NO882888L - PROCEDURE FOR THE PREPARATION OF HETEROAROMATIC DERIVATIVES OF ADENOSIN. - Google Patents

Description

The hitherto unknown compounds according to the present invention are related to the N<6->substituted adenosines according to pending US patent application no. 756,922 which is a "continuation" of the now issued US patent application no. 621,943, which is again a "continuation" of the now issued US Patent Application No. 519,284. Moreover, the application PD No. 3576 submitted at the same time as this one is related to the present invention, and it is hereby incorporated into the present description with its entire content.

The present compounds are stronger N<6->substituted adenosine analogues that have both A1- and A2-selective receptor binding, compared to what has previously been found among adenosine analogues. The compounds have particularly beneficial central nervous system and cardiovascular activities, such as analgesic, antipsychotic, sedative, antihypertensive and cardiotonic, especially antianginal and vasodilatory activities. In particular, the strong antipsychotic and cardiovascular effects according to the present invention are unexpected.

The above-mentioned pending US patent application no. 756,922 and references stated therein provide background for the present invention, including literature descriptions of investigations, which have shown that the compound according to the present invention possesses the activity described here. Pending US application No. 756,922 is therefore hereby incorporated with its entire content as part of the present description.

The present invention relates to a compound of formula or a pharmaceutically acceptable acid addition salt thereof, where Ar<1> and Ar<2> are independently phenyl, which is unsubstituted or substituted with halogen, hydroxy, thiol, lower alkoxy, lower thioalkyl, lower alkanoyloxy, lower carboxyalkyl, lower alkyl, nitro, amino, lower S(0)n-alkyl, where n is 0, 1 or 2, sulfonamide or trifluoromethyl, or a heteroaryl selected from 2- or 3-thienyl or 2- or 3-furanyl, where thienyl or furanyl is unsubstituted or substituted by lower alkyl or halogen.

It is a general condition that at least one of Ar<1>or

Ar<2> is the heteroaryl group and that neither Ar<1> nor Ar<2> has more

than one substituent.

R2', R3' and R5' are each independently hydrogen, alkanoyl with

two to twelve carbon atoms in a straight or branched alkyl chain, which may be substituted with amino, benzoyl or benzoyl substituted with lower alkyl, lower alkoxy, halogen or trifluoromethyl, further R2' and R3' may be linked together to form a five- membered alkylidene ring with a total of up to 20 carbon atoms, such as isopropylidene or a cyclic phosphate diester, and R5' can be a phosphate, hydrogen or dihydrogen phosphate, or an alkali metal or ammonium or dialkali or diammonium salt thereof, such as PO3Na2.

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above formula I with a pharmaceutically acceptable carrier, as well as a method for treating mammals by administering to such mammals a dosage form of a compound of the above formula and which is defined above.

In the compounds of formula I, the term "lower alkyl" is intended to include a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl ,

amyl, isoamyl, neopentyl, hexyl and the like.

Halogen includes in particular fluorine, chlorine or bromine.

Lower alkoxy and thioalkyl are O-alkyl or S-alkyl with

from 1 to 6 carbon atoms as defined above for "lower alkyl".

Lower alkanoyloxy is a straight chain or branched chain

0

11

O-C alkyl group with from 1 to 6 carbon atoms in the alkyl chain, as defined above.

0

i) Lower carboalkoxy is a straight or branched C-0 alkyl group having from 1 to 6 carbon atoms in the alkyl chain, as defined above.

The compounds of formula I are useful both in the free base form and in the form of acid addition salts. Both forms fall within the scope of the invention. In practice, use of the salt form corresponds to use of the base form. Suitable pharmaceutically acceptable salts that fall within the scope of the invention are those derived from mineral acids, such as hydrochloric acid and sulfuric acid, as well as organic acids, such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like which respectively give the hydrochloride, sulfamate, ethanesulfonate, benzenesulfonate onate, p-toluenesulfonate and the like. (See, for example, "Pharmaceutical Salts," J. Pharm. Sci., (1977) 66(1):1-19).

The acid addition salts of the aforementioned basic compounds are prepared either by dissolving the free base in aqueous solution or aqueous alcohol solution or other suitable solvents, containing the appropriate acid, and isolating the salt by evaporation of the solution, or by reacting the free base and acid in an organic solvent, whereby the salt is precipitated directly or obtained by concentrating the solution.

