FR2463142A1 - NOVEL PURINE COMPOUNDS, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITION CONTAINING SAME - Google Patents

Abstract

THE INVENTION RELATES TO THE FIELD OF THE CHEMISTRY OF DRUGS. IT CONCERNS NEW HETEROCYCLIC CARBON COMPOUNDS OF FORMULA: (CF DRAWING IN BOPI) (IN WHICH NH, S OR O AND R AND R ARE ORGANIC RADICALS) AND THEIR PHARMACEUTICAL ACCEPTABLE ADDITIONAL SALTS, AS WELL AS THEIR PROCESS OF PREPARATION. THE NEW COMPOUNDS OF THE INVENTION HAVE IN PARTICULAR BRONCHODILATORY PROPERTIES.

Description

The present invention as a whole relates to carbonaceous compounds

  heterocyclic that have the property

  to be drugs and to affect the biological processes

  cal. More particularly, the invention relates to novel bronchodilators which are endowed with non-adrenergic properties of smooth muscle relaxation, which render them

  particularly interesting for combating broncho-

  acute spasm and as auxiliary substances to control the symptoms of obstructive pulmonary disease

  chronic (eg asthma, bronchitis, emphysema).

  The invention also relates to therapeutic methods and compositions using one or more of the

  new compounds as active ingredients.

  With regard to the types of bronchodila-

  non-adrenergic agents, the xanthine derivatives of

  group of theophylline are particularly remarkable

  quables. For example, aminophylline, which is salt

  ethylene diamine of theophylline, is a bronchodila-

  effective management system that can be administered

  orally or rectally, which is useful in patients who

  require direct relaxation of the bronchial muscle.

  Despite their widespread use, bronchodilators

  Adrenergic agents of the xanthine class have major disadvantages related to gastric irritation and side effects on the cardiovascular system and the central nervous system. Therefore, it is necessary to find new and effective bronchodilatators

  power is increased and / or which produce adverse effects

  less numerous or less pronounced. Pharmaceutical tests

  classical logic have shown that examples represent

  The compounds of the present invention exhibit superior bronchodilator activity compared to aminophylline, with fewer side effects on the

  cardiovascular system and on the central nervous system.

  The basic cycle of purine includes a nucleus

  hexagonal of pyrimidine fused to a pentagonal

  dazole as represented by the following formula which shows the numbering system adopted herein. 2. 8 Various types of purine derivatives are known in which the basic substance, namely purine, is

  substituted in one or more of 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. Chem. Soc., 83, 2574 (1961), the synthesis of the compound of formula: 20 as a potential antitumor agent from 6-chloro-9- (tetrahydro-2-pyranyl) purine. 2. U.S. Patent No. 3,228,937 discloses 6-benzylamino-9-tetrahydropyran-2-yl-9H-purine: 3. as an inhibitor of wilting and wilting.

leafy green plants.

  3. R. Marumoto et al., Chem. Pharm. Bull., 23 (4), 759-774 (1975) describe, inter alia, compounds of the formula: ## STR2 ## wherein 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) the synthesis of the compound of formula: R R

  wherein R is cyclohexyl or 2-cyclohexyl

  hexenyl, as potential anticancer agents.

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

- _EOR

as an anti-inflammatory agent.

  6. U.S. Patent No. 3,862,189 relates to compounds of the formula: wherein R 1 is, inter alia, R 1 is amino, alkylamino, aralkylamino, etc .; and R2 is phenylalkyl, substituted phenylalkyl, tetrahydroquinoylalkyl, etc., useful as

  anti-anginal agents and bronchodilators.

  7. U.S. Patent 3,930,005 discloses compounds of the formula: wherein R 2 and R 3 may be, for example, hydrogen and R 1 may be, inter alia, lower alkoxy, such as talented agents

anti-inflammatory activity.

  8. K. Kikugawa et al. Describe in Chem. Pharm. Bull., 25, (7), 1811-1821 (1977) the synthesis of various 2-thio-adenine derivatives of formula: NR2

1 {-S $ '

  in which, among others, R and R1 are groups

  alkyl, cycloalkyl, etc. as aggregation inhibitors

  platelets. Representative examples of these compounds include those wherein R is propyl or n-hexyl and R 1 is n-hexyl; R and R1 are cyclopentyl groups. The authors conclude

  of this study that the ribosyl portion of the 2-

  thio-adenosine is essential for the effective inhibition of platelet aggregation and can not be

  replaced by other substituents.

