WO1995018817A1 - Novel adenosine derivatives, preparation methods therefor, and pharmaceutical compositions containing same - Google Patents

Abstract

Derivatives of formula (I), addition salts thereof, and the therapeutical use thereof as pain killers, antihypertensive agents and drugs having antiproliferative properties, are disclosed.

Description

 New adenosine derivatives. their methods of preparation, pharmaceutical compositions containing them.

The present invention relates, as new products, to the adenosine derivatives of general formula (I) below and their addition salts, in particular the pharmaceutically acceptable addition salts.

The compounds in question have a very interesting pharmacological profile insofar as they are endowed with antiproliferative properties and can be used with profit in therapy, in the treatment of cancer, psoriasis, atherosclerosis, phenomena of restenosis or any other pathology due to cell proliferation in mammals and in particular in humans.

In addition, the compounds in question are also endowed on the one hand and particularly with analgesic properties, on the other hand with antihypertensive properties.

The present invention also relates to the process for the preparation of said products, the synthesis intermediates and the application of these products in therapy.

These adenosine derivatives are characterized in that they correspond to the general formula (I):

Formula (I)

in which

R, and R ₂ can be in position 2, 5, 6, 7 or 8 of rimidazopyridine and independently represent:

- the hydrogen atom

- a lower alkyl radical of 1 to 6 carbon atoms

- a halogen atom - a radical 0- (CH ₂ ) _n - R ₄ in which n is an integer from 0 to 5 and R ₄ represents the hydrogen atom, a lower alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical C ₃ -C ₇ , an O-lower alkyl radical of 1 to 6 carbon atoms, a phenyl radical unsubstituted or substituted by one to four identical or different substituents chosen from a halogen atom, a lower alkyl radical of 1 with 6 carbon atoms or an O-alkyl radical having 1 to 6 carbon atoms, a pyπdyl radical, or even a naphthyl radical,

- a phenyl radical

R ₃ represents

- a group -CO-NHR ₅ , in which R ₅ represents a lower alkyl radical of 1 to 6 carbon atoms, a C ₃ -C ₇ cycloalkyl radical, a radical - (CH ₂ ) _m OR6 or a radical - ( CH ₂ ) _m -NR ₇ R ₈ in which, m is an integer from 2 to 5, Rε is a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms and R ₇ and R ₈ represent simultaneously an alkyl radical lower than 1 to 6 carbon atoms or form together with the nitrogen atom to which they are attached a heterocycle chosen from morpholine, pipéndine, pyrrolidine,

- a CH ₂ OH group

Advantageously, the derivatives according to the invention are the derivatives of formula (I) mentioned above in which

Ri and R ₂ which can be in position 2, 6 7 or 8 of the imidazo pyπdine independently represent

- ^the hydrogen atom

- a lower alkyl radical of 1 to 6 carbon atoms

- a halogen atom - a radical 0- (CH ₂ ) _n -R in which n is an integer of 0 to 2 and R ₄ represents a lower alkyl radical of 1 to 6 carbon atoms, a Ccloalkyl radical ₃ -C, an O-lower alkyl radical of 1 to 6 carbon atoms, a phenyl radical which is not substituted or substituted by one or two identical or different substituents chosen from a halogen atom, an alkyl radical lower from 1 to 6 carbon atoms or an O-alkyl radical lower from 1 to 6 carbon atoms, a naphthyl radical,

- a phenyl radical

R ₃ represents

- a group -CO-NHR ₅ , in which R5 represents a lower alkyl radical of 1 to 6 carbon atoms, a C ₃ -C cycloalkyl radical or a 2-morpholιno ethyl radical, - a group -CH ₂ OH

In the description and the claims, the term “lower alkyl radical” means a hydrocarbon chain having from 1 to 6 carbon atoms, linear or branched. A lower alkyl radical is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl radical, tert-butyl, pentyl, isopentyl, hexyl, isohexyl

The term “C ₃ -C cycloalkyl radical” is understood to mean a saturated cyclic radical; it is preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl radical

Halogen means a chlorine, bromine, iodine or fluorine atom

Given the therapeutic potential of adenosine itself, many derivatives of this nucleoside have been described in the literature. We can, for example, cite the following documents

J Med Chem 1982, 25, 197-207 Biochem Pharm 1986, 35, 2467-2481

J Med Chem 1992, 35, 407-422 Current Cardiov Patents 1989, 1, 560-576

The most well-known effects of adenosine derivatives are most often linked to the cardiovascular system

Thus the document WO-A-9205177 reveals derivatives of adenosine for their application in the treatment of cardiovascular diseases

The characteristic compounds described in this prior document have, in position 6 of adenosine, a substituent comprising a heterocycle comprising a sulfur atom Compounds derived from adenosine have also been described for their application in the treatment of gastrointestinal disorders (EP-A-0 423 777 and EP-A- 0 423 776)

Recently, it has been discovered that adenosine derivatives can act on pain at the spinal level via an adenosynergic mechanism, but it has been stressed the difficulty of obtaining non-toxic and active products orally. Document WO-A-9314102 from the applicant describes such compounds. The latter are characterized by the presence, in position 6 of adenosine, of a group (ιndolyl-3) -2-ethylamιno. However, the applicant has discovered that d 'a surprising and unexpected way, the use of substituents ιmιdazo [i, 2-a] pyπdιne in position N ⁶ of adenosine combined or not with the transformation of the primary alcohol of sugar into amide function gave the products a profile pharmacological particularly interesting not only in the analgesic field but also in the field of inhibition of cell proliferation

Advantageously, in the context of the present invention, a compound of formula (I) will be used in which at least one of the following conditions is achieved

- R ₁ represents the phenylmethoxy group

- R- | represents the group (2,5-dιméthylphenényl) méthoxy

- R-i represents the cyclopentyloxy group

- R ₂ represents the hydrogen atom

- R ₂ represents a met yl radical - R ₃ represents an N-cyclopropylcarboxamide radical

- R ₃ represents an N-ethylcarboxamide radical

- R ₃ represents an N-2-morpholιnoéthylcarboxamιde radical

The particularly preferred compounds of the invention are those which are chosen from the derivatives of formula

OH OH

According to the invention, the compounds of formula (I) can be synthesized as follows: the action of an amine of formula (II):

Formula (II) in which, Ri and R ₂ are defined as above, on the 6-boside bosides of formula (III)

Formula (III)

in which X represents a halogen, chlorine or bromine atom preferably,

R ₃ is as defined above, R ₉ and R ^ represent groups which protect the alcohol function, such as acetyl, benzoyl or benzyl for example, or can form together another protective group of dioxolane structure, for example, in a solvent such as an alcohol for example or an aprotic solvent such as dimethyl formamide, in the presence of a base, such as triethylamine, pyridine or a sodium, potassium or calcium carbonate or also in the presence of two amine equivalents of formula ( II) at a temperature between 20 ° and 140 ° C will lead to the compounds of formula (IV)

Formula (IV) in which Ri, R ₂ , R3 9 and R ₁ 0 are defined as above In the case where the radical R ₃ represents the group CH ₂ OH, it may be oxidized to acid for example

- with chromic anhydride according to the method described by R.R SCHMIDT and H J FRITZ Chem Ber 1970, 1122, 1867

- or with potassium permanganate in the presence of ammonia according to the method described by

P.J HARPER and A HAMPTON J Org Chem 1970, 35 n ° 5, 1688

- or by the RuC_3 / Nal0 _{4 system} according to the method described by AK SINGH and RS VARMA Tet Lett 1992, 17, 2307

The nbouronic acid thus obtained is converted to the acid chloride by the action of thionyl chloride, for example, then to the amide by the action of an amine according to the methods known to those skilled in the art. The protection of secondary alcohols ORg , 0R _{1 (3} can be carried out according to different methods, for example in basic medium such as ammoniacal alcohol or in acidic medium such as a solution of normal hydrochloric acid or formic acid, at temperatures varying from 0 ° to 70 ° C depending on the nature of the protective groups

These reaction sequences make it possible to transform the derivatives of formula (IV) into derivatives of formula (I) The compounds of formula (II) can be obtained from imidazo compounds

[l, 2-a] pyπdιne not substituted in position 3 of formula (V)

Formula (V)

in which Riet R ₂ are defined as above,

- either by Vilsmeier-Haack reaction followed by condensation with nitromethane in the presence of ammonium acetate to obtain derivatives of formula (VI)

Formula (VI)

in which Rt and R ₂ are defined as above, these derivatives then being reduced by catalytic hydrogenation in the presence of Raney nickel or by the double hydride of aluminum and lithium to yield the compounds of formula (II)

- Either by Mannich reaction with dimethylamine, then formation of quaternary methyl ammonium salts followed by substitution by the CN group by the action of a cyanide to obtain the compounds of formula (VII)