In general, the compounds of formula I according to the present invention are prepared using a method according to Scheme I.

The method shown in Scheme I converts the aryl aldehyde of formula VI into the corresponding w-nitrostyrene of formula V. The compounds of formula V are then reacted with an organometallic aryl compound of formula IV (preferably a Grignard or a lithium derivative) in an aprotic solvent medium system (preferably toluene-ether) at a low temperature (preferably -10° to -40°C). The thus prepared diarylnitroethane of formula III is then reduced to the corresponding diarylethylamine of formula II (preferably with LiAlH4i ether) which is then coupled with 6-chloropurine riboside as described in the previously cited US Patent Application No. 756,922. In this way, the desired compounds of formula I are prepared.

The starting materials for the above-described method for preparing compounds of formula I are generally known, commercially available or can be prepared using methods that are either known or analogous to known methods.

Variations in the described methods which are known to a normally trained professional fall within the scope of the invention.

The products from the methods can be isolated using conventional means, such as extraction, distillation, chromatography and the like.

The compounds of formula I provide the most selective potent A1 receptor and A2 receptor binding adenosines yet found and therefore have surprising and unexpected activity. Particularly noteworthy is the greater intraperitoneal MAST activity of the mentioned compounds. Description of tests for obtaining such data can be found in incorporated US Patent Application No. 756,922.

Data are shown in the following tables.

Example 6 has an ED50 value of 1.75 mg/kg for avoidance blockade in SIDRAT.

The test is adapted to show a percentage reduction in mean arterial blood pressure, where A is more than 20% and C is 10-20% reduction. In both cases with a duration of at least 2 hours.

The present invention therefore also includes a pharmaceutical composition for the treatment of psychoses, sleep disorders, pain or cardiovascular diseases, comprising an antipsychotic, sedative, analgesic or cardiovascular effective amount of a compound of formula I as defined above, together with a pharmaceutically acceptable carrier .

The present invention further includes a method for the treatment of psychoses, sleep disorders, pain or cardiovascular diseases in mammals with such disorders, comprising administering to such mammals either orally or parenterally, a corresponding pharmaceutical composition with a compound of formula I as defined above, in appropriate dosage form.

The compositions and methods of administration are to be understood in accordance with the state of the art, for example as described in US patent application no. 756,922.

The amount of active compound in a unit dose preparation may be varied or adjusted from 0.1 mg to 200 mg, preferably 1 mg to 100 mg according to the particular application and to the strength of the active ingredient. If desired, the compositions may also contain other compatible therapeutic agents.

In therapeutic use as described above, the dosage range for a 70 kg subject is from 0.1 to 150 mg/kg body weight per day, or preferably 0.1 to 10 mg/kg body weight per day. However, the doses can be varied, depending on the patient's requirements, the severity of the condition and the compound used.

Determining the appropriate dose for a particular situation is a professional matter. In general, treatment is initiated with smaller doses that are less than the optimal dose of the compound. The dose is then increased by small amounts, until the optimal effect is achieved. For convenience, the total daily dose may be divided and administered in portions during the day, if desired.

The following examples further illustrate the invention.

EXAMPLE 1

N, 6-(2-(thien-2-yl)-2-phenethyl)adenosine

Nitrostyrene (12.65 g, 33%) was prepared from 2-thiophene-carboxaldehyde (23.4 mL, 0.25 mol) and nitromethane (15.3 g,

0.25 mol) as described in Example 10 below.

The amine (0.90 g, 32%) was prepared from E,2-(thien-2-yl)nitroethene (2.16 g, 0.014 mol) and phenylmagnesium bromide (7.2 mL, 0.021 mol) followed by LiAlH 4 reduction (1.60 g, 0.042 mol) as described in Example 10 below.

The nucleoside (0.22 g, 20%) was prepared from the amine (0.47 g, 0.0023 mol), 6-chloropurine riboside (0.66 g, 0.0023 mol) and triethylamine (0.3 mL, 0.0025 mol) as a foam, m.p. 68-72°C, as described in Example 10 below.