  Japanese Patent Application Laid-open No. 52-71,492 (Farmdoc 53190Y) discloses compounds of the formula: wherein R 1 is a straight-chained or branched C1-C10 alkyl group; C5 to C10 cycloalkyl group,

  a C 7 to C 11 aralkyl group or a piperazino

  wherein R 2 is a C 7 -C 11 aralkyl group, a monosubstituted aralkyl group, a cinnamyl group or a fluorenyl group; R 3 is a C 1 -C 10 straight or branched chain alkyl group, a cycloalkyl group; C 5 to C 10, a C 7 to C 11 aralkyl group or a piperazinoethyl group as defined above, excluding 7 compounds in which R 1 and R 3 are methyl groups, R 1 is a methyl group and R 3 is a methyl group; ethyl group and R1 is a C5-C10 cycloalkyl group and R3 is a C1-C4 alkyl, C5-C10 cycloalkyl or C7-C11 aralkyl group. The compounds are expected to have an inhibitory effect on platelet aggregation and

  on the dilation activity of the coronary vessels.

  10. British Patent No. 1,493,684 discloses 2-thio-

  adenosines substituted on the sulfur atom,

  as being inhibitors of platelets and coronary vasodilators, and having the formula: ## STR2 ## where, inter alia, R is an alkyl group

  straight or branched chain C1 to C10.

  11. J. A. Montgomery et al. Describe in J. Am. Chem. Soc., 80, 409-411 (1958) adenine derivatives of the formula: N32 R 8. wherein R is n-butyl, cyclopentyl or

  cyclohexyl, as anticancer agents.

  12. The Belgian Patent No. 853 086 (Farmdoc 70719Y) describes compounds of formula:

Q I

  Y, wherein X is C1-C6 alkoxy or -NHR; R is a hydrogen atom or an alkyl group

  inferior; Y is a C 1 to C 6 alkyl, cycloalkyl group,

  C3-C10 alkyl or hydroxycycloalkyl, phenyl, halogenated

  genophenyl, trifluoromethylphenyl, bicycloalkyl or hydroxybicycloalkyl having up to 12 carbon atoms, or a group - AR1; A is a methylene or ethylene group; R 1 is phenyl, halophenyl,

  trifluoromethyl-phenyl, bicycloalkyl or hydroxybi-

  cycloalkyl having up to 12 carbon atoms; Q is H, C1-C6 alkyl, C3-C10 cycloalkyl or hydroxycycloalkyl, bicycloalkyl or hydroxybicycloalkyl having up to 12 carbon atoms, phenyl, halophenyl, trifluoromethylphenyl or AR1; or X is halogen or di- (lower alkyl) amino; Y is methyl, ethyl, cyclopentyl, phenyl, halophenyl, trifluoromethylphenyl or benzyl and Q has the definition given above. These compounds are

  considered useful for the treatment of psoriasis.

  The present invention relates to purines

formula news: -

9. N2

NOT

NOT

R - A N N

i

R

  in which A is an NH group, a sulfur atom or an oxygen atom, R is a C1 to C4 alkyl or alkoxy group

  lower or cyclohexyl group; R1 is a cyclo-

  hexyl, 2-cyclohexenyl or a pyran residue; provided that

  that when A is an NH group, R is a lower alkyl group than

  C1 to C4 and R1 a cyclohexyl or 2-cyclohexyl group.

  hexenyl; and that when A is an oxygen atom, R is a C1-C4 alkoxy group and R1 is a pyran residue, or a pharmaceutically acceptable acid addition salt thereof. The latter effectively inhibit histamine-induced bronchial constriction by acting directly on the trachea muscle to relax the

  spasms with minimal cardiovascular side effects

  lar. Thus, the compounds belong to the non-class

  adrenergic bronchodilators.

