BACKGROUND OF THE INVENTION

The novel compounds of the present invention are related to the N -substituted adenosines of copending applications U.S. Serial Number 756,922 which is a continuation of U.S. Serial Number 621,943, now abandoned which is a continuation of U.S. Serial Number 519,284 now abandoned. Also the application PD Number 3576 filed concurrently herewith is related to the present invention and is incorporated herein by reference.

The present compounds provide more potent N -substituted adenosine analogs, having both Al and A2 selective receptor binding compared to that previously found among adenosine analogs. The compounds have highly desirable central nervous system and cardiovascular activities, such as analgesic, antipsychotic, sedative, antihypertensive, and cardiotonic, especially antianginal and vasodilator, activities. Particularly, the high antipsychotic and cardiovascular effects of the present invention are unexpected.

The above noted copending application U.S. Serial Number 756,922 and references therein provide background for the present invention including descriptions of literature assays in which the compounds of the present invention are found to possess the activity as described herein. Therefore, copending application U.S. Serial Number 756,922 is also incorporated by reference.

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula (I)

or a pharmaceutically acceptable acid addition salt thereof wherein Ar 1 and Ar2 are independently phenyl unsubstituted or substituted by halogen, -hydroxy, thiol, lower alkoxy, lower thioalkyl, lower alkanoyloxy, lower carboalkoxy, lower alkyl, nitro, amino, lower S(O) -alkyl wherein n is 0, 1, or 2, sulfonamide or trifluoromethyl? or a heteroaryl selected from 2- or 3-thienyl or 2- or 3-furanyl wherein the thienyl or furanyl is unsubstituted or substituted by lower alkyl, or halogen.

With the overall proviso that at least one of

Ar 1 or Ar2 is the -heteroaryl and both of the Ar1 and

2 Ar have no more than one substitution at once.

R ₂ ' R ₃ ', and R _ς * are each independently hydrogen, alkanoyl having two to twelve carbon atoms in a straight or branched alkyl chain which may be substituted by amino, benzoyl or benzoyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl; additionally, R-' and R ₃ ' may be nked together to form a five-membered alkylidene ring having a total of up to twenty carbons such as, for example, isopropylidene or a cyclic phosphate diester, and R _ς ' may be a phosphate, hydrogen or dihydrogen phosphate, or an alkali metal or ammonium

or dialkali or diammonium salt thereof, such as, for example, PO-Na ₂ .

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, and to a method of treating mammals by administering to such mammals a dosage form of a compound of the formula noted above and as defined above.

In the compounds of the formula I, the term "lower alkyl" is meant to include a straight or branched alkyl group having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, amyl, isoamyl, neopentyl, hexyl, and the like.

Halogen includes particularly fluorine, chlorine or bromine.

Lower alkoxy and thioalkyl are 0-alkyl or s-alkyl of from 1 to 6 carbon atoms as defined above for "lower alkyl".

Lower alkanoyloxy is a straight or branched

O II O-C-alkyl group of from 1 to 6 carbon atoms in the alkyl chain as defined above. Lower carboalkoxy is a straight or branched

O II C-O-alkyl group of from 1 to 6 carbon atoms in the alkyl chain 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 are within the scope of the invention. In practice, use of the salt form amounts to use of the base form. Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid and sulfuric acid; and

organic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving the hydrochloride, sulfamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like, respectively. (See for example, "Pharmaceutical Salts," J. Pharm. Sci. (1977) 66(1):1-19.)

The acid addition salts of said basic compounds are prepared either by dissolving the free base in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution. Generally, the compounds of formula I of the present invention are prepared by a process of Scheme I.

Scheme 1

1) CH ₃ N0 ₂ /NaOH i _/ ^ _/NO ,

2) CH ₃ S0 ₂ C1

VI 2eq. Of triethylamiηe

H-,

III II

6-chlororpurine » iboside

The process shown in Scheme 1 converts the aryl aldehyde of the formula VI to the corresponding w-nitrostyrene of the formula V. The compounds of formula V are then reacted with an aryl organo etallic of the formula IV (preferably a Grignard or a lithium derivative) in an aprotic solvent system (preferably toluene ether) at a low temperature (preferably -10° - -40°C) . The diarylnitroethane of the formula III so produced is then reduced to the corresponding diary-Lethyla ine of the formula II (preferably with LiAlH. in ether), which is then coupled with 6-chloropurine riboside as described in the previously noted patent application U.S. Serial Number 756,922. In this manner the desired compounds of formula I are produced.