EXAMPLE 2

N, 6-(2-(thien-3-yl)-2-phenethyl)adenosine

The nitrostyrene (27.2 g, 70%) was prepared from 3-thiophene-carboxaldehyde (22.0 mL, 0.25 mol) and nitromethane (15.3 g,

0.25 mol) as described in Example 10 below.

The amine (3.28 g, 29%) was prepared from E,2-(thien-3-yl)nitroethene (8.50 g, 0.055 mol) and phenylmagnesium bromide (28.5 mL, 0.0855 mol) followed by LiAlH4 -reduction (6.5 g, 0.17 mol), as described in Example 10 below.

The nucleoside (1.21 g, 37%) was prepared from the amine (1.44 g, 0.007 mol), 6-chloropurine riboside (2.00 g, 0.007 mol) and triethylamine (1.0 mL, 0.0077 mol ) as a white foam, m.p. 80-100°C, as described in Example 10 below.

EXAMPLE 3

N, 6-( 2-( 3- methoxyphenyl)- 2-( thien- 2- yl) ethyl) adenosine

The nitrostyrene (16.8 g, 77%) was prepared from 2-thiophene-carboxaldehyde (13.0 mL, 0.14 mol) and nitromethane (8.5 g,

0.14 mol), as described in Example 10 below.

The amine (1.69 g, 20%) was prepared from E,2-(thein-2-yl)nitroethene (5.64 g, 0.036 mol), 3-methoxybromobenzene (9.2 mL, 0.073 mol), magnesium ( 1.40 g, 0.058 mol) followed by LiAlH 4 reduction (5.46 g, 0.144 mol), as described in Example 10 below.

The nucleoside (0.83 g, 23%) was prepared from the amine (1.69 g, 0.0073 mol), 6-chloropurine riboside (1.86 g, 0.0065 mol) and triethylamine (0.95 mL, 0.0072 mol) as a solid, m.p. 71-80°C, as described in Example 10 below.

EXAMPLE 4

N, 6-( 2-( 3- chlorophenyl)- 2-( thien- 2- yl) ethyl) adenosine

The nitrostyrene (12.65 g, 33%) was prepared from 2-thiophene-carboxaldehyde (23.4 mL, 0.25 mol) and nitromethane (15.3 g,

0.25 mol), as described in Example 10 below.

The amine (1.71 g, 36%) was prepared from E,2-(thien-2-yl)nitroethene (3.1 g, 0.02 mol), 3-chlorobromobenzene (4.7 mL,

0.04 mol), magnesium (0.77 g, 0.032 mol) followed by LiAlH 4 reduction (2.30 g, 0.06 mol), as described in Example 10 below.

The nucleoside (1.12 g, 37%) was prepared from the amine (1.47 g, 0.006 mol), 6-chloropurine riboside (1.72 g, 0.006 mol) and triethylamine (0.9 mL, 0.0066 mol ), as a solid, m.p. 99-104°C, as described in Example 10 below.

EXAMPLE 5

N, 6-( 2-( 3- chlorophenyl)- 2-( thien- 3- yl) ethyl) adenosine

The nitrostyrene (27.2 g, 70%) was prepared from 3-thiophene-carboxaldehyde (22.0 mL, 0.25 mol) and nitromethane (15.3 g,

0.25 mol), as described in Example 10 below.

The amine (0.87 g, 18%) was prepared from E,2-(thien-3-yl)nitroethene (3.1 g, 0.02 mol), 3-chlorobromobenzene (4.7 mL,

0.04 mol), magnesium (0.77 g, 0.032 mol) followed by LiAlH 4 reduction (2.30 g, 0.06 mol), as described in Example 10 below.

The nucleoside (0.86 g, 49%) was prepared from the amine (0.87 g, 0.0037 mol), 6-chloropurine riboside (1.00 g, 0.0035 mol) and triethylamine (0.5 mL, 0.0039 mol) as a solid, m.p. 104-110°C, as described in Example 10 below.

EXAMPLE 6

N, 6-(2,2-dithien-2-ylethyl)adenosine

The amine (1.11 g, 53%) was prepared from E,2-thien-2-yl-nitroethene (1.55 g, 10 mmol, see Example 1), 2-bromothiophene (2.45 g, 15 mmol) and magnesium (0.48 g, 20 mmol) followed by LiAlH 4 reduction (1.11 g, 30 mol), as described in Example 10 below.