Formula (VII)

in which R ^ and R ₂ are defined as above, these derivatives then being reduced by catalytic hydrogenation in the presence of Raney nickel and ammonia or by the double hydride of aluminum and lithium to give the compounds of formula (II)

The imidazop, 2-a] pyπdιne compounds of formula (V) are described in the literature or can be prepared by the conventional methods described in particular by H L BLEWITT in Spécial Topics in Heterocyclic Chemistry, A WEISSBERGER,

E C TAYLOR, Eds, Wiley, New York, 1977 p 117 and more recently by

JA KAMINSKI et al J Med Chem 1985, 2S .. 876-892 The most common method consists in reacting 2-amιno pyndine derivatives of formula (VIII)

Formula (VIII)

in which R ^ and R ₂ are defined as above, with α-halo carbonyl compounds,

In the case where the carbonyl compounds are asymmetrical, two imidazo

[1, 2-a] pyndιnes can be obtained whose structure is determined by conventional identification methods in organic chemistry The compounds of formula (VIII) can be obtained according to various methods described in the literature depending on the nature of the substituents R ^ and R ₂ as defined above We will use for example the methods described in the literature with references

J Org Chem 1970, 25 4254-4256 Synthesis 1981, 971 -973

Another route for the synthesis of the imidazo [1, 2-a] pyndine compounds of formula (V), in particular when Ri or R ₂ represents a phenyl radical in position 8 is described with reference

David D Davey J Org Chem 1987, 52. 1863-1867 and consists in reacting a cyclopropyl phenyl ketone with an imidazole at the reflux of decaline in the presence of a catalytic amount of polyphosphoπque acid FOLLOWED by a dehydrogenation of the derivative 5 6- hydro obtained according to the scheme

The use of a 4-chlorobutyrophenone in place of a cyclopropyl phenyl ketone leads to the same result

The 6-halopuπnes of formula (III) are prepared from inosine according to methods described in the literature

R R SCHMIDT and H J FRITZ, Chem Ber 1970, Û2. 1867 H M KISSMAN and J WEISS, J Org Chem 1956, 21, 1053 B.R BAKER; K HEWSON; H THOMAS and J A JOHNSON JR J Org Chem 1957, 22, 954 J ZEMLICKA and F SORM, Coll Czech Chem Commun 1965. _3Û, (6). 1880

The compounds of formula (I) as defined above as well as their addition salts, in particular the pharmaceutically acceptable addition salts are endowed with a good affinity for the adenosine receptors This affinity gives them good analgesic activity but also antihypertensive properties In addition, the Applicant has demonstrated that these compounds of formula (I) have good antiproliferative activity

These properties justify the application of the derivatives of formula (i) in therapy and the invention also relates, as medicaments, to the products as defined by formula (I) above, as well as their salts. addition, in particular the pharmaceutically acceptable addition salts

Thus, the invention also covers a pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as defined above, or one of its pharmaceutically acceptable addition salts, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or support

These compositions can be administered by the oral, rectal, parenteral, transdermal or ocular route.

These compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, suppositories, injections, transdermal systems and eye drops. are prepared according to the usual methods The active principle, consisting of a pharmaceutically effective amount of at least one compound of formula (I) defined as above or one of its pharmaceutically acceptable addition salts, can be there incorporated into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-glycates synthetic, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavors and colors

The invention also covers a pharmaceutical composition with analgesic activity which makes it possible in particular to treat pain favorably, characterized in that it comprises a pharmaceutically effective amount of at least one compound of the abovementioned formula (I) or one of its addition salts. pharmaceutically acceptable, optionally incorporated into a pharmaceutically acceptable excipient, vehicle or support.

The invention also covers a pharmaceutical composition with antihypertensive activity making it possible to favorably treat hypertension, characterized in that it comprises a pharmaceutically effective amount of at least one compound of the abovementioned formula (I) or one of its addition salts pharmaceutically acceptable, optionally incorporated into a pharmaceutically acceptable excipient, vehicle or support

The invention also covers a pharmaceutical composition with antiproliferative activity which makes it possible in particular to favorably treat any pathology due to cell proliferation characterized in that it comprises a pharmaceutically effective amount of at least one compound of the above-mentioned formula (I) or one of its salts of pharmaceutically acceptable addition, optionally incorporated into a pharmaceutically acceptable excipient, vehicle or support

The invention also covers a process for the preparation of a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) as defined above or one of its addition salts is incorporated pharmaceutically acceptable in a pharmaceutically acceptable excipient, vehicle or support. According to one embodiment, a pharmaceutical composition with analgesic activity is prepared, making it possible in particular to treat pain, according to another embodiment, a pharmaceutical composition with antihypertensive activity is prepared, making it possible in particular to favorably treat hypertension, according to another embodiment, a pharmaceutical composition with antiproliferative activity is prepared, making it possible in particular to favorably treat cancer, psoriasis, atherosclerosis, restenosis phenomena or any other pathology due to cell proliferation According to another alternative embodiment, a pharmaceutical composition is prepared formulated in the form of capsules or tablets dosed from 1 to 1000 mg or in the form of injectable preparations dosed from 0.1 mg to 500 mg. Formulations may also be used in the form of suppositories, ointments, creams, gels, aerosol preparations or eye drops

The invention also covers a method for the therapeutic treatment of mammals, characterized in that a therapeutically effective amount of at least one compound of formula (I) as defined above, or one of its addition salts is administered to this mammal. Pharmaceutically acceptable According to an embodiment of this treatment process, the compound of formula (I), either alone or in combination with a pharmaceutically acceptable excipient, is formulated in capsules or tablets dosed from 1 mg to 1000 mg for the administration by the oral route, or in the form of injectable preparations dosed from 0.1 to 500 mg or also in the form of suppositories, ointments, creams, gels, aerosol preparations or eye drops In human and animal therapy, the compounds of formula ( I) and their salts can be administered alone or in combination with a physiologically acceptable excipient in any form, in particular orally in the form of capsules or tablets or parenterally in the form of an injectable solution Other forms of administration such as suppositories, ointments, creams, gels or aerosol preparations may be considered

As will be clear from the pharmacology tests given at the end of the description, the compounds according to the invention can be administered in human therapy in the abovementioned indications by oral route in the form of tablets or capsules doses of 1 mg to 1000 mg or parenterally under form of injections dosed from 0.1 mg to 500 mg in one or more daily doses for an adult of average weight 60 to 70 kg

In animal therapy the usable daily dose is between 0.1 and 100 mg per kg

Other characteristics and advantages of the invention will be better understood on reading the following of some examples which are in no way limitative, but given by way of illustration Example 1: β-D-Ribofuranuronamide, l - (6-chloro-9H-purin-9-yl) -N-cyclo propyl-1 -deoxy-2,3-0- (l -methylethylidene)

O

Formula III X = CI, R ₃ = C - NH, R ₉ R, ₀ = isopropylidene

20 g of 2 ', 3'-0-ιsopropylιdene 6 chloro puπne 5' uronic acid prepared according to SCHMIDT RR and FRITZ HJ Chem Ber 1970, 103 (6) 1867-71 in 500 ml of anhydrous CHCI ₃ stabilized with amylene are doors at reflux for 5 h in the presence of 86 ml of

SOCI ₂ and 10 ml anhydrous DMF

SOCI ₂ in excess as well as the solvents are distilled. The residue is taken up with 200 ml of anhydrous chloroform and added dropwise under nitrogen to a mixture of 150 ml of CHCl 3 and 41 ml of cyclopropylamine previously cooled to 5 ° C. The temperature of the reaction mixture is kept below 10 ° C when adding the acid chloride

Leave to act for an additional 30 minutes, then wash 3 times with a diluted HCl solution and then with a sodium bicarbonate solution. A final washing with water allows, after drying and evaporation of the solvent, to obtain 26 3 g of a brown oil Purification by chromatography on silica gel (eluent CH ₂ CI ₂ 90% / Acetone

10%) leads to 15 7 g of β-D-Ribofuranuronamide, l - (6-chloro-9H-purιn-9-yl) -N-cyclo propyl-1 -deoxy-2,3-0- (l -methylethylιdene ) as an amorphous solid

According to the procedure of Example 1 but using the appropriate amines, the compounds of Examples 2 to 6 were prepared

Example 2: β-D-Ribofuranuronamide, 1 - (6-c loro-9H-purin-9-yl) -1 -deoxy-

N-ethyl-2,3-0- (l -met ylethylidene)

O

Formula III X = CI R, = C - NH— CH— CH ₃ , R ₉ R, ₀ = isopropylidene

Yellowish oil purified by chromatography on silica gel (eluent 95% chloroform / 5% methanol) to give a solid with melting point 91 ° C Example 3: β-D-Ribofuranuronamide, 1 - (6-c loro-9H-purin-9-yl) -l -deoxy- N- (1-hydroxy-2-met ylpropan-2-yl) -2.3 -0- (1 -methyl ethylidene)

