Patent GB-1476106-A (GB)
Title: Araliphatic nitrogen compounds processes for their preparation and pharmaceutical compositions containing them
IPC: C07D521/00
Filed: 1975-10-23
Abstract: 1476106 Araliphatic nitrogen compounds and pharmaceutical uses thereof MERCK PATENT GmbH 23 Oct 1975 [26 Oct 1974 28 May 1975] 43628/75 Heading C2C The invention relates to compounds of formula wherein R is a 4-biphenylyl or 4-phenoxyphenyl radical which is unsubstituted or which is mono- or polysubstituted by F, Cl and/or Br, A is -CH(CH 3 )-CH 2 -(CH 2 ) n -, or Z is -NR<SP>1</SP>R<SP>2</SP>, imidazol-1-yl, phthalimido or 3,4-dihydro-4-oxo-phthalazin-1-yl-amino, R<SP>1</SP> and R<SP>2</SP>, which may be the same or different, are H, alkyl, azaalkyl or acyl having in each case 1-6 C atoms or together are alkylene having 4-7 C atoms, 3-oxapentamethylene or 3-R<SP>3</SP>- 3-azapentamethylene, R<SP>3</SP> is H, alkyl or hydroxyalkyl having in each case up to 6 C atoms, and n is 0, 1 or 2, and their physiologically acceptable acid addition salts. These compounds may be obtained by any one of the following methods: (i) reducing a compound of Formula II wherein Q is a radical which can be reduced to the group -A-Z, and R, A and Z have the above-stated meanings; or (ii) treating a compound which corresponds to Formula I, but in which the amino group and/or the hydroxyl group is present in a functionally modified form, with a solvolysing agent; or (iii) reacting a compound of Formula III wherein E is or -A-X, m is 0 or 1, X is Cl, Br, I OH or OH which is functionally modified in a reactive manner, and R and A have the above-stated meanings, with a compound of the formula H-Z or with a reactive derivative thereof; or (iv) treating an amine of Formula IV wherein R, A and X have the above-stated meanings, with an agent which splits off HX; or (v) reacting an amine of Formula V wherein R, A and X have the above-stated meanings, with a compound of the formula H 2 NR<SP>3</SP>, wherein R<SP>3</SP> has the above-stated meaning; or (vi) diazotizing a compound of Formula VI wherein R<SP>4</SP> is a 4-biphenylyl or 4-phenoxyphenyl radical which is mono- or poly-substituted by NH 2  and, if desired, additionally mono- or poly-substituted by F, Cl and/or Br, and A and Z have the above-stated meanings, and halogenating the resulting diazonium salt; or (vii) reacting a compound of Formula VII or a salt thereof, with a compound of Formula VIII or with a salt thereof, wherein one of the groups Q<SP>1</SP> and Q<SP>2</SP> is OH, the other is X, R<SP>5</SP> is an unsubstituted p-phenylene radical or a p-phenylene radical which is mono- or poly-substituted by F, Cl and/or Br, R<SP>6</SP> is an unsubstituted phenyl radical or a phenyl radical which is mono- or poly-substituted by F, Cl and/or Br, and A, Z and X have the above-stated meanings. A resulting hydroxy compound of Formula I may, if desired, be treated with a dehydrating agent or a resulting compound of Formula I may, if desired, be treated with a reducing agent. In a resulting compound of Formula I, one or more chlorine or bromine atoms may, if desired, be introduced by treatment with chlorinating or brominating agents and/or the Z radical may be converted into another Z radical by treatment with an alkylating, acylating, solvolysing and/or reducing agent. When a base of Formula I is obtained by any of the foregoing procedures, it may be converted into a physiologically acceptable acid addition salt by treatment with an acid. The following intermediates are prepared in Example I: 4-Acetylbiphenyl prepared by Friedel-Crafts acetylation of biphenyl; 3 - p - Biphenyl - 3 - hydroxy - butyric acid ethyl esters obtained by the reaction of 4- acetylbiphenyl with bromoacetic acid ethyl ester/Zn; 3 - p - Biphenyl - butyric acid by hydrolysing the above ester. The invention also comprises a pharmaceutical composition comprising at least one compound of Formula I in association with an inert, physiologically acceptable carrier.