The nucleoside (1.29 g, 53%) was prepared from 2,2-dithien-2-ylethylamine (1.11 g, 5.3 mmol), 6-chloropurine riboside (1.45 g, 5 mmol) and triethylamine (1.01 g, 10 mmol) as a pale khaki colored solid foam, m.p. 89-97°C, as described in Example 10 below.

EXAMPLE 7

N, 6-( 2-( thien-2- yl)- 2-( thien-3- yl) ethyl) adenosine

The amine (1.68 g, 32%) was prepared from E,2-(thien-3-yl)nitroethene (3.88 g, 0.025 mol, see Example 2), 2-bromothiophene (5.2 mL, 0, 05 mol), magnesium (0.96 g, 0.04 mol) followed by LiAlH 4 reduction (2.88 g, 0.076 mol), as described in Example 10 below.

The nucleoside (1.34 g, 50%) was prepared from the amine (1.20 g, 0.0057 mol), 6-chloropurine riboside (1.63 g, 0.0057 mol) and triethylamine (0.8 mL, 0.0063 mol) as a solid, m.p. 94-105°C, as described in Example 10 below.

EXAMPLE 8

N, 6-(2-(furan-2-yl)-2-phenethyl)adenosine

The nitrostyrene (8.25 g, 49%) was prepared from 2-furaldehyde

(11.3 g, 0.12 mol) and nitromethane (7.3 g, 0.12 mol), as described in Example 10 below.

The amine (2.02 g, 54%) was prepared from E,2-(furan-2-yl)nitroethene (2.78 g, 0.02 mol), phenylmagnesium bromide (10.3 mL, 0.03 mol) followed by of LiAlH 4 reduction (2.30 g, 0.06 mol), as described in Example 10 below.

The nucleoside (0.22 g, 9%) was prepared from the amine

(0.94 g, 0.005 mol), 6-chloropurine riboside (1.43 g, 0.005 mol), and triethylamine (0.7 mL, 0.0055 mol) as a beige solid, m.p. 74-83°C, as described in Example 10 below.

EXAMPLE 9

N, 6-( 2-( 3- chlorophenyl)- 2- furan- 2- yl) ethyl) adenosine

The amine (2.60 g, 29%) was prepared from E,2-(furan-2-yl)nitroethylene (5.56 g, 0.04 mol, see Example 8), 3-chlorobromobenzene (9.4 mL, 0.08 mol), magnesium (1.54 g, 0.064 mol) followed by LiAlH 4 reduction (4.60 g, 0.12 mol), as described in Example 10 below.

The nucleoside (2.21 g, 67%) was prepared from the amine

(1.58 g, 0.007 mol), 6-chloropurine riboside (2.01 g, 0.007 mol) and triethylamine (1 mL, 0.0077 mol) as a solid, m.p. 87-103°C, as described in Example 10 below.

EXAMPLE 10

N6-( 2-( 5- methylthien- 2- yl)- 2- phenethyl) adenosine

a) E,2-(5-methylthien-2-yl)nitroethene.

Aqueous sodium hydroxide (5M, 15 ml) was added during 15

minutes added dropwise to a solution of 5-methylthiophene-2-carboxaldehyde (9.45 g, 0.075 mol) and nitromethane (4.58 g,

0.075 mol) in methanol (28 mL). After an additional 10 minutes, the reaction mixture was cooled by pouring onto dilute hydrochloric acid (0.5M, 165 mL) and then extracted with ether (2 x 50 mL). The combined extracts were washed with water and saturated brine and dried (MgSO 4 ). The solvent was removed under reduced pressure and the remaining oil was dissolved in CH 2 Cl 2 (120 mL) and stirred under N 2 at 0°C. Mesyl chloride (4.9 mL, 0.063 mol) in CH 2 Cl 2 (15 mL) was added over 10 min, and then triethylamine (15 mL, 0.11 mol) in CH 2 Cl 2 (15 mL) was added in

within 20 minutes. After 10 minutes, the reaction mixture was poured into dilute hydrochloric acid (0.5M, 135 ml). The layers were separated and the aqueous layer extracted with CH 2 Cl 2 (2 x 25 mL). The combined organic phases were washed with water, saturated brine and dried (Na 2 SO 4 ). The solvent was removed under reduced pressure to afford the nitrostyrene (4.42 g, 35%) as a yellow solid. NMR (CDCl 3 ) δ 8.1 (d, 1H); 7.2-7.3 (2H, m); 6.80

