WO1988003147A1 - Selected n6-substituted adenosines having selective a2 binding activity - Google Patents
Selected n6-substituted adenosines having selective a2 binding activity Download PDFInfo
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- WO1988003147A1 WO1988003147A1 PCT/US1987/002719 US8702719W WO8803147A1 WO 1988003147 A1 WO1988003147 A1 WO 1988003147A1 US 8702719 W US8702719 W US 8702719W WO 8803147 A1 WO8803147 A1 WO 8803147A1
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- 0 CC(*1OC(C)(C)O*1CC(O)=O)([n]1c(N=CCN=C2Cl)c2nc1)OC Chemical compound CC(*1OC(C)(C)O*1CC(O)=O)([n]1c(N=CCN=C2Cl)c2nc1)OC 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
Definitions
- the compounds of the present invention are related to the N -substituted adenosines of copending application U.S. Serial Number 756,922 filed June 17, 1985 which is a continuation of U.S. Serial Number 621,943 filed June 22, 1984 now abandoned, which is a continuation in part of U.S. Serial Number 519,284 filed August 1, 1983 now abandoned.
- the instant compounds have a surprisingly greater affinity for A- receptors than A, receptors.
- the compounds have highly desirable central nervous system and cardiovascular activities, such as analgesic, antipsychotic, sedative, antihypertensive, and cardiotonic activity, especially, antianginal and vasodilator effects.
- references related to the novel process of the present invention include European Application 222330A, J. Med. Chem., Vol. 29, No. 9, pp. 1683-89 (1986) or WO8600310, and J. Med. Chem., Vol. 23, pp. 313-9 (1986) or U.S. Patent No. 3,852,268. None of these references show the preparation of a 5 ' uronamide from inosine isopropylidene of the present novel process having unexpected advantages.
- the present invention relates to a compound of the formula (I)
- X 1 , X 2 , X 3 , Y 1 , Y 2 and Y 3 may be independently selected from hydrogen, halogen, lower alkyl, lower alkylthio or alkoxy, and X 1 , X 1 , X 3 may also be trifluoromethyl with the proviso that Y 2 or Y 3 must be hydrogen except when Y 1 is hydrogen and Y 2 and Y 3 taken together are -(CH)- 4 with the further overall proviso that at least two of X 1 , X 2 , X 3 , Y 1 , Y 2 and Y 3 are not hydrogen.
- R 2 ' and R 3 ' 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 2 ' and R 3 ' may be linked together to form either 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 5 ' 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 3 Na 2 ; Z is -(CH 2 )-Q wherein Q is selected from the group consisting of hydrogen; hydroxy; halogen; cyano; azido; amino; lower alkoxy; lower acyloxy;
- L is 0-4;
- R 6 is hydrogen or when L is 0 then R 6 may also be a side chain of a naturally occurring amino acid, such as, benzyl as found in a phenylalanine ester, or isopropyl as found in a valinyl ester or
- J is O, S, NR 7 wherein R 7 is hydrogen, lower alkyl or cy ⁇ loalkyl of from 3 to 7 carbons such as cyclopropyl, cyclobutyl, cyclopentyl and the like or 1- or 2-methylcyclopropyl, 1-, or 2-ethylcyclobutyl and the like; and
- T is (a) NR 4 R 5 wherein R 4 is straight chain lower alkyl having 1-4 carbon atoms; hydroxy, lower alkoxy or halogen substituted straight chain lower alkyl having 1-4 carbon atoms cyclopropyl; secondary alkyl having 3-6 carbon atoms; hydroxy, lower alkoxy or halogen substituted secondary alkyl having 3-6 carbon atoms; alkenyl having 3 to 6 carbon atoms; aralkyl having 1 to 4 carbons in the alkyl chain and optionally substituted in the aryl nucleus with hydroxy, halogen, lower alkoxy or lower alkyl groups; and heteroarylalkyl having 1 to carbons in the alkyl chain and optionally substituted in the heteroaryl nucleus with hydroxy, halogen, lower alkoxy or lower alkyl groups, and
- R 5 is hydrogen or straight chain lower alkyl having 1 to 4 carbons; or (b) OR 4 wherein R 4 is as defined above.
- the present invention also relates to a pharmaceutical composition
- 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 I as defined above.
- the present invention is a novel process for preparing a compound of the formula
- 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 chlorine or bromine.
- Lower alkoxy and thioalkoxy are 0-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for "lower alkyl”.
- 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.
- 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.
- Preferred compounds of formula I are
- X 1 and X 3 are as defined above and Y is Y 1 when Y 1 is not hydrogen.
- the most preferred compound of the present invention is of the formula I., wherein X 1 and X 3 are methoxy and Y is methyl.
- the present invention is also novel processes for the preparation of a compound of formula I as follows:
- the compounds of formula I may be synthesized by conversion of an aryl aldehyde of formula (V)
- X 1 , X 2 and X 3 are as defined above.
- the conversion is accomplished by (1) treating with nitromethane in basic medium, i.e. in a solvent such as methanol, ethanol, or aqueous methenyl in the presence of NaOH, and (2) chlorosulfonylmethan in the presence of about two equivalents of triethylamine in an aprotic solvent such as dichloromethane.
- Y 1 , Y 2 and Y 3 are as defined above and M is a moiety preferably such that IVa is a Grignard or lithium derivative in an aprotic solvent system (preferably toluene-ether) at a low temperature (preferably from -10° to -40°C) using reaction conditions known by an ordinarily skilled artisan to be required by the Grignard or lithium derivative.
- an aprotic solvent system preferably toluene-ether
- a low temperature preferably from -10° to -40°C
- X 1 , X 2 , X 3 , Y 1 , Y 2 , and Y 3 are as defined above.
- X 1 , X 2 , X 3 , Y 1 , Y 2 and Y 3 are as defined above.
- the novel process shown above to make the uronamide portions on the compound of formula I is generally carried out by treating the compound of formula X with ethyl orthoformate and tosic acid in acetone, to give isopropylidene XI in 80-90% yields. Oxidation of XI with chromic acid in acetone gives the uronic acid XII in 53-60% yield.
- compound XIV can be generated from uronic acid XII, by amidation of the uronic acid moiety as described to give XIV followed by displacement of the C6-C1 under the same conditions as described previously.
- the compounds of formula I are now found to possess surprising and unexpected preference in binding A 2 adenosine receptors.
- the compounds of the present invention can be said to preferably bind to A 2 receptors.
- a 2 binding indicates a different mechanism of action from that previously indicated for adenosine derivatives known for common utilities.
- Such utilities in view of the novel A 2 binding preference is unexpected compared to the differing affinities for the A 1 and A 2 receptors indicated in the above cited U.S. Serial Number 756,922.
- the compounds of the present invention represent a novel mechanism of action which cannot be predicted from previously disclosed data. Further the demonstrated difference between A 2 and A 1 receptor binding is in the range of 1.5 to 35 fold. Additionally, activity in the animal tests of the present compounds exceeds that expected based on the measured A 1 receptor binding of these compounds and, therefore, is also surprising.
- the effect of the compound of Example 19 is not reversed in the MAST test by an A 1 selective antagonist unlike selected compounds of examples from SN 756,922 noted above. Also, the compound of Example 19 is now found to have a different effect on dopamine receptors from selected compounds of the examples in USSN 756,922 again as noted above.
- These compounds of formula I are active in animal tests which are predictive of neuroleptic activity for the treatment of major psychoses such as schizophrenia.
- the compounds of the invention also have sedative/hypnotic properties and as such, are useful in the treatment of pain.
- the compounds of the present invention are useful in the treatment of congestive heart failure.
- the compounds of formula I are now found to possess vasodilator properties with a marked selectivity for coronary over peripheral vasculature and a positive inotropic effect which increases blood flow useful in the treatment of angina and congestive heart failure.
- adenosine see patent application PD-3545.
- the present invention also includes a pharmaceutical composition for treating psychoses, sleep disorders, pain, or cardiovascular diseases comprising a corresponding antipsychotic, sedative, analgesic, or cardiovascular disease effective amount of a compound of the formula I as defined above with a pharmaceutically acceptable carrier.
- cardiovascular diseases means usefulness as antihypertensive agents for the treatment of high blood pressure. Also the treatment increases coronary blood flow, for example, as a vasodilator and therefore is useful in the treatment of angina and congestive heart failure as well.
- 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 pharmaceutical composition having a compound of the formula I as defined above in appropriate dosage form.
- 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 1 mg to 500 mg preferably to 5 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.
- the mammalian dosage range for a 70 kg subject is from 0.01 to 100 mg/kg of body weight per day or preferably 0.1 to 50 mg/kg of body weight per day.
- the dosages 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 with 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.
- Aqueous sodium hydroxide (2.5 M, 20 ml) was added dropwise over 15 min to a solution of 2,6-dimethylbenzaldehyde (6.7 g, 50 mmol) and nitromethane (3.1 g, 50 mmol) in methanol (25 ml) stirred under N 2 at 0°C. After a further 15 mins the reaction mixture was quenched by pouring onto dilute hydrochloric acid (0.5 M, 100 ml) and extracting with ether (3x25 ml). The combined extracts were washed with water (2x25 ml) and saturated brine (25 ml) and dried (MgSO 4 ).
- Vigorous gas evolution and mild exotherm After 3 hr the reaction was quenched by cautious, sequential, dropwise addition of water (1 ml), aqueous sodium hydroxide solution (10% w/v, 1 ml) and water (3 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 (3x25 ml).
- 2-(2,6-Dimethylphenyl)-2-(4-methylphenyl)ethylamine (0.92 g, 38%) was prepared from E,2-(2,6-dimethylphenyl) nitroethene (1.77 g, 10 mmol, see Example 1), 4-bromotoluene (2.56 g, 15 mmol) and Mg (0.36 g, 15 mmol), followed by LiAlH 4 reduction (1.11 g, 30 mmol) as described in Example 1.
- the nucleoside (1.20 g, 62%) was prepared from the amine (0.92 g, 3.8 mmol) 6-chloropurine riboside (1.11 g, 3.8 mmol) and triethylamine (0.81 g, 8 mmol) as a pale yellow solid foam, mp 113-22°C as described in Example 1.
- EXAMPLE 3 N,6-(2-(3,5-Dimethylphenyl)-2-phenethyl)adenosine
- nitrostyrene (2.25 g, 79%) was prepared from 3,5-dimethylbenzaldehyde (2.1 g, 0.16 mole) and nitromethane (0.9 g, .016 mole) as described in Example 1.
- the amine (0.57 g, 21%) was prepared from E,2-(3,5-dimethylphenyl)nitroethene (2.25 g, .012 mole), phenylmagnesium bromide (6.3 ml, .019 mole), followed by LiAlH 4 reduction (1.38 g, .036 mole) as described in Example 1.
- the nucleoside (0.62 g, 47%) was prepared from the amine (0.57 g, .0025 mole), 6-chloropurine riboside (0.66 g, .0023 mole) and triethylamine (0.3 ml, .0025 mole) as a solid, mp 94-97°C as described in Example 1.
- nitrostyrene (19.38 g, 97%) was prepared from 1-naphthaldehyde (15.62 g, 100 mmol) and nitromethane (6.1 g, 100 mmol) as described in Example 1.
- the amine (3.78 g, 59%) was prepared from E,2-naphth-1-ylnitroethene (4.88 g, 25 mmol), and phenylmagnesium bromide (27 mmol), followed by LiAlH 4 reduction (2.22 g, 60 mmol) as described in Example 1.
- the nucleoside (3.43 g, 67%) was prepared from 2-napth-l-yl-2-phenethylamine (2.56 g, 10 mmol), 6-chloropurine riboside (2.87 g, 10 mmol) and triethylamine (2.0 g, 20 mmol) as a white powder, mp 120-8°C as described in Example 1.
