WO1988003147A1 - Adenosines a substitution n6 selectionees ayant une activite de liaison a2 selective - Google Patents

Adenosines a substitution n6 selectionees ayant une activite de liaison a2 selective Download PDF

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Publication number
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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Prior art keywords
compound
adenosine
ethyl
dimethoxyphenyl
formula
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PCT/US1987/002719
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English (en)
Inventor
Alexander James Bridges
Daniel Fred Ortwine
Bharat Kalidas Trivedi
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Warner-Lambert Company
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Publication of WO1988003147A1 publication Critical patent/WO1988003147A1/fr
Priority to DK357788A priority Critical patent/DK357788A/da
Priority to NO882887A priority patent/NO882887L/no

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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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Abstract

Adénosines de formule (I) dans laquelle Ar représente (II), (III), ou (IV), A représentant l'oxygène ou le soufre. Les adénosines ont une activité de liaison de récepteur A2 très sélective et ont des propriétés utiles pour le traitement de maladies cardiovasculaires telles que l'hypertension, l'angine ou l'ischémie du myocarde, la douleur, l'insomnie et la psychose. Est également décrite une nouvelle préparation d'adénosines sélectionnées.
PCT/US1987/002719 1986-10-31 1987-10-19 Adenosines a substitution n6 selectionees ayant une activite de liaison a2 selective WO1988003147A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DK357788A DK357788A (da) 1986-10-31 1988-06-29 Udvalgte n6-substituerede adenosiner med selektiv a2-bindende aktivitet
NO882887A NO882887L (no) 1986-10-31 1988-06-29 Utvalgte n6-substituerte adenosiner med selektiv a2-bindende aktivitet.

Applications Claiming Priority (4)

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US92518586A 1986-10-31 1986-10-31
US925,185 1986-10-31
US9083087A 1987-08-28 1987-08-28
US090,830 1987-08-28

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Cited By (38)

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Publication number Priority date Publication date Assignee Title
EP0378518A2 (fr) * 1989-01-11 1990-07-18 Nippon Zoki Pharmaceutical Co. Ltd. Dérivés de l'adénosine ayant une activité d'antihypertenseurs
US5055569A (en) * 1989-10-19 1991-10-08 G. D. Searle & Co. N-(6)-substituted adenosine compounds
EP0490818A1 (fr) * 1990-12-07 1992-06-17 Sandoz Ltd. Hydrate de 6-cyclohexyl-2'-0-methyl-adenosine et son utilisations
US5219839A (en) * 1992-01-31 1993-06-15 Laboratories Upsa Adenosine derivatives, their methods of preparation and pharmaceutical compositions in which they are present
FR2685918A1 (fr) * 1992-01-08 1993-07-09 Union Pharma Scient Appl Nouveaux derives de l'adenosine, leurs procedes de preparation, compositions pharmaceutiques les contenant.
EP0601322A2 (fr) * 1992-10-27 1994-06-15 Nippon Zoki Pharmaceutical Co., Ltd. Inhibiteur de déaminase d'adénosine
US5364862A (en) * 1990-09-25 1994-11-15 Rhone-Poulenc Rorer Pharmaceuticals Inc. Compounds having antihypertensive and anti-ischemic properties
WO1996002553A2 (fr) * 1994-07-14 1996-02-01 Glaxo Group Limited DERIVES AMINO PURINE-β-D-RIBOFURANURONAMIDE
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
WO1997033591A1 (fr) * 1996-03-13 1997-09-18 Novo Nordisk A/S Procede de traitement d'affections associees aux cytokines chez les mammiferes
US5932558A (en) * 1993-04-15 1999-08-03 New York University Adenosine receptor agonists for the promotion of wound healing
WO2000023457A1 (fr) * 1998-10-16 2000-04-27 Pfizer Limited Derives d'adenine
WO2001027131A1 (fr) * 1999-10-14 2001-04-19 Pfizer Limited Derives de la purine
WO2001027130A1 (fr) * 1999-10-14 2001-04-19 Pfizer Limited Derives de purine
US6242429B1 (en) 1998-06-24 2001-06-05 Nippon Zoki Pharmaceutical Co., Ltd. Arabinosyladenine derivatives
WO2002000676A1 (fr) * 2000-06-27 2002-01-03 Pfizer Limited Derives de purine
US6407076B1 (en) * 1997-11-08 2002-06-18 Smithkline Beecham Corporation Adenosine analogues and related method of treatment
US6426337B1 (en) 1996-12-24 2002-07-30 Smithkline Beecham Corporation 2-(Purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
US6495528B1 (en) 1998-06-23 2002-12-17 Smithkline Beecham Corporation 2-(Purin -9-yl)-tetrahydrofuran-3,4-diol derivatives
US6624158B2 (en) 2000-09-15 2003-09-23 Pfizer Inc Purine derivatives
EP1375508A1 (fr) * 2002-06-27 2004-01-02 Aventis Pharma Deutschland GmbH Dérivés de l'adénosine N6-substitués et leur utilisation comme médicament
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
WO2008107502A1 (fr) * 2007-03-02 2008-09-12 Universidad De Zaragoza Composition destinée à traiter des maladies infectieuses
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor
US8080664B2 (en) 2007-02-23 2011-12-20 Universidad De Zaragoza Use of compounds as inhibitors for Helicobacter flavodoxin
US8367840B2 (en) 2007-03-02 2013-02-05 Universidad De Zaragoza Composition for treating infectious diseases caused by Helicobacter
US8772474B2 (en) 2010-12-22 2014-07-08 Alios Biopharma, Inc. Cyclic nucleotide analogs
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog
US9073960B2 (en) 2011-12-22 2015-07-07 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9441007B2 (en) 2012-03-21 2016-09-13 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
USRE48171E1 (en) 2012-03-21 2020-08-25 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof

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US4755594A (en) * 1986-01-31 1988-07-05 Warner-Lambert Company N6 -substituted adenosines

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FR2195434A1 (fr) * 1972-08-08 1974-03-08 Boehringer Mannheim Gmbh
EP0139358A2 (fr) * 1983-08-01 1985-05-02 Warner-Lambert Company Adénosines substituées en N6 par un radical diarylakyl, leur méthode de préparation et les compositions pharmaceutiques les contenant
EP0152944A2 (fr) * 1984-02-23 1985-08-28 Roche Diagnostics GmbH Utilisation de dérivés d'adénosine comme produit anti-allergique, et médicaments les contenant
EP0181129A2 (fr) * 1984-10-26 1986-05-14 Warner-Lambert Company Déoxyribose analogues d'adénosine substitués en N6

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FR2195434A1 (fr) * 1972-08-08 1974-03-08 Boehringer Mannheim Gmbh
EP0139358A2 (fr) * 1983-08-01 1985-05-02 Warner-Lambert Company Adénosines substituées en N6 par un radical diarylakyl, leur méthode de préparation et les compositions pharmaceutiques les contenant
EP0152944A2 (fr) * 1984-02-23 1985-08-28 Roche Diagnostics GmbH Utilisation de dérivés d'adénosine comme produit anti-allergique, et médicaments les contenant
EP0181129A2 (fr) * 1984-10-26 1986-05-14 Warner-Lambert Company Déoxyribose analogues d'adénosine substitués en N6