(1H, d); 2.57 (p, 3H).

b) 2-(5-methylthien-2-yl)-2-phenylethylamine

Phenylmagnesium bromide (3M in ether, 7 mL, 0.021 mol) was

added dropwise to a solution of E,2-(5-methyl-thien-2-yl)nitroethene (3.14 g, 0.019 mol) in toluene (100 mL), and stirred under N2 at -30°C. After 1 hour, the reaction mixture was cooled by pouring into dilute hydrochloric acid (0.5M, 60 mL). The layers were separated and the aqueous layer extracted with ether (2 x 25 mL). The combined organic phases were washed with water (2 x

25 ml, emulsions common at this stage), saturated brine (25 ml) and dried (MgSO 4 ). The solvent was removed under reduced pressure to afford the crude diarylnitroethane (2.79 g) as an oil. The oil was dissolved in ether (130 mL) and over 20 minutes added dropwise to a suspension of LiAlH 4 (2.88 g, 76 mmol) in ether (325 mL) stirred under N 2 at 25°C. Powerful gas evolution and mild exothermic! After 20 hours, the reaction mixture was cooled by careful sequential dropwise addition of water (3 mL), aqueous sodium hydroxide solution (10% w/v, 3 mL) and water (9 mL). Powerful gas development and exothermic! The mixture was vacuum filtered and the residue washed with ether (100 mL). The combined filtrates were extracted with dilute hydrochloric acid (0.1M, 2 x 100 ml). The aqueous layer was washed with ether (2 x 50 mL), basified with NaOH pellets (1.0 g 25 mmol) and extracted with ether (2 x 25 mL). The combined extracts were washed with water (2 x 25 ml, often emulsions), saturated saline (25 ml) and dried (MgSO 4 ). The solvent was removed under reduced pressure to give the desired amine (1.36 g, 31%) as an oil. NMR (CDCl 3 ) δ 7.3 (5H, s); 6.55-6.7 (2H, m); 4.10 (2H, t, J=7Hz); 3.27 (2H, d, J=7Hz); 2.43 (3H, s); 1.40 (2H, br. p). c) N,6-(2-(5-methylthien-2-yl)-2-phenylethyl)adenosine 6-chloropurine riboside (1.61 g, 5.6 mmol), 2-(5-methylthien-2-yl)-2-phenylethylamine (1.36 g, 6.3 mmol) and triethylamine (0.8 mL , 6.2 mmol) was refluxed in ethanol (50 mL) under N 2 in 48 h. The solvent was removed under reduced pressure to give a solid foam which was purified by silica gel chromatography eluting with 6/1 CHCl 3 /MeOH. The solvent was removed under reduced pressure and the resulting foam recrystallized from methanol to give the desired nucleoside as a solid, m.p. 107-111°C.

Calculated for C23H25N504S. 0.15H2O

C, 58.75; H, 5.42; N, 14.89

Found: C, 58.38; H, 5.34; N, 14.85

EXAMPLE 11

N, 6-( 2-( 3- methylthien- 2- yl)- 2- phenethyl) adenosine

The nitrostyrene (6.65 g, 53%) was prepared from 3-methyl-2-thiophenecarboxaldehyde (9.45 g, 0.075 mol) and nitromethane (4.58 g, 0.075 mol), as described in Example 10.

The amine (1.50 g, 19%) was prepared from E,2-(3-methylthien-2-yl)nitroethene (6.00 g, 0.0355 mol) and phenylmagnesium bromide (18.7 mL, 0.056 mol), followed by LiAlH4 reduction (5.41 g, 0.14 mol) as described in Example 10.

The nucleoside (0.90 g, 31%) was prepared from the amine

(1.50 g, 0.0069 mol), 6-chloropurine riboside (1.78 g, 0.0062 mol) and triethylamine (0.9 mL, 0.0068 mol) as a solid, m.p. 93-100°C, as described in Example 10.

