz), 8.04 (1H, s).

Analysis: C,% H,% N,% calculated for 53.00 6.07 28.10 found 52.73 6.13 28.50.

35 18.

EXAMPLE 3 2-n-propoxy-9- (tetrahydropyran-2-yl) -9H-adenine 5 d®2 'ύθ

a-C3H7-0 N

0 15

A solution of 253 mg (1 mmol) of 2-chloro-9- (tetrahydropyran-2-yl) -9H-adenine in 10 ml of 1N sodium n-propylate is refluxed under a nitrogen atmosphere for 1 hour. n-propanol. The reaction mixture is neutralized with acetic acid and evaporated to dryness in vacuo. By trituration of the residual material with water, 213 mg of product is obtained which crystallizes from a mixture of ethyl acetate and n-hexane giving 147 mg (57%) of 2-n-propoxy-9 - (tetrahydropyran-2-yl) -9H-adenine 25 analytically pure melting at 138.5-140 ° C.

Infrared spectrum (KBr): 3500, 1630, 1605 cm-1. Ultraviolet spectrum: 268 nm (£ 12600). NMR spectrum

(CDC13) ï δ 1.03 (3H, J = 7.5 Hz), 1.4-2.3 (8H, m), 3.4-4.2 (2H, m), 4.2 (2H , t, J = 7.5 Hz), 5.4-5.7 (1H, m), 5.81 (2H, 30 wide, s), 7.71 (1H, s).

Analysis: C,% H,% N,% calculated for C1? H1qN, -09 56.30 6.91 25.25 found 56.05 6.93 25.26.

35 '19.

EXAMPLE 4 2- (2-butoxv) -9- (tetrahydropyran-2-yl) -9H-adenine nh2 "0

The title compound is obtained by reacting 2-chloro-9- (tetrahydropyran-2-yl) -9H-adenine with 1N sodium 2-butoxide in 2-butanol according to the procedure of example 3.

EXAMPLE 5 20 9- (2-cyclohexenyl) -2-n-propylamino-9H-adenine 25 T * Il / ό 30

A mixture of 300 mg (1.2 mmol) of 2-chloro-9- (2-cyclohexenyl) -9H-adenine and 0.3 ml of n-propylamine in 3 ml of anhydrous methanol is heated at 110 ° C for 15 hours in a sealed tube and evaporated in vacuo to give an oil. The oil subjected to column chromatography of 20 g of silica gel, with a mixture of chloroform and methanol as eluent, gives an oil which, by coevaporation with ethyl acetate, gives 282 mg of 9- (2-cyclohexenyl) -2-n-propylamino-9H-adenine melting at 73-80 ° C.

20.

i ·

Infrared spectrum (KBr): 3300, 3150, 2920, 2860, 1630, 1600, 1535, 1490, 1470, 1405, 1360, 1200 cm-1. Ultraviolet spectrum: 259 nm (5700), 290 nm (£.

lllClA

5300). NMR spectrum (DMS0-dg): δ 0.90 (3H, t, J = 4.5 Hz), 1.3-5 2.2 (8H, m), 3.26 (2H, t, J = 6 Hz), 4.6-5.1 (1H, m), 5.5-6.2 (3H, m), 6.56 (2H, s), 7.50 (1H, s).

Analysis: C,% H,% N,% calculated for ^ 14 ^ 20 ^ 6: I / IOCH2CO2C2HÇ .. 1/2 ^ 0 59.60 7.59 28.97 10 59.48 7.16 28.72 EXAMPLE 6 9- (2-cyclohexenyl) -2-cyclohexylamino-9H-adenine 15 NH2 \ O — k X> \ 20 \ _ / F | ό! 25

A mixture of 300 mg (1.2 mmol) of 2-chloro-9- (2-cyclohexenyl) -9H-adenine and 1 ml of cyclohexylamine in 3 ml of ethanol is heated at 120-125 ° C for 30 89 hour period in a sealed tube, then evaporated in vacuo to give an oil. Purification of the residual oil by chromatography on a column of silica gel gives 288 mg (77%) of 9- (2-cyclohexenyl) -2-cyclohexylamino-9H-adenine, melting at 108-111 ° C.

35 Infrared spectrum (KBr): 3315, 3170, 2925,

2845, 1630, 1600, 1530, 1470, 1405 cm Ultravio- spectrum,. , EtOH

and: max 224 nm (26500), 259 nm (e 11100), 291 nm (£ 9900). NMR spectrum (CDCI3): δ 0.9-2.3 (16H, m), 3.75 (1H, -4 I * 21.

wide, s), 4.95 (1H, wide, s), 5.4-6.2 (2H, ra), 7.42 (1H, s).