- the amine (1.39 g, 47%) was prepared from E,2-(3,5-dichlorophenyl)nitroethene (2.18 g, 10 mmol), 2,6-dimethylbromobenzene (2.78 g, 15 mmol) and Mg (0.36 g, 15 mmol) followed by LiAlH 4 reduction (1.11 g, 30 mmol) as described in Example 1.
- the nucleoside (2.05 g, 77%) was prepared from 2-(3,5-dichlorophenyl)-2-(2,6-dimethylphenyl) ethylamine
- nitrostyrene (10.18 g, 93.4%) was prepared from 2,6-dichlorobenzaldehyde (8.75 g, 50 mmol) and nitromethane (3.05 g, 50 mmol) as described in Example 1.
- the amine (1.95 g, 45%) was prepared from E,2-(2,6-dichlorophenyl)nitroethene (3.27 g, 15 mmol) and phenylmagnesium bromide (18 mmol) followed by LiAlH 4 reduction (2.22 g, 60 mmol) as described in Example 1.
- the nucleoside (1.55 g, 61%) was prepared from the amine (1.48 g, .0056 mole), 6-chloropurine riboside (1.40 g, .0049 mole) and triethylamine (1.4 ml, .01 mole) as a solid, mp 102-12°C as described in Example 1.
- the amine (1.09 g, 41%) was prepared from E,2-(3,5-dichlorophenyl)nitroethene (2.18 g, see Example 5) and phenylmagnesium bromide (15 mmol), followed by LiAlH 4 reduction (1.11 g, 30 mmol) as described in Example 1.
- the nucleoside (1.63 g, 77%) was prepared from 2-(3,5-dichlorophenyl)-2-phenethylamine (1.09 g, 4.1 mmol) 6-chloropurine riboside (1.08 g, 4.1 mmol) and triethylamine (0.81 g, 8 mmol) as an offwhite solid foam, mp 110-115°C as described in Example 1.
- EXAMPLE 8 N,6-(2-(3-Chlorophenyl)-2-(3,5-dichlorophenyl)ethyl)adenosine
- the amine (1.08 g, 36%) was prepared from E,2-(3,5-dichlorophenyl)nitroethene (2.18 g, 10 mmol, see Example 5) 3-bromochlorobenzene (3.83 g, 20 mmol) and Mg (0.36 g, 15 mmol), followed by LiAlH 4 reduction (1.11 g, 30 mmol) as described in Example 1.
- the nucleoside (1.53 g, 77%) was prepared from 2-(3-chlorophenyl)-2-(3,5-dichlorophenyl)ethylamine (1.08 g, 3.6 mmol), 6-chloropurine riboside (1.05 g, 3.6 mmol) and triethylamine (0.71 g, 7 mmol) as a white solid foam, mp 107-23°C as described in Example 1.
- the nitrostyrene (14.41 g, 97%) was prepared from 3,5-dimethoxybenzaldehyde (12.2 g, 73 mmol) and nitromethane (4.6 g, 75 mmol) as described in Example 1.
- the amine (0.46 g , 26%) was prepared from
- the amine (10.4 g, 59%) was prepared from E,2-(3,5-dimethox ⁇ phenyl)nitroethene (14.41 g, 68 mmol, see Example 10) and phenylmagnesium bromide (100 mmol), followed by LiAlH 4 reduction (7.77 g, 210 mmol) as described in Example 1.
- the nucleoside (17.14 g, 83%) was prepared from the amine (10.4 g, 40 mmol), 6-chloropurine riboside (11.5 g, .40 mmol), and triethylamine (8.08 g, 80 mmol) as an offwhite solid foam, mp 97-105°C as described in Example 1.
- the nitrostyrene (7.65 g, 49%) was prepared from 2,5-dimethoxybenzaldehyde (12.5 g, .075 mole) and nitromethane (4.58 g, .075 mole) as described in Example 1.
- the amine (1.04 g, 21%) was prepared from
- the nucleoside (0.29 g, 6% based on nitrostyrene) was prepared from crude 2-(2,6-dimethoxyphenyl)-2-phenethylamine (0.49 g), 6-chloropurine riboside (0.58 g, 2 mmol) and triethylamine (0.40 g, 4 mmol), as described in Example 1, except for an additional purification on preparative silica gel chromatography plates, eluting twice with 8% CH 3 OH in CHCl 3 , as a yellow brown solid foam, mp 112-21°C.
- nitrostyrene (32.5 g, 91%) was prepared from 2-methoxybenzaldeh ⁇ de (27.2 g, 0.2 mole) and nitromethane (12.2 g, 0.2 mole) as described in Example 1.
- the amine (1.81 g, 28%) was prepared from E,2-(2-methoxyphenyl)nitroethene (4.48 g, .025 mole), 3-methoxybromobenzene (6.3 ml, .05 mole), magnesium (0.97 g, .04 mole), followed by LiAlH 4 reduction (2.43 g, .064 mole) as described in Example 1.
- the nucleoside (1.20 g, 37%) was prepared from the amine (1.80 g, .007 mole), 6-chloropurine riboside (1.72 g, .006 mole) and triethylamine (0.9 ml, .0066 mole) as a beige foam, mp 103-05°C as described in Example 1.
- nitrostyrene (12.23 g, 39%) was prepared from 3,4-dimethoxybenzaldehyde (24.9 g, .15 mole) and nitromethane (9.15 g, .15 mole) as described in Example 1.
- the amine (1.18 g, 12%) was prepared from E,2-(3,4-dimethoxyphenyl)nitroethene (8.82 g, .042 mole), phenylmagnesium bromide (20.7 ml, .06 mole), followed by LiAlH 4 reduction (2.55 g, .067 mole) as described in Example 1.
- the nucleoside (1.24 g, 59%) was prepared from the amine (1.16 g, .0045 mole), 6-chloropurine riboside (1.09 g, .0038 mole) and triethylamine (0.6 mole, .0042 mole) as a solid, mp 96-104°C as described in Example 1.
- the nitrostyrene (2.73 g, 88%) was prepared from 3 , 5-diethoxybenzaldehyde ( 2. 68 g, .014 mole ) and nitromethane (0.86 g, .014 mole) as described in Example 1.
- the amine (1.25 g, 37%) was prepared from
- the nucleoside (1.62 g, 74%) was prepared from the amine (1.23 g, .004 mole), 6-chloropurine riboside (1.15 g,
- the amine (0.48 g, 14%) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (2.22 g, .011 mole, see Example 10), 1-bromonaphthalene (3.1 ml, .022 mole), and magnesium (0.43 g, .018 mole), followed by LiAlH 4 reduction (0.90 g, .024 mole) as described in Example 1.
- the nucleoside (0.22 g, 25%) was prepared from the amine (0.48 g, .0016 mole), 6-chloropurine riboside (0.40 g, .0014 mole) and triethylamine (0.2 ml, .0015 mole) as a solid, mp 114-118.5°C as described in Example 1.
- the amine (1.90 g, 67%) was prepared from E,2-(3,5-dimethoxy)nitroethene (2.09 g, 10 mmol, see Example 10), 2-bromotoluene (2.57 g, 15 mmol) and magnesium (0.36 g, 15 mmol), followed by LiAlH 4 reduction (1.11 g, 30 mmol) as described in Example 1.
- the nucleoside (2.85 g, 79%) was prepared from
- the amine (2.05 g, 71%) was prepared from
- the nucleoside (2.23 g, 79%) was prepared from
- the amine (1.70 g, 59%) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (2.09 g, 10 mmol, see Example 10), 3-bromoanisole (2.80 g, 15 mmol) and magnesium (0.48 g, 20 mmol) followed by LiAlH 4 reduction (1.11 g, 30 mmol) as described in Example 1.
- the nucleoside (2.42 g, 76%) was prepared from 2-(3,5-dimethoxyphenyl)-2-(3-methoxyphenyl)ethylamine (1.70 g, 6 mmol), 6-chloropurine riboside (1.72 g, 6 mmol) and triethylamine (1.21 g, 12 mmol) as a beige solid foam, mp 90-101°C as described in Example 1.
- the amine (0.84 g, 4%) was prepared from E,2-(3,4,5-trimethoxyphenyl)nitroethene (15.72 g, .066 mole), phenylmagnesium bromide (29.6 ml, .089 mole), followed by
- the nucleoside (1.25 g, 85%) was prepared from the amine (0.82 g, .0029 mole), 6-chloropurine riboside (0.75 g, .0026 mole), and triethylamine (0.4 ml, .0029 mole) as a solid, mp 95-99°C as described in Example 1.
- the amine (5.26 g, 46%) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (8.36 g, .04 mole, see Example 10), 2-methoxybromobenzene (10.2 ml, .08 mole), and magnesium (1.57 g, .064 mole), followed by LiAlH 4 reduction (5.98 g, .16 mole) as described in Example 1.
- the nucleoside (5.15 g, 90%) was prepared from the amine (3.16 g, .011 mole), 6-chloropurine riboside (2.86 g, .01 mole) and triethylamine (1.4 ml, .011 mole) as a solid, mp 93-97°C a described in Example 1.
- the amine (0.70 g, 9%) was prepared from E,2-(3,4,5-trimethoxyphenyl)nitroethene (5.98 g, .025 mole, se Example 22), 2-methoxybromobenzene (6.4 ml, .05 mole), magnesium (0.97 g, .04 mole), followed by LiAlH 4 reduction (2.43 g, .064 mole) as described in Example 1.
- the nucleoside (0.67 g, 54%) was prepared from the amine (0.70 g, .0022 mole), 6-chloropurine riboside (0.57 g, .002 mole), and triethylamine (0.3 ml, .0022 mole) as a grey foam, mp 99-104°C as described in Example 1.
- nitrostyrene (5.48 g, 87%) was prepared from 3,5-bis(trifluoromethyl)benzaldehyde (5.77 g, 22 mmol) and nitromethane (2.69 g, 44 mmol) as described in Example 1.
- the amine (0.76 g, 42%) was prepared from E,2-(3,5-bis(trifluoromethyl)phenyl)nitroethene (1.43 g, 5 mmol), 2-bromoanisole (1.39 g, 7.5 mmol), and magnesium (0.18 g, 7.5 mmol) followed by LiAlH 4 reduction (0.55 g, 15 mmol) as described in Example 1.
- the nucleoside (0.97 g, 75%) was prepared from 2-(2-methoxyphenyl)-2-(3,5-bis(trifluoromethyl) phenyl)ethylamine (0.76 g, 2.1 mmol), 6-chloropurine riboside (0.61 g, 2.1 mmol), and triethylamine (0.40 g, 4 mmol) as a white solid foam, mp 105-12°C as described in Example 1.
- the amine (0.92 g, 27%) was prepared from E,2-(3,5-bis(trifluoromethyl)phen ⁇ l)nitroethene (2.85 g, 10 mmol, see Example 27) and phenylmagnesium bromide (15 mmol) followed by LiAlH 4 reduction (1.11 g, 30 mmol) as described in Example 1.
- the nucleoside (1.20 g, 75%) was prepared from 2-(3,5-bis(trifluoromethyl)phenyl)-2-phenethylamine (0.92 g, 2.7 mmol), 6-chloropurine riboside (0.80 g, 2.7 mmol) and triethylamine (0.60 g, 6 mmol) as a pale yellow solid foam, mp 99-105°C as described in Example 1.
- the nucleoside (3.53 g, 90%) was prepared from ( -)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (2.02 g, 7.45 mmol), 6-chloropurine riboside (2.16 g, 7.5 mmol) and NEt 3 (1.51 g, 15 mmol) in ethanol (70 ml) at reflux stirred under N 2 for 18 hours. On cooling the desired nucleoside crystallized out (3.53 g, 90%) as white microscopic needles, mp 195-197°C. Rotation ⁇ 3 (DMSO) -78.1°. Diastereoisomeric excess > 90%.