EXAMPLE 12

N, 6-( 2-( 2- methylfuran-3- yl)- 2- phenethyl) adenosine

The nitrostyrene (1.86 g, 25%) was prepared from 2-methyl-3-furaldehyde (5.38 g, 0.049 mol) and nitromethane (3.00 g, 0.049 mol) as described in Example 10.

The amine (0.44 g, 44%) was prepared from E,2-(2-methylfuran-3-yl)nitroethene (0.77 g, 0.005 mol) and phenylmagnesium bromide (2.7 mL, 0.008 mol), followed by LiAlH4 reduction (0.66 g, 0.017 mol) as described in Example 10.

The nucleoside (0.66 g, 73%) was prepared from the amine

(0.44 g, 0.0022 mol), 6-chloropurine riboside (0.57 g, 0.002 mol)

and triethylamine (0.3 mL, 0.0022 mol) as a light brown solid, m.p. 93-96°C, as described in Example 10.

EXAMPLE 13

N, 6-( 2-( 3- methylfuran- 2- yl)- 2- phenethyl) adenosine

The nitrostyrene (0.59 g, 48%) was prepared from 3-methyl-2-furaldehyde (0.92 g, 0.008 mol) and nitromethane (0.49 g, 0.008 mol), as described in Example 10.

The amine (0.08 g, 10%) was prepared from E,2-(3-methylfuran-2-yl)nitroethene (0.59 g, 0.0039 mol) and phenylmagnesium bromide (2.1 mL, 0.0063 mol) ), followed by LiAlH 4 reduction (0.18 g, 0.0047 mol), as described in Example 10.

The nucleoside (0.12 g, 74%) was prepared from the amine

(0.08 g, 0.0004 mol), 6-chloropurine riboside (0.10 g, 0.00036 mol) and triethylamine (0.1 mL, 0.0008 mol) as a solid, m.p. 68-78°C, as described in Example 10.

EXAMPLE 14

N, 6-( 2-( 5- bromothien- 2- yl)- 2- phenethyl) adenosine

E,2-(thien-2-yl)nitroethene (12.65 g, 33%) was prepared

from thiophene-2-carboxaldehyde (23.4 ml, 0.25 mol) and nitromethane (15.3 g, 0.25 mol) as described in Example 10.

2-thien-2-yl-2-phenethylamine (0.90 g, 32%) was prepared

from E,2-(thien-2-yl)nitroethene (2.16 g, 14 mmol) and phenylmagnesium bromide (7.2 mL, 21 mmol) followed by LiAlH 4 reduction (1.60 g, 42 mmol), as described in Example 10.

2-(5-Bromothien-2-yl)-2-phenethylamine. A solution of bromine (1.12 g, 7 mmol) in CHCl 3 (25 mL) was added dropwise over 20 minutes to a solution of 2-thien-2-yl-2-phenethylamine (1.19 g, 6, 5 mmol) in CHCl 3 (25 mL) and stirred under N 2 at 0°C. After an additional 20 minutes, the reaction mixture was extracted with dilute hydrochloric acid (0.1M, 2 x 50 mL). The aqueous layer was washed with CHCl 3 (2 x 25 mL), then basified with NaOH pellets (1.2 g, 30 mmol), and then extracted with ether (3 x 25 mL). The combined extracts were washed with water (2 x 25 ml), saturated brine (25 ml) and dried (MgSO 4 . Solution-

the solvent was removed under reduced pressure to afford the desired bromide (0.85 g, 49%) as a pale yellow oil.

The nucleoside (1.26 g, 72%) was prepared from 2-(5-bromothien-2-yl)-2-phenethylamine (0.85 g, 3.3 mmol), 6-chloropurine riboside (0.96 g , 3.3 mmol) and triethylamine (0.61 g, 6 mmol) as a whitish solid foam, m.p. 101-109°C, as described in Example 10.