  It should be noted that the term "lower alkyl" embraces both straight and branched chain groups having 1 to 4 carbon atoms. Examples of

  these groups are methyl, ethyl, propyl, iso-

  propyl, 1-butyl, 1-methylpropyl, 2-methylpropyl and tert-butyl. The term "halogen" refers to chlorine,

bromine, fluorine and iodine.

  For purposes of this specification, the term "pharmaceutically acceptable acid addition salt" refers to the salt form of a compound of formula (I) obtained by combination with an inorganic or organic non-organic acid. toxic which is relatively free from 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 acid, hydrochloric acid, phosphoric acid, hydrobromic acid,

  iodohydric, sulphamic, methanesulphonic, benzene sulpho

  nicotine, paratoluenesulphonic, acetic, lactic, succinate

  malic, malic, maleic, mucic, tartaric, citric, gluconic, benzoic, cinnamic, isethionic, fumaric,

  levulinic and related acids.

  The conversion 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 a selected acid in a solvent. inert organic such as

  ethanol, benzene, ethyl acetate, ether, a hydro-

  halogenated carbide, etc. The isolation of the salt is carried out by known techniques, for example by triggering the precipitation with a non-polar solvent (such as ether)

  wherein the salt has limited solubility.

  According to the present invention, certain compounds of formula (I) can be prepared by a process

  reacting a 2-halo-9- (tetrahydropyran)

  2-yl) -9H-adenine of formula (II): N 2 N

N (II)

N N

  wherein X is bromine, fluorine, iodine or preferably

  chlorine, with an alkali metal alcoholate of formula ROM wherein R is as defined above and M represents sodium or potassium, in an inert solvent, preferably a lower alkanol of formula ROH wherein R is to the definition given above, to produce the compound of formula (I) in the form of the free base. High temperatures of from about 200 ° C. in the course of the reaction are used, preferably at the reflux temperature of the inert solvent or in a sealed tube.

  2-Halo-9- (tetrahydropyran-2-yl) -9H-

  intermediate adenines of formula (II) are obtained according to

  with the following reaction scheme valid for 2-

  Preferred chloro-9- (tetrahydropyran-2-yl) -9H-adenine (IIa): Cl 2 Cf <9 gK 3 P cfw [(III) (1)

  In general, 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 mixture saturated reaction is heated from about 30 to about 1500C in a sealed tube to

to carry out the reaction.

  Compounds of formula (I) may also be prepared by methods illustrated in accordance with the following reaction scheme: 12. NH 2 catalytic hydrogenation Ci (III) t RMI, hydrogenation

Qatalytique - = -

  NE1 Launches the [(1b) (la) Compounds of formula (I) wherein A is

  an NH group can be obtained by condensation of the 2-

  chloro-9- (2-cyclohexenyl) -9H-adenine (II) or 2-chloro

  9-cyclohexyl-9H-adenine (III) with a compound RNH2 in a reaction-inert solvent, preferably a lower alkanol such as methanol or ethanol, to produce the desired free base of formula ( Ia) or (Ib). The reaction is preferably conducted in a closed reactor such as a sealed tube at elevated temperatures ranging from about

50 to 200 C.

  Compounds of formula (I) wherein A is

  a sulfur atom can be obtained by reaction of 2-

  chloro-9- (2-cyclohexenyl) -9H-adenine (II) or 2-chloro-9-

  (IT) R 11 F, 13. cyclohexenyl-9H-adenine (III) with an alkali metal mercaptide of the formula RS-alk, wherein alk represents sodium, potassium or lithium and R has the definition given above, in an inert solvent until the desired free base of the product of formula (I) has been formed, and optionally converting the product to one of its salts

  addition of pharmaceutically acceptable acids.

  by conventional methods illustrated herein. The desired "RS-alk" alkali metal mercaptides are normally obtained by treatment of 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" as used herein refers to any solvent

  (eg dimethylformamide) chemically inert

  with respect to the starting 2-chloradenines (II) and (III) or

  mercaptides RS-alk. High temperatures ranging from

  50 to 150 ° C are preferably used in the reaction which is conducted for a period of from 0.5 to

24 hours.

