Patent GB-1493006-A (GB)
Title: Cyclic-substituted derivatives of 1-amino-2-propanol
IPC: C07C67/00
Filed: 1975-05-02
Abstract: 1493006 Cyclic substituted derivatives of 1 - amino - 2 - propanol; their preparation and pharmaceutical compositions CIBA-GEIGY AG 2 May 1975 [14 May 1974 (2)] 18491/75 Heading C2C The invention comprises compounds of general Formula (I) wherein one of Ar 1  and Ar 2  is an optionally substituted monocyclic aromatic heterocyclic ring containing 1 or 2 nitrogen atoms bonded to the oxygen atom via a ring carbon atom and the other is a similar group or an optionally substituted aromatic hydrocarbon radical and Alk is a lower alkylene group which separates the nitrogen and oxygen atoms by at least two carbon atoms arid their salts which may be prepared by (a) reacting a compound of general Formula II wherein at least one of X 1  and X 2  is a group which is replaceable by hydrogen by solvolysis or reduction and the other represents hydrogen or a group replaceable by hydrogen by solvolysis or reduction or X 1  and H 2  together represent a radical replaceable by two hydrogen atoms by solvolysis or reduction or a salt thereof with a reagent capable of replacing said radical(s) X 1  and/or X 2  by hydrogen, e.g. by solvolysis or reduction and if desired converting the resulting compound of Formula I into a salt or a further compound of Formula I by known reactions, (b) reacting a compound of Formula (III) with a compound of Formula (IV) wherein one of X 3  and X 5  represents a reactive esterified OH group and the other represents -NH 2  and X 4  represents OH or wherein X 3  and X 4  together represent an epoxy group and X 5  represents -NH 2  and if desired the above mentioned additional process steps are carried out, (c) reacting a compound of Formula (V) or a salt thereof with a compound of Formula (VIa) or (VIb) wherein X 6  is a reactive esterified OH group and X 7  is OH or X 6  and X 7  together denote an epoxy group and, if desired, carrying out the above mentioned additional process steps or (d) reduction of a compound of formula (VII) wherein -X 8 -O- is one of the radicals of Formula VIIb to VIIe -CH=N-Alk-O (VIIb); -CH 2 -N = Alk 1 -O- (VIIc); -CH 2 -NH-Alk 2 -O (VIIe) wherein Alk 1  represents the alkenylidene radical Alk, Alk 2  represents the oxa or thioxa alkylene radical corresponding to Alk, in which the carbon atom of the radical Alk bonded to the nitrogen atom contains the oxo or thioxo group and X 9  represents an oxo or thioxo group and, if desired, carrying out the above mentioned additional process steps. 2 - and 6 - (2 - N,N - Dibenzylaminoethoxy)- nicotinic acid amides are prepared by reacting 2 - N,N - dibenzylaminoethanol with sodium hydride followed by 2- and 6-chloronicotinic acid amide respectively and are hydrogenated to obtain 2 - and 6 - (2 - N - benzylaminoethoxy)nicotinic acid amides which are further reacted with 3 - (2 - methylphenoxy) - 1,2- epoxypropane to obtain 1 - {N - benzyl - N- [2 - (3 - and 5 - carbamoyl - 2 - pyridyloxy)- ethyl]amino} - 3 - (2 - methylphenyloxy) - 2 - propanol. 3 - (2 - Allylphenoxy) - 1 - {N - benzyl - N - [2- (5 - carbamoyl - 2 - pyridyloxy)ethylamino} - 2- propanol is prepared by reaction of 3-(2-allylphenoxy) - 1,2, - epoxypropane with 6 - (2- N-benzylaminoethyloxy)nicotinic acid amide. 