The starting materials in the above described process to prepare the compounds of formula I are

generally known, commercially available or can be prepared by methods either known or analogous to those known.

Variations in the present processes known to an ordinarily skilled artisan are within the present invention.

The products of the processes may be isolated by conventional means, such as extraction, distillation, chromatography and the like. The compounds of formula I provide the most selective potent Al receptor and A2 receptor binding adenosines now found and thus possess surprising and unexpected activity. Particularly noteworthy is the greater intraperitoneal MAST activity of the present compounds. Description of the assays to obtain such data is found in U.S. Application Serial Number 756,922 incorporated by reference above.

The data is as shown in the following tables.

Table 1. Adenosine Receptor Binding

ample RBA1 RBA2 (IC ₅₀ n

1 9 22

2 11 26

3 8 14

4 3 10

5 2.5 11

6 8 15

7 7 21

10 8 7 19

9 2 9

10 11 30

11 18 53

12 13 12

15 13 13 12

14 13 30

Table 2. IP ¹ MAST Activity

Example Dose mg/kg % IMA ² % SFO ^Σ

0.3 6 0

20 1 43 0

3 66 0

3 92 0

10 93 22

0.1 10 0

25 0.3 13 0

1.0 77 0

3.0 83 11

10 85 0

30 88 0

Example Dose mg/kg % IMA % S

3 1 23 0

3 66 0

10 87 0

4 1 37 0

3 61 11

10 74 0

5 1 32 0

3 72 0

10 81 0

6 0. ,1 13 0

0. ,3 30 0

1 70 11

3 94 33

10 96 11

30 97 77

7 0. 1 32 0

0. 3 41 0

1 60 0

1 62 22

3 78 0

10 84 0

8 0. 3 36 0

1. 0 78 0

3. 0 93 11

Example Dose mg/kg % I % SFO

0.03 13 0

0.1 22 0

0.3 33 0

1.0 75 0

3.0 85 0

10 87 0

10 1 -34 0

3 28 0

10 58 0

11 0.3 -4 0

1.0 31 0

3.0 40 0

3.0 66 0

10 78 11

30 83 0

12 1 54 0

3 77 11

10 91 11

30 94 22

14 1 4 0

3 48 0

10 73 0

¹ Intraperitoneal

² Inhibition of mouse activity

³ Screen fall off (% inhibition of screen test failure)

Example 6 has an ED _5Q of 1.75. mg/kg in avoidance blockade in SIDRAT.

Table 3. AHP3 Results

Example Rating/Dose (mg/kg)

^" 5 2 C 6 3

3 C @ 10

4 A @ 10

5 A β 10

6 A % 3 ° 7 A @ 10

9 A e 10

9 C β 1 .

The testing is graded to show percent decrease 5 in mean arterial blood pressure where A is greater than 20% and C is a 10-20% decrease, in each case lasting for at least two hours.

Accordingly, the present invention also includes a pharmaceutical composition for treating psychoses, 0 sleep disorders, pain, or cardiovascular diseases comprising an antipsychotic, sedative, analgesic or cardiovascular effective amount of a compound of the formula I as defined above together with a pharmaceutically acceptable carrier. 5 The present invention further includes a method for treating psychoses, sleep disorders, pain, or cardiovascular diseases in mammals suffering therefrom comprising administering to such mammals either orally or parenterally a corresponding 0 pharmaceutical composition having a compound of the formula I as defined above in appropriate dosage form.

The compositions and methods of administration are as understood by the present state of the art, for example, as disclosed in U.S. Serial Number 756,922. The quantity of active compound in a unit dose of preparation may be varied or adjusted from 0.1 mg to 200 mg preferably to 1 to 100 mg according to the particular application and the potency of the active ingredient. The compositions can, if desired, also contain other compatible therapeutic agents.

In therapeutic use as described above, the mammalian dosage range for a 70 kg subject is from 0.1 to 150 mg/kg of body weight per day or preferably 0.1 to 10 mg/kg of body weight per day. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed.

Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage 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) denosine

The nitrostyrene (12.65 g, 33%) was prepared from 2-thiophenecarboxaldehyde (23.4 ml, .25 mole) and nitromethane (15.3 g, .25 mole) as described in Example 10 hereinafter.