- EXAMPLE 30 N 6 -((+)-2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethyl) adenosine
- the nucleoside was prepared from (+)-2-(3,5-dimethoxy- phenyl)-2-(2-methylphenyl)ethylamine (2.03 g, 7.5 mmol) 6-chloropurine riboside (2.16 g, 7.5 mmol) and NEt 3 (1.51 g, 15 mmol) in ethanol at reflux stirring under N 2 for 18 hours. The solvent was removed under reduced pressure, the residue added to water (50 ml) and extracted with ethyl acetate (2x25 ml). The combined organic phases were washed with water (25 ml), saturated brine (25 ml), and dried (MgSO 4 ).
- 6-Chloropurine riboside-2',3'-di-o-isoprop ⁇ lidene Triethyl orthoformate (59.2 g, 0.4 mol) was added to a suspension of 6-chloropurine riboside (28.75 g, 0.10 mol) and tosic acid monohydrate (18 g, 0.095 mol) in acetone (1 L) stirred under N 2 at 25°. After 3 hours the now clear solution was concentrated under reduced pressure, and the residue was poured onto K 2 HPO 4 solution (26.1 g in 800 ml) and extracted with ethyl acetate (2x200 ml).
- N 6 -(2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethyl) adenosine-2',3'-di-o-isopropylidene-5'-uronic acid (1.50 g, 2.6 mmol) was stirred in aqueous TFA (10 ml, 1:9) under N 2 at 0°C for 4 hours.
- Triethylamine (0.61 g, 6 mmol) and methylamine hydrochloride (0.27 g, 4 mmol) were added sequentially 1 minute apart to a suspension of N-methyl-2-fluoropyridinium tosylate (0.42 g, 1.5 mmol) and N 6 -(2-(3,5-dimethoxyphenyl)-2-(2-methyl- phenyl)ethyl)adenosine-2',3'-di-o-isopropylidene-5'-uronic acid (Example 32, 0.58 g, 1 mmol) in CH 2 Cl 2 (5 ml) stirred under N 2 at 0°C.
- Triethylamine (0.20 g, 2 mmol) and cyclopropylamine (0.11 g, 2 mmol) were added sequentially 2 minutes apart to a mixture of N-methyl-2-fluoropyridinium tosylate (0.42 g,
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- Saccharide Compounds (AREA)
Abstract
Adenosines of formula (I), wherein Ar is (II), (III) or (IV), wherein A is oxygen or sulfur. The adenosines have highly selective A2 receptor binding activity and useful properties advantageous in treating cardiovascular diseases, such as hypertension, angina or myocardial ischemia, pain, insomnia and psychosis. Also a novel preparation of selected adenosines.
Description
SELECTED N6-SUBSTITUTED ADENOSINES HAVING SELECTIVE A2 BINDING ACTIVITY
This is a continuation-in-part of US Application Serial Number 925,185 filed October 31, 1986.
BACKGROUND OF THE INVENTION
The compounds of the present invention are related to the N -substituted adenosines of copending application U.S. Serial Number 756,922 filed June 17, 1985 which is a continuation of U.S. Serial Number 621,943 filed June 22, 1984 now abandoned, which is a continuation in part of U.S. Serial Number 519,284 filed August 1, 1983 now abandoned. The instant compounds have a surprisingly greater affinity for A- receptors than A, receptors. The compounds have highly desirable central nervous system and cardiovascular activities, such as analgesic, antipsychotic, sedative, antihypertensive, and cardiotonic activity, especially, antianginal and vasodilator effects.
Thus, the above noted copending application and references therein provide a background for the present invention including descriptions of literature assays in which the compounds of the present invention have been found to possess activity as described herein. Therefore, copending application U.S. Serial Number 756,922 is incorporated by reference.
References related to the novel process of the present invention include European Application 222330A, J. Med. Chem., Vol. 29, No. 9, pp. 1683-89 (1986) or WO8600310, and J. Med. Chem., Vol. 23, pp. 313-9 (1986) or U.S. Patent No. 3,852,268. None of these references show the preparation of a 5 ' uronamide from inosine isopropylidene of the present novel process having unexpected advantages.
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 is
wherein X1, X2, X3, Y1, Y2 and Y3 may be independently selected from hydrogen, halogen, lower alkyl, lower alkylthio or alkoxy, and X1, X1, X3 may also be trifluoromethyl with the proviso that Y2 or Y3 must be hydrogen except when Y1 is hydrogen and
Y2 and Y3 taken together are -(CH)-4 with the further overall proviso that at least two of X1, X2, X3, Y1, Y2 and Y3 are not hydrogen.
R2' and R3' 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, R2' and R3' may be linked together to form either a five-membered alkylidene ring having a total of up to twenty carbons such as, for example, isopropylidene, or a cyclic phosphate diester and R5' may be a phosphate, hydrogen or dihydrogen phosphate, or an alkali metal or ammonium or dialkali or diammonium salt thereof, such as, for example, PO3Na2; Z is -(CH2)-Q wherein Q is selected from the group consisting of hydrogen; hydroxy; halogen; cyano; azido; amino; lower alkoxy; lower acyloxy; lower thioalkyl; lower sulfonylalkyl;
wherein L is 0-4; and
R6 is hydrogen or when L is 0 then R6 may also be a side chain of a naturally occurring amino acid, such as, benzyl as found in a phenylalanine ester, or isopropyl as found in a valinyl ester or
wherein k is 0-4;
-P(=Y)(OR")2, -P(=Y) (OR") (OR"') and taken together with R3 is
wherein Y is oxygen or sulfur and R" and R"' are independently hydrogen or lower alkyl; or (2)
wherein J is O, S, NR7 wherein R7 is hydrogen, lower alkyl or cyσloalkyl of from 3 to 7 carbons such as cyclopropyl, cyclobutyl, cyclopentyl and the like or 1- or 2-methylcyclopropyl, 1-, or 2-ethylcyclobutyl and the like; and
T is (a) NR4R5 wherein R4 is straight chain lower alkyl having 1-4 carbon atoms; hydroxy, lower alkoxy or halogen substituted straight chain lower alkyl having 1-4 carbon atoms cyclopropyl; secondary alkyl having 3-6 carbon atoms; hydroxy, lower alkoxy or halogen substituted secondary alkyl having 3-6 carbon atoms; alkenyl having 3 to 6 carbon atoms; aralkyl having 1 to 4 carbons in the alkyl chain and optionally substituted in the aryl nucleus with hydroxy, halogen, lower alkoxy or lower alkyl groups; and heteroarylalkyl having 1 to carbons in the alkyl chain and optionally substituted in the
heteroaryl nucleus with hydroxy, halogen, lower alkoxy or lower alkyl groups, and
R5 is hydrogen or straight chain lower alkyl having 1 to 4 carbons; or (b) OR4 wherein R4 is as defined above.
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 I as defined above.
Finally, the present invention is a novel process for preparing a compound of the formula
In the compounds of t xhe 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 chlorine or bromine. Lower alkoxy and thioalkoxy are 0-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for "lower alkyl".
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. Preferred compounds of formula I are
wherein X1 and X3 are as defined above and Y is Y1 when Y1 is not hydrogen.
Another group of preferred compounds of formula I is
The most preferred compound of the present invention is of the formula I., wherein X1 and X3 are methoxy and Y is methyl.
The present invention is also novel processes for the preparation of a compound of formula I as follows:
Generally, the compounds of formula I may be synthesized by conversion of an aryl aldehyde of formula (V)
V
wherein X1, X2 and X3 are as defined above; to the corresponding w-nitrostyrene of the formula (IV)
IV
wherein X1, X2 and X3 are as defined above. The conversion is accomplished by (1) treating with nitromethane in basic medium, i.e. in a solvent such as methanol, ethanol, or aqueous methenyl in the presence of NaOH, and (2) chlorosulfonylmethan in the presence of about two equivalents of triethylamine in an aprotic solvent such as dichloromethane.
The w-nitrostyrene of the formula IV is then treated with an organometallic compound of the formula IVa
IV
wherein Y1, Y2 and Y3 are as defined above and M is a moiety preferably such that IVa is a Grignard or lithium derivative in an aprotic solvent system (preferably toluene-ether) at a low temperature (preferably from -10° to -40°C) using reaction conditions known by an ordinarily skilled artisan to be required by the Grignard or lithium derivative. Treatment with the organometallic compound gives a compound of formula (III)
wherein X1, X2, X3, Y1, Y2, and Y3 are as defined above.
The compound of formula III is then reduced by treatment with, for example, lithium aluminum hydride using conditions within the skill of an ordinarily skilled artisan to give a compound of the formula (II)
II
wherein X1, X2, X3, Y1, Y2 and Y3 are as defined above.
Finally, the compound of formula II is coupled with 6-chloropurine riboside in the presence of triethylamine according to the procedure as described in application U.S. Serial Number 756,922 to obtain a compound of formula I as defined above.
The above described process can be shown as follows:
Although the N6 sidechain is made as described above, a particularly preferred novel process to make the uronamide portion of the molecule of the compound I is also the present invention. It is shown as follows:
The novel process shown above to make the uronamide portions on the compound of formula I is generally carried out by treating the compound of formula X with ethyl orthoformate and tosic acid in acetone, to give isopropylidene XI in 80-90% yields. Oxidation of XI with chromic acid in acetone gives the uronic acid XII in 53-60% yield. This can be converted to acid XIII in 80% yield by treatment with an appropriate 2,2-diarylethylamine and triethylamine in ethanol, and then amidated with an appropriate primary amine and a condensing agent such as dicyclohexylcarbodiimide/1-hydroxybenzotriazole or N-methyl-2-fluoropyridinium tosylate/triethylamine, to give the protected nucleoside XIV, which on acid hydrolysis, preferably with aqueous TFA at 0°C gives the desired nucleoside XV. Alternatively compound XIV can be generated from uronic acid XII, by amidation of the uronic acid moiety as described to give XIV followed by displacement of the C6-C1 under the same conditions as described previously.
Although this process is related to those previously claimed in World Appl. 8600310 following the procedure of J. Med. Chem., Vol. 23, pp. 313-9 (1986) it has several distinct advantages. In the present process the isopropylidenation of inosine is physically awkward whereas the X to XI transformation is operationally very simple. Furthermore the oxidation of inosine isopropylidene to the corresponding uronic acid according to previously known processes is also tedious, and in our hands never gave the claimed yields (=65%) but consistently lower yields (20-25%). The conversion of XI to XII was found to be reproducible in 50-60% yield, and the entire reaction can be carried out in 2-4 hours, a major savings in time. We were unsuccessful in several attempts to convert inosine isopropylidene-5'-uronic acid into intermediate XIV, under conditions claimed previously, whereas our procedures reproducibly allowed for XV (or XIV) to be produced from the corresponding uronic acids in 60-95% yields. Therefore, the present process unexpectedly provides a process overall operationally much simpler than previously claimed processes, and that the complete process X to XV can be carried
out on a laboratory scale in 20-30% overall yield in 3 working days.
The starting materials in the above described processes to prepare the compounds of the formula I are generally known, commercially available or can be prepared by methods either known or analogous to those known.
Variations in the processes of the present invention are within the skill of an ordinary artisan. The products of the processes are isolated by conventional means such as extraction, distillation, chromatography and the like.
The compounds of formula I are now found to possess surprising and unexpected preference in binding A2 adenosine receptors.
By molecular modeling the compounds of the present invention can be said to preferably bind to A2 receptors. Such A2 binding indicates a different mechanism of action from that previously indicated for adenosine derivatives known for common utilities. Such utilities in view of the novel A2 binding preference is unexpected compared to the differing affinities for the A1 and A2 receptors indicated in the above cited U.S. Serial Number 756,922. Thus, the compounds of the present invention represent a novel mechanism of action which cannot be predicted from previously disclosed data. Further the demonstrated difference between A2 and A1 receptor binding is in the range of 1.5 to 35 fold. Additionally, activity in the animal tests of the present compounds exceeds that expected based on the measured A1 receptor binding of these compounds and, therefore, is also surprising. Further among the present compounds, the effect of the compound of Example 19 is not reversed in the MAST test by an A1 selective antagonist unlike selected compounds of examples from SN 756,922 noted above. Also, the compound of Example 19 is now found to have a different effect on dopamine receptors from selected compounds of the examples in USSN 756,922 again as noted above. These compounds of formula I are active in animal tests which are predictive of neuroleptic activity for the treatment of major psychoses such as schizophrenia. The compounds of the
invention also have sedative/hypnotic properties and as such, are useful in the treatment of pain.