2 - (2 - N - Benzylaminoethoxy) - 3 - picoline is obtained by reacting 2-N-benzylaminoethanol with sodium hydride and then with 2- bromo-3-methylpyridine and is then reacted with 3 - (4 - methylaminocarbonylphenoxy)- 1,2-epoxypropane to prepare 1 - {N - benzyl- N - [2 - (3 - methyl - 2 - pyridyloxy) - ethyl]- amino} - 3 - (4 - methylaminocarbonylphenoxy)- 2-propanol. 6 - (3 - N - Benzylaminopropyloxy)nicotinic acid amide is prepared by reaction of 3-N- benzylaminopropanol with sodium hydride followed by 6-chloronicotinic acid amide and is then reacted with 1,2 - epoxy - 3 - (2 - methylphenoxy)propane to obtain 1 - {N - benzyl- N - [3 - (5 - carbamoyl - 2 - pyridyloxy)propyl]- amino}3 - (2 - methylphenoxy) - 2 - propanol. 6 - (2 - Aminoethoxy)nicotinic acid amide is prepared by hydrogenation of 6-(2-N,N-dibenzylaminoethoxy)nicotinic acid amide. 3 - (2 - Oxopropoxy) - 2 - pyridine carboxylic acid amide is prepared by reacting 3-hydroxy-2- pyridine carboxylic acid amide with chloroacetone in the presence of K 2 CO 3 . 6-Chloronicotinic acid amide is prepared by reaction of methylamine with 6-chloronicotinic acid chloride and is reacted with the product of reaction of 2-N,N-dibenzylaminoethanol and NaH to obtain 6 - (2 - N,N - dibenzylaminoethoxy)nicotinic acid N - methylamide which on catalytic hydrogenation gives 6-(2-aminoethoxy)nicotinic acid N,N-methylamide. 1 - {N - Benzyl N-[2 - (5 - carbamoyl - 2 - pyridyloxy)ethyl]amino} - 3 - (4 - benzyloxyphenoxy) - 2-propanol is prepared by reaction of 1-(4- benzyloxyphenoxy)-2,3-epoxypropane with 6- (2-benzylaminoethoxy)nicotinic acid amide. 1 - {N - Benzyl - N - [2 - (5 - carbamoyl - 2- pyridyloxy)ethyl]amino} - 3 - phenoxy - 2 - propanol is prepared by reaction of 1,2-epoxy-3- phenoxypropane with 6-(2-benzylaminoethoxy)- nicotinic acid amide. 2 - Benzylamino - 2 - methyl - 1 - propanol is prepared by reaction of benzaldehyde with 2- amino - 2 - methyl - 1 - propanol and is reacted with NaH followed by 6-chloronicotinic acid amide to obtain 6-(benzylamino-2,2-dimethylethoxy)nicotinic acid amide which is in turn reacted with 1 - (2 - methylphenoxy) - 2,3- epoxypropane to obtain 1 - {N - benzyl - N- [2 - (5 - carbamoyl - 2 - pyridyloxy) - 1,1 - dimethylethyl]amino} - 3 - (2 - methylphenoxy)- 2-propanol. 1 - {N - Benzyl - N . [2 - (5 - carbamoyl - 2- pyridyloxy)ethyl]amino} - 3 - (2 - methoxyphenoxy) - 2 - propanol is prepared by reaction of 1-(2-methoxyphenoxy)-2,3-epoxypropane and 6-(2-benzylaminoethoxy)nicotinic acid amide. 2 - (2 - N,N - Dibenzylaminoethoxy)- pyrimidine is prepared by reaction of 2-N,N-dibenzylaminoethanol with NaH followed by 2-chloropyrimidine and is hydrogenated to obtain 2- (2 - N - benzylaminoethoxy pyrimidine as its hydrogen fumarate which is in turn reacted with 3 - (2 - methylphenoxy) - 1,2 - epoxypropane to obtain 1 - {N - benzyl - N - [(2 - pyrimidinyloxy)- ethyl]amino} - 3 - (2 - methylphenoxy) - 2 - propanol. 2 - (N,N - Dibenzylaminoethyl)- 3 - methylpyrazine is prepared by reaction of 2-N,N- dibenzylaminoethanol with sodium hydride followed by 2 - methyl - 3 - chloropyrazine and is hydrogenated to obtain 2-methyl-3-(2-aminoethoxy)pyrazine. 