The amine (0.90 g, 32%) was prepared from E,2-(thien-2-yl)nitroethene (2.16 g, .014 mole), and phenylmagnesium bromide (7.2 ml, .021 mole), followed by LiAlH. reduction (1.60 g, .042 mole) as described in Example 10 hereinafter.

The nucleoside (0.22 g, 20%) was prepared from the amine (0.47 g, .0023 mole), 6-chloropurine riboside (0.66 g, .0023 mole) and triethylamine (0.3 ml, .0025 mole) as a foam, mp 68-72 ^β C as described in Example 10 hereinafter.

EXAMPLE 2 N,6-(2-(Thien-3-yl)-2-phenethyl)adenosine

The nitrostyrene (27.2 g, 70%) was prepared from 3-thiophenecarboxaldehyde (22.0 ml, .25 mole) and nitromethane (15.3 g, .25 mole) as described in Example 10 hereinafter.

The amine (3.28 g, 29%) was prepared from E,2-(thien-3-yl)nitroethene (8.50 g, .055 mole) and phenylmagnesium bromide (28.5 ml, .0855 mole), followed by LiAlH, reduction (6.5 g, .17 mole) as described in Example 10 hereinafter.

The nucleoside (1.21 g, 37%) was prepared from the amine (1.44 g, .007 mole), 6-chloropurine riboside (2.00 g, .007 mole) and triethylamine (1.0 ml, .0077 mole) as a white foam, mp 80-100 ^β C as described in Example 10 hereinafter.

EXAMPLE 3 N,6-(2-(3-Methoxyphenyl)-2-(thien-2-γl)ethyl) adenosine The nitrostyrene (16.8 g, 77%) was prepared from 2-thiophenecarboxaldehyde (13.0 ml, .14 mole) and nitromethane (8.5 g, .14 mole) as described in Example 10 hereinafter.

The amine (1.69 g, 20%) was prepared from E,2-(thien-2-yl)nitroethene (5.64 g, .036 mole), 3-methoxybromobenzene (9.2 ml, .073 mole), magnesium (1.40 g, .058 mole), followed by LiAlH. reduction (5.46 g, .144 mole) as described in Example 10 hereinafter.

The nucleoside (0.83 g, 23%) was prepared from the amine (1.69 g, .0073 mole), 6-chloropurine riboside (1.86 g, .0065 mole), and triethylamine (0.95 ml, .0072 mole) as a solid, mp 71-80°C as described in Example 10 hereinafter.

EXAMPLE 4 N,6-(2-(3-Chlorophenγl)-2-(thien-2-yl)ethyl) adenosine The nitrostyrene (12.65 g, 33%) was prepared from 2-thiophenecarboxaldehyde (23.4 ml, .25 mole) and nitromethane (15.3 g, .25 mole) as described in Example 10 hereinafter.

The amine (1.71 g, 36%) was prepared from E,2-(thien-2-yl)nitroethene (3.1 g, .02 mole),

3-chlorobromobenzene (4.7 ml, .04 mole), magnesium (0.77 g, .032 mole), followed by LiAlH. reduction (2.30 g, .06 mole) as described in Example 10 hereinafter. The nucleoside (1.12 g, 37%) was prepared from the amine (1.47 g, .006 mole), 6-chloropurine riboside (1.72 g, .006 mole) and triethylamine (0.9 ml, .0066 mole) as a solid, mp 99-104 ^β C as described in Example 10 hereinafter.

EXAMPLE 5

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

The nitrostyrene (27.2 g, 70%) was prepared from 3-thiophenecarboxaldehyde (22.0 ml, .25 mole) and

nitromethane (15.3 g, .25 mole) as described in Example 10 hereinafter.

The amine (0.87 g, 18%) was prepared from E,2-(thien-3-γl)nitroethene (3.1 g, .02 mole), 3-chlorobromobenzene (4.7 ml, .04 mole), magnesium (0.77 g, .032 mole), followed by LiAlH. reduction (2.30 g, .06 mole) as described in Example 10 hereinafter.

The nucleoside (0.86 g, 49%) was prepared from the amine (0.87 g, .0037 mole), 6-chloropurine riboside (1.00 g, .0035 mole) and triethylamine (0.5 ml, .0039 mole) as a solid, mp 104-110 ^β C as described in Example 10 hereinafter.