Additionally, the compounds of the present invention are useful in the treatment of congestive heart failure. Particularly, the compounds of formula I are now found to possess vasodilator properties with a marked selectivity for coronary over peripheral vasculature and a positive inotropic effect which increases blood flow useful in the treatment of angina and congestive heart failure. For a similar effect with an adenosine see patent application PD-3545.
The biological data from assays corresponding to those described in U.S. Serial Number 756,922 for the compounds in the present invention are summarized in the following tables for the noted examples described hereinafter. Accordingly, the present invention also includes a pharmaceutical composition for treating psychoses, sleep disorders, pain, or cardiovascular diseases comprising a corresponding antipsychotic, sedative, analgesic, or cardiovascular disease effective amount of a compound of the formula I as defined above with a pharmaceutically acceptable carrier.
Treatment of cardiovascular diseases means usefulness as antihypertensive agents for the treatment of high blood pressure. Also the treatment increases coronary blood flow, for example, as a vasodilator and therefore is useful in the treatment of angina and congestive heart failure as well.
1Intraperitoneal
2Inhibition of mouse activity 3 Screen fall off (% inhibition of screen test failure)
Accordingly, 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 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 1 mg to 500 mg preferably to 5 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 0.01 to 100 mg/kg of body weight per day or preferably 0.1 to 50 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 with 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-(2,6-Dimethylphenyl)-2-phenylethyl)adenosine
a) E,2-(2,6-Dimethylphenyl)nitroethene
Aqueous sodium hydroxide (2.5 M, 20 ml) was added dropwise over 15 min to a solution of 2,6-dimethylbenzaldehyde (6.7 g, 50 mmol) and nitromethane (3.1 g, 50 mmol) in methanol (25 ml) stirred under N2 at 0°C. After a further 15 mins the reaction mixture was quenched by pouring onto dilute hydrochloric acid (0.5 M, 100 ml) and extracting with ether (3x25 ml). The combined extracts were washed with water (2x25 ml) and saturated brine (25 ml) and dried (MgSO4). The solvent was removed under reduced pressure and the residual yellow oil was dissolved in CH2Cl2 (150 ml) and stirred under N2 at 0°C. Mesyl chloride (5.7 g, 50 mmol) in CH2Cl2 (25 ml) and then triethylamine (10.1 g, 100 mmol) in CH2Cl2 (25 ml) were added sequentially to the solution. After 1.5 hr the reaction
mixture was poured onto dilute hydrochloric acid (0.5 M, 200 ml). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (50 ml). The combined organic phases were washed with water (2x50 ml), saturated brine (50 ml), and dried (MgSO4). The solvent was removed under reduced pressure to give the nitrostyrene (8.33 g, 96%) as a light brown oil. Nmr (CDCl3) δ 8.22 (1H, d, J=14 Hz), 6.9-7.4 (4H, m), 2.41 (6H s).
b) 2-(2,6-Dimethylphenyl)-2-phenylethylamine Phenylmagnesium bromide (2.9 M in ether, 5 ml, 14.5 mmol) was added dropwise over 10 min to a solution of E,2-(2,6-dimethylphenyl)nitroethene (1.77 g, 10 mmol) in toluene (50 ml) stirred under N2 at -30°. The solution reddened, and after a further 15 min at -30° the reaction was quenched by addition of dilute hydrochloric acid (0.4 M,
50 ml). The layers were separated, and the aqueous layer was extracted with toluene (25 ml). The combined organic phases were washed with water (25 ml, emulsions usual at this step), saturated brine (25 ml), and dried (MgSO4). The solvent was removed under reduced pressure to give the crude diarylnitroethane (2.05 g) as a yellow oil. This was dissolved in ether (25 ml) and added dropwise over 20 min to a suspension of LiAlH4 (1.11 g, 30 mmol) in ether (100 ml), stirred under N2 at 25°. Vigorous gas evolution and mild exotherm; After 3 hr the reaction was quenched by cautious, sequential, dropwise addition of water (1 ml), aqueous sodium hydroxide solution (10% w/v, 1 ml) and water (3 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 (3x25 ml). The combined extracts were washed with water (2x25 ml , ( frequent emulsions ) ) , saturated brine ( 25 ml ) , and dried (MgSO4). The solvent was removed under reduced pressure to give the desired amine (1.00 g, 44%) as a pale yellow oil.
Nmr (CDCl3) δ 7.1-7.3 (5H, m), 6.9-7.1 (3H, m), 4.56 (1H, d of d, J=6,8 Hz), 3.61-3.35 (2H, ABq of ds, JAB = 12.5 Hz, Jd=6,8 Hz), 2.18 (6H, s), 1.16 (2H, br s).
c) N,6-(2-(2,6-Dimethylphenyl)-2-phenethyl)adenosine 6-Chloropurine riboside (1.28 g, 4.4 mmol),
2-(2,6-dimethylphenyl)-2-phenylethylamine (1.00 g, 4.4 mmol) and triethylamine (0.89 g, 8.8 mmol) were refluxed in ethanol (40 ml) under N2 with stirring for 15 h. The solvent was removed under reduced pressure to give a pale brown solid foam, which was added to ethyl acetate (50 ml), washed with water (2x25 ml, emulsion!), saturated brine (25 ml), and dried (MgSO4). The solvent was removed under reduced pressure, and the residual solid foam was purified by silica gel chromatography eluting with 5% CH3OH in CHCl3. The solvent was removed under reduced pressure to give the desired nucleoside (1.44 g, 67%) as an offwhite solid foam, mp 112-124°C. Calcd. for C26H29N5O4 . 0.13 CHCl3
C, 63.91; H, 5.93; N, 14.27; Cl, 2.82 Found C, 63.42; H, 6.05; N, 14.26; Cl, 2.83.
EXAMPLE 2
N,6-(2-(2,6-Dimethylphenyl)-2-(4-methylphenyl)ethyl)adenosine
2-(2,6-Dimethylphenyl)-2-(4-methylphenyl)ethylamine (0.92 g, 38%) was prepared from E,2-(2,6-dimethylphenyl) nitroethene (1.77 g, 10 mmol, see Example 1), 4-bromotoluene (2.56 g, 15 mmol) and Mg (0.36 g, 15 mmol), followed by LiAlH4 reduction (1.11 g, 30 mmol) as described in Example 1.
The nucleoside (1.20 g, 62%) was prepared from the amine (0.92 g, 3.8 mmol) 6-chloropurine riboside (1.11 g, 3.8 mmol) and triethylamine (0.81 g, 8 mmol) as a pale yellow solid foam, mp 113-22°C as described in Example 1.
EXAMPLE 3 N,6-(2-(3,5-Dimethylphenyl)-2-phenethyl)adenosine
The nitrostyrene (2.25 g, 79%) was prepared from 3,5-dimethylbenzaldehyde (2.1 g, 0.16 mole) and nitromethane (0.9 g, .016 mole) as described in Example 1.
The amine (0.57 g, 21%) was prepared from E,2-(3,5-dimethylphenyl)nitroethene (2.25 g, .012 mole), phenylmagnesium bromide (6.3 ml, .019 mole), followed by LiAlH4 reduction (1.38 g, .036 mole) as described in Example 1. The nucleoside (0.62 g, 47%) was prepared from the amine (0.57 g, .0025 mole), 6-chloropurine riboside (0.66 g, .0023 mole) and triethylamine (0.3 ml, .0025 mole) as a solid, mp 94-97°C as described in Example 1.
EXAMPLE 4 N,6-(2-Naphth-l-yl-2-phenethyl)adenosine
The nitrostyrene (19.38 g, 97%) was prepared from 1-naphthaldehyde (15.62 g, 100 mmol) and nitromethane (6.1 g, 100 mmol) as described in Example 1.
The amine (3.78 g, 59%) was prepared from E,2-naphth-1-ylnitroethene (4.88 g, 25 mmol), and phenylmagnesium bromide (27 mmol), followed by LiAlH4 reduction (2.22 g, 60 mmol) as described in Example 1.
The nucleoside (3.43 g, 67%) was prepared from 2-napth-l-yl-2-phenethylamine (2.56 g, 10 mmol), 6-chloropurine riboside (2.87 g, 10 mmol) and triethylamine (2.0 g, 20 mmol) as a white powder, mp 120-8°C as described in Example 1.
EXAMPLE 5 N,6-(2-(3,5-Dichlorophenyl)-2-(2,6-dimethylphenyl)ethyl) adenosine The nitrostyrene (8.48 g, 97%) was prepared from
3,5-dichlorobenzaldehyde (7.00 g, 40 mmol) and nitromethane (2.44 g, 40 mmol) as described in Example 1.
The amine (1.39 g, 47%) was prepared from E,2-(3,5-dichlorophenyl)nitroethene (2.18 g, 10 mmol),
2,6-dimethylbromobenzene (2.78 g, 15 mmol) and Mg (0.36 g, 15 mmol) followed by LiAlH4 reduction (1.11 g, 30 mmol) as described in Example 1.
The nucleoside (2.05 g, 77%) was prepared from 2-(3,5-dichlorophenyl)-2-(2,6-dimethylphenyl) ethylamine
(1.39 g, 4.7 mmol), 6-chloropurine riboside (1.35 g, 4.7 mmol) and triethylamine (0.95 g, 9.4 mmol) as a white solid foam, mp 125-35°C as described in Example 1.
EXAMPLE 6 N,6-(2-(2,6-Dichlorophenyl)-2-phenethyl)adenosine
The nitrostyrene (10.18 g, 93.4%) was prepared from 2,6-dichlorobenzaldehyde (8.75 g, 50 mmol) and nitromethane (3.05 g, 50 mmol) as described in Example 1.
The amine (1.95 g, 45%) was prepared from E,2-(2,6-dichlorophenyl)nitroethene (3.27 g, 15 mmol) and phenylmagnesium bromide (18 mmol) followed by LiAlH4 reduction (2.22 g, 60 mmol) as described in Example 1.
The nucleoside (1.55 g, 61%) was prepared from the amine (1.48 g, .0056 mole), 6-chloropurine riboside (1.40 g, .0049 mole) and triethylamine (1.4 ml, .01 mole) as a solid, mp 102-12°C as described in Example 1.
EXAMPLE 7 N,6-(2-(3,5-Dichlorophenyl)-2-phenethyl)adenosine
The amine (1.09 g, 41%) was prepared from E,2-(3,5-dichlorophenyl)nitroethene (2.18 g, see Example 5) and phenylmagnesium bromide (15 mmol), followed by LiAlH4 reduction (1.11 g, 30 mmol) as described in Example 1.
The nucleoside (1.63 g, 77%) was prepared from 2-(3,5-dichlorophenyl)-2-phenethylamine (1.09 g, 4.1 mmol) 6-chloropurine riboside (1.08 g, 4.1 mmol) and triethylamine (0.81 g, 8 mmol) as an offwhite solid foam, mp 110-115°C as described in Example 1.
EXAMPLE 8 N,6-(2-(3-Chlorophenyl)-2-(3,5-dichlorophenyl)ethyl)adenosine
The amine (1.08 g, 36%) was prepared from E,2-(3,5-dichlorophenyl)nitroethene (2.18 g, 10 mmol, see Example 5) 3-bromochlorobenzene (3.83 g, 20 mmol) and Mg (0.36 g, 15 mmol), followed by LiAlH4 reduction (1.11 g, 30 mmol) as described in Example 1.