  The compounds of formula (I) in which R 1 is a cyclohexyl group (i.e. (Ib)) are also prepared correctly by catalytic hydrogenation of the corresponding products (Ia). For example, a satisfactory procedure is to hydrogenate a compound of formula (Ia) in a non-reducible inert solvent (for example methanol, ethanol, water or aqueous methanol, aqueous ethanol) in the presence of a

  conventional hydrogenation catalyst. Examples of

  Suitable lysers include palladium black, Pd-

  BaSO4, PtO2, Ru-C, Rh-C, Raney nickel, CuCrO, RhCl (P (C6H5) 3) and RuCl (P (C6H5) 3) 3. Palladium on carbon is a preferred catalyst. Advantageous results have been obtained at ambient temperature and at atmospheric pressure, although the temperature and

  pressure are not decisive for the hydrogenation stage.

  nation. 14. Compounds of formula (I), and their pharmaceutically acceptable salts, according to the invention are useful in a method for producing a bronchodilator effect in a mammal in need thereof, by systemic administration to said mammal an effective dose of about 0.1 to 20 mg / kg of body weight of

  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-

  cyclohexyl-9H-adenine and 9- (2-cyclohexyl) -2-n-propylthio-

  9H-adenine. It is meant by systemic administration

  both the oral and parenteral routes, for example

  Intramuscular, intravenous, intramuscular

  peritoneal and subcutaneous. Similarly, the active ingredient can be administered by inhalation by means of a suitable aerosol preparation. Oral administration is preferred.

  According to another of its aspects, the present invention

  tion offers a pharmaceutical composition in the form

  unitary logic, useful for the relief of broncho-

  in mammals. This composition comprises,

  as an active ingredient, a bronchodilating amount

  of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, in admixture with an acceptable carrier or diluent of the

pharmaceutical point of view.

  The pharmacologically active compounds of the present invention may be administered as individual therapeutic agents or in admixture with other therapeutic agents. They can be administered alone, but they are usually administered in the form of

  pharmaceuticals. Examples of these compositions include

  tablets, cachets, capsules, powders,

  sprayable compositions for aerosols, suspensions

  in water or in oil, syrups, elixirs and

aqueous solutions.

  The nature of the pharmaceutical composition and the pharmaceutical carrier or diluent naturally depends on the desired route of administration. For example, oral compositions may be in the form of tablets or capsules and may contain conventional excipients such as binders (for example syrup, gum arabic, gelatin, sorbitol, gum tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricants (eg magnesium stearate, talc, polyethylene glycol or silica), disintegrating agents (eg starch) or wetting agents (eg lauryl sulphate sodium). Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions and emulsions, syrups, elixirs, etc., or may be presented in the form of a dry product to be

  reconstituted with water or another suitable vehicle

  ble before use. These liquid preparations may contain conventional additives such as delivery agents.

  suspension, perfumes, diluents or emulsifiers.

  For parenteral administration or inhalation, solutions or suspensions of a compound of formula (I) may be used with conventional pharmaceutical vehicles, for example in the form of an aerosol sprayable composition for inhalation, in the form of an aqueous solution for intravenous injection or in the form of a

  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

1

Cl 16.

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

  purine The pH of a 2.0 g solution is adjusted to 2

  (10.6 mmol) of 2,6-dichloropurine and 2 ml

  dihydro-2H-pyran in 20 ml of ethyl acetate by addition of anhydrous ptoluenesulphonic acid. The reaction mixture was heated at 60 ° C for 1 hour, neutralized with concentrated ammonium hydroxide, washed with water, dried over sodium sulfate and evaporated in vacuo. Crystallization of the residual material in a mixture of ethyl acetate and n-hexane gives

  2.6 g (96%) of 2,6-dichloro-9- (tetrahydropyran-2-yl) -9H-

Purine melting at 119-121 C.

  Infrared spectrum (KBr): 3100, 1600, 1560 cm -1.

  Ultraviolet spectrum xMeOH 273 nm (ú 9900). Nuclear Magnetic Resonance (CDCl3): 6 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 C10H10N4O

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, -1 MeOH

  1605 cm -1 Ultraviolet spectrum y max 263 nm (E 14300).

  Ymax Nuclear Magnetic Resonance (DMSO-d6): 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,

broad, s), 8.28 (1H, s).