O CH ₃

Formula III X = Cl, R ₃ = C - NH— C— CH ₂ —OH, R ₉ R, ₀ = isopropylidene

CH ₃

Brown oil purified by chromatography on silica gel (eluent 90% chloroform / 10% methanol)

Example 4: β-D-Ribofuranuronamide, l - (6-chloro-9H-purin-9-yl) -l -deoxy- N-isopropyl-2, 3-0- (1 -methylethylidene)

Formula III X = CI, R ₃ = isopropylidene

Orange oil purified by chromatography on silica gel (eluent CHCI3 90% / Acetone 10%)

Example 5 β-D-Ribofuranuronamide, l - (6-chloro-9H-purin-9-yl) -i -deoxy-

N- (2-methoxyethyl) -2,3-0- (l-methylethylidene)

O

Formula III X = CI, R ₃ = C - NH— CH ₂ - CH— OCH ₃ , R ₉ R, _C = isopropylidene

Brown oil purified by chromatography on silica gel (eluent 95% chloroform / 5% methanol)

Example 6 β-D-Ribofuranuronamide, l - (6-chloro-9H-purin-9-yl) -l -deoxy- N- (2-morpholi noethyl) -2,3-0- (1 -methylethylidene) O

Formula III X = CI, R ₃ = C— NH-CH ₂ - CH ₂ - NO,

R ₉ R, ₀ = isopropylidene

Amorphous solid obtained after purification by chromatography on silica gel (eluent 90% chloroform / 10% methanol).

Example 7: 2-amino-3 - [(2,5-dimethylphenyl) methoxy] pyridine

Formula VIII: R, = 3 - [(2,5-dimethylphenyl) methoxy], R ₂ = H

A mixture of 22 g of 2-amino 3-hydroxy pyridine, 31 ml of 2,5-dimethyl benzyl chloride and 1.1 g of adogen 464 dissolved in 100 ml of aqueous NaOH (40%) and 100 ml of dichloromethane is stirred 16 h at 25 ^C C. the dichloromethane was separated and the aqueous phase diluted with 200 ml of water. Extract with dichloromethane (2 x 100 ml). The combined organic phases are washed with water, dried and concentrated to give 50.9 g of a brown solid. Purification by recrystallization from ethanol makes it possible to obtain 28.5 g of 2-amino-3 - [(2,5-dimethy_pheπyl) methoxy] pyridine. Melting point ^• 133 ° C.

Example 8: 2-amino-3- (2-methoxyethyloxy) pyridine

Formula VIII = 3 - [(2-methoxyethyl) oxy], R ₂ = H

To a suspension of 8 g of NaOH ground in 200 ml of methanol placed under nitrogen, 22 g of 2-amιno-3-hydroxypyridine are introduced in portions. After a quarter of an hour, concentrate to dryness and take up again with 280 ml of DMSO Add dropwise 20.8 ml of 2-bromoethyl methyl ether, avoiding that the temperature of the reaction medium does not exceed ambient temperature. room temperature maintaining the nitrogen atmosphere

The reaction mixture is poured into 1600 ml of water and extracted with chloroform (4 x 200 ml). The combined organic phases are washed with water, dried and concentrated to give 23 g of an oil. The purification by chromatography on silica gel (eluent CHCI ₃ 95% / isopropylamine 5%) makes it possible to obtain 21.5 g of 2-amιno-3- (2-methoxyethyloxy) pyridine in the form of oil.

According to either of the procedures of Examples 7 or 8, the following compounds of Examples 9 to 15 were prepared ^•

Example 9: 2-amino-3- (2-pyridylmethoxy) pyridine

Formula VIII ^* R, = 3 - [(2-pyπdyl) methoxy], R ₂ = H

Purified by chromatography on silica gel (eluent 95% chloroform / 5% methanol).

Melting point: 98 ° C.

Example 10: 2-amino-3- (2-piperidinoethyloxy) pyridine

Formula VIII: R, = 3 - [(2-pιperidιnoethyl) oxy], R ₂ = H

Melting point: 104 ° C.

Example 11: 2-amino-3- (isopropyloxy) pyridine

Formula VIII - Ri = 3-ιsopropyloxy, R ₂ = H

Oil purified by chromatography on silica gel (eluent 95% chloroform / 5% methanol)

Example 12: 2-amino-3- (cyclopentyloxy) pyridine

Formula VIII R, = 3-cyclopentyloxy, R ₂ = H

Greenish oil that slowly crystallizes Example 13: 2-amino-3 - [(3-methoxyphenyl) methoxy] pyridine

Formula VIII: R ^ = 3 - [(3-methoxyphenyl) methoxy], R ₂ = H

Melting point: 114 ° C

Example 14: 2-amino-3 - [(3,4-dichlorophenyl) methoxy] pyridine

Formula VIII: R ^ = 3 - [(3,4-dιchlorophenyl) methoxy], R ₂ = H

Melting point 165 ° C

Example 15 2-amino-3 - [(naphthyl) methoxy] pyridine

Formula VIII: R ^ = 3 - [(naphthyl) methoxy]; R ₂ = H

Melting point 145 ° C

Example 16: 8- (phenylmethoxy) imidazo [1,2-a] pyridine

Formula V. = 8- (pheπylmethoxy), R ₂ = H

To a solution of 10 g of 2-amtno-3- (phenylmethoxy) pyrιdιne in 50 ml of 95% ethanol, add 9 ml of chloroacetaldehyde (45% in water) then 8 4 g of NaHC0 ₃ . The mixture is brought to reflux for 15 hours. Filter the insoluble material and wash with 95% ethanol. The mother liquors are concentrated, taken up in water and basified with a 5% NaOH solution. Extract with chloroform and wash the organic phases at water then dry and concentrate The oil obtained is triturated in ether to give 9 4 g of 8- (phenylmethoxy) ιmιdazo [1, 2-a] pyridine in the form of a brown solid Melting point 110 ° C

According to the preceding procedure of Example 16 using the appropriate α halo ketones, the following compounds of Examples 17 to 31 were prepared Example 17: 8 - [(2,5-dimethylphenyl) methoxy] imidazo [1,2-a] pyridine

Formula V Rx, = 8 - [(2,5-dιmethylphenyl) methoxy], R ₂ = H

Melting point 143 ° C

Example 18: 2-methyl-8 - [(2,5-dimethylphenyl) methoxy] imidazo [1, 2-a] pyridine

Formula VR, = 8 - [(2,5-dιmethylphenyl) methoxy] R ₂ = 2-CH ₃

Oil purified by chromatography on silica gel (eluent 95% chloroform / 5% isopropylamine) crystallizing slowly

Example 19: 8- (2-methoxyethyloxy) imidazo [1, 2-a] pyridine

Formula VR, = 8 - [(2-methoxyethyl) oxy], R ₂ = H

Oil purified by chromatography on silica gel (eluent 95% chloroform / 5% isopropylamine) crystallizes slowly

Melting point 80 ° C

Example 20: 8- (2-pyridylmethoxy) imidazo [1,2-a] pyridine

Formula V: R, = 8 - [(2-pyπdyl) methoxy], R ₂ = H

Oil used as is without purification

Example 21: 8- (2-piperidιnoethyloxy) imidazo [1,2-a] pyridine

Formula VR, = 8 - [(2-pιpeπdιnoethyl) oxy], R ₂ = H

Yellowish oil purified by chromatography on silica gel (eluent 95% chloroform / 5% isopropylamine) crystallizes slowly Example 22: 8- (isopropyioxy) imidazo [1, 2-a] pyridine

Formula V: R = 8-ιsopropyloxy, R ₂ = H

Brown oil used as is without purification.

Example 23: 8- (cyclopentyloxy) imidazo [1,2-a] pyridine

Formula V: R- _\ = 8-cyclopentyloxy, R ₂ ≈ H

Melting point: 94 ° C.

Example 24: lmidazo [1, 2-a] pyridine

Formula V: R, = R ₂ = H

Oil purified by chromatography on silica gel (eluent 95% chloroform / 5% methanol).

Example 25. 6-chloro imidazo [1, 2-a] pyridine

Formula V: R, = 6-chloro, R ₂ = H

Oil purified by chromatography on silica gel (eluent 95% chloroform / 5% methanol).