The nucleoside (1.53 g, 77%) was prepared from 2-(3-chlorophenyl)-2-(3,5-dichlorophenyl)ethylamine (1.08 g, 3.6 mmol), 6-chloropurine riboside (1.05 g, 3.6 mmol) and triethylamine (0.71 g, 7 mmol) as a white solid foam, mp 107-23°C as described in Example 1.
EXAMPLE 9 N,6-(2-(3-Chlorophenyl)-2-(2,6-dichlorophenyl)ethyl)adenosine The amine (1.21 g, 40%) was prepared from
E,2-(2,6-dichlorophenyl)nitroethene (2.18 g, 10 mmol, see Example 6), 3-bromochlorobenzene (3.83 g, 20 mmol) and Mg (0.36 g, 15 mmol) followed by LiAlH4 reduction (1.11 g, 30 mmol) as described in Example 1. The nucleoside (0.84 g, 38%) was prepared from
2-(3-chlorophenyl)-2-(2,6-dichlorophenyl)ethylamine (1.21 g, 4 mmol), 6-chloropurine riboside (1.15 g, 4 mmol) and triethylamine (0.81 g, 8 mmol) as a pale yellow solid foam, mp 113-25°C as described in Example 1.
EXAMPLE 10
N,6-(2-(3-Chlorophenyl)-2-(3,5-dimethoxyphenyl)ethyl)adenosine
The nitrostyrene (14.41 g, 97%) was prepared from 3,5-dimethoxybenzaldehyde (12.2 g, 73 mmol) and nitromethane (4.6 g, 75 mmol) as described in Example 1. The amine (0.46 g , 26%) was prepared from
E,2-(3,5-dimethoxyphenyl)nitroethene (1.25 g, .006 mole), 3-chlorobromobenzene (2.9 ml, .025 mole), magnesium (0.48 g, .02 mole), followed by LiAlH4 reduction (1.40 g, .037 mole) as described in Example 1.
The nucleoside (0.36 g, 44%) was prepared from the amine (0.40 g, .0014 mole), 6-chloropurine riboside (0.40 g, .0014 mole) and triethylamine (0.2 ml, .0015 mole) as an offwhite solid, mp 81-86°C as described in Example 1.
EXAMPLE 11 N,6-(2-(3,5-Dimethoxyphenyl)-2-phenethyl)adenosine
The amine (10.4 g, 59%) was prepared from E,2-(3,5-dimethoxγphenyl)nitroethene (14.41 g, 68 mmol, see Example 10) and phenylmagnesium bromide (100 mmol), followed by LiAlH4 reduction (7.77 g, 210 mmol) as described in Example 1.
The nucleoside (17.14 g, 83%) was prepared from the amine (10.4 g, 40 mmol), 6-chloropurine riboside (11.5 g, .40 mmol), and triethylamine (8.08 g, 80 mmol) as an offwhite solid foam, mp 97-105°C as described in Example 1.
EXAMPLE 12
N,6-(2-(2,5-Dimethoxyphenyl)-2-phenethyl)adenosine
The nitrostyrene (7.65 g, 49%) was prepared from 2,5-dimethoxybenzaldehyde (12.5 g, .075 mole) and nitromethane (4.58 g, .075 mole) as described in Example 1. The amine (1.04 g, 21%) was prepared from
E,2-(2,5-dimethoxyphenyl)nitroethene (7.0 g, .033 mole), phenylmagnesium bromide (15.8 ml, .047 mole), followed by LiAlH4 reduction (2.90 g, .076 mole) as described in Example 1. The nucleoside (0.43 g, 23%) was prepared from the amine (1.04 g, .004 mole), 6-chloropurine riboside (1.03 g,
.0036 mole) and triethylamine (0.5 ml, .004 mole) as a solid, mp 96-100°C as described in Example 1.
EXAMPLE 13 N,6-(2-(2,6-Dimethoxyphenyl)-2-phenethyl)adenosine The nitrostyrene (6.87 g, 82%) was prepared from
2,6-dimethoxybenzaldehyde (6.5 g, 37 mmol) and nitromethane (2.29 g, 37 mmol) as described in Example 1.
The amine (0.49 g) was prepared in very impure form from E,2-(2,6-dimethoxγphenyl)nitroethene (2.09 g, 10 mmol) and phenyl lithium (15 mmol in ether/cyclohexane), followed by LiAlH4 (1.11 g, 30 mmol) as described in Example 1. The nucleoside (0.29 g, 6% based on nitrostyrene) was prepared from crude 2-(2,6-dimethoxyphenyl)-2-phenethylamine (0.49 g), 6-chloropurine riboside (0.58 g, 2 mmol) and triethylamine (0.40 g, 4 mmol), as described in Example 1, except for an additional purification on preparative silica gel chromatography plates, eluting twice with 8% CH3OH in CHCl3, as a yellow brown solid foam, mp 112-21°C.
EXAMPLE 14 N,6-(2-(2-Methoxyphenyl)-2-(3-methoxyphenyl)ethyl)adenosine
The nitrostyrene (32.5 g, 91%) was prepared from 2-methoxybenzaldehγde (27.2 g, 0.2 mole) and nitromethane (12.2 g, 0.2 mole) as described in Example 1.
The amine (1.81 g, 28%) was prepared from E,2-(2-methoxyphenyl)nitroethene (4.48 g, .025 mole), 3-methoxybromobenzene (6.3 ml, .05 mole), magnesium (0.97 g, .04 mole), followed by LiAlH4 reduction (2.43 g, .064 mole) as described in Example 1.
The nucleoside (1.20 g, 37%) was prepared from the amine (1.80 g, .007 mole), 6-chloropurine riboside (1.72 g, .006 mole) and triethylamine (0.9 ml, .0066 mole) as a beige foam, mp 103-05°C as described in Example 1.
EXAMPLE 15 N,6-(2-(3,4-Dimethoxyphenyl)-2-phenethyl)adenosine
The nitrostyrene (12.23 g, 39%) was prepared from 3,4-dimethoxybenzaldehyde (24.9 g, .15 mole) and nitromethane (9.15 g, .15 mole) as described in Example 1.
The amine (1.18 g, 12%) was prepared from E,2-(3,4-dimethoxyphenyl)nitroethene (8.82 g, .042 mole), phenylmagnesium bromide (20.7 ml, .06 mole), followed by LiAlH4 reduction (2.55 g, .067 mole) as described in Example 1.
The nucleoside (1.24 g, 59%) was prepared from the amine (1.16 g, .0045 mole), 6-chloropurine riboside (1.09 g, .0038 mole) and triethylamine (0.6 mole, .0042 mole) as a solid, mp 96-104°C as described in Example 1.
EXAMPLE 16
N,6-(2-(3,5-Diethoxyphenyl)-2-phenethyl)adenosine
The nitrostyrene (2.73 g, 88%) was prepared from 3 , 5-diethoxybenzaldehyde ( 2. 68 g, .014 mole ) and nitromethane (0.86 g, .014 mole) as described in Example 1. The amine (1.25 g, 37%) was prepared from
E,2-(3,5-diethoxyphenyl)nitroethene (2.73 g, .012 mole), phenylmagnesium bromide (6.3 ml, .019 mole), followed by LiAlH4 reduction (1.17 g, .031 mole) as described in Example 1.
The nucleoside (1.62 g, 74%) was prepared from the amine (1.23 g, .004 mole), 6-chloropurine riboside (1.15 g,
.004 mole) and triethylamine (0.6 ml, .0044 mole) as a white foam, mp 88-93°C as described in Example 1.
EXAMPLE 17 N,6-(2-(3,5-Dimethoxyphenyl)-2-thien-2-yl)ethyl)adenosine The amine (1.60 g, 27%) was prepared from
E,2-(3,5-dimethoxyphenyl)nitroethene (5.23 g, .025 mole, see Example 10), 2-bromothiophene (5.2 ml, .05 mole) and magnesium (0.96 g, .04 mole), followed by LiAlH4 reduction (3.80 g, .10 mole) as described in Example 1. The nucleoside (1.61 g, 59%) was prepared from the amine (1.38 g, .0052 mole), 6-chloropurine riboside (1.35 g, .0047 mole), and triethylamine (0.7 ml, .0052 mole) as a solid, mp 80-83°C as described in Example 1.
EXAMPLE 18 N,6-(2-(3,5-Dimethoxyphenyl)-2-naphth-l-ylethyl)adenosine
The amine (0.48 g, 14%) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (2.22 g, .011 mole, see
Example 10), 1-bromonaphthalene (3.1 ml, .022 mole), and magnesium (0.43 g, .018 mole), followed by LiAlH4 reduction (0.90 g, .024 mole) as described in Example 1.
The nucleoside (0.22 g, 25%) was prepared from the amine (0.48 g, .0016 mole), 6-chloropurine riboside (0.40 g, .0014 mole) and triethylamine (0.2 ml, .0015 mole) as a solid, mp 114-118.5°C as described in Example 1.
EXAMPLE 19 N,6-(2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosin
The amine (1.90 g, 67%) was prepared from E,2-(3,5-dimethoxy)nitroethene (2.09 g, 10 mmol, see Example 10), 2-bromotoluene (2.57 g, 15 mmol) and magnesium (0.36 g, 15 mmol), followed by LiAlH4 reduction (1.11 g, 30 mmol) as described in Example 1. The nucleoside (2.85 g, 79%) was prepared from
2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (1.90 g, 6.7 mmol), 6-chloropurine riboside (1.94 g, 6.7 mmol) and triethyl amine (1.31 g, 13 mmol) as an offwhite solid foam, mp 105-12°C as described in Example 1.
EXAMPLE 20
N,6-(2-(3,5-Dimethoxyphenyl)-2-(2,6-dimethylphenyl)ethyl) adenosine
The amine (2.05 g, 71%) was prepared from
E,2-(3,5-dimethoxyphenyl)nitroethene (2.09 g, 10 mmol, see Example 10), 2,6-dimethylbromobenzene (2.78 g, 15 mmol) and magnesium (0.36 g, 15 mmol), followed by LiAlH4 reduction
(1.11 g, 30 mmol) as described in Example 1.
The nucleoside (2.23 g, 79%) was prepared from
2-(3,5-dimethoxyphenyl)-2-(2,6-dimethylphenyl) ethylamine (2.05 g, 7 mmol), 6-chloropurine riboside (2.05 g, 7 mmol) and triethylamine (1.41 g, 14 mmol) as a white solid foam, mp
107-17°C as described in Example 1.
EXAMPLE 21 N,6-(2-(3,5-Dimethoxyphenyl)-2-(3-methoxyphenyl)ethyl)adenosine
The amine (1.70 g, 59%) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (2.09 g, 10 mmol, see Example 10), 3-bromoanisole (2.80 g, 15 mmol) and magnesium (0.48 g, 20 mmol) followed by LiAlH4 reduction (1.11 g, 30 mmol) as described in Example 1.
The nucleoside (2.42 g, 76%) was prepared from 2-(3,5-dimethoxyphenyl)-2-(3-methoxyphenyl)ethylamine (1.70 g, 6 mmol), 6-chloropurine riboside (1.72 g, 6 mmol) and triethylamine (1.21 g, 12 mmol) as a beige solid foam, mp 90-101°C as described in Example 1.
EXAMPLE 22 N,6-(2-(3,4,5-Trimethoxyphenyl)-2-phenethyl)adenosine The nitrostyrene (31.21 g, 63%) was prepared from 3,4,5-trimethoxybenzaldehyde (40.8 g, .21 mole) and nitromethane (12.4 g, .20 mole) as described in Example 1.
The amine (0.84 g, 4%) was prepared from E,2-(3,4,5-trimethoxyphenyl)nitroethene (15.72 g, .066 mole), phenylmagnesium bromide (29.6 ml, .089 mole), followed by
LiAlH4 reduction (1.83 g, .048 mole) as described in Example 1.
The nucleoside (1.25 g, 85%) was prepared from the amine (0.82 g, .0029 mole), 6-chloropurine riboside (0.75 g, .0026 mole), and triethylamine (0.4 ml, .0029 mole) as a solid, mp 95-99°C as described in Example 1.