  Analysis: C,% HN, N% Ci,% calculated for C10H12ClN50

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 CH30

  A solution of 253 mg (1 mmol) of 2-chloro-9-

  (Tetrahydropyran-2-yl) -9H-adenine in 10 ml of 1N sodium methoxide in methanol, heated at 100 ° C. in a sealed tube for a period of 16 hours, cooled and filtered, gives 154 mg of product. A second crop (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).

  -1 Infrared spectrum (KBr): 3300, 1640, 1600 cm 1 Ultraviolet spectrum: At MeOH 267 nm (ú 12100). NMR Spectrum Max (DMSO-d6): δ 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,% H1% N,% calculated for C11H15N5O2

53.00 6.07 28.10

found 52.73 6.13 28.50.

18.

EXAMPLE 3

  2-n-propoxy-9- (tetrahydropyran-2-yl) -9H-adenine N7

2

  n-C37-O 1Y is refluxed under nitrogen for

  1 hour a solution of 253 mg (1 mmol) of 2-chloro-9-

  (tetrahydropyran-2-yl) -9H-adenine in 10 ml of 1N sodium n-propoxide in n-propanol. The reaction mixture is neutralized with acetic acid and evaporated to dryness in vacuo. Trituration of the residual material with water gives 213 mg of product which crystallizes from a mixture of ethyl acetate and n-hexane to give 147 mg (57%) of 2-n-propoxy-9 - (tetrahydropyran-2-yl) -9H-adenine

  analytically pure melting at 138.5-140WC.

  Infrared spectrum (KBr): 3500, 1630, 1605 cm -1.

  Ultraviolet spectrum: MeOH 268 nm (a 12600). NMR Spectrum (CDCl3): 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,

broad, s), 7.71 (1H, s).

  Analysis: C,% H% N,% calculated for C13H19N502

56.30 6.91 25.25

found 56.05 6.93 25.26.

19.

EXAMPLE 4

  2- (2-butoxy) -9- (tetrahydropyran-2-yl) -9H-adenine OE3 The title compound is obtained by reaction of

  2-chloro-9- (tetrahydropyran-2-yl) -9H-adenine with. 2-

  1N sodium butoxide in 2-butanol in accordance with

procedure of Example 3.

EXAMPLE 5

  9- (2-cyclohexenyl) -2-n-propylamino-9H-adenine NE

  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 hours in a sealed tube and evaporated in vacuo to give an oil. The oil is subjected to column chromatography with 20 g of silica gel, eluting with a mixture of

  chloroform and methanol, gives an oil which, by

  evaporation with ethyl acetate gives 282 mg of 9- (2-

  cyclohexenyl) -2-n-propylamino-9H-adenine, melting at 73-80C.

  20. Infrared spectrum (KBr): 3300, 3150, 2920,

  2860, 1630, 1600, 1535, 1490, 1470, 1405, 1360, 1200 cm -1.

  Ultraviolet spectrum: EtmaOH 259 nm (6,500), 290 nm (υ

  5300). NMR Spectrum (DMSO-d6): δ 0.90 (3H, t, J = 4.5Hz), 1.3-

  2.2 (8H, m), 3.26 (2H, t, J = 6Hz), 4.6-5.1 (1H, m), 5.5-6.2

  (3H, m), 6.56 (2H, s), 7.50 (1H, s).

  Analysis: C,% HL% N,% calculated for C14H20N6: 1 / 10CH3CO2C2H5. 1 / 2:20

59.60 7.59 28.97

59.48 7.16 28.72

EXAMPLE 6

  9- (2-cyclohexenyl) -2-cyclohexylamino-9H-adenine N-D9NH% a '>

  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 a period of 89 hours in a sealed tube and then evaporated under

* empty by giving an oil. The purification of the oil

  duel by silica gel column chromatography gives

  288 mg (77%) of 9- (2-cyclohexenyl) -2-cyclohexylamino-9H-

adenine melting at 108-111 C.