Cited By (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0378518A3 (en) * 1989-01-11 1990-12-27 Nippon Zoki Pharmaceutical Co. Ltd. Adenosine derivatives having pharmaceutical activity as antihypertensives
EP0378518A2 (fr) * 1989-01-11 1990-07-18 Nippon Zoki Pharmaceutical Co. Ltd. Dérivés de l'adénosine ayant une activité d'antihypertenseurs
US5055569A (en) * 1989-10-19 1991-10-08 G. D. Searle & Co. N-(6)-substituted adenosine compounds
US5364862A (en) * 1990-09-25 1994-11-15 Rhone-Poulenc Rorer Pharmaceuticals Inc. Compounds having antihypertensive and anti-ischemic properties
US5561134A (en) * 1990-09-25 1996-10-01 Rhone-Poulenc Rorer Pharmaceuticals Inc. Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties
EP0774259A1 (fr) * 1990-12-07 1997-05-21 Novartis AG Nouvelle utilisation des composés organiques
EP0490818A1 (fr) * 1990-12-07 1992-06-17 Sandoz Ltd. Hydrate de 6-cyclohexyl-2'-0-methyl-adenosine et son utilisations
WO1993014102A1 (fr) * 1992-01-08 1993-07-22 Laboratoires Upsa Nouveaux derives de l'adenosine, leurs procedes de preparation, compositions pharmaceutiques les contenant
US5229505A (en) * 1992-01-08 1993-07-20 Laboratoires Upsa N6 -[3-(1-substituted)indolylethyl] adenosine 5'-carboxamides and their pharmaceutical compositions
FR2685918A1 (fr) * 1992-01-08 1993-07-09 Union Pharma Scient Appl Nouveaux derives de l'adenosine, leurs procedes de preparation, compositions pharmaceutiques les contenant.
AU661894B2 (en) * 1992-01-08 1995-08-10 Laboratoires Upsa New adenosine derivatives, preparation methods and pharmaceutical compositions containing them
US5219839A (en) * 1992-01-31 1993-06-15 Laboratories Upsa Adenosine derivatives, their methods of preparation and pharmaceutical compositions in which they are present
WO1993015100A1 (fr) * 1992-01-31 1993-08-05 Laboratoires Upsa Nouveaux derives de l'adenosine, leurs procedes de preparation, compositions pharmaceutiques les contenant
FR2687678A1 (fr) * 1992-01-31 1993-08-27 Union Pharma Scient Appl Nouveaux derives de l'adenosine, leurs procedes de preparation, compositions pharmaceutiques les contenant.
EP0601322A3 (fr) * 1992-10-27 1994-10-12 Nippon Zoki Pharmaceutical Co Inhibiteur de déaminase d'adénosine.
US5705491A (en) * 1992-10-27 1998-01-06 Nippon Zoki Pharmaceutical Co., Ltd. Adenosine deaminase inhibitor
US5773603A (en) * 1992-10-27 1998-06-30 Nippon Zoki Pharmaceutical Co., Ltd. Method for treating allergic diseases with adenosine derivatives
EP0601322A2 (fr) * 1992-10-27 1994-06-15 Nippon Zoki Pharmaceutical Co., Ltd. Inhibiteur de déaminase d'adénosine
US5932558A (en) * 1993-04-15 1999-08-03 New York University Adenosine receptor agonists for the promotion of wound healing
US5589467A (en) * 1993-09-17 1996-12-31 Novo Nordisk A/S 2,5',N6-trisubstituted adenosine derivatives
WO1996002553A3 (fr) * 1994-07-14 1996-03-07 Glaxo Group Ltd DERIVES AMINO PURINE-β-D-RIBOFURANURONAMIDE
WO1996002553A2 (fr) * 1994-07-14 1996-02-01 Glaxo Group Limited DERIVES AMINO PURINE-β-D-RIBOFURANURONAMIDE
WO1997033591A1 (fr) * 1996-03-13 1997-09-18 Novo Nordisk A/S Procede de traitement d'affections associees aux cytokines chez les mammiferes
US6528494B2 (en) 1996-12-24 2003-03-04 Brian Cox 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
US6426337B1 (en) 1996-12-24 2002-07-30 Smithkline Beecham Corporation 2-(Purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
US6407076B1 (en) * 1997-11-08 2002-06-18 Smithkline Beecham Corporation Adenosine analogues and related method of treatment