EXAMPLE 23 N,6-(2-(3,5-Dimethoxyphenyl)-2-(2-methoxyphenyl)ethyl)adenosine
The amine (5.26 g, 46%) was prepared from E,2-(3,5-dimethoxyphenyl)nitroethene (8.36 g, .04 mole, see Example 10), 2-methoxybromobenzene (10.2 ml, .08 mole), and magnesium (1.57 g, .064 mole), followed by LiAlH4 reduction (5.98 g, .16 mole) as described in Example 1.
The nucleoside (5.15 g, 90%) was prepared from the amine (3.16 g, .011 mole), 6-chloropurine riboside (2.86 g, .01 mole)
and triethylamine (1.4 ml, .011 mole) as a solid, mp 93-97°C a described in Example 1.
EXAMPLE 24 N,6-(2-(3,4,5-Trimethoxyphenyl)-2-(methylphenyl)ethyl)adenosine The amine (1.01 g, 31%) was prepared from
E,2-(3,4,5-trimethoxyphenyl)nitroethene (2.39 g, 10 mmol, see Example 22), 2-bromotoluene (2.57 g, 15 mmol), and magnesium (0.36 g, 15 mmol) followed by LiAlH4 reduction (1.11 g, 30 mmol) as described in Example 1. The nucleoside (1.16 g, 66%) was prepared from
2-(3,4,5-trimethoxyphenyl)-2-(2-methylphenyl ethylamine (1.01 g, 3 mmol), 6-chloropurine riboside (0.89 g, 3 mmol) and triethylamine (0.61 g, 6 mmol) as a white solid foam, mp 107-15°C as described in Example 1.
EXAMPLE 25
N,6-(2-(2-Methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethyl) adenosine
The amine (0.70 g, 9%) was prepared from E,2-(3,4,5-trimethoxyphenyl)nitroethene (5.98 g, .025 mole, se Example 22), 2-methoxybromobenzene (6.4 ml, .05 mole), magnesium (0.97 g, .04 mole), followed by LiAlH4 reduction (2.43 g, .064 mole) as described in Example 1.
The nucleoside (0.67 g, 54%) was prepared from the amine (0.70 g, .0022 mole), 6-chloropurine riboside (0.57 g, .002 mole), and triethylamine (0.3 ml, .0022 mole) as a grey foam, mp 99-104°C as described in Example 1.
EXAMPLE 26 N,6-(2-(2-Methoxyphenyl)-2-(3-(trifluoromethyl)phenyl)ethyl) adenosine The nitrostyrene (9.84 g, 91%) was prepared from
3-(trifluoromethyl)benzaldehyde (8.7 g, 50 mmol) and nitromethane (3.1 g, 50 mmol) as described in Example 1.
The amine (1.72 g, 57%) was prepared from E,2-(3-(trifluoromethyl)phenyl)nitroethene (2.17 g, 10 mmol), 2-bromoanisole (2.81 g, 15 mmol) and magnesium (0.36 g, 15 mmol) as described in Example 1. The nucleoside (2.22 g, 71%) was prepared from
2-(2-methoxyphenyl)-2-(3-(trifluoromethyl)phenyl) ethylamine (1.72 g, 5.7 mmol), 6-chloropurine riboside (1.78 g, 6.2 mmol) and triethylamine (1.2 g, 12 mmol) as a pale yellow solid foam, mp 100-108°C as described in Example 1.
EXAMPLE 27
N,6-(2-(2-Methoxyphenyl)-2-(3,5-bis(trifluoromethyl)phenyl) ethyl)adenosine
The nitrostyrene (5.48 g, 87%) was prepared from 3,5-bis(trifluoromethyl)benzaldehyde (5.77 g, 22 mmol) and nitromethane (2.69 g, 44 mmol) as described in Example 1.
The amine (0.76 g, 42%) was prepared from E,2-(3,5-bis(trifluoromethyl)phenyl)nitroethene (1.43 g, 5 mmol), 2-bromoanisole (1.39 g, 7.5 mmol), and magnesium (0.18 g, 7.5 mmol) followed by LiAlH4 reduction (0.55 g, 15 mmol) as described in Example 1.
The nucleoside (0.97 g, 75%) was prepared from 2-(2-methoxyphenyl)-2-(3,5-bis(trifluoromethyl) phenyl)ethylamine (0.76 g, 2.1 mmol), 6-chloropurine riboside (0.61 g, 2.1 mmol), and triethylamine (0.40 g, 4 mmol) as a white solid foam, mp 105-12°C as described in Example 1.
EXAMPLE 28 N,6-(2-(3,5-Bis(trifluoromethyl)phenyl-2-phenethyl)adenosine
The amine (0.92 g, 27%) was prepared from E,2-(3,5-bis(trifluoromethyl)phenγl)nitroethene (2.85 g, 10 mmol, see Example 27) and phenylmagnesium bromide (15 mmol) followed by LiAlH4 reduction (1.11 g, 30 mmol) as described in Example 1.
The nucleoside (1.20 g, 75%) was prepared from 2-(3,5-bis(trifluoromethyl)phenyl)-2-phenethylamine (0.92 g,
2.7 mmol), 6-chloropurine riboside (0.80 g, 2.7 mmol) and triethylamine (0.60 g, 6 mmol) as a pale yellow solid foam, mp 99-105°C as described in Example 1.
EXAMPLE 29 N6-((-)-2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethyl) adenosine
(±) 2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (40.65 g, 0.15 mol) and [2R,3R]dibenzoyl tartaric acid monohydrate (56.4 g, 0.15 mol) were dissolved in refluxing EtOH (=700 ml) and then recrystallized 5 times, seeding with crystals of optically enriched salt (produced in 94% EE by recrystallizing a small sample 10 times) to give 5.78 g of salt, EE = 93.4%, mp 175.5-177°C, (MeOH) -93.5°. The
ammonium salt (5.00 g) was partitioned between dilute NaOH solution (1N, 30 ml) and ether (50 ml). The layers were separated and the aqueous layer was extracted with further ether (25 ml). The combined organic phases were washed with water (2x25 ml), saturated brine (25 ml) and dried (MgSO4). The solvent was removed under reduced pressure to give (-)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine
(2.08 g) as a cloudy pale yellow oil α (MeOH) -57.4°, EE =
93.4%.
The nucleoside (3.53 g, 90%) was prepared from ( -)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (2.02 g, 7.45 mmol), 6-chloropurine riboside (2.16 g, 7.5 mmol) and NEt3 (1.51 g, 15 mmol) in ethanol (70 ml) at reflux stirred under N2 for 18 hours. On cooling the desired nucleoside crystallized out (3.53 g, 90%) as white microscopic needles, mp 195-197°C. Rotation ^3 (DMSO) -78.1°. Diastereoisomeric
excess > 90%.
EXAMPLE 30 N6-((+)-2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethyl) adenosine
The mother liquors, from the first crystallization of (±) 2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl ammonium di-o-benzoyl[2R,3R]tartrate, described in Example 29, were evaporated to dryness. It was then stirred with dilute NaOH solution (0.4 M, 500 ml) and ether (100 ml) until all solid had dissolved. The layers were separated and the aqueous layer was extracted with further ether (2x100 ml). The combined ethereal extracts were washed with NaOH solution (0.25 M, 100 ml), water (100 ml), saturated brine (100 ml), and dried (MgSO4). The solvent was removed under reduced pressure to give 2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (17.2 g) 2:1 enriched in the (+) enantiomer. This was combined with
D-dibenzoyltartrate.H2O (23.88 g, 63.5 mmol) and recrystallized three times from ethanol, seeding with crystals of optically enriched salt, to give 6.60 g of salt. EE = 91%, mp 169-71°C, (MeOH) +96°. The salt (5.00 g) was partitioned between
NaOH solution ( 1 M, 30 ml ) and ether ( 50 ml ) . The layers were separated, and the ethereal layer was extracted with further ether (25 ml). The combined organic phase was washed with water (2x25 ml), saturated brine (25 ml), and dried (MgSO4). The solvent was removed under reduced pressure to give (+)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine
The nucleoside was prepared from (+)-2-(3,5-dimethoxy- phenyl)-2-(2-methylphenyl)ethylamine (2.03 g, 7.5 mmol) 6-chloropurine riboside (2.16 g, 7.5 mmol) and NEt3 (1.51 g, 15 mmol) in ethanol at reflux stirring under N2 for 18 hours. The solvent was removed under reduced pressure, the residue added to water (50 ml) and extracted with ethyl acetate (2x25 ml). The combined organic phases were washed with water (25 ml), saturated brine (25 ml), and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was
reσrystallized from EtOH (25 ml) at 0°C to give N6-((+)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl) adenosine (2.86 g, 74%) as white needles, mp 168-169°C. Rotation (DMSO) -5.5°. Diastereoisomeric excess 80%.
EXAMPLE 31 5'-Bromo-5'-deoxy-N6-(2-(3,5-dimethoxyphenyl)-2-(2-methyl- phenyl)ethyl)adenosine
A solution of 5'-bromo-5'-deoxy-S-phenylthioinosine- S,S-dioxide-2',3'-di-o-isopropylidene (3.0 g, 6 mmol), 2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (1.83 g,
6 mmol) and NEt3 (1.21 g, 12 mmol) was stirred in CHCl3 (30 ml under N2 at 25°C for 40 hours. The mixture was poured onto NaH2PO4 solution (0.4 M, 50 ml), the layers separated, and the aqueous layer extracted with further CHCl3 (30 ml). The organic extracts were washed with water (2x30 ml), saturated brine (30 ml), and dried (MgSO4). The solvent was removed under reduced pressure, and the residual solid foam was added to 10% aqueous TFA (10 ml) and stirred under N2 at 0°C for 45 minutes. The reaction mixture was poured onto Na2CO3 solution (1 M, 200 ml) and extracted with EtOAc (3x50 ml). The combine extracts were washed with water (2x25 ml), saturated brine (25 ml), and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (225 g) eluting with 5% MeOH in CHCl3 to give 5'-bromo-5'-deoxy-N -(2-(3,5-dimethoxyphenyl)- 2-(2-methylphenyl)ethyl)adenosine (2.07 g, 56%) as a pale yellow solid foam, mp 76-91°C.
EXAMPLE 32 N6-(2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine
5'-uronic acid
6-Chloropurine riboside-2',3'-di-o-isopropγlidene Triethyl orthoformate (59.2 g, 0.4 mol) was added to a suspension of 6-chloropurine riboside (28.75 g, 0.10 mol) and tosic acid monohydrate (18 g, 0.095 mol) in acetone (1 L) stirred under N2 at 25°. After 3 hours the now clear solution was concentrated under reduced pressure, and the residue was poured onto K2HPO4 solution (26.1 g in 800 ml) and extracted with ethyl acetate (2x200 ml). The combined extracts were washed with water (2x100 ml), saturated brine (100 ml), and dried (MgSO4). The solvent was removed under reduced pressure to give 6-chloropurine riboside-2 ' , 3 ' -di-o-isopropylidene ( 28.5 g, 87%) as a light yellow crystalline solid, mp 155-158°C.
6-Chloropurine riboside-2',3'-di-o-isopropylidene-5'-uronic acid
A solution of chromic acid (2 M) in aqueous sulfuric acid (3 M, 100 ml) was added over 1 hour to a partial solution of 6-chloropurine riboside-2',3'-di-o-isopropylidene (32.65 g, 100 mmol) in acetone (500 ml) stirred under N2 at 25° without cooling. After a further 15 minutes the mixture was celite filtered, and the residue was rinsed with EtOAc (2x250 ml). The combined filtrates were washed with Na2S2O5 solution
(0.5 M, 50 ml) and water (3x50 ml). The organic phase was extracted with NaOH solution (0.5 M, 250 ml). The basic extract was washed with EtOAc (200 ml) and acidified with concentrated HCl. The yellow oil was extracted with ethyl acetate (3x100 ml), and the organic phase was washed with wate
(100 ml), saturated brine (100 ml), and dried (MgSO4). The solvent was removed under reduced pressure to give 6-chloropurine riboside-2',3'-di-o-isopropylidene-5'-uronic acid (20.3 g, 57%) as a light orange solid, mp 135-152°C.