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

  2845, 1630, 1600, 1530, 1470, 1405 cm 1. Ultraviolet spectrum

  EtOH let: max 224 nm (ú 26500), 259 nm (E 11100), 291 nm (E 9900). NMR Spectrum (CDCI 3): δ 0.9-2.3 (16H, m), 3.75 (1H, 21. broad, s), 4.95 (1H, br, s), 5.4-6, 2 (2H, m), 7.42 (1H, s). Analysis: C% H,% NI% Calculated for C17H24N6

65.36 7.74 26.90

found 65.40 7.95 26.71.

EXAMPLE 7

  9-cyclohexyl-2-n-propylamino-9H-adenine NE2 n-C3HI N

  A solution of 160 mg (0.59 mmol) of 9- (2-

  Cyclohexenyl) -2-n-propylamino-9H-adenine in 16 ml of methanol is hydrogenated for about 18 hours with 160 mg of 10% palladium on charcoal and filtered to remove the catalyst. The concentration of the filtrate under vacuum

  gives 141 mg (88%) of 9-cyclohexyl-2-n-propylamino-9H-

fondant adenine at 155-156 C.

  Infrared spectrum (KBr): 3310, 3160, 2930, -1

  2850, 1635, 1535, 1485, 1475, 1410 cm. Ultraviolet spectrum

  let: X EtOH max 223 nm (E 24100), 258.5 nm (5800 nm), 289.5 nm (6840 nm). NMR Spectrum (DMSO-d6): 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,% calculated for C14H22N6.1 / 2H20

59.34 8.18 29.66

found 59.68 7.98 29.51.

22.

EXAMPLE 8

  9-cyclohexyl-2-cyclohexylamino-9H-adenine NE

  A solution of 180 mg (0.58 mmol) of 9- (2-

  Cyclohexenyl) -2-cyclohexylamino-9H-adenine in 10 ml of ethanol is hydrogenated for about 18 hours with

  mg of 10% palladium fixed on charcoal and filtered.

  Concentration of the filtrate under vacuum gives 175 mg (97%) of 9-cyclohexyl-2-cyclohexylamino-9H-adenine.

at 109-117C.

  Infrared spectrum (KBr): 3315, 3160, 2930,

  2850, 1630, 1590, 1530, 1470, 1405 cm -1. Ultraviolet spectrum

  kEtOH22 let: Xmax 224 nm (E 25600), 259 nm (10100), 290.5 nm (<9100). NMR Spectrum (CDCl3) δ3 0.9-2.4 (20H, m), 3.43-4.9

(2H, m), 7.42 (1H, s).

  Analysis: C,% H1% N,% Calculated for C17H26N6.1 / 2C2H50H

64.06 8.66 24.90

found 64.65 8.59 25.26.

23.

EXAMPLE 9

  9-cyclohexyl-2- (2-butylamino) -9H-adenine NE, I X

CE.CE X

C 81 3 2 9e

  By reaction of 2-chloro-9-cyclohexyl-9H-adenine with sec-butylamine in accordance with the procedure

  In Example 5, the title compound was obtained.

EXAMPLE 10

  9- (2-cyclohexenyl) -2-n-propylthio-9H-adenine NE2 '

Z-C3H7-S

  È. A mixture of 159 mg (0.64 mmol) of 2-chloro-9- (2-cyclohexenyl) 9H-adenine, 223 mg (4.65 mmol), is refluxed for a period of 5 hours under a nitrogen atmosphere. 50% sodium hydride and 2 ml of n-propylmercaptan in ml of N, N-dimethylformamide and then poured into water

  iced and the mixture is neutralized with hydrochloric acid

  1N. The excess mercaptan is evaporated off under reduced pressure and the residual solution is extracted with chloroform which is then washed with water, which

  dehydrate on sodium sulfate and filter. We evaluate

  pore the filtrate and the residual material is purified by chromatography.

  silica gel matography (5 g) using 1% methanol in chloroform as eluent to give 167 mg (90%) of 9- (2cyclohexenyl) -2-n-propylthio-9H-adenine

melting at 108-113 C.

