Patent GB-1065191-A (GB)
Title: 5-substituted aza-dibenzo-cycloheptenes and the preparation thereof
IPC: C07D213/84
Filed: 1964-04-21
Abstract: The invention comprises compounds of the formula <FORM:1065191/C2/1> wherein the dotted line represents an optional double bond, A represents hydrogen or one of the substituents halogen, trifluoromethyl, alkoxy, C1- 12 alkyl, hydroxy and acyloxy attached to one or more of the 6-, 7-, 8- and 9-positions, B represents, together with the carbon atoms to which it is attached, a pyridine ring and Z represents one of the groups <FORM:1065191/C2/2> in which either U and W are both hydrogen or U is a univalent group containing an amino group the nitrogen atom of which is separated from C-5 of the tricyclic nucleus by at least two carbon atoms and W is H or OH, and V is an oxygen atom or a divalent group containing an amino group the nitrogen atom of which is separated from C-5 of the tricyclic nucleus by at least two carbon atoms; and pharmaceutically acceptable acid addition salts thereof. The compounds wherein Z is other than a carbonyl group are prepared by (a) reacting a compound of the formula <FORM:1065191/C2/3> or a reactive derivative thereof, with a reactive derivative of a compound of the formula VH2, wherein V is as defined above except that it is not an oxygen atom, or reacting a reactive derivative of a compound of the Formula IIB with a compound of the formula VH2, wherein V has the meaning given immediately above, so as to replace the group at position C-5 of the aza-dibenzo cycloheptene compound by the group Z or a group convertible into the group Z by one or more of the steps of hydrolysis, dehydration, reduction and dehydrogenation and if necessary subjecting the product thus obtained to any one or more of the steps of hydrolysis, dehydration, reduction and dehydrogenation required to convert it into the desired final product; or (b) subjecting to intramolecular condensation a compound which differs from a compound of Formula I only in that the cycloheptene ring is broken at one point only which is adjacent to the 5-position or the 10-position or the 11-position, and that at least one of the carbon atoms adjacent to the break bears a reactive group, provided that, when the break in the cycloheptene ring is between the 11-position and the pyridine ring or between the 10-position and the benzene ring, the carbon atom at the 10-position or the carbon atom at the 11-position may bear a = O substituent to promote the reactivity of the reactive group towards formation of a carbon-carbon bond so as to cyclize the compound to form the cycloheptene ring, and, when a 10- or 11-carbonyl group is present, reducing the carbonyl group to H2.  The terms "reactive derivative" and "reactive group" are defined in the Specification. The reactive derivative of a compound of Formula IIB may be an organo-metallic derivative, e.g. an organo-Mg-halogen, organo-zinc, organo - cadmium, organo - mercury or organo-alkali metal compound with the metallic atom or group being attached to the 5-position, or the 5-keto derivative.  The reactive derivative of the compound VH2 may be the keto compound V = O, an organo-alkali metal compound or may have the formula <FORM:1065191/C2/4> The compounds wherein Z is a carbonyl group are prepared by cyclizing a compound of the formula <FORM:1065191/C2/5> or a functional derivative thereof, e.g. a corresponding ester, amide, nitrile or isomeric lactone. Alternatively the acid may be converted to the acid chloride which is then cyclized by treatment with a Friedel-Crafts catalyst.  Ortho - styryl - or ortho - phenethyl - pyridine-carboxylic acids of the Formula VIII and the compounds of the invention of Formula IIA are preferably prepared according to the following reaction schemes <FORM:1065191/C2/6> <FORM:1065191/C2/7> <FORM:1065191/C2/8> <FORM:1065191/C2/9> In the above reaction schemes the reagents exemplified may be replaced by other reagents which will achieve the desired result. The unsaturated acids may be converted into the saturated acids and vice versa by usual methods.  1 - Aza - 5H - 10,11 - dihydro dibenzo [a,d] cyclohepten-5-one N-oxide is prepared by treating 1 - aza - 5H - 10,11 - dihydro [a,d] cyclohepten-5-one with hydrogen peroxide.  3 - Phenethyl - 4 - cyano - pyridine is prepared by hydrogenating 3 - styryl - 4 - nitro-pyridine N-oxide to form 3-phenethyl-4-amino-pyridine hydrochloride, diazotizing this compound and treating the so-formed diazonium salt with cuprous cyanide.  The same compound is also formed by treating the diazonium salt prepared as above with aqueous sulphuric acid to form 3 - phenethyl - 4 - hydroxy - pyridine, reacting this compound with phosphorus oxybromide to form 3 - phenethyl - 4 - bromopyriydine and reacting this compound with cuprous cyanide.  3 - Phenethyl - 2 - cyano - pyridine is prepared by refluxing 3-phenethyl-pyridine N-oxide with acetic anhydride to form 2-hydroxy-3-phenethyl-pyridine, reacting this compound with phosphorus oxybromide to form 3-phenethyl-2-bromo-pyridine and reacting this compound with cuprous cyanide.  Pharmaceutical compositions comprise a compound of the invention, in which Z is other than a carbonyl group, together with a pharmaceutical carrier.  The compositions have antihistaminic, antiserotonin and antianaphylactic activity and may be in a form suitable for enteral or parenteral administration.