Analytical sample recrystallized from aqueous MeOH, mp 180-210 (dec).
N6-(2-(3,5-Dimethoxyphenyl)-2-(2-methγlphenyl)ethyl)adenosine-
2',3'-di-o-isopropylidene-5'-uronic acid A solution of 6-chloropurine riboside-2',3'-di-o- isopropylidene-5'-uronic acid (3.41 g, 10 mmol),
2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethylamine (2.71 g,
10 mmol) and NEt3 (3.03 g, 30 mmol) were refluxed in EtOH
(100 ml) stirring under N2 for 18 hours. The solvent was removed under reduced pressure, and the residue was dissolved in NaOH solution (0.25 M, 50 ml), washed with EtOAc (2x25 ml), acidified with concentrated HCl, and then extracted with EtOAc
(3x30 ml). The combined organic extracts were washed with water (2x25 ml), saturated brine (25 ml), and dried (MgSO4). The solvent was removed under reduced pressure to give N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-
2',3'-di-o-isopropylidene-5'-uronic acid (4.94 g, 82%) as a light yellow solid foam, mp 113-121°C.
N6-(2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine- 5'-uronic acid N6-(2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethyl) adenosine-2',3'-di-o-isopropylidene-5'-uronic acid (1.50 g, 2.6 mmol) was stirred in aqueous TFA (10 ml, 1:9) under N2 at 0°C for 4 hours. The reaction mixture was quenched by pouring onto EtOAc (50 ml), and most of the TFA was washed out with NaOH solution (2.2 M, 50 ml) and NaH2PO4 solution (0.2 M, 50 ml). The organic phase was washed with saturated brine (50 ml), dried (MgSO4), and the solution concentrated under reduced pressure before residual volatiles were azeotroped three times with toluene. The residual solid foam was dissolved in EtOH (24 ml) and triturated with ether to give N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine
5'-uronic acid (0.71 g, 51%) as a white powder, mp 129-139°C.
EXAMPLE 33 N6-(2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-
5'-uronamide
Dicyclohexylcarbodiimide (0.55 g, 2.7 mmol) was added to a suspension of 1-hydroxybenzotriazole (0.32 g, 2.4 mmol) in CH2Cl2 (20 ml) containing N6-(2-(3,5-dimethoxyphenyl)-2-
(2-methylphenyl)ethyl)adenosine-2',3'-di-o-isopropylidene-5'- uronic acid (Example 32, 1.15 g, 2 mmol) stirred under N2 at
0°. After 10 minutes NH3 was bubbled through the mixture for 15 minutes at 0°C, and then the mixture was allowed to warm up to 25°C. It was then vacuum filtered, the residue rinsed with CH2Cl2 (10 ml) and the solvent removed from the combined filtrates under reduced pressure. The residual glassy solid was dissolved in aqueous TFA (10 ml, 1:9) and stirred under N2 at 0°C for 2.5 hours. The reaction mixture was poured onto NaOH solution (125 ml, 1 M) and was extracted with EtOAc (100 ml). The organic layer was washed with water (50 ml), saturated brine (50 ml), and dried (MgSO4)' Tne solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica (150 g) eluting with 5% MeOH in CHCl3 to give N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl) ethyl)adenosine-5'-uronamide (0.71 g, 61%) as a white crystalline solid, mp 181-184°C.
EXAMPLE 34 N5'-Methyl-N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl) adenosine-5'-uronamide
Triethylamine (0.61 g, 6 mmol) and methylamine hydrochloride (0.27 g, 4 mmol) were added sequentially 1 minute apart to a suspension of N-methyl-2-fluoropyridinium tosylate (0.42 g, 1.5 mmol) and N6-(2-(3,5-dimethoxyphenyl)-2-(2-methyl- phenyl)ethyl)adenosine-2',3'-di-o-isopropylidene-5'-uronic acid (Example 32, 0.58 g, 1 mmol) in CH2Cl2 (5 ml) stirred under N2 at 0°C. After 1 hour the reaction mixture was diluted with EtOAc (25 ml) and washed with dilute HCl (1 M, 10 ml), water (10 ml), saturated brine (10 ml), and dried (MgSO4). The
solvent was removed under reduced pressure, and the residual solid foam was dissolved in aqueous TFA (5 ml, 1:9 at 0°C) and stirred under N2 for 2 hours. The reaction was quenched by addition of EtOAc (50 ml), and washing with NaOH solution (1 M, 50 ml) dilute Na2CO3 solution (50 ml), and saturated brine (25 ml), and drying (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by preparative
TLC (silica) eluting with 10% MeOH in CHCl3 to give N5' -methyl-N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl) ethyl)adenosine-5'-uronamide (0.36 g, 64%) as a white glassy foam, mp 122-127°C.
EXAMPLE 35 N5'-Ethyl-N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl) adenosine-5'-uronamide Dicyclohexylcarbodiimide (0.52 g, 2.5 mmol) was added to a suspension of 1-hydroxybenzotriazole (0.27 g, 2 mmol) in CH2Cl2 (20 ml) containing N6-(2-(3,5-dimethoxγphenyl)-2-(2-methyl- phenyl)ethyl)adenosine-2',3'-di-o-isopropylidene-5'-uronic acid (Example 32, 1.15 g, 2 mmol) stirred under N2 at 0°C. After 10 minutes ethylamine (0.27 ml, 4 mmol) was added. After 16 hours the reaction mixture was filtered, and the residue was rinsed with CH2Cl2 (10 ml). The solvent was removed from the combined filtrates under reduced pressure and the residual light yellow solid foam was dissolved in aqueous TFA (10 ml, 1:9) at 0°C an stirred under N2 for 75 minutes. The reaction mixture was quenched with EtOAc (100 ml) and washed with NaOH solution (1 M, 100 ml), saturated Na2CO3 solution (50 ml), saturated brine (50 ml), and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (100 g) eluting with 5% MeOH in CHCl3 to give N5'-ethyl-N6-(2-(3,5-dimethoxyphenγl)-2- (2-methylphenyl)ethyl)adenosine-5'-uronamide (0.86 g, 72%) contaminated with =10 mol% dicyclohexylurea, as a pale yellow solid foam, mp 103-112°C.
EXAMPLE 36
N5'-Cyclopropyl-N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl) ethyl)adenosine-5'-uronamide
Triethylamine (0.20 g, 2 mmol) and cyclopropylamine (0.11 g, 2 mmol) were added sequentially 2 minutes apart to a mixture of N-methyl-2-fluoropyridinium tosylate (0.42 g,
1.5 mmol) and N6-(2-(3,5-dimethoxyphenyl)-2-(2-methγlphenγl) ethyl)adenosine-2',3'-di-o-isopropylidene-5'-uronic acid (Example 32, 0.58 g, 1.0 mmol) stirred in CH2Cl2 (5 ml) under N2 at 25°C. After 15 minutes the reaction mixture was diluted with EtOAc (25 ml), and washed with dilute HCl (0.5 M, 10 ml), water (10 ml), saturated brine (10 ml), and dried (MgSO4). The solvent was removed under reduced pressure and the residual solid foam was stirred in aqueous TFA (5 ml, 1:9) under N2 at 0°C for 2 hours. The reaction mixture was quenched with EtOAc (50 ml), and washed with NaOH solution (1 M, 50 ml), dilute Na2CO3 solution (50 ml), saturated brine (25 ml), and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by preparative TLC, eluting with 10% MeOH in CH2Cl2, to give N5 -cyclopropyl-N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-5'-uronamide (0.39 g, 67%) as a white glass, mp 117-126°C.
EXAMPLE 37 N5'-Ethyl-N6-((-)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl) ethyl)adenosine-5'-uronamide
N-Ethyl-6-chloropurine-ribofuranuronamide-2',3'-di-o- isopropylidene
Triethylamine (1.01 g, 10 mmol) was added to a suspension of 6-chloropurine ribofuranuronic acid-2',3'-di-o- isopropylidene (1.70 g, prepared in Example 32) and N-methyl-2 fluoropyridinium tosylate (2.12 g, 7.5 mmol) stirred in CH2Cl2 (25 mL) under N2 at 0°C. After 15 minutes ethylamine (1 mL, =15 mmol) was added. After a further 1 hour the reaction mixture was poured onto dilute HCl, (IN, 25 mL), the layers
separated, and the aqueous layer extracted with CH2Cl2 (25 mL The combined organic phases were washed with water (25 mL), saturated brine (25 mL), and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified flash chromatography on silica gel, eluting with hexane/EtOAc to give N-ethyl-6-chloropurine-ribofuranuronamide-2',3'-di-o- isopropylidene (1.20 g, 65%) as an offwhite solid foam; mp 73-80°C.
N5'-Ethyl-N6-((-)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl) ethyl)adenosine-5'-uronamide
( -)-2-(3,5-Dimethoxyphenyl)-2-(2-methylphenyl)ethylamine (0.17 g, 0.6 mmol, prepared as in Example 29), N-ethyl-6-chloropurine-ribofuranuronamide-2',3'-di-o- isopropylidene (0.22 g, 0.6 mmol) and triethylamine (0.12 g, 1.2 mmol) were refluxed in EtOH (6 mL) under N2 for 20 hours. The volatiles were removed under reduced pressure and the residual glass was stirred in aqueous TFA (1:9, 5 mL) under N2 at 0°C for 2 hours. The mixture was diluted with EtOAc (50 m and washed with dilute NaOH (1M, 50 mL), dilute Na2CO3 solution (50 mL), saturated brine (50 mL), and dried (MgSO4). The solvent was removed under reduced pressure, and the residue wa purified by preparative tic (10% MeOH in CHCl3, rf 0.28) to give N5'-ethyl-N6-((-)-2-(3,5-dimethoxyphenyl)-2-
(2-methylphenyl)ethyl)adenosine-5-uronamide (0.28 g, 83%) as a white glass; mp 110-120°C.
Claims
1. A compound of the formula
I
or
wherein A is oxygen or sulfur and wherein X1, X2, X3, Y1, Y2 and Y3 may be independently selected from hydrogen, halogen, lower alkyl, lower alkylthio or alkoxy, and X1, X2, X3 may also be trifluoromethyl with the proviso that
Y2 or Y3 must be hydrogen and Y2 and Y3 taken together are -(CH)-4 with the further overall proviso that at least two of X1, X2, X3, Y1, Y2 and Y3 are not hydrogen.
R2' and R3' 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, R2' and R3' may be linked together to form either a five-membered alkylidene ring having a total of up to twenty carbons such as, for example, isopropylidene, or a cyclic phosphate diester and R5' may be a phosphate, hydrogen or dihydrogen phosphate, or an alkali metal or ammonium or dialkali or diammonium salt thereof; and Z is -(CH2)-Q wherein Q is selected from the group consisting of hydrogen, hydroxy, halogen, cyano, azido, amino, lower alkoxy, lower acyloxy, lower thioalkyl, lower sulfonylalkyl,
wherein Y is oxygen or sulfur and R" and R'" are independently hydrogen or lower alkyl; or (2)
wherein J is O, S, NR7 wherein R7 is hydrogen, lower alkyl or cycloalkyl of from 3 to 7 carbons such as cyclopropyl, cyclobutyl, cyclopentyl and the like or 1- or 2-methylcyclopropyl, 1-, or 2-ethylcyclobutyl and the like; and T is (a) NR4R5 wherein R4 is straight chain lower alkyl having 1-4 carbon atoms; hydroxy, lower alkoxy or halogen substituted straight chain lower alkyl having 1-4 carbon atoms; cyclopropyl; secondary alkyl having 3-6 carbon atoms; hydroxy, lower alkoxy or halogen substituted secondary alkyl having 3-6 carbon atoms; alkenyl having 3 to 6 carbon atoms; aralkyl having 1 to 4 carbons in the alkyl chain and optionally substituted in the aryl nucleus with hydroxy, halogen, lower alkoxy or lower alkyl groups; and heteroarylalkyl having 1 to 4 carbons in the alkyl chain and optionally substituted in the heteroaryl nucleus with hydroxy, halogen, lower alkoxy or lower alkyl groups, and
R5 is hydrogen or straight chain lower alkyl having 1 to 4 carbons; or (b) OR4 wherein R4 is as defined above.