  Infrared spectrum (KBr): 3310, 3150, 2920, 1655, 1585, 1450, 1320, 1240 cm -1. Ultraviolet spectrum: EtmaxOH 237 nm (ú 23300), 278 nm (L 13750). NMR Spectrum Max (CDCl 3): δ 1.01 (3H, t, J = 7Hz), 1.90 (8H, m), 3.07 (2H, t, J = 7Hz), 5.10 (1H; , m), 5.82 (2H, s), 5.92 (2H, m), 7.60 (1H, s). Analysis: CI% H% N,% SI% 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 Ns)

NOT

  -. It is moderately refluxed during a period of

  2.5 hours a mixture of 136 mg (0.54 mmol) of 2-chloro-9-

  cyclohexyl-9H-adenine, 2.3 ml of n-propylmercaptan and 220 mg

  (4.5 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 remove the excess mercaptan. Residual material is agitated by

  shakes with chloroform and water and the organic phase

  washed with water, dried over sodium sulfate and evaporated in vacuo leaving an oil. The oily residue is purified by chromatography on silica gel using a 1:99 mixture of methanol and chloroform to give a substance which gives, by crystallization in cyclohexane, 112 mg (70%) of 9-cyclohexyl. -2-n-propylthio-9H-adenine under the

  form of colorless prisms melting at 149-150C.

  Infrared spectrum (KBr): 3300, 3120, 2920, 1650, 1585, 1435, 1305, 1220 cm -1. Ultraviolet spectrum: XEtOH 237 nm (E 23900), 278 nm (t 13800). Nuclear Magnetic Resonance Spectrum (CDCl3): 1.06 (3H, t, J = 7Hz), 1.80 (12H, m), 3.14 (2H, t, J = 7Hz), 6, 07 (2H, s),

7.70 (1H, s).

  Analysis: Cf% H% N,% S,% calculated for C14H21N5S

58.10 6.62 24.20 11.08

found 58.07 7.27 23.98 10.83.

  Another process for the preparation of the compound

  The title uses the product of Example 10 as the starting material. Thus, the catalytic hydrogenation of 9- (2-cyclohexenyl) -2-npropylthio-9H-adenine in ethanol

  with 10% palladium on charcoal gives 9-

  cyclohexyl-2-n-propylthio-9H-adenine.

EXAMPLE 12

Pharmacological evaluation

  A. In vitro bronchodilator activity. -

  Tracheal chains of guinea pigs 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 by a

  percent of the maximum response obtained with 0.1 μg / ml of iso-

  protenerol before each experiment. Bronchodilac activity

  (in vitro) aminophylline and test compounds of Examples 1 to 3 are hereinafter expressed as EC 50 values. (concentration in μg / ml which produces a relaxation equal to

  % of maximal response at 0.1 μg / ml of isoproterenol).

  Results of in vitro tests Example n of the compound-EC50 (g / ml)

1 0.45

2> 3

3 0.17

0.47

6 0.24

10.7 0.75

8 0.21

0.02

11 0.19

Aminophylline 16.6

  B. Bronchodilator and hypotensive activity in vivo. -

  In vivo bronchodilator activity of

  aminophylline and test compounds were evaluated according to

  to a modified version of the method described by L.G.W. James, in J. Pharm. Pharmac., 21, 379 (1969) by measurement of intratracheal pressure reduction (ITP) in guinea pigs. The trachea of an anesthetized guinea pig is provided

  of a cannula and the PIT is recorded under artificial respiration.

  on a polygraphic apparatus. Blood pressure

  arterial hypertension (PSA, reflecting hypotensive activity) is also

  measured during the experiment. We use the way

  intravenous or intraduodenal route of administration.

  The results reproduced below express the bronchodilator activity (PIT) by a DE50 value (dose in mg / kg)

  causing a 50% reduction in the pressure within the

  tracheal and hypotensive activity (PSA) by a DE20 value (dose in mg / kg that reduces 20% arterial blood pressure). The ratio of the hypotensive DE20 to the bronchodilator ED50 reflects an assessment of the separation of

  the desired bronchodilator activity of a cardiac effect.

  undesirable (hypotensive) vascularity in the compounds. Compounds with the highest PSA / PIT ratios have the greatest separation of bronchodilator activity and

Hypotensive side effect.