Analysis: C,% H,% N,% calculated for C17H24N6 5 65.36 7.74 26.90 found 65.40 7.95 26.71.

EXAMPLE 7 9-cyclohexvl-2-n-propylamino-9H-adenine 10 Γ2 n-C, HILI— JL>

15 "3 T

O

20

A solution of 160 mg (0.59 nunole) of 9- (2-cyclohexenyl) -2-n-propylamino-9H-adenine in 16 ml of inethanol is hydrogenated for approximately 18 hours with 160 mg of 10% palladium fixed on charcoal and filtered to remove the catalyst. Concentration of the filtrate under vacuum gives 141 mg (88%) of 9-cyclohexyl-2-n-propylamino-9H-adenine, melting at 155-156 ° C.

Infrared spectrum (KBr); 3310, 3160, 2930, 2850, 1635, 1535, 1485, 1475, 1410 cm "1. Ultraviolet spectrum

™. îEtOH

JU iet. Amax 223 nm (£ 24,100), 258.5 nm {& 8800), 289.5 nm (ε 8400). NMR spectrum (DMSO-dg): δ 0.89 (3H, t, J = 7.5 Hz), 1.1-2.2 (12H, m), 3.13 (2H, t, J = 6Hz) , 3.7-4.4 (1H, m), 6.06, 1H, t, J = 6Hz), 6.52 (2H, s), 7.19 (1H, s).

Analysis: C,% H,% N,% 35 calculated for C- | 4H22Ng. 1 / 2H20 59.34 8.18 29.66 found 59.68 7.98 29.51.

22.

* * EXAMPLE 8 9-cyclohexyl-2-cyclohexylamino-9H-adenine m2 <ο-λΧ)

"- U

A solution of 180 mg (0.58 mmol) of 9- (2-15 cyclohexenyl) -2-cyclohexylamino-9H-adenine in 10 ml of ethanol is hydrogenated for approximately 18 hours with 150 mg of 10% palladium fixed on charcoal and filtered. By concentration of the filtrate under vacuum, 175 mg (97%) of 9-cyclohexyl-2-cyclohexylamino-9H-adenine, melting 20 at 109 ° -117 ° C., are obtained.

Infrared spectrum (KBr): 3315, 3160, 2930, 2850, 1630, 1590, 1530, 1470, 1405 cm “1. Ultraviolet spectrum: λ ^ ° Η 224 nm (6 25600), 259 nm (& 10100), 290.5 nm (E 9100). NMR spectrum (CDCl-j): δ 0.9-2.4 (20H, m), 3.43-4.9 (2H, m), 7.42 (1H, s).

Analysis: C,% H,% N,%

calculated for 1 / 2C9H, -0H

64.06 8.66 24.90 found 64.65 8.59 25.26.

i · 23.

EXAMPLE 9 9-cyclohexyl-2- (2-butylamino) -9H-adenine 5 NH2 CH-CH.CHNH K, • “6

By reaction of 2-chloro-9-cyclohexyl-9H-adenine with sec.-butylamine in accordance with the procedure of Example 5, the title compound is obtained.

EXAMPLE 10 2 ° 9- (2-cyclohexenyl) -2-n-propylthio-9H-adenine NH2

25 -'SrA

a-C3H7-S ^^ N> X ^ | ό 30 v

A mixture of 159 mg (0.64 mmol) of 2-chloro-9- (2-cyclohexenyl) -9H-adenine, 223 mg (4.65 mmol) is refluxed over a period of 5 hours under a nitrogen atmosphere. 35% sodium hydride and 2 ml of n-propylmercaptan in 10 ml of Ν, Ν-dimethylformamide, then poured into ice water and the mixture is neutralized with 1N hydrochloric acid. Excess mercaptan is removed by evaporation f 24.

's under reduced pressure and the residual solution is extracted with chloroform which is then washed with water, which is dried over sodium sulfate and filtered. The filtrate is evaporated and the residual material is purified by chromatography on silica gel (5 g) using 1% methanol in chloroform as eluent, to obtain 167 mg (90%) of 9- (2- cyclohexenyl) -2-n-propylthio-9H-adenine melting at 108-113 ° C.

Infrared spectrum (KBr): 3310, 3150, 2920, 10 1655, 1585, - 1450, 1320, 1240 cm ”1. Ultraviolet spectrum ï

XmaxH 237 nra (ε 2330 °) f 278 nm (13750). NMR spectrum

(CDC13): δ 1.01 (3H, t, J = 7 Hz), 1.90 (8H, m), 3.07 (2H, t, J = 7 Hz), 5.10 (1H, m) , 5.82 (2H, s), 5.92 (2H, m), 7.60 (1H, s).

