Patent GB-1399109-A (GB)
Title: Basically substituted alkyltheophyline derivatives
IPC: C07D473/08
Filed: 1972-09-06
Abstract: 1399109 Basically substituted alkylthiophyllines DEUTSCHE GOLDUND SILBERSCHEIDEANSTALT 6 Sept 1972 [6 Sept 1971 28 Oct 1971] 41364/72 Heading C2C Novel compounds of the Formula (I) in which R<SP>1</SP> denotes H or CH 3 , R<SP>2</SP> and R<SP>3</SP>, which may be the same or different, each represent H, CH 3 , OH or -CH 2 OH, R<SP>4</SP> is H or CH 3 , R<SP>5</SP> is C 1-6  alkyl, C 7-12  phenylalkyl or -NR<SP>6</SP>R<SP>7</SP>, in which R<SP>6</SP> and R<SP>7</SP>, which may be the same or different, each represents H or C 1-6  alkyl, or taken together with the N atom to which they are attached represent a 5, 6 or 7- membered ring which may optionally contain an oxygen atom, a further nitrogen atom or a sulphur atom and which may optionally be substituted by one or two C 1-4  alkyl groups, and Alk represents a linear propylene group, or R<SP>5</SP> is H, R<SP>1</SP> is H, R<SP>2</SP> is OH in the 4-position, R<SP>3</SP> is CH 3  or -CH 2 OH in the 3-position, R<SP>4</SP> is H or CH 3  in the 5-position and Alk denotes a propylene group which may optionally be substituted by one or more C 1-3  alkyl groups, with the proviso that if R<SP>5</SP> is a phenalkyl group, no more than two of R<SP>2</SP>, R<SP>3</SP> and R<SP>4</SP> can be H atoms; and the acid addition salts of these compounds, may be obtained by (a) reacting a compound corresponding to the general Formula (II) with a compound corresponding to Formula (III) in which Y denotes a ketone oxygen atom or a hydroxy group and one of X and Z represents a halogen atom and the other represents an amino group or where Z is an amino group, X and Y form an ethylene oxide ring together with a hydrogen atom on the carbon to which Y is attached and, if the compound produced has a keto group on the carbon atom adjacent to the benzene ring, this keto group is reduced into a hydroxy group; or (b) by condensing a compound of Formula (IV) with a compound of Formula (V) in which V and W are different from one another, and V represents -CHO or -CH 2 NH 2  (in which ease the linear carbon chain of -CH 2 CH 2 V can also be substituted by C 1-3  alkyl groups, whilst W denotes -C(R<SP>1</SP>) = O or -CH(R<SP>1</SP>)NH 2 , and Y denotes ketone oxygen or OH plus H, accompanied or followed by hydrogenation. In some cases, the phenolic hydroxy groups and amino groups are protected during reactions (a) and (b) and subsequently the protecting groups are removed. The compounds (I) can be converted into salts by known methods and those which contain asymmetric carbon atoms can be split up into optically active isomers by methods known per se, for example by means of an optically active acid. Alternatively optically active or diastereomeric starting materials can be used to yield the corresponding pure optically active form or diastereomeric configuration as end product. Starting materials are prepared as follows: 8 - diethylaminotheophylline is reacted with 1 - chloro - 3 - bromopropane forming 7- chloropropyl - 8 - diethylamino - theophylline which is then reacted with benzylamine to form 7 - (3 - benzylaminopropyl) - 8 - diethylaminotheophylline; 8 - morpholino - theophylline is similarly converted to 7-(3-benzylaminopropyl)- 8 - morpholino - theophylline and hydrogenated to remove the benzyl group ; similar compounds are obtained in which R 5  is benzyl, butyl, piperidino, 3-methylmorpholino; 7-(3-benzylaminobutyl) - theophylline is reacted with 4- chloroacetyl - 2 - methylphenol to form 7 - {3 - [2 - (3 - methyl - 4 - hydroxyphenyl)- 2 - oxoethyl - benzylamino] - butyl} - theophylline, HCl; 7-(3-benzylaminopropyl)-theophylline and 3 - acetoxymethyl - 4 - acetoxy- # - bromoacetophenone yield 7 - {3 - [2 - (3- hydroxymethyl - 4 - hydroxyphenyl) - 2 - oxoethyl benzylamino] - propyl} - theophylline, HCl; 3,5 - dimethyl - 4 - hydroxy - phenacyl chloride and 7 - (3 - benzylamino butyl)- theophylline yield 7 - {3 - [3,5 - dimethyl - 4- hydroxyphenyl) - 2 - oxoethylbenzylamino]- butyl}-theophylline, HCl. Pharmaceutical compositions having bronchial activity and therapeutically valuable circulatory effects comprise a compound of Formula I together with at least one pharmaceutical additive, excipient or diluent in forms suitable for administration enterally, parenterally, orally or perlingually.