EXAMPLE 6 N,6-(2,2-Dithien-2-ylethγl)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^ reduction (1.11 g, 30 mmol) as described in Example 10 hereinafter.

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 light khaki solid foam, mp 89-97 ^β C, as described in Example 10 hereinafter.

EXAMPLE 7 ,6-(2-(Thien-2-yI)-2-(thien-3-yl)ethyl)adenosine The amine (1.68 g, 32%) was prepared from

E,2-(thien-3-yl)nitroethene (3.88 g, .025 mole, see Example 2), 2-bromothiophene (5.2 ml, .05 mole), magnesium (0.96 g, .04 mole), followed by LiAlH.

reduction (2.88 g, .076 mole) as described in Example 10 hereinafter.

The nucleoside (1.34 g, 50%) was prepared from the amine (1.20 g, .0057 mole), 6-chloropurine riboside (1.63 g, .0057 mole) and triethylamine (0.8 ml, .0063 mole) as a solid, mp 94-105 ^β C as described in Example 10 hereinafter.

EXAMPLE 8 N,6-(2-(Furan-2-yl)-2-phenethγl)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 hereinafter.

The amine (2.02 g, 54%) was prepared from E,2-(furan-2-γl)nitroethene (2.78 g, .02 mole), phenylmagnesium bromide (10.3 ml, .03 mole), followed by LiAlH. reduction (2.30 g, .06 mole) as described in Example 10 hereinafter.

The nucleoside (0.22 g, 9%) was prepared from the amine (0.94 g, .005 mole), 6-chloropurine riboside (1.43 g, .005 mole) and triethylamine (0.7 ml, .0055 mole) as a beige solid, mp 74-83 ^β C as described in Example 10 hereinafter.

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)nitroethene (5.56 g, .04 mole, see Example 8), 3-chlorobromobenzene (9.4 ml, .08 mole), magnesium (1.54 g, .064 mole), followed by LiAlH. reduction (4.60 g, .12 mole) as described in Example 10 hereinafter.

The nucleoside (2.21 g, 67%) was prepared from the amine (1.58 g, .007 mole), 6-chloropurine riboside (2.01 g, .007 mole) and triethylamine (1 ml.

.0D77 mole) as a solid, mp 87-103°C as described in Example 10 hereinafter.

EXAMPLE 10 N,6-(2-(5-Methy1thien-2-y1)-2-phenethy1)adenosine

a) E,2-(5-Methylthien-2-γl)nitroethene

Aqueous sodium hydroxide (5 M, 15 ml) was added dropwise over 15 min to a solution of 5-methγlthiophene-2-carboxaldehyde (9.45 g, .075 mole) and nitromethane (4.58 g, .075 mole) in methanol (28 ml). After a further 10 min the reaction was quenched by pouring onto dilute hydrochloric acid (0.5 M, 165 ml) and extracting with ether (2x50 ml). The combined extracts were washed with water and with saturated brine and dried (MgSO.). The solvent was removed under reduced pressure and the residual oil was dissolved in CH-Cl- (120 ml) and stirred under N ₂ at 0°C. Mesyl chloride (4.9 ml, .063 mole) in CH ₂ C1 ₂ (15 ml) was added over 10 min and then triethylamine (15 ml, .11 mole) in CH ₂ C1 ₂ (15 ml) added over 20 min. After 10 min the reaction mixture was poured onto dilute hydrochloric acid (0.5 M, 135 ml). The layers were separated and the aqueous layer was extracted with CH ₂ C1 ₂ (2x25 ml). The ^" combined organic phases were washed with water, saturated brine and dried (Na ₂ SO.). The solvent was removed under reduced pressure to give the nitrostyrene (4.42 g, 35%) as a yellow solid. NMR (CDC1 ₃ ) δ 8.1 (d, IH) , 7.2-7.3 (2H, m) , 6.80 (IH, d), 2.57 (s, 3H).