15 Analysis: C,% H,% N,% S,%

calculated for C14H19N5S

58.10 6.62 24.20 11.08 found 57.90 7.01 23.90 11.41.

EXAMPLE 11 9-cyclohexyl-2-n-propylthio-9H-adenine nh2 25 <uxX> s-W N i,

O

A mixture of 136 mg (0.54 mmol) of 2-chloro-9-35 cyclohexyl-9H-adenine, 2.3 ml of n-propylmercaptan and 220 mg (4 mg) is moderately refluxed over a period of 2.5 hours. , 5 mmol) of sodium hydride in 12 ml of N, N-dimethyl-formamide. After cooling, the mixture is neutralized with 1N hydrochloric acid and evaporated to drive out 25.

'Λ * excess mercaptan. The residual material is shaken with chloroform and water and the organic phase is washed with water, dried over sodium sulfate and evaporated in vacuo leaving an oil. Purification of the oily residue is carried out by chromatography on silica gel using a mixture of methanol and chloroform at 1:99 to obtain a substance which gives, by crystallization from cyclohexane, 112 mg (70%) of 9- cyclohexyl-2-n-propylthio-9H-adenine in the form of colorless prisms melting at 149-150 ° C.

Infrared spectrum (KBr): 3300, 3120, 2920, 1650, 1585, 1435, 1305, 1220 cm “**. Ultraviolet spectrum: XmaxH 237 nm (e 23900) '278 nm (e 13800). Nuclear magnetic resonance spectrum (CDC13): δ 1.06 (3H, t, 15 J = 7 Hz), 1.80 (12H, m), 3.14 (2H, t, J = 7 Hz), 6, 07 (2H, s), 7.70 (1H, s).

Analysis: C,% H,% N,% S,%

calculated for C-j ^^ - jN ^ S

58.10 6.62 24.20 11.08 20 found 58.07 7.27 23.98 10.83.

Another process for preparing the title compound uses the product of Example 10 as the starting material. Thus, catalytic hydrogenation of 9- (2-cyclohexenyl) -2-n-propylthio-9H-adenine in ethanol with 10% palladium fixed on carbon gives 9-cyclohexyl-2-n- propylthio-9H-adenine.

EXAMPLE 12

Pharmacological evaluation 30 A. In vitro bronchodilator activity. -

Guinea pig tracheal chains are prepared by the method described by A. Akcasu in Arch. Int. Pharmacodyn. Ther., 122, 201 (1959). The response to each test compound is noted by the Magnus method and expressed as a percentage of the maximum response obtained with 0.1 ug / ml of isoproteenenol before each experiment. The bronchodilator activity (in vitro) of aminophylline and of the test compounds of Examples 1 to 3 is expressed below by a CE5q value! 26.

ft * "(concentration in ug / ml which produces a relaxation equal to 50% of the maximum response to 0.1 ug / ml of isoproterenol).

In vitro test results

Example n ° of the compound CE, -q (μς / ιηΐ) 5 1 ”0.45 2> 3 3 0.17 5 0.47 6 0.24 10 .7 0.75 8 0.21 10 0.02 11 0.19

Aminophylline 16.6 15 B. Bronchodilator and hypotensive activity in vivo. - The in vivo bronchodilator activity of aminophylline and the test compounds was evaluated according to a modified version of the method described by L.G.W. James, in J. Pharm. Pharmac., 21 ^ 379 (1969) by measuring the reduction in intratracheal pressure (PIT) in the guinea pig. The trachea of an anesthetized guinea pig is provided with a cannula and the PIT is recorded under artificial respiration on a polygraph device. Arterial blood pressure (PSA; reflecting hypotensive activity) is also measured during the experiment. The intravenous route or the intraduodenal route of administration is used. The results reproduced below express the bronchodilator activity (PIT) by a value DE, -q (dose in mg / kg) resulting in a reduction of 50% of the intra-tracheal pressure and the hypotensive activity (PSA) by a DE2Q value (dose in mg / kg which reduces arterial blood pressure by 20%). The ratio of hypotensive to bronchodilator DEj.q reflects an assessment of the separation of desirable bronchodilator activity from an undesirable cardiovascular (hypotensive) effect in the compounds. The compounds with the highest PSA / PIT ratios have the greatest separation of bronchodilator activity and hypotensive side effect.

1 "27.