  27. Intravenous test results Example n (mg / kg) Ratio of PIT compound, DE50 PSA, DE20 PSA / PIT

1 0.23> 1 -

2 2.2> 1 -

3 0.26 1.9 7.3

1.4> 3> 2.1

6> 3 2.4 <0.8

7 0.49 2.8 5.7

8 1.5> 3> 2

0.31> 3> 9.7

11 1.1> 3> 2.7

  Aminophylline 0.58 1.4 2.4 Results of intraduodenal tests Example n (mg / kg) Ratio of PIT compound, DE50 PSA, DE20 PSA / PIT

3 1.4 13.5 9.6

Aminophylline 5.9 9.5 1.6

EXAMPLE 13

  Pharmaceutical compositions A. Tablets. The compounds of formula (I) are formulated into tablets according to the following example: Materials Amount 2-n-propoxy-9- (tetrahydropyran-2-yl) -9H-adenine 20.0 g Magnesium stearate 1.3 Corn starch 12.4 g Corn starch 1.3 g Lactose 215.0 g The above materials are blended in a jacketed blender and then granulated and processed.

  in 250 mg tablets 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 can be conveniently obtained.

5.0 mg of active ingredient.

  B. Capsules. The purine derivatives of formula (I) are formulated in capsules according to the following example: 28. Materials Amount 2-npropoxy-9- (tetrahydropyran-2-yl) -9H-adenine 50.0 g Lactose 221.0 Magnesium stearate 4.0 g The above materials are blended in a jacketed blender and hard gelatin capsules.

  No. 1 are charged with 275 mg of the formulated composition.

  Each capsule contains 50 mg of active ingredient.

29.

Claims (6)

1. - A compound of formula NH NOT R - A N N   R1 wherein A is NH, S or O, R is C1-C4 alkyl or lower alkoxy or   cyclohexyl group and R1 is cyclohexyl, 2-cyclohexyl and   hexenyl or a pyran residue, provided that when A   is an NH group, R is a C1 to C4 alkyl group or a cycloalkyl group;   hexyl and that R 1 is cyclohexyl or 2-cyclohexyl   nyle; that when A is S, R is C 1 -C 4 alkyl and R 1 is cyclohexyl or 2-cyclohexenyl; and when A is O, R is a C1-C4 alkoxy group and R1 is a pyran residue   or an addition salt acceptable from the pharmaceutical point of view tick of this compound.   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-cyclohexyl   hexyl-2-n-propylthio-9H-adenine, 9- (2-cyclohexenyl) -2-n-   9-propylamino-9H-adenine, 9- (2-cyclohexenyl) -2-cyclohexyl-   amino-9H-adenine, 9-cyclohexyl-2-n-propylamino-9H-adenine or 9cyclohexyl-2-cyclohexylamino-9H-adenine or a pharmaceutically acceptable acid addition salt thereof   of this compound according to claim 1.   3. - A Bronchodilated Pharmaceutical Composition   in the unit dosage form comprising a pharmaceutically acceptable carrier and a bronchodilator effect amount of a compound according to the claim 1 or 2.   4. - Process for producing a compound according to claim 1 in the case where A is an oxygen atom,   characterized by reacting a compound of 2-   halogen-9- (tetrahydropyran-2-yl) -9H-adenine of formula: NH N N NOT   wherein X is halogen, with an alkali metal alkoxide of formula ROM wherein R is as defined in claim 1 and M is sodium or potassium, in an inert solvent, to produce the compound of formula (I) in the form of the free base.   5. - Process for preparing a next compound   claim 1, wherein A is an NH group,   in that it consists in condensing a 2-halogeno-9- (2-   cyclohexenyl) -9H-adenine or a 2-halo-9-cyclohexyl-9H-   adenine with an amine of formula RNH2 in an inert solvent   to produce the free base of the compound of formula (I).   6. - Process for producing a compound of   formula (I) in which A is a sulfur atom,   in that it consists in reacting a 2-halogeno-9- (2-   cyclohexenyl) -9H-adenine or a 2-chloro-9-cyclohexyl-9H-   adenine with an alkali metal mercaptide of formula RS-alk 31. wherein alk is sodium, potassium or lithium, in an inert solvent to produce the free base of the compound of formula (I).