3 - Benzyl - 5 - hydroxymethyl - 2 - phenyloxazolidine is prepared by reaction of benzaldehyde with 3 - benzylamino - 1,2 - propanediol prepared by reaction of benzylamine and glycerol glycid. The oxazolidine is treated with sodium hydride followed by 2-bromo-3-methylpyridine to obtain 1 - benzylamino - 3 - (3 - methyl - 2- pyridyloxy) - 2 - propanol which is hydrogenated to obtain 1 - amino - 3 - (3 - methyl - 2- pyridyloxy)-2-propanol. 4 - (2 - Bromoethoxy)benzamide is prepared by reacting 4-hydroxybenzamide and 1,2-dibromoethane and is reacted with 1-benzylamino - 3 - (3 - methyl - 2 - pyridyloxy) - 2- propanol to obtain 1 - {N - benzyl - N - [2 - (4- carbamoylphenoxy)ethyl]amino} - 3 - (3 - methyl- 2-pyridyloxy)-2-propanol. 1 - [2 - (2 - Carbamoylphenoxy) - 1 - methylethylideneamino] - 3 - (3 - methyl - 2 - pyridyloxy)-2-propanol is prepared by reaction of 1- amino - 3 - (3 - methyl - 2 - pyridyloxy) - 2- propanol with 1-(2-carbamoylphenyloxy)acetone. 1 - [2 - (2 - Carbamoyl - 3 - pyridyloxy) - 1- methylethylideneamino]- 3 - (3 - methyl - 2 - pyridyloxy) - 2 - propanol is prepared by reaction of 1 - amino - 3 - (3 - methyl - 2 - pyridyloxy) - 2 - propanol with 3 - (2 - oxopropyloxy- 2-pyridine carboxylic acid amide. 4 - (2 - Chloro - 3 - pyrazinyloxymethyl) - 2,2- dimethyl - 1,3 - dioxolane and its 2 - methyl- 3 - pyrazinyloxymethyl analogue are prepared by reaction of 2,3-dichloropyrazine and 2- chloro-3-methylpyrazine respectively with 2,2- dimethyl - 4 - hydroxymethyl - 1,3 - dioxolane and are treated with HCl to obtain ; 3 - (2 - Chloro or methyl) - 3 - pyrazinyloxy)- 2 - hydroxy - 1 - propanol which are in turn reacted with triethyl orthoacetate to obtain 2 - ethoxy - 4 - (2 - chloro (or methyl) - 3 - pyrazinyloxymethyl)- 2 - methyl - 1,3 - dioxolane which on reaction with trimethylchlorosilane gives 2 - acetoxy - 3 - (2 - chloro (or methyl)- 3 - pyrazinyloxy - 1 - propylchloride from which 2 - chloro and 2 - methyl - 3 - (2,3 - epoxypropoxy) - pyrazine are obtained on reaction with tetrabutylammonium bisulphate. 1 - {N - Benzyl - N - [3 - (2 - carbamoylphenoxy)propyl]amino} - 3 - (3 - methyl - 2- pyridyloxy) - 2 - propanol is prepared by reaction of 1 - benzylamino - 3 - (3 - methyl- 2 - pyrimidyloxy) - 2 - propanol and o - (3- bromopropoxy)benzamide. 1 - Benzylamino - 3 - (2 - pyrimidinyloxy)- 2-propanol is prepared by reaction of 3-benzyl-5- hydroxymethyl-2-phenyloxazolidine with sodium hydride followed by 2-chloropyrimidine and is reacted with 2-(4-bromoethoxy)benzamide to obtain 1 - {N - benzyl - N - [2 - (4 - carbamoylphenoxy)ethyl]amino} - 3 - (2 - pyrimidinyloxy)- 2-propanol hydrochloride. 1 - {N - Benzyl - N - [2 - (2 - carbamoylphenoxy). ethyl]amino} - 3 - (2 - chloro - 3 - pyrazinyloxy)- 2-propanol is prepared by reaction of 2-(N- benzylaminoethoxy)benzamide and 2-chloro-3- (2,3-epoxypropoxy)pyrazine. Pharmaceutical compositions having #-receptor blocking, blood pressure lowering and vasodilatory activity and antagonistic activity against the vasoconstricting effect of noradrenaline for enteral or parenteral administration comprise a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable excipient.