Example 26: 6-methyl imidazo [1, 2-a] pyridine

Formula V: R, = 6-CH3, R ₂ = H

Oil used as is without purification

Example 27: 7-methyl imidazo [1, 2-a] pyridine

Formula V: R, = 7-CH ₃ , R ₂ = H Oil used as is without purification

Example 28 2-phenyl imidazo [1, 2-a] pyridine

Formula VR, = 2-phenyl, R ₂ = H

Oil purified by chromatography on silica gel (eluent 95% chloroform / 5% methanol)

Example 29 8 - [(3-met oxyphenyl) methoxy] imidazo [1, 2-a] pyridine

Formula V: R, = 8 - [(3-methoxyphenyl) methoxy], R ₂ = H

Brown oil used as is without purification

Example 30 8 - [(3,4-dichlorophenyl) methoxy] imidazo [1, 2-a] pyridine

Formula V: ^ = 8 - [(3,4-dιchlorophenyl) methoxy], R ₂ = H

Melting point 118 ° C

Example 31: 8- (nap tylmet oxy) imidazo [1,2-a] pyridine

Formula VR, = 8- (naphthylmethoxy), R ₂ = H

Melting point 116 ° C

Example 32 8-phenyl imidazo [1,2-a] pyridine

Formula VR ^ = 8-phenyl, R ₂ = H

This compound was prepared in two stages according to the reference J Org Chem 1987, vol 52, p 1863-1867 and uses crude without purification Melting point 107 ^C C (bed 69-70X) Example 33: 3- (2-aminoethyl) -8 - [(2,5-dιmethylphenyl) methoxy] imidazo [1,2-a] pyridine, hydrochloride

Formula II R] = 8 - [(2,5-dιmethylphenyl) methoxy], R ₂ = H

a) Preparation of 3 - [(dιmethylamιno) methyl] -8 - [(2,5-dιmethylphenyl) methoxy] ιmιdazo [1, 2-a] pyrιdιne hydrochloride

A mixture of 26 6 g of [(2,5-demethylphenyl) methoxy] ιmιdazo [1, 2-a] pyπdιne prepared in Example 17, 9 is refluxed for 2 hours, 9 1 g of dimethylamine hydrochloride, 3 4 g of paraformaldehyde and 100 ml of methanol Concentrate the solution to 2/3 Add at room temperature 10 ml of concentrated HCl and stir for several hours A precipitate appears gradually Filter wash with ether to obtain 37 9 g of 3 - [(dιmethylamιno) methyl ] -8 - [(2,5-dιmethylphenyl) methoxy] ιmιdazo [1, 2-a] pyrιdιne, hydrochloride

Melting point 220 ° C

b) Preparation of the iodide of 8 - [(2,5-dιmethylphenyl) methoxy] 3 - [(trιmethylammonιo) methyl] ιmιdazo [1, 2-a] pyrιdιne

Dissolve 379 g of the hydrochloride prepared as above in 300 ml of water (heat slightly if necessary) Bring the pH to 11 -12 by adding a 50% NaOH solution Cool to 0 ° C and extract with dichloromethane Wash the organic phases combined with a H ₂ O / NaCl solution to dry and concentrate to obtain 32 3 g of a brown oil

Dissolve the oil previously obtained in 150 ml of ethanol Cool to 0 ° C and add dropwise 6 8 ml of ICH ₃

Stir at room temperature overnight. The solid obtained is filtered πncé with I ethanol and then with I ether to give 38 4 gd lodide of 8 - [(2 5-dιmethylphenyl) methoxy] -3- [(trιmethylamrnonιo) methyl] ιmιdazo [l , 2-a] pyrιdιne

Melting point 227X

c) Preparation of 3- (cyanomethyl) -8 - [(2 5-dιmethylphenyl) methoxy] ιmιdazo [1, 2-a] pyrιdιne A mixture of 204 5 g of quaternary ammonium prepared in Example 33b, 1200 ml of DM F and 34 g of NaCN with stirring is heated at bam-maπe for 6 h Cool at room temperature then pour into 3 l of water mixture / ice Extract with chloroform The combined organic phases are washed with water, dried and concentrated to give 112 9 g of a brown solid

Melting point 164 ° C

Purification by chromatography on silica gel (eluent 90% chloroform / 10% methanol) gives 73 7 g of 3- (cyanomethyl) -8 - [(2,5-dιmethylphenyl) methoxy] ιmιdazo [1, 2- a] pyrιdιne in the form of a solid cream

Melting point 168 ° C

d) Preparation of 3- (2-amιnoethyl) -8 - [(2,5-dιmethylphenyl) methoxy] ιmιdazo [l, 2-a] pyridme

Formula II R ^ = 8 - [(2,5-dιmethylphenyl) methoxy], R ₂ = H

Catalytically reduced, in the presence of Ni Raney, for 8 h, in an autoclave under 90 kg of hydrogen pressure and at 100 ° C., a mixture of 40 g of cyanomethyl derivative obtained according to the preceding preparation 33c), in 500 ml of ammoniacal methanol The reaction mixture is filtered through celite Concentrate the organic phase then resume with chloroform The insoluble material is eliminated and the organic phase concentrated to give 51.2 g of an oil

Take up the oil in 150 ml of isopropanol Acidify with 26 ml of an isopropanol / HCl solution (5 6 N) The solid obtained is filtered, nnce with I isopropanol then with ether to give 33 8 g of 3- ( 2-amιnoethyl) -8 - [(2,5-dιmethylphenyl) methoxy] ιmιdazo [1, 2-a] pyridene hydrochloride

Melting point 229

Example 34: 3- (2-am inoethyl) -8- (phenylmethoxy) imidazo [1, 2-a] pyridine

Formula II Rx. = 8- (phenylmethoxy), R ₂ = H

a) Preparation of 3-formyl-8- (phenylmethoxy) ιmιdazo [1, 2-a] pyrιdιne A mixture of 10 g of 8- (phenylmethoχy) ιmιdazo [l, 2-a] pyrιdιne prepared in Example 16 and 31 ml of DM F is cooled to 10 ° C Add dropwise 4 7 ml of POCI ₃ Leave to return at room temperature then heat 30 min at 100 ° C Cool and add 85 ml of H ₂ 0 and 16 ml of NaOH (50%) Heat 1 h at 90 ° C then leave to cool. The solid obtained is filtered and then washed with water until the pH of the mother liquors is neutral. 8 8 g of 3-formyl-8- (phenylmethoxy) ιmιdazo [1, 2-a] pyrιdιne are thus obtained

Melting point 167 ° C

b) Preparation of 3- (2-nιtroethenyl) -8- (phenylmethoxy) ιmιdazo [1, 2-a] pyridene

The aldehyde prepared above (5 g) is reacted with 40 ml of nitromethane and 1 g of ammonium acetate Bring the mixture to reflux for 1 hour The solid obtained is washed with water and then purified by chromatography on silica gel (eluent dichloromethane 95% / acetone 5%) to give 1 g of 3- (2-nιtroethenyl) -8- (phenylmethoxy) imιdazo [1, 2-a] pyrιdιne expected (melting point 204 ° C) and 1.5 g of starting aldehyde which can be recycled

c) Preparation of 3- (2-amιnoethyl) -8- (phenylmethoxy) ιmιdazo [1, 2-a] pyπdιne

Formula II R ^ = 8- (phenylmethoxy), R ₂ = H

The compound obtained in Example 34b) is dissolved (3 g) in warm 200 mL THF This mixture is then introduced dropwise into a suspension of 3 g of LιAIH ₄ in 50 ml of THF At the end of the ^introduction the mixture is brought to reflux for 1 h 30 The excess of LιAIH ₄ is destroyed at 0 ° C. with an aqueous solution of Na ₂ S0 ₄ Filter through celite Rinse with ethyl acetate The concentration of the organic phases makes it possible to '' obtain 3- (2-amιnoethyl) -8- (phenylmethoxy) ιmιdazo [l, 2-a] pyrιdιne in the form of a brown oil punctured by chromatography on silica gel (eluent CHCI ₃ 95% / isopropylamine 5%)

According to the procedures of Examples 33 or 34, the compounds of Examples 35 to 45 were prepared

Example 35: 3- (2-aminoethyl) -2-methyl-8 - [(2,5-dimethylphenyl) methoxy] imidazo [1,2-a] pyridine Formula II: R, = 8 - [(2,5-dιmethylphenyl) metho ^χ y], R ₂ = 2-CH ₃

Purified brown oil after treatment with hydrochloric isopropanol (6N). Melting point of the hydrochloride: 272 ° C.

Example 36: 3- (2-aminoethyl) -8- (2-methoxyethyloxy) imidazo [1, 2-a] pyridine

Formula II: R, = 8 - [(2-methoxyethyl) oxy], R ₂ = H

Brown oil purified by chromatography on silica gel (eluent 90% chloroform / 10% isopropylamine)

Example 37: 3- (2-aminoethyl) -8- (cyclopentyloxy) imidazo [1, 2-a] pyridine

Formula II ^* Ri = 8-cyclopentyloxy, R ₂ = H

Brown oil used as is without purification.

Example 38: 3- (2-aminoethyl) -8- (isopropyloxy) imidazo [1, 2-a] pyridine

Formula II: R ^ = 8-isopropyloxy, R ₂ = H

Brown oil used as is without purification.