«Results of intravenous tests Example n ° (mg / kg) Report

of the compound PIT, DEr-g PSAZ_DE20 PSA / PIT

1 0.23> 1 5 2 2.2> 1 3 0.26 1.9 7.3 5 1.4> 3> 2.1 6> 3 2.4 <0.8 7 0.49 2.8 5.7 10 8 1.5> 3> 2 10 0.31> 3> 9.7 11 1.1> 3> 2.7

Aminophylline 0.58 1.4 2.4 Results of intraduodenal tests 15 Example No. (mg / kg) Ratio of the compound PIT, DE ^ -g PSA, DE ^ g PSA / PIT 3 1.4 13.5 9.6

Aminophylline 5.9 9.5 1.6 20 EXAMPLE 13

Pharmaceutical compositions A. Tablets. - The compounds of formula (I) are formulated into tablets in accordance with the following example:

Material Quantity 25 2-n-propoxy-9- (tetrahydropyran-2-yl) -9H-adenine 20.0 g

Magnesium stearate 1.3 g

Corn starch 12.4 g

Corn starch swelling 1.3 g

Lactose 215.0 g The above materials are mixed in a double jacket mixer, then granulated and made into tablets of 250 mg each. Each tablet contains approximately 20 mg of active ingredient. The tablets can be scored tablets which can be divided into four, so that dosage units of 5.0 mg of active ingredient can be conveniently obtained.

B. Capsules. - The purine derivatives of formula (I) are formulated in capsules in accordance with the following example:! i 28.

Material Quantity 2-n-propoxy-9- (tetrahydropyran-2-yl) -9H-adenine 50.0 g

Lactose 221.0 g

Magnesium stearate 4.0 g The above materials are mixed in a double jacket mixer and hard gelatin capsules # 1 are loaded with 275 mg of the formulated composition. Each capsule contains 50 mg of active ingredient.

♦ "

Claims (6)

1. A compound of formula: 2. 2-methoxy-9- (tetrahydropyran-2-yl) -9H-adenine, 2-n-propoxy-9- (tetrahydropyran-2 ~ yl) -9H-adedine, 9- (2-cyclohexenyl ) -2-n-propylthio-9H-adenine, 9-cyclo-hexyl-2-n-propylthio-9H-adenine, 9- (2-cyclohexenyl) -2-n-propylamino-9H-adenine, 9 - (2-cyclohexenyl) -2-cyclohexyl-amino-9H-adenine, 9-cyclohexyl-2-n-propylamino-9H-adenine or 9-cyclohexyl-2-cyclohexylamino-9H-adenine or a salt 35 ' Addition of pharmaceutically acceptable acid of this compound according to claim 1. 3. A bronchodilator pharmaceutical composition in the unit dosage form comprising a ΐ 30. pharmaceutically acceptable carrier and an amount with bronchodilator effect of a compound according to claim 1 or 2. 4. A method of producing a compound according to claim 1 in case A is an oxygen atom, characterized in that it consists in reacting a compound of 2-halo-9- (tetrahydropyran-2-yl ) -9H-adenine of formula: 10 - NH0 A \\ 15 H y \ λ__y ° 20 in which X is a halogen, with an alkali metal alcoholate of formula ROM in which R has the definition given in claim 1 and M is sodium or potassium, in an inert solvent, for producing the compound of formula * (I) in the form of the free base. 5. Process for the preparation of a compound according to claim 1, in which A is an NH group, characterized in that it consists in condensing a 2-halo-9- (2-cyclohexenyl) -9H- adenine or a 2-halo-9-cyclohexyl-9H-adenine with an amine of formula RNH ^ in an inert solvent to produce the free base of the compound of formula (I). 5 NH „Λλ. / ks / 10 R - A N! Ri * 15 in which A represents NHr S or Of R is a C1 to C4 alkyl or lower alkoxy group or a cyclohexyl group and R, j is a cyclohexyl, 2-cyclo-hexenyl group or a pyran residue, provided that when A 20 is an NH group, R is a C1-C4 alkyl or cyclohexyl group and when either a cyclohexyl or 2-cyclohexe-nyl group; that when A represents S, R is a C1-C4 alkyl group and R-j a cyclohexyl or 2-cyclohexenyl group; and that when A represents 0f R is a C 4 -C 4 alkoxy group and R-j is a pyran residue or a pharmaceutically acceptable addition salt of this compound. 6. Process for the production of a compound of formula (I) in which A is a sulfur atom, characterized in that it consists in reacting a 2-halo-9- (2-cyclohexenyl) -9H-adenine or a 2-chloro-9-cyclohexyl-9H-adenine with an alkali metal mercaptide of formula RS-alk in which alk is sodium, potassium or lithium, in an inert solvent to produce the free base of the compound of formula (I). ; '31. * «