US6762170B1 (en) 1998-01-31 2004-07-13 Smithklinebeecham Corporation 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
US6495528B1 (en) 1998-06-23 2002-12-17 Smithkline Beecham Corporation 2-(Purin -9-yl)-tetrahydrofuran-3,4-diol derivatives
US6242429B1 (en) 1998-06-24 2001-06-05 Nippon Zoki Pharmaceutical Co., Ltd. Arabinosyladenine derivatives
WO2000023457A1 (fr) * 1998-10-16 2000-04-27 Pfizer Limited Derives d'adenine
US6448236B1 (en) 1999-10-14 2002-09-10 Pfizer Inc Purine derivatives
WO2001027130A1 (fr) * 1999-10-14 2001-04-19 Pfizer Limited Derives de purine
WO2001027131A1 (fr) * 1999-10-14 2001-04-19 Pfizer Limited Derives de la purine
AP1442A (en) * 1999-10-14 2005-06-29 Pfizer Purine derivatives
AP1372A (en) * 2000-06-27 2005-02-21 Pfizer Purine derivatives.
US6921753B2 (en) 2000-06-27 2005-07-26 Pfizer Inc Purine derivatives
US7238676B2 (en) 2000-06-27 2007-07-03 Pfizer Inc. Purine derivatives
WO2002000676A1 (fr) * 2000-06-27 2002-01-03 Pfizer Limited Derives de purine
US6624158B2 (en) 2000-09-15 2003-09-23 Pfizer Inc Purine derivatives
WO2004003002A1 (fr) * 2002-06-27 2004-01-08 Aventis Pharma Deutschland Gmbh Nouveaux analogues de l'adenosine et leur utilisation comme agents pharmaceutiques
EP1375508A1 (fr) * 2002-06-27 2004-01-02 Aventis Pharma Deutschland GmbH Dérivés de l'adénosine N6-substitués et leur utilisation comme médicament
US7265111B2 (en) 2002-06-27 2007-09-04 Sanofi-Aventis Deutschland Gmbh Adenosine analogues and their use as pharmaceutical agents
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor
US8080664B2 (en) 2007-02-23 2011-12-20 Universidad De Zaragoza Use of compounds as inhibitors for Helicobacter flavodoxin
JP2010521424A (ja) * 2007-03-02 2010-06-24 ユニバーシダード デ ザラゴザ 感染症の治療のための組成物
WO2008107502A1 (fr) * 2007-03-02 2008-09-12 Universidad De Zaragoza Composition destinée à traiter des maladies infectieuses
US8367840B2 (en) 2007-03-02 2013-02-05 Universidad De Zaragoza Composition for treating infectious diseases caused by Helicobacter
US8461202B2 (en) 2007-03-02 2013-06-11 Universidad De Zaragoza Composition for treating infectious diseases
ES2304220A1 (es) * 2007-03-02 2008-09-16 Universidad De Zaragoza Composicion para el tratamiento de enfermedades infecciosas.
US9278990B2 (en) 2010-09-22 2016-03-08 Alios Biopharma, Inc. Substituted nucleotide analogs
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8772474B2 (en) 2010-12-22 2014-07-08 Alios Biopharma, Inc. Cyclic nucleotide analogs
US9365605B2 (en) 2010-12-22 2016-06-14 Alios Biopharma, Inc. Cyclic nucleotide analogs
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US10464965B2 (en) 2011-12-22 2019-11-05 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
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US11021509B2 (en) 2011-12-22 2021-06-01 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9605018B2 (en) 2011-12-22 2017-03-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US9441007B2 (en) 2012-03-21 2016-09-13 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9394330B2 (en) 2012-03-21 2016-07-19 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US9856284B2 (en) 2012-03-21 2018-01-02 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US10485815B2 (en) 2012-03-21 2019-11-26 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
USRE48171E1 (en) 2012-03-21 2020-08-25 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog

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