Example 39: 3- (2-aminoethyl) imidazo [1,2-a] pyridine

Formula II: R, = R ₂ = H

Brown oil purified by chromatography on silica gel (eluent 90% chloroform / 10% isopropylamine)

Hydrochloride melting point ^* 217 ° C

This compound partly contains 3- (2-amιnoethyl) 5,6,7,8-tetrahydro imidazo [1, 2-a] pyridιne which will be separated at the later stage Example 40: 3- (2-aminoethyl) -6-methyl imidazo [1, 2-a] pyridine

Formula II R, = 6-methyl, R ₂ = H

Brown oil purified by chromatography on silica gel (eluent 90% chloroform / 10% isopropylamine)

Hydrochloride melting point 190 ° C

Example 41: 3- (2-aminoethyl) -7-methyl imidazo [l, 2-a] pyridine

Formula II R, = 7-CH ₃ , R ₂ = H

Oil purified after treatment in hydrochloric isopropanol Melting point of hydrochloride 250 ^C C

Example 42 3- (2-aminoethyl) -2-phenyl imidazo [1,2-a] pyridine

Formula II R, = 2-phenyl, R ₂ = H

Brown oil purified by chromatography on silica gel (eluent 95% chloroform / 5% isopropylamine)

Hydrochloride melting point> 260

Example 43 3- (2-aminoethyl) -8 - [(3-methoxyphenyl) methoxy] imidazo [1, 2-a] pyrid ι ne

Formula II R, = 8 - [(3-methoxyphenyl) methoxy], R ₂ = H

Brown oil purified by chromatography on silica gel (eluent 95% chloroform / 5% isopropylamine)

Example 44 3- (2-amιnoethyl) -8 - [(3,4-dιc h lorophenyl) methoxy] imidazo [i, 2-a] pyrid ι ne

Formula II R, = 8 - [(3 4-dιchlorophenyl) methoxy], R ₂ = H Brown oil purified by chromatography on silica gel (eluent 95% chloroform / 5% isopropylamine).

Example 45: 3- (2-aminoehyl) -8- (naphthylmethoxy) imidazo [1, 2-a] pyridine

Formula II: R-) == 8- (naphthylmethoχy), R ₂ = H

Hydrochloride melting point: 150-5 ° C

Example 46: 3- (2-aminoethyl) -8-phenyl imidazo [1,2-a] pyridine

Formula II: Ri = 8-phenyl, R ₂ = H

Oil purified by three chromatographies on successive silica gel (eluent chloroform 95% / isopropylamine 5% twice then chloroform 80% / methanol

20%).

Example 47: β-D-ribofuranuronamide, N-cyclopropyl-l -deoxy-1- [6 - [[2- [8- (phenylmethoxy) imidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl] -2.3-0- (1-methylethylidene)

Formula IV: R = 8-phenylmethoχy, R ₂ ≈ H,

A mixture of 7.3 g of 3- (2-amιnoethyl) 8- (phenylmethoxy) imidazo [1, 2-a] pyridine prepared in Example 34, 7.9 g of β-D-ribofuranuronamide, 1- (6-chloro- 9H-purin-9-yl), N-cyclopropyl-1 -deoxy-2,3-0- (l -methylethylιdene) prepared in Example 1, 100 ml of ethanol and 9.6 ml of triethylamine is heated under reflux for 7 h under nitrogen atmosphere.

Concentrate then resume with chloroform, wash with water and with a solution of water and NaCl. Dry, concentrate to obtain 14 g of an amorphous solid.

Purification by chromatography on silica gel (eluent 95% chloroform / 5% methanol) leads to 12.8 g of β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1 - [6- [[2- [8- ( phenylmethoxy) ιmιdazo [1.2-a] pyrιdin-3-yl] ethyl] amino] -9H-purin-9-yl] -2.3-0- (1 - methylethylidene) as an amorphous white solid

According to the procedure of Example 47, the amorphous compounds of Examples 48 to 62 were prepared by reaction of 3- (2-aminoethyl) ιmidazo [1, 2-a] pyridιne differently substituted on the appropriate 6-chloro purines.

Example 48: β-D-ribofuranuronamide, N-cyclopropyl-i -deoxy-1 - [6 - [[2- [8 - [(2,5-dimethylphenyl) methoxy] imidazo [1, 2-a] pyridin- 3 -yl] ethyl] amino] -9H-purin-9-yl] -2.3-0- (1 -methylethylidene)

Formula IV. R, = 8 - [(2,5-dimethylphenyl) methoxy], R ₂ = H,

Example 49: β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1- [6 - [[2- [8- (2-methoxyethyloxy) imidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl] -2.3-0- (l -methylethylidene)

Formula IV R, = 8 - [(2-methoxyethyl) oxy], R ₂ = H,

Example 50: β-D-ribofuranuronamide, N-cyclopropyl-1-deoxy-1 - [6 - [[2- [8 - [(2,5-dimethylphenyl) methoxy] -2-methylimidazo [1,2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl] -2.3-0- (1- methylethylidene)

Formula IV R, = 8 - [(2,5-dιmethylphenyl) methoxy]. R ₂ = 2-CH ₃ ,

Example 51: β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1 - [6 - [[2- [8- (cyclopentyloxy) imidazo [1,2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl] -2.3-0- (1 -methylethylidene)

Formula IV: Ri = 8-cyclopentyloxy, R ₂ = H,

Example 52: β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1 - [6 - [[2- [8- (isopropyloxy) imidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl] -2, 3-0 (1 -methylethylidene)

Formula IV: R ^ = isopropyloxy, R ₂ = H,

Example 53: β-D-ribofuranuronamide, N- (2-morphollnoethyl) -l-deoxy-1- [6- [[2- [8 - [(2,5-dimethylphenyl) methoxy] imidazo [1, 2-a ] pyridin-3- yl] ethyl] ami no] -9H-purin-9-yl] -2, 3-0 (1 -methylethylidene)

Formula IV: R, = 8 - [(2,5-dimethylphenyl) methoxy], R ₂ = H,

⁰ n / / \ v \ rCuH _;

R ₃ = C— NH— CH ₂ -CH ₂ - NO, R ₉ R ₁₀ = C

^{/ V} CH ₃

Purified by chromatography on silica gel (eluent 90% chloroform / methanol

10%). Example 54: β-D-ribofuranuronamide, N-ethyl-1 -deoxy-1 - [6-

[[2- [8 - [(2,5-dimethylphenyl) methoxy] imidazo [1, 2-a] pyridin-3- yl] ethyl] amino] -9H-purin-9-yl] -2, 3-0 (1 -methylethylidene)

Formula IV ^* Rx. = 8 - [(2,5-dιmethylphenyl) methoxy], R ₂ = H,

O

\ .CH,

R ₃ = C— NH— CH ₂ - CH ₃ , RgRio ^≈ C

/ CH,

Purified by chromatography on silιce gel (eluent 90% chloroform / methanol

10%).

Example 55: β-D-ribofuranuronamide, N-cyclopropyl-1-deoxy-l - [6-

[[2- [imidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl] - 2.3-0 (1 -methylethyl idene)

Formula IV ^* R, = H, R ₂ = H, R ₃ = C - NH-

\, CH ₃ ^{RgRl0 =} / ^C ^ CH ₃

Purified by chromatography on silica gel (eluent 80% chloroform / 20% methanol)

Melting point 207X The compound β-D-ribofuranuronamide, N-cyclopropyl-1 -deoχy-1 - [6 - [[2- [5,6,7,8 tetrahydroimidazo [1, 2] is also obtained in the form of an amorphous solid -a] pyrιdιn-3-yl] ethyl] amιno] -9H-punn-9-yl] -2, 3-0 (1 -methylethylidene).

Example 56 β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1 - [6- [[[2- [6-methylimidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H- pu ri n-9-yl] - 2, 3-0 (1 -met hylethylidene) Formula IV: R, = 6-CH ₃ , R ₂ = H, R ₃ = C- -NH

Example 57: β-D-ribofuranuronamide, N-cyclopropyl-1-deoxy-1- [6-

[[2- [2-phenylimidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H- purin-9-yl] -2, 3-0 (1 -methylethylidene)

Formula IV: Ri = 2-phenyl, R ₂ = H,

Example 58: β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1 - [6-

[[2- [7-methylimidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H- pu ri n-9-yl] -2, 3-0 (1 -met hylethylidene)

O

Formula IV: R, = 7-CH ₃ , R ₂ = H, R ₃ = C NH-

Melting point: 228 ° -230 ^c C.

