Patent GB-1472766-A (GB)
Title: Hydroxycinnoline derivatives processes for their preparation and their use in pharmaceutical compositions
IPC: C07D409/04
Filed: 1974-11-07
Abstract: 1472766 Hydroxy cinnoline derivatives IMPERIAL CHEMICAL INDUSTRIES Ltd 14 Oct 1975 [7 Nov 1974] 48205/74 Heading C2C [Also in Division A5] The invention comprises compounds having the formula wherein R<SP>1</SP> stands for a hydroxy, C 1-6 -alkoxy, C 3-6  - alkoxyalkoxy, C 7-10  - phenylalkoxy or phenoxy radical, and R<SP>2</SP> stands for an amino, C 2-6 -alkanoyl, cyano, carboxy, C 1-5 -alkylthio, C 1-5  - alkylamino, di - C 1-5  - alkylamino, cycloalkylamino of not more than 6 carbon atoms, 2,2 - dimethyl - 5 - oxocyclohexenylamino, 2- hydroxy - 2 - phenylethylamino, 2 - nitroethylenylamino, C 2-20  - alkanoylamino, benzamido, nitrobenzamido, (C 2-4  - alkanoyloxy)benzamido, (C 1-3  - alkoxy)benzamido, di - (C 1-3  - alkoxy)- benzamido, tri - (C 1-3  - alkoxy)benzamido, benzene sulphonamido, p - toluene - sulphonamido, (C 1-3  - alkane)sulphonamido, (C 1-3 - alkoxy)carbonylamino, polyhalogeno(C 1-3 -alkoxy)carbonylamino, benzyloxycarbonylamino, (C 1-5  - alkyl)xanthone - 3 - carbonylamino, glycylamino, N,N - dimethylglycylamino, alanylamino, valylamino, phenylalanylamino, aspartylamino, # - alanylamino, phenylglycylamino, N<SP>2</SP> - (C 1-5  - alkyl)ureido, N<SP>2</SP> - [(C 2-5 - alkoxycarbonyl)(benzyl)methyl]ureido, N<SP>2</SP> - phenylureido; N<SP>2</SP> - monohalogenophenylureido, N<SP>2</SP> - dihalogenophenylureido, N<SP>2</SP> - phenylthioureido, thioureylene, nitrophenyl, (C 2-5 -alkoxycarbonyl)phenyl or 2,5 - dioxopyrrolin - 3 - yl radical, or an aromatic heterocyclic radical of 5 or 6 ring atoms and containing a nitrogen, oxygen or sulphur atom as a ring atom and which heterocyclic radical may optionally be substituted by a C 1-3 -alkyl or aldehydo radical or by a halogen atom, or a pharmaceuticallyacceptable salt thereof, but excluding 6-amino- 4-hydroxycinnolin-3-yl carboxylic acid or a pharmaceutically-acceptable salt thereof. The compounds of formula I may be prepared by (a) in the case where R<SP>2</SP> stands for a nitrophenyl, (C 2-5  - alkoxycarbonyl)phenyl or 2,4 - dioxopyrrolin-3-yl radical, or an aromatic heterocyclic radical of 5 or 6 ring atoms and containing a nitrogen, oxygen or sulphur atom as a ring atom and which heterocyclic radical may optionally be substituted by a C 1-3 -alkyl or aldehydo radical or by a halogen atom, first diazotizing a compound of the formula I in which R<SP>2</SP> stands for an amino radical, and then reacting the resulting diazonium salt with a compound of the formula R<SP>2</SP>H, wherein R<SP>2</SP> is an aromatic radical having the meaning stated immediately above; (b) in the case where R<SP>2</SP> stands for an amino radical, reducing the corresponding compound wherein R<SP>2</SP> stands for a nitro group; (c) in the case where R<SP>2</SP> stands for a C 2-6 -alkanoyl radical, oxidizing the corresponding compound wherein R<SP>2</SP> stands for a C 2-6  alkyl radical; (d) in the case where R<SP>2</SP> stands for an acylamino radical, acylating the corresponding compound wherein R<SP>2</SP> stands for an amino radical; (e) in the case where R<SP>2</SP> stands for a cyano radical, diazotizing the corresponding compound wherein R<SP>2</SP> stands for an amino radical, and reacting the resulting diazonium salt with cuprous cyanide; (f) in the case where R<SP>1</SP> and R<SP>2</SP> stand for a carboxy radical, hydrolysing the corresponding compound wherein R<SP>1</SP> has the meaning stated in claim 1 and R<SP>2</SP> stands for a cyano radical; (g) in the case where R<SP>2</SP> stands for an aminoacylamino radical, removing the protecting radical from the corresponding protected aminoacylamino derivative; (h) in the case where R<SP>2</SP> stands for a dimethylamino radical, reacting the corresponding compound wherein R<SP>2</SP> stands for an amino radical with formaldehyde and formic acid; (i) in the case where R<SP>2</SP> stands for a C 3-5 -alkylamino radical of the formula -NHCHR<SP>3</SP>R<SP>4</SP>, wherein R<SP>3</SP> stands for hydrogen or an alkyl radical and R<SP>4</SP> stands for an alkyl radical, or R<SP>2</SP> stands for a cycloalkylamino radical of not more than 6 carbon atoms, reacting the corresponding compound wherein R<SP>2</SP> stands for an amino radical with the appropriate carbonyl compound under reducing conditions; (j) in the case where R<SP>2</SP> stands for a N,N-dimethylglycylamino radical, reacting the corresponding compound wherein R<SP>2</SP> stands for a glycylamino radical with hydrogen and formaldehyde in the presence of a suitable hydrogenation catalyst; (k) in the case where R<SP>2</SP> stands for a 2-hydroxy-2-phenyl-ethylamino radical, reacting the corresponding compound wherein R<SP>2</SP> stands for an amino radical with styrene oxide; (1) in the ease where R<SP>1</SP> stands for a C 1-6 -alkoxy, C 3-6 -alkoxyalkoxy, C 7-10 - phenylalkoxy or phenoxy radical, and R<SP>2</SP> stands for a substituted ureido or thio-ureido radical, reacting the corresponding compound wherein R<SP>2</SP> stands for an amino radical with the appropriate isocyanate or isothiocyanate; (m) in the case where R<SP>2</SP> stands for a C 1-5 -alkylthio radical, diazotizing the corresponding compound wherein R<SP>2</SP> stands for an amino radical, and then reacting the diazonium salt with an appropriate alkali metal xanthate, and then decomposing the xanthate so obtained by heating it in the presence of a suitable solvent; and (n) in the case where R<SP>2</SP> stands for a 2-nitroethylenylamino radical, reacting the corresponding compound wherein R<SP>2</SP> stands for an amino radical with methazonic acid in the presence of dilute hydrochloric acid. The compounds of formula I are active inhibitors of the effects following the combination of reagin like antibodies and their antigens and may be used, preferably in admixture with pharmaceutically acceptable carriers, for the treatment of allergic asthma, hay fever, urticaria or autoimmune diseases and may be administered by inhalation, intravenously, orally or as a suppository.