2. A compound of Claim 1 wherein Z is -(CH2)-Q wherein Q is OH.
3. A compound of Claim 2 wherein R2' and R3' are OH, and Ar is
wherein Z is as defined above, Y is Y1 as defined above when Y1 is not hydrogen.
A ccompound of Claim 2 wherein X1, X2, wherein Ar is
5. A compound of Claim 1 and being N,6-(2-(2,6- dimethylphenyl)-2-phenethγl)adenosine.
6. A compound of Claim 1 and being N,6-(2-(2,6- dimethylphenyl)-2-(4-methylphenyl)ethyl)adenosine.
7. A compound of Claim 1 and being N,6-(2-(3,5- dimethylphenyl)-2-phenethyl)adenosine.
8. A compound of Claim 1 and being N,6-(2-naphth- 1-yl-2-phenethyl)adenosine.
9. A compound of Claim 1 and being N,6-(2-(3,5- dichlorophenyl)-2-(2,6-dimethylphenyl)ethyl)adenosine.
10. A compound of Claim 1 and being N,6-(2-(2,6- dichlorophenyl)-2-(phenethyl)adenosine.
11. A compound of Claim 1 and being N,6-(2-(3,5- dichlorophenyl)-2-phenethyl)adenosine.
12. A compound of Claim 1 and being N,6-(2-(3- chlorophenyl)-2-(3,5-dichlorophenyl)ethyl)adenosine.
13. A compound of Claim 1 and being N,6-(2-(3- chlorophenyl)-2-(2,6-dichlorophenyl)ethyl)adenosine.
14. A compound of Claim 1 and being N,6-(2-(3- chlorophenyl)-2-(3,5-dimethoxyphenyl)ethyl)adenosine.
15. A compound of Claim 1 and being N,6-(2-(3,5- dimethoxyphenyl)-2-phenethyl)adenosine.
16. A compound of Claim 1 and being N,6-(2-(2,5- dimethoxyphenyl)-2-phenethyl)adenosine.
17. A compound of Claim 1 and being N,6-(2-(2,6- dimethoxyphenyl)-2-phenethyl)adenosine.
18. A compound of Claim 1 and being N,6-(2-(2- methoxyphenyl)-2-(3-methoxyphenyl)ethyl)adenosine.
19. A compound of Claim 1 and being N,6-(2-(3,4- dimethoxyphenyl)-2-phenethyl)adenosine.
20. A compound of Claim 1 and being N,6-(2-(3,5- diethoxyphenyl)-2-phenethyl)adenosine.
21. A compound of Claim 1 and being N,6-(2-(3,5- dimethoxyphenyl)-2-thien-2-yl)ethyl)adenosine.
22. A compound of Claim 1 and being N,6-(2-(3,5- dimethoxypheny1)-2-naphth-1-ylethyl)adenosine.
23. A compound of Claim 1 and being N,6-(2-(3,5- dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine.
24. A compound of Claim 1 and being N,6-(2-(3,5- dimethoxyphenyl)-2-(2,6-dimethylphenyl)ethyl)adenosine.
25. A compound of Claim 1 and being N,6-(2-(3,5- dimethoxyphenyl)-2-(3-methoxyphenyl)ethyl)adenosine.
26. A compound of Claim 1 and being N,6-(2-(3,4,5- trimethoxyphenyl)-2-phenethyl)adenosine.
27. A compound of Claim 1 and being N,6-(2-(3,5- dimethoxyphenyl)-2-(2-methoxyphenyl)ethyl)adenosine.
28. A compound of Claim 1 and being N,6-(2-(3,4,5- trimethoxyphenyl)-2-(methylphenyl)ethyl)adenosine.
29. A compound of Claim 1 and being N,6-(2-(2- methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethyl)adenosine.
30. A compound of Claim 1 and being N,6-(2-(2- methoxyphenyl)-2-(3-trifluoromethylphenyl)ethyl)adenosine
31. A compound of Claim 1 and being N,6-(2-(2- methoxyphenyl)-2-(3,5-bis(trifluoromethyl)phenyl)ethyl) adenosine.
32. A compound of Claim 1 and being N6-((-)-2-(3,5- dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine.
33. A compound of Claim 1 and being N6-((+)-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine.
34. A compound of Claim 1 and being 5'-bromo-5'-deoxy-N6- (2-3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine.
35. A compound of Claim 1 and being N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-5'-uronic acid.
36. A compound of Claim 1 and being N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-5'-uronamide.
37. A compound of Claim 1 and being N5'-methyl-N6-(2-
(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine- 5'-uronamide.
38. A compound of Claim 1 and being N5'-ethyl-N6-(2-
(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine- 5'-uronamide.
39. A compound of Claim 1 and being N 5'-cγclopropyl-N6-
(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl) adenosine-5'-uronamide.
40. A compound of Claim 1 and being N,6-(2-(3,5-bis (trifluoromethyl)phenyl)-2-phenethyl)adenosine.
41. A compound of Claim 1 and being N5'-ethyl-N6-((-)-2-(3,5- dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine-5'- uronamide.
42. A pharmaceutical composition for treating psychoses, pain, angina or congestive heart failure comprising an antipsychoses, analgesic, antianginal or anticongestive heart failure effective amount of a compound of Claim 1 and a pharmacologically acceptable carrier.
43. A method of treating psychoses in mammals suffering therefrom comprising administering to said mammals a compound of Claim 1 in unit dosage form.
44. A method of treating pain in mammals suffering therefrom comprising administering to said mammals a compound of Claim 1 in unit dosage form.
45. A method of treating angina in mammals suffering therefrom comprising administering to said mammals a compound of Claim 1 in unit dosage form.
46. A method of treating congestive heart failure in mammals suffering therefrom comprising administering to said mammals a compound of Claim 1 in unit dosage form.
47. A process for preparing a compound of Claim 1 which comprises coupling a compound of the formula
II
with 6-chloropurine riboside in the presence of triethyleneamine to obtain the compound of Claim 1.
48. A process for the preparation of a compound of Claim 1 which comprises A) treating a compound of the formula
wherein X1, X2 and X3 are as defined above; with 1) CH3NO2 in the presence of NaOH and 2) CH3SO2Cl in the presence of triethylamine; B) treating the product of A) with a compound of the formula
wherein Y1, Y2 and Y3 are as defined above, and M is a Grignard or lithium moiety; in an aprotic solvent; then C) reducing the product of B) by treating with LiAlH4 and finally D) coupling the product of C) with 6-chloropurine riboside of the formula
wherein Z is as defined above in the presence of triethylamine to obtain the compound of Claim 1.
49. A method for preparing a compound of the formula
with H2CrO4 in acetone.
50. A process for the preparation of the compound of the formula
which comprises (1) treating a compound of the formula
with ethyl orthoformate and tosic acid in acetone; and then (2) treating the product of step (1) with H2CrO4 in acetone.
51. A process for the preparation of a compound of Claim 1 wherein Z is
wherein J is O and T is NR4R5 when R4 and R5 are as defined above which comprises
(1) reacting a compound of the formula X
with ethyl formate and tosic acid in acetone; to obtain the compound of the formula
XI
(2) treating the compound of the formula XI of step (1) with H2CrO4 in acetone; to obtain the compound of the formula
XI I
then (3) (a) treating the compound of the formula XII of step (2) with
wherein Ar1 and Ar2 are as defined above in the presence of triethylamine; to obtain the compound of formula
XIII
and then treating the compound of formula XIII with HNR4R5 in the presence of a coupling agent, to obtain
XIV
and alternatively further treating the compound of the formula XIV to obtain the compound of formula I wherein Z is
wherein J is O and T is NR4R5 wherein R4 and R5 are as defined above and R2' and R3' are other than propylidene; or then (3)(b) treating the compound of formula XII of step (2) with HNR4R5 to obtain the compound of formula
X
and then treating the compound of formula XVI with
and alternatively, further teaching the compound of the formula XIV to obtain the compound of formula I wherein Z is
wherein J is O and T is NR4R5 wherein R4 and R5 are as defined above and R2' and R3' are other than propylidene.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK357788A DK357788D0 (en) | 1986-10-31 | 1988-06-29 | SELECTED N6-SUBSTITUTED ADENOSINES WITH SELECTIVE A2 BINDING ACTIVITY |
NO882887A NO882887D0 (en) | 1986-10-31 | 1988-06-29 | SELECTED N6-SUBSTITUTED ADENOSINES WITH SELECTIVE A2 BINDING ACTIVITY. |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US92518586A | 1986-10-31 | 1986-10-31 | |
US925,185 | 1986-10-31 | ||
US9083087A | 1987-08-28 | 1987-08-28 | |
US090,830 | 1987-08-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1988003147A1 true WO1988003147A1 (en) | 1988-05-05 |
Family
ID=26782679
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1987/002719 WO1988003147A1 (en) | 1986-10-31 | 1987-10-19 | Selected n6-substituted adenosines having selective a2 binding activity |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU8276187A (en) |
GR (1) | GR871667B (en) |
WO (1) | WO1988003147A1 (en) |
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EP0378518A2 (en) * | 1989-01-11 | 1990-07-18 | Nippon Zoki Pharmaceutical Co. Ltd. | Adenosine derivatives having pharmaceutical activity as antihypertensives |
US5055569A (en) * | 1989-10-19 | 1991-10-08 | G. D. Searle & Co. | N-(6)-substituted adenosine compounds |
EP0490818A1 (en) * | 1990-12-07 | 1992-06-17 | Sandoz Ltd. | 6-cyclohexyl-2'-0-methyl-adenosine hydrate and uses thereof |
US5219839A (en) * | 1992-01-31 | 1993-06-15 | Laboratories Upsa | Adenosine derivatives, their methods of preparation and pharmaceutical compositions in which they are present |
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US5364862A (en) * | 1990-09-25 | 1994-11-15 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Compounds having antihypertensive and anti-ischemic properties |
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US5561134A (en) * | 1990-09-25 | 1996-10-01 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties |
US5589467A (en) * | 1993-09-17 | 1996-12-31 | Novo Nordisk A/S | 2,5',N6-trisubstituted adenosine derivatives |
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US5932558A (en) * | 1993-04-15 | 1999-08-03 | New York University | Adenosine receptor agonists for the promotion of wound healing |
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US6407076B1 (en) * | 1997-11-08 | 2002-06-18 | Smithkline Beecham Corporation | Adenosine analogues and related method of treatment |
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US6495528B1 (en) | 1998-06-23 | 2002-12-17 | Smithkline Beecham Corporation | 2-(Purin -9-yl)-tetrahydrofuran-3,4-diol derivatives |
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EP1375508A1 (en) * | 2002-06-27 | 2004-01-02 | Aventis Pharma Deutschland GmbH | N6-substituted adenosine analogues and their use as pharmaceutical agents |
US6762170B1 (en) | 1998-01-31 | 2004-07-13 | Smithklinebeecham Corporation | 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives |
US6921753B2 (en) | 2000-06-27 | 2005-07-26 | Pfizer Inc | Purine derivatives |
US7265111B2 (en) | 2002-06-27 | 2007-09-04 | Sanofi-Aventis Deutschland Gmbh | Adenosine analogues and their use as pharmaceutical agents |
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GR871667B (en) | 1988-03-03 |
AU8276187A (en) | 1988-05-25 |
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