Example 59: β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1- [6-

[[2- [8- (3-methoxy phenyl) methoxy] im idazo [1,2-a] py ridi n-3- yljethyl] amino] -9H-purin-9-yl] -2, 3-0 ( 1 -methylethylidene)

Formula IV: R, = 8 - [(3-methoxyphenyl) methoxy], R ₂ = H

Example 60: β-D-ribofuranuronamide, N-cyclopropyl-l -deoxy-l- [6-

[[2- [8- (3,4-dichlorophenyl) methoxy] imidazo [1,2-a] pyridin-3- yl] ethyl] ami no] -9H-purin-9-yl] -2, 3-0 (1 -methylethylidene)

Formula IV: R = 8 - [(3,4-dichlorophenyl) methoxy], R ₂ = H,

Example 61: β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1- [6-

[[2- [8-phenylimidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H- purin-9-yl] -2, 3-0 (1 -methylethylidene)

Formula IV: R-, = 8-phenyl, R ₂ = H,

O

CH ₃

CH ₃

Example 62: β-D-ribofuranuronam ide, N-cyclopropyl-l -deoxy-1- [6-

[[2- [8- (naphthylmethoxy) imidazo [1, 2-a] pyridin-3-yl] ethyl] am ino] -9H-purin-9-yl] -2, 3-0 (1 -methylethylidene)

Formula IV: R ₁ = 8- (naphthylmethoχy), R ₂ = H,

O

CH ₃

\ /

R ₃ = C NH- CH ₃ Example 63: β-D-ribofuranuronamide, N-cyclopropyl-l -deoxy-1 - [6 - [[2- [8- (phenylmethoxy) imidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl]

Formula IRT = 8-phenylmethoxy, R ₂ = H,

A mixture of 13 g of β-D-nbofuranuronamide of Example 47 and 378 ml of formic acid at 50% is heated at 70 ^C for 1 h 15 mm Remove formic acid by evaporation and taken up in water concentrate This operation is repeated again, then the residue taken up in methanol and concentrated again. Resume in water, triturate to obtain 9 6 g of a white solid.

Melting point 191 ° C

Recnstalialisation in methoxyethanol makes it possible to obtain 7 4 g of β-D- πbofuranuronamide, N-cyclopropyl-1 -deoxy-1 - [6 - [[2- [8- (phenylmethoxy) ιmιdazo [1, 2- a] pyrιdιn-3-yl] ethyl) amιno] -9H-puπn-9-yl]

Gross formula C29H ₃ ON _e 0 ₅ , 0 3 H ₂ 0

Melting point 177 ° C

According to the procedure of Example 63, the compounds of Examples 64 to 88 were prepared

Example 64 β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1- [6- [[2- [8 - [(2,5-dimethylphenyl) methoxy] imidazo

[1, 2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl]

Formula IR, = 8 - [(2.5-dιmethylphenyl) methoxy], R ₂ = H,

Purifies by two successive chromatographies on silica gel [eluent (90% chloroform / 10% methanol) and (80% chloroform / 20% methanol) respectively] Crude formula C ₃₁ H3 ₄ N ₈ 0 ₅ 0 3 H ₂ 0 Melting point: 147 ° C

Example 65: β-D-ribofuranuronamide, N-cyclopropyl-l -deoxy-l - [6- [[2- [8- (2-methoxyethyloxy) imidazo [1, 2-a] pyridin-3yl] ethyl] amino] -9H-purin-9-yl]

Formula I. R- ^ = 8 - [(2-methoxyethyi) oxy], R ₂ = H,

Purified by chromatography on silica gel (eluent 90% chloroform / 10% methanol)

Gross formula C ₂ 5 H3oN _θ 0 ₆ , 0 2 H ₂ 0 Melting point 174 ° C

Example 66: β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1- [6- [[2 - [[8- (2,5-dimethylphenyl) methoxy] -2-methyl imidazo [1,2-a ] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl]

Formula IR, = 8 - [(2,5-dιmethylphenyl) methoxy], R ₂ = 2-CH ₃ ,

Purified by chromatography on silica gel (eluent 90% chloroform / 10% methanol) followed by re-installation in isopropanol

Gross formula C ₃₂ H ^ NeOs. 0 4 H ₂ 0 Melting point 162 ^{* '} C

Example 67: β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1 - [6- [[2- [8- (cyclopentyloxy) imidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl] Formula I: R, = 8-cyclopentyloχy, R ₂ = H,

Purified by chromatography on silica gel (eluent 90% chloroform / 10% methanol).

Crude formula: C ₂ H32N ₈ 0 ₅ ; 0.9 H ₂ 0 Melting point: 162 ° C

Example 68: β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1 - [6-

[[2- [8- (isopropyloxy) imidazo [1,2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl]

Formula I: Ri = 8-isopropyloxy, R ₂ = H,

Purified by chromatography on silica gel (eluent 80% chloroform / 20% methanol) and recrystallized from acetonitrile. Raw formula: C ₂ 5H3oN ₈ θ5 Melting point: 151 ° C

Example 69: β-D-ribofuranuronamide, N- (morpholinoethyl) -l-deoxy-1 - [6- [[2- [8 - [(2,5-dimethylphenyl) methoxy] im idazo [1,2-a] pyridin-3- yl] ethyl] amino] -9H-purin-9-yl]

Formula I: R, = 8 - [(2.5-dimethylphenyl) methoxy], R ₂ ≈ H,

O

R ₃ = C— NH— CH ₂ -CH ₂ - O Purified by chromatography on silica gel (eluent 90% chloroform / 10% methanol) and reinstalled in isopropanol Crude formula ^* C ₃₄ H ι N 0 _$ Melting point 134 ° C

Example 70: β-D-ribofuranuronamide, N-ethyl-l -deoxy-l - [6-

[[2- [8 - [(2,5-dιmethylphenyl) methoxy] imidazo [l, 2-a] pyridin-3- yl] ethyl] amino] -9H-purin-9-yl]

Formula I R- ^, = 8 - [(2,5-dιmethylphenyl) methoxy], R ₂ = H,

O

I I

R ₃ = C— NH— CH ₂ - CH ₃

Purifies by chromatography on silica gel (eluent 90% chloroform / methanol

10%) and re-installed in isopropanol

Gross formula C-JO H ^ NSOS, 0 3 H ₂ 0 Melting point 140 ° C

Example 71 β-D-ribofuranuronamide, N-cyclopropyl-1-deoxy-1 - [6-

[[2- [imidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl]

Formula IR, = R ₂ = HR ₃ = C NH <J

Purifies after two recnstallisations successively in ethanol then in methoxyethanol

Gross formula C ₂ 2H ₂₄ N ₈ θ ₄ Melting point 261 ° C

Example 72 β-D-ribofuranuronamide, N-cyclopropyl-l -deoxy-1 - [6-

[[2- [6-methylimidazo [1, 2-a] pyrιdin-3-yl] ethyl] amino] -9H- purin-9-yl] O

| ι

Formula I R. = 6-CH ₃ , R ₂ = HR ₃ = C - NH-

Purified by recrystallization from methoxyethanol Crude formula C ₂ 3H26N ₈ 0 ₄ Melting point 260 ° C

Example 73 β-D-ribofuranuronamide, N-cyclopropyl-1-deoxy-l- [6-

[[2- [2-phenylimidazo [l, 2-a] pyridιn-3-yl] ethyl] amino] -9H- purin-9-yl]

Formula IR, = 2-phenyl, R ₂ = H, R ₃ =

Purified by chromatography on silica gel (eluent 80% chloroform / 20% methanol) Crude formula C ₂₈ H2 ₈ N ₈ 0 _4.0 0.0 4 H ₂ 0

Melting point 175 ° C

Example 74 β-D-ribofuranuronamide, N-cyclopropyl-l -deoxy-l - [6-

[[2- [7-methylimidazo [l, 2-a] pyridin-3-yl] ethyl] amino] -9H- purin-9-yl]

Formula I R. = 7-CH ₃ , R ₂ = HR ₃ = C NH

Puπfie by recπstal sation in DMF Crude formula C ₂ 3H26N ₈ θ ₄ 0 1 H ₂ 0 Melting point 252 ^C C Example 75. β-D-ribofuranuronamide, N-cyclopropyl-l-deoxy-l - [6-

[[2- [8 - [(3-methoxyphenyl) methoxy] imidazo [1, 2-a] pyridin-3- yljethyl] amino] -9H-purin-9-yl]

Formula IR ₁ = 8 - [(3-methoxyphenyl) methoxy], R ₂ = H,

Purified by recnstallisation in ^isopropanol

Gross formula C ₃₀ H ₃₂ N ₈ O ₆ Melting point 171 ° C

Example 76 β-D-ribofuranuronamide, N-cyclopropyl-1-deoxy-1 - [6- [[2- [8 - [(3,4-dichlorophenyl) methoxy] imidazo [1,2-a] pyridin-3- yljethyl] amino] -9H-purin-9-yl]

Formula IR, = 8 - [(3,4-dιchlorophenyl) methoxy], R ₂ = H, o

R ₃ = C NH-

Punfied by recnstalling in I isopropanol Crude formula C ₂ 9H23Cl2N ₈ θ5 Melting point 161 ° C

