Patent GB-1438574-A (GB)
Title: 1,n6-ethenoadenosine cyclophosphate and cyclophosphonate compounds
IPC: C07C47/14
Filed: 1973-09-14
Abstract: 1438574 Nucleotide derivatives; bromoaldehydes and ketones SYNTEX (USA) Inc 14 Sept 1973 [10 Oct 1972 11 July 1973] 43226/73 Headings C2P and C2C The invention comprises 1,N<SP>6</SP>-ethenoadenosine 3<SP>1</SP>,5<SP>1</SP>-cyclic phosphate and phosphonate compounds of the general formula (A) wherein one of R<SP>1</SP> and R<SP>2</SP> is H and the other is H, C 1 -C 10  alkyl, phenyl, substituted phenyl or 2-naphthyl, R<SP>3</SP> is H, halogen, hydroxy, alkoxy, aryloxy, aralkoxy, SH, alkylthio, arylthio, aralkylthio, ozido, amino, acylamino, alkylamino, aralkylamino, dialkylamino or diaralkylamino, the alkyl and groups being defined as C 1 -C 8  alkyl and the aryl groups being defined as aryl groups containing from C 6 -C 12  ring carbon atoms which may be substituted by nitro, amino, alkyl, alkoxy, halo and alkylthio, S is a sugar residue selected from B to E R<SP>4</SP> is OH or a conventional group convertible to OH by hydrolysis, R<SP>5</SP> is H or a pharmaceutically acceptable cation and one of R<SP>6</SP> and R<SP>7</SP> is H and the other of R<SP>6</SP> and R<SP>7</SP> is a C 1 -C 6  alkyl group or R<SP>5</SP> and R<SP>7</SP> are identical C 1 -C 6  alkyl groups, provided that when each of R<SP>1</SP> and R<SP>2</SP> is hydrogen and S is a phosphated or phosphonylated sugar residue of formula (B) in which R<SP>4</SP> is OH, then R<SP>3</SP> is other than H and when S is a sugar residue of formula B in which R<SP>4</SP> is OH and R<SP>3</SP> is H, then one of R<SP>1</SP> and R<SP>2</SP> is other than H. The products which when isolated normally exist as Zwitter ions may be obtained by reacting a compound (I) with an halo-aldehyde or -ketone of the formulµ HaloCHRCHO and HaloCH 2 C(O)R wherein each R is H, C 1 -C 10  alkyl, phenyl, substituted phenyl or 2-naphthyl, and each halo is Cl, Br or I. The reaction is preferably conducted in aqueous solution buffered at a pH of about 5 and a co-solvent may also be added, e.g. dimethyl formamide, dimethyl sulphoxide or hexamethylphosphoric triamide. The aldehyde compound yields the α-substituted products, i.e. where R<SP>1</SP> is R and is other than hydrogen and the ketone yields the #-substituted products where R<SP>2</SP> is R and is other than hydrogen. The pharmaceutically acceptable cations R<SP>5</SP> may suitably be cations of the Ba, Ca, Na, K, NH 4 , trimethylammonium or triethylammonium salts. The products have therapeutic uses, e.g. in disorders attributable to pituitary disfunction, and may be used in admixture with pharmaceutically acceptable carriers in pharmaceutical compositions which may be in the form of tablets, pills, capsules, powders, sustained release formulations, solutions, suspensions, elixirs or aerosols. The starting materials of Formula (I) and various nucleoside intermediates used in their preparation can be prepared in conventional manner and several examples for the preparation of such intermediates and starting materials are given. The starting materials in which R<SP>3</SP> is H can be brominated to form the 8-bromo compounds which can then be converted to compounds in which R<SP>3</SP> is OH, SH, azido, or an organic-oxy, -thio, or -amino group as defined. The 8-azide compounds can be converted to the 8-amino compounds by catalytic reduction and the latter compounds then acylated to form the acylamino compounds. The 8-chloro and 8-iodo compounds can be prepared from the 8-methylthio or 8-thio compounds by reaction with Cl 2  and HCl at -10‹ to - 20‹ C. or with iodine and NaI while the 8-fluoro compounds can be prepared by diazotization of the 8- amino compounds in the presence of fluoboric acid followed by irradiation with ultra-violet light or heating. When R<SP>4</SP> is hydroxy it can be esterified by reaction with a carboxylic acid or anhydride of 1 to 22 carbon atoms in a solvent such as pyridine or the tetrahydropyran-2-yl, tetrahydrofuran-2-yl or 4-methoxytetrahydropyran-4-yl ethers can be prepared or such esterification or etherification can be carried out on the final product of Formula (A). α-Bromovaleraldehyde is obtained by dropwise addition of bromine to a solution of valeraldehyde and di-t-butyl-peroxide in ether at -10‹ C. under illumination from a tungsten lamp. Several other haloaldehydes of Formula (II) above obtainable in a similar manner are also specified. n-Propyl bromomethyl ketone is obtained by adding n-butyric acid bromide slowly to an ice cold ethereal solution of diazomethane and then passing in dry hydrogen bromide until an excess is present. n-Propyl chloromethyl ketone may be obtained similarly from the acid chloride and hydrogen chloride and several other bromo ketones of Formula III above which are obtainable in an analogous manner from the acid bromide and HBr are specified.