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

Phenylmagnesium bromide (3 M in ether, 7 ml, .021 mole) was added dropwise to a solution of

E,-2-(5-methyl-thien-2-yl)nitroethene (3.14 g, .019 mole) in toluene (100 ml) stirred under N ₂ at -30°C. After 1 hr the reaction mixture was quenched by pouring onto dilute hydrochloric acid (0.5 M, 60 ml). The layers were separated and the aqueous layer was extracted with ether (2x25 ml). The combined organic phases were washed with water (2x25 ml, emulsions usual at this step), saturated brine (25 ml), and dried (MgS0 ₄ ). The solvent was removed under reduced pressure to give the crude diarylnitroethane (2.79 g) as an oil. This was dissolved in ether (130 ml) and added dropwise over 20 min to a suspension of LiAlH. (2.88 g, 76 mmol) in ether (325 ml) stirred under N ₂ at 25°. Vigorous gas evolution and mild exotherm! After 20 hr the reaction was quenched by cautious sequential, dropwise addition of water (3 ml), aqueous sodium hydroxide solution (10% w/v, 3 ml) and water (9 ml). Vigorous gas evolution and exotherm! The mixture was vacuum filtered, and the residue was washed with ether (100 ml). The combined filtrates were extracted with dilute hydrochloric acid (0.1 M, 2x100 ml). The aqueous layer was washed with ether (2x50 ml), made basic with NaOH pellets (1.0 g, 25 mmol) and extracted with ether (2x25 ml). The combined extracts were washed with water (2x25 ml, (frequent emulsions)), saturated brine (25 ml), and dried (MgSO.). 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=7 Hz), 3.27 (2H, d, J=7 Hz), 2.43 (3H, s), 1.40 (2H, br s).

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) were refluxed in ethanol (50 ml) under N ₂ for 48 hours. The solvent was removed under reduced pressure to give a solid foam which was purified by silica gel chromatography eluting with 6/1 of CHCl ₃ /MeOH. The solvent was removed under reduced pressure and the resulting foam was recrystallized from methanol to give the desired nucleoside as a solid, mp 107-111°C.

Calcd. for ^C 23 ^H 25 ^N 5°4 ^{S *} °* ^{15 H} 2° 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,

.075 mole) and nitromethane (4.58 g, .075 mole) as described in Example 10.

The amine (1.50 g, 19%) was prepared from E,2-(3-methylthien-2-yl)nitroethene (6.00 g, .0355 mole), and phenylmagnesium bromide (18.7 ml, .056 mole), followed by LiAlH. reduction (5.41 g, .14 mole) as described in Example 10.

The nucleoside (0.90 g, 31%) was prepared from the amine (1.50 g, .0069 g) , 6-chloropurine riboside (1.78 g, .0062 mole) and triethylamine (0.9 ml,

.0068 mole) as a solid, mp 93-100 ^β 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, .049 mole) and nitromethane (3.00 g, .049 mole) as described in

Example 10.

The amine (0.44 g, 44%) was prepared from E,2-(2-methylfuran-3-yl)nitroethene (0.77 g, .005 mole), and phenylmagnesium bromide (2.7 ml, .008 mole), followed by LiAlH ₄ reduction (0.66 g, .017 mole) as described in Example 10.

The nucleoside (0.66 g, 73%) was prepared from the amine (0.44 g, .0022 mole), 6-chloropurine riboside (0.57 g, .002 mole) and triethylamine (0.3 ml, .0022 mole) as a light brown solid, mp 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, .008 mole) and nitromethane (0.49 g, .008 mole) as described in Example 10.

The amine (.08 g, 10%) was prepared from E,2-(3-methyIfuran-2-yl)nitroethene (0.59 g, .0039 mole), and phenylmagnesium bromide (2.1 ml, .0063 mole), followed by LiAlH ₄ reduction (0.18 g, .0047 mole) as described in Example 10.

The nucleoside (0.12 g, 74%) was prepared from the amine (.08 g, .0004 mole), 6-chloropurine riboside (0.10 g, .00036 mole) and triethylamine (0.1 ml, .0008 mole) as a solid, mp 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. 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 CHC1 ₃ (25 ml) was added dropwise over 20 min to a solution of 2-thien-2-yl-2-phenethylamine (1.19 g, 6.5 mmol) in CHC1 ₃ (25 ml), stirred under N ₂ at 0 ^β C. After a further 20 min the reaction mixture was extracted with dilute hydrochloric acid (0.1 M, 2x50 ml). The aqueous layer was washed with CHC1 ₃ (2x25 ml), then made basic with NaOH pellets (1.2 g, 30 mmol), and extracted with ether (3x25 ml). The combined extracts were washed with water (2x25 ml), saturated brine (25 ml) and dried (MgSO.). The solvent was removed under reduced pressure to give the desired bromide (0.85 g, 49%) as a light 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 an off-white solid foam, mp 101-9°C as described in Example 10.