Example 77 β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1 - [6-

[[2- [8-phenylιmidazo [l, 2-a] pyridin-3-yl] ethyl] amino] -9H- purin-9-yl]

O

Formula I R. = 8-phenyl, R ₂ = HR ₃ = C NH-— J

Puπfié by chromatography on silica gel (eluent CHCI ₃ 90% / MeOH 10%) and recnstalled in I isopropanol Crude formula C2 ₈ H28N ₈ 0 ₄ Melting point 157-9 ° C

Example 78 β-D-ribofuranuronamide, N-cyclopropyl-1 -deoxy-1 - [6-

[[2- [8- (naphthylmethoxy) lmidazo [1,2-a] pyrid in-3-yl] ethyl] amino] -9H-purin-9-yl]

Formula I Ri = δ- (naphthylmethoxy), R ₂ = H,

Reconstructed in isopropanol Crude formula C ₃₃ H ₃₂ N ₈ θ5 Melting point 156 ° C

Example 79: N ⁶ 2 - [[8- (2,5-dimethylphenyl) methoxy] im idazo [1, 2a] pyridin-3-yl] ethyl adenosine

Formula I: R, = 8 - [(2 5-dιmethylphenyl) methoxy], R ₂ = H,

R ₃ = CH ₂ OH

A mixture of 4 8 g of hydrochloride prepared in Example 33d), 4 5 g of 6-chloroadenosine, 5 3 ml of triethylamine and 100 ml of ethanol is brought to reflux for 7 h Concentrate the solution obtained Resume with CHCI ₃ and wash with water and with a saturated H 0 / NaCl solution. Dry the organic phase and concentrate. The solid obtained is punctured by chromatography on silica gel (eluent CHCI ₃ 90% / methanol 10%). Recnstallation in methanol leads to 4 3 g of N ⁶ 2 - [[8- (2,5-dιmethylphenyl) methoxy] ιmιdazo [1, 2a] pyπdιn-3-yl] analytically pure ethyl adenosine

Gross formula C ₂₈ H ₃₁ N ₇ 0 ₅ , 0 3 H ₂ 0 Melting point 1 1 ° C Example 80: β-D-ribofuranuronamide, N-cyclopropyl-l-deoxy-i- [6- [[2- [5,6,7,8-tetrahydro imidazo [1, 2-a] pyridin-3-yl] ethyl] amino] -9H-purin-9-yl]

Formula I: R R = 5,6,7,8 tetrahydro

Purified by chromatography on silica gel (eluent CHCI ₃ 80% / isopropylamine

20%)

Gross formula: C ₂₂ H ₂₈ N ₈ 0 ₄ Melting point: 118 ° C

PHARMACOLOG IE

The pharmacological activity of the products of the examples was evaluated according to three distinct approaches fixation on the adenosine receptors, demonstration of an analgesic activity by the phenylbenzoquinone test, demonstration of an activity inhibiting proliferation. cell growth factor induced in Balbc 3T3 fibroblasts

I Procedure

1 • Attachment to adenosine receptors

Principle

The affinity of the products of the examples for the central adenosinergic A1 and A2 receptors of rats is determined by the competition technique using a radioactive ligand fixed specifically, either on the A1 receptors (pH] PIA), or on the A2 receptors ([3 H] NECA)

Method

• A 1 receptor study method

- Membrane preparation

After sacnfice of the animal by decapitation, the brain is quickly removed and washed in cold physiological saline The two hemispheres are separated, weighed and each of them is introduced into a polyallomer tube containing 25 volumes of cold homogenization buffer (TRIS HCI 50 mM, pH 7 4) The homogenization is carried out using an Ultra-Turrax for 30 seconds The ground material obtained is centrifuged at 1000 g for 10 minutes at 4 ° C

The supernatant is centrifuged again at 48,000 g for 20 minutes at 4 ° C. At the end of this step, the pellet is taken up in 4 volumes of homogenization buffer resuspended using a vortex and homogenized with Ultra-Turrax. Adenosine deaminase is then added in an amount of 1 U / ml of homogenate.

Thus treated, the homogenate is stirred for 30 minutes at room temperature; then it is centrifuged at 48,000 g for 30 minutes at 4 ° C.

The pellet obtained is resuspended in 10 volumes of homogenization buffer and passed to Ultra-Turrax for 20 seconds.

The homogenate thus prepared is used for the competition trials. It is kept at 4 ° C if the studies take place during the day, or stored at -20 ° C.

- Competition test

After thawing the homogenate at room temperature, it is passed to Potter (6 manual round trips, speed 6) diluted 2/5 in the incubation buffer and placed in the water bath thermostatically controlled at 4 ° C under agitation until the end of the experiment.

50 μl of pH] PIA at 100 nM, ie 2.5 nM, in the final reaction medium, taking into account the 1/40 dilution, and 50 μl of product of the example at the final concentrations envisaged (10 ^* 5 M and 10 ^{* 7} M) are introduced into the reaction tubes in the presence of 900 μl of incubation buffer (TRIS HCI 50 mM, pH 7.4). The reaction is triggered by the addition of 1 ml of homogenate.

The tubes are shaken and incubated in a water bath at 20 ° C for 30 minutes. At the end of the incubation, the tubes are filtered on Whatman GF / B paper. Each tube is washed twice with 2 ml of rinsing buffer (TRIS HCI 50 mM, pH 7.4), then the filters themselves are rinsed with 3 ml of this same buffer.

The filters are then transferred to counting flasks and 10 ml of scintillating liquid (Ready Solv HP / b. Beckman) are added.

The vials are stored in the refrigerator overnight after shaking, then the radioactivity is determined in a liquid scintillation counter.

For each concentration studied, 3 tests are carried out. The non-specific binding of [ ³ H] PIA is assessed by measuring the amount of radioactivity retained on the filter in the presence of 10 ^{* 5} M of phenylisopropyladenosine (PIA) The value of non-specific fixation is systematically subtracted from that of the tests

• A ₂ receptor study method

- Membrane preparation

After decapitation of the animal, the brain is quickly removed and washed in cold physiological saline The two hemispheres are separated and on each of them, the stnatum is removed (Bruns et al, 1986), weighed and introduced into a polyallomer tube containing 10 volumes of cold homogenization buffer (TRIS HCI 50 mM, MgCl ₂ 10 mM, pH 7 7. The tissue is homogenized with an Ultra-Turrax for 30 seconds The ground material is centrifuged at 50,000 g for 10 minutes at 4 ^C C

The pellet obtained is resuspended in 10 volumes of homogenization buffer using a vortex and homogenized with Ultra-Turrax

Adenosine deammase is then added in an amount of 1 U / ml of homogenate. The homogenate thus treated is stirred at room temperature for 30 minutes.

At the end of the incubation, it is centrifuged at 50,000 g for 10 minutes at 4 ° C

The pellet is taken up in 5 volumes of cold homogenization buffer, passed through Ultra-Turrax and the homogenate thus prepared is finally frozen at -70 ° C.

- Competition test

After thawing the homogenate at room temperature, 15 volumes of incubation buffer are added. The homogenate is vortexed, passed through a Potter (6 round trips, speed 6), diluted 1/10 in the buffer. incubation and finally placed in the thermostatic bath at 4 ^r C with stirring until the end of the experiment

50 μl of [ ³ H] NECA ai 60nM, or 4 nM, in the final reaction medium, taking into account the 1/40 dilution and 50 μl of product of the example at the final concentrations envisaged (10 ⁵ M and 10 ^{* 7} M) are introduced into the reaction tubes in the presence of 900 μl of incubation buffer (TRIS HCI 50 mM, MgCl ₂ 10 mM, cyclopentyl adenosine 0.11 μM, pH 7 7) The reaction is triggered by the addition of 1 ml of homogenate For all the compounds studied, the procedure is similar

The tubes are shaken and incubated in a master bath at 25 ° C for 60 minutes At the end of the incubation, the tubes are filtered on Whatman GF / B paper Each tube is washed twice with 2 ml of rinsing buffer (TRIS 50 mM HCl, 10 mM MgCl ₂ , pH 77), then the filters themselves are rinsed with 3 ml of this same buffer before being transferred to counting flasks

10 ml of scintillating liquid (Ready Solv HP / b, Beckman) are added to all the vials These are shaken and stored in the refrigerator overnight The radioactivity is determined in a liquid scintillation counter

For each concentration studied, 3 tests are carried out. The non-specific binding of [ ³ H] NECA is determined by measuring the amount of radioactivity retained on the filter in the presence of 5 μM of N-ethylcarboxamido-adenosine (NECA). The value of the binding non-specific is systematically deduced from that of the tests

• Data processing

The results are expressed by product as a percentage (n = 3) of displacement of the labeled radio gand at the concentrations of 10 ⁵ M and 10 ^{* 7} M

2- Phenylbenzoquinone test

Method

The iπtrapeπtoneale injection of phenylbenzoquinone causes twisting and stretching movements in mice Analgesics prevent or reduce this syndrome which can be considered as the externalization of diffuse abdominal pain The 0 02% phenylbenzoquinone solution in water is administered in a volume of 1 ml / 100 g

The products of the examples are administered orally one hour before the injection of phenylbenzoquinone

Stretching and twisting are counted for each mouse during a 5 minute observation period

I Results

The results of the experiments demonstrating the affinity of the products of the examples for the adenosine receptors and their analgesic properties are presented in Tables 1 and 2 respectively.