Claims (21)

1. Compound of formula (I) wherein Ar<1> and Ar<2> are independently phenyl, which is unsubstituted or substituted with halogen, hydroxy, thiol, lower alkoxy, lower thioalkyl, lower alkanoyloxy, lower alkyl, nitro, amino, lower S(0)n -alkyl, where n is 0, 1 or 2, sulfonamide or trifluoromethyl, or heteroaryl selected from 2- or 3-thienyl or 2- or 3-furanyl, wherein thienyl or furanyl is unsubstituted or substituted with lower alkyl or halogen; under the general assumption that at least one of Ar <1> or Ar <2> is the heteroaryl group and that neither Ar <1> nor Ar <2> can have more than one substituent, R2', R3' and R5' are each independently hydrogen, alkanoyl of 2 to 12 carbon atoms in a straight or branched alkyl chain which may be substituted with amino, benzoyl or benzoyl substituted with lower alkyl, lower alkoxy, halogen or trifluoromethyl, wherein R2< 1> and R 3 ' can further be bound together to form a 5-membered alkylidene ring with a total of up to 20 carbon atoms, such as isopropylidene or a cyclic phosphate ester, and R 5 ' can be a phosphate, hydrogen or dihydrogen phosphate, or an alkali metal or ammonium or dialkali or diammonium salt thereof, such as PO 3 Na 2 . 2. Compound according to claim 1, where at least one of Ar <1> or Ar <2> is 2- or 3-thienyl which is unsubstituted or substituted with lower alkyl or halogen. 3. Compound according to claim 1, in which at least one of Ar <1> or Ar <2> is 2- or 3-furanyl which is unsubstituted or substituted with lower alkyl or halogen. 4. A compound according to claim 2, which is N,6-(2-thien-2-yl)-2-phenethyl)adenosine. 5. A compound according to claim 2, which is N,6-(2-thien-3-yl)-2-phenethyl)adenosine. 6. A compound according to claim 2, which is N,6-(2-(3-methoxyphenyl)-2-(thien-2-yl)ethyl)adenosine. 7. A compound according to claim 2, which is N,6-(2-(3-chlorophenyl)-2-(thien-2-yl)ethyl)adenosine. 8. A compound according to claim 2, which is N6-(2-(3-chlorophenyl)-2-(thien-3-yl)ethyl)adenosine. 9. A compound according to claim 2, which is N,6-(2,2-di-thien-2-ylethyl)adenosine. 10. A compound according to claim 2, which is N,6-(2-(thien-2-yl)-2-(thien-3-yl)ethyl)adenosine. 11. A compound according to claim 3, which is N,6-(2-(furan-2-yl)-2-phenethyl)adenosine. 12. A compound according to claim 3, which is N,6-(2-(3-chlorophenyl)-2-(furan-2-yl)ethyl)adenosine. 13. A compound according to claim 2, which is N,6-(2-(5-methylthien-2-yl)-2-phenethyl)adenosine. 14. A compound according to claim 2, which is N,6-(2-(3-methylthien-2-yl)-2-phenethyl)adenosine. 15. A compound according to claim 3, which is N,6-(2-(2-methylfuran-3-yl)-2-phenethyl)adenosine. 16. A compound according to claim 3, which is N,6-(2-(3-methylfuran-2-yl)-2-phenethyl)adenosine. 17. A compound according to claim 3, which is N,6-(2-(5-bromothien-2-yl)-2-phenethyl)adenosine. 18. A composition for the treatment of psychoses or cardiovascular disease, characterized in that it comprises an antipsychotic or cardiovascular effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier. 19. Method for treating psychosis in a mammal, which comprises the administration of a compound according to claim 1, in the form of unit doses. 20. Method for the treatment of cardiovascular diseases in a mammal, which comprises the administration of a compound according to claim 1, in the form of unit doses. 21. Process for producing a compound according to claim 1, characterized by the fact that one (1) treats a compound of formula Ar CHO (VI), wherein Ar <1> has the above meaning, with A) CH3 NO2 in the presence of NaOH and then B) CH3 SO2 C1 in the presence of triethylamine, to obtain a product of formula (2) reacts the compound of formula V with a compound of formula Ar <2> M (IV), wherein Ar <2> is as defined above, and M is a G rignard or lithium moiety, in a solvent mixture which comprising toluene and ethyl ether, and further treating with LiAlH4 to obtain a product of formula and (3) coupling the product of (2) with 6-chloropurine riboside in the presence of triethylamine to obtain a compound according to claim 1.