Table 1

% of movement of the radio

Product of example A1 A2

1E-5M 1E-7M 1E-5M 1E-7M

Example 63 94 45 89 13

Example 64 90 41 86 15

Example 65 100 98 80 1

Example 66 93 29 84 12

Example 67 96 44 80 6

Table 2

Phenylbenzoquinone test

% Inhibition

Example products at 30 mg / kg V.O.

Example 63 39

Example 64 57

Example 65 25

Example 66 63

Example 67 57 Measurement of the inhibition of cell proliferation induced by a growth factor in smooth Balbc fibroblasts 3T3

I Pnncipe

The inhibition of cell proliferation induced by a growth factor (eg PDGF) is evaluated by measuring the incorporation of 3H-thymιdene into the fibroblasts Balbc 3T3

II Procedure

The Balbc 3T3 fibroblasts are cultured at 37 ° C., in 5% C0 ₂ , until the sub-confluence and then placed for 18 hours in quiescence in a medium poor in serum. They are then pretreated for one hour with the molecule to be tested ( 10 ^{* 5} M and / or 10 ^{* 6} M) then stimulated for 22 hours by a growth factor (example PDGF) The incorporation of 3H-thymιdιne is carried out during the last 2 hours All these steps are carried out at 37 ° C. , in 5% C0 ₂ The reaction is terminated by aspiration of the reaction medium, detachment of the cells, then filtration of the lysed cells through glass fiber filters

III Expression of results

The results are expressed as a percentage of inhibition of the stimulation of the incorporation of 3H-thymedene induced by the growth factor.

The results obtained, presented in Table 3 show that the compounds of formula (I) powerfully inhibit the proliferation of PDBF-stimulated Balbc 3T3 fibroblasts Table 3

% inhibition of the incorporation of stimulated 3H-thymιdιne

Product of the example by the PDGF

1 E - 5 M 1 E - 6 M

Example 64 - 7 2

Example 66 8 0

Example 67 6 3

III Toxicology

The tolerance of the products of the examples described was assessed in mice after oral administration. This proved to be good up to the dose of 300 mg / kg.

I V Conclusion

The products of the examples described in the present invention have particularly advantageous analgesic properties. In addition, these same compounds powerfully inhibit cell proliferation of smooth muscle cells.

Claims

 REVENUE DICATI ONS

1 Adenosine deviations characterized in that they correspond to the general formula (I)

Formula (I)

in which

Ri and R ₂ which can be in position 2, 5, 6 7 or 8 of rimidazopyridine, independently represent

- the hydrogen atom

- an alkyl radical containing 1 to 6 carbon atoms

- a halogen atom - a radical 0- (CH ₂ ) _n - R ₄ in which n is an integer from 0 to 5 and R ₄ represents the hydrogen atom, an alkyl radical less than 1 to 6 atoms of carbon, a C ₃ -C cycloalkyl radical, an O-lower alkyl radical of 1 to 6 carbon atoms a phenyl radical unsubstituted or substituted by one to four identical or different substituents chosen from a halogen atom, a radical lower alkyl of 1 to 6 carbon atoms or an O-lower alkyl radical of 1 to 6 carbon atoms, a pyπdyl radical or a naphthyl radical - a phenyl radical

R ₃ represents

- a group -CO-NHR ₅ in which R ₅ represents a lower alkyl radical of 1 to 6 carbon atoms, a radical C ₃ -C cycloalkyl, a radical - (CH ₂ ) _m -OR ₆ or a radical - (CH ₂ ) _m -NR ₇ R ₈ in which, m is an integer from 2 to 5, R ₆ is hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms and R and R ₈ simultaneously represent an lower alkyl radical of

1 to 6 carbon atoms or form together with the nitrogen atom to which they are attached a heterocycle chosen from morpholme, pipeπdine, pyrrolidine,

- A CH ₂ OH group and their addition salts, in particular the pharmaceutically acceptable addition salts

2 derivatives of formula (I) according to claim 1, characterized in that

Ri and R ₂ which may be in position 2, 6, 7 or 8 of ^the imidazo pyndine independently represent

- the hydrogen atom - an alkyl radical lower than 1 to 6 carbon atoms

- a radical 0- (CH ₂ ) _n -R,

in which n is an integer from 0 to 5 and R represents a lower alkyl radical of 1 to 6 carbon atoms, a C ₃ -C cycloalkyl radical, an O-lower alkyl radical of 1 to 6 carbon atoms, a phenyl radical unsubstituted or substituted by one or two identical or different substituents chosen from a halogen atom, an lower alkyl radical of 1 to 6 carbon atoms or an O-lower alkyl radical of 1 to 6 carbon atoms, a radical naphthyl,

- a phenyl radical

R ₃ represents

a group -CO-NHR ₅ in which R ₅ represents a lower alkyl radical of 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical or a 2-morpholιnoethyle radical,

a group -CH ₂ OH as well as their addition salts, in particular the pharmaceutically acceptable addition salts

3. Derivatives according to claim 1 or 2, characterized in that Ri is chosen from a phenylmethoxy group, a (2,5-dimethylphenyl) methoxy group or a cyclopentyloxy group.

4. Derivatives according to claim 1 or 2, characterized in that R ₂ represents the hydrogen atom or a methyl radical.

5. Derivatives according to claim 1 or 2, characterized in that R ₃ represents an N-cyclopropyl carboxamide radical, an N-ethylcarboxamide radical or an N-2-morpholinoethyl carboxamide radical.

6. Derivatives according to claim 1, characterized in that they are chosen from the derivatives of formula:

OH OH

7. A method of preparing the compounds of formula (I) according to any one of claims 1 to 6 characterized in that it comprises the reaction of an amine of formula

in which R ^ and R ₂ are as defined in formula (I) on the 6-halopunnes nbosides of formula

in which, X represents a halogen atom, R3 is as defined in formula (I), Rg and R ₁ 0 represent groups protecting the alcohol function such as acetyl, benzoyl or benzyl for example, or can forming together another protective group of dioxalane structure for example, in a solvent, such as an alcohol for example or an aprotic solvent such as dimethyl formamide, in the presence of a base, such as methylamine, pyπdine or a sodium or potassium carbonate or in the presence of two equivalents of the amine at a temperature between 20 and 140 ° C, and in the case where the radical R ₃ represents the group CH ₂ OH, its oxidation by the action of chromic anhydride, permanganate potassium or by the RuCI ₃ / Nal0 _{4 system} , the πbouronic acid thus obtained being converted into acid chloride by the action of thionyl chloride for example then into an amide by the action of an amine, then deprotection of the alcohols ls secondary OR ₉ and OR ₁ 0 for example in basic medium such as in ammoniacal alcohol or in acid medium such as in a solution of normal hydrochloric acid or formic acid at a temperature varying from 0 ° to 70 ° C. depending on the nature of the protective groups, and optionally the transformation of the compound thus obtained into a pharmaceutically acceptable salt 8 Pharmaceutical composition characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 6 or one of its pharmaceutically acceptable addition salts, optionally incorporated in a pharmaceutically acceptable excipient, vehicle or support

9 Pharmaceutical composition with analgesic activity, characterized in that it contains a pharmaceutically effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 6 or one of its addition salts pharmaceutically acceptable, optionally incorporated into a pharmaceutically acceptable excipient, vehicle or carrier

10 Pharmaceutical composition with antihypertensive activity, characterized in that it contains a pharmaceutically effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 6 or one of its addition salts pharmaceutically acceptable, optionally incorporated into a pharmaceutically acceptable excipient, vehicle or carrier

11 Pharmaceutical composition with antiproliferative activity, characterized in that it contains a pharmaceutically effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 6 or one of its addition salts pharmaceutically acceptable, optionally incorporated into a pharmaceutically acceptable excipient, vehicle or carrier

12 Process for the preparation of a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 6 or one of its salts is incorporated. pharmaceutically acceptable addition to a pharmaceutically acceptable excipient, vehicle or carrier

13 The method of claim 12, caractéπse in that the pharmaceutical composition is formulated in the form of capsules, tablets dosed from 1 to 1000 mg or in the form of injectable preparations dosed from 0.1 to 500 mg