Patent GB-1368243-A (GB)
Title: Monochromone-2-carboxylic acids
IPC: C07D311/24
Filed: 1971-06-03
Abstract: 1368243 Chromone - 2 - carboxylic acids FISONS Ltd 2 Aug 1971 [25 Aug 1970 15 Sept 1970 11 Dec 1970 3 June 1971] 40777/70 43984/70 58860/70 and 18807/71 Heading C2C The invention comprises compounds of Formula I in which R 5  represents hydrogen, hydroxy or, -OR<SP>1</SP> 5  in which R<SP>1</SP> 5  is a straight or branched saturated, or ethylenically unsaturated, hydrocarbon group which group is optionally substituted by an -OH or by a 5 or 6 membered oxygen-containing heterocyclic ring, R<SP>1</SP> 5  together with any substituents thereon containing from 3 to 8 carbon atoms inclusive; R 6  represents hydrogen, alkyl containing from 1 to 6 carbon atoms inclusive, alkenyl containing from 2 to 6 carbon atoms inclusive, or phenyl; R 7  represents hydrogen or lower alkoxy-lower alkoxy; R 8  represents hydrogen, alkyl containing from 1 to 6 carbon atoms inclusive, or alkenyl containing from 2 to 6 carbon atoms inclusive; provided that (i) R 8  does not represent propyl when R 5  represents hydroxypropxy; (ii) R 8  does not represent ethyl when R 5  is but-3-enoxy; (iii) two or three of R 5 , R 6 , R 7  and R 8  are other than H, save that (a) when R<SP>1</SP> 5  represents a straight-chain C 5-7  alkyl or alkenyl group or a branched chain C 6-8  alkyl or alkenyl group, then 0, 1 or 2 of R 6 , R 7 , R 8  are other than H; or (b) when R 6  represents Ph, then 0, 1 or 2 of R 7 , R 8  are other than H; (iv) R 6  and R 8  are both ethyl or are both sec. butyl only when R 5  is not hydrogen; (v) R 6  is alkyl containing from 4 to 6 carbon atoms when R 7  is lower alkoxy-lower alkoxy; and (vi) at least one of R 6  and R 8  contains 2 or more carbon atoms when R 5  is hydrogen or hydroxy; and pharmaceutically acceptable derivatives thereof, and processes for making them by: (a) cyclizing a compound of Formula II in which R 5 , R 6 , R 7 , R 8  and the provisos are as defined above, and A<SP>1</SP> and A<SP>2</SP> represent the pairs of groups: (i) -COCH 2 COCOR<SP>11</SP> and -OM; or (ii) -H and -O-C(COOM)=CH-COOM in which R<SP>11</SP> represents -OM, or a group which is hydrolysable thereto; and M represents hydrogen or an alkali metal, and if necessary or desired hydrolysing the group R<SP>11</SP>; (b) selectively hydrolysing or oxidizing a compound of Formula III in which R 5 , R 6 , R 7 , R 8  and the provisos are as defined above, and D is a group which is hydrolysable or oxidizable to a -COOH group; provided that when D is a group oxidizable to a -COON group none of R 5 , R 6 , R 7  and R 8  represent an alkyl group other than a t-butyl group; (c) selectively dehydrogenating a compound of Formula IV or an ester thereof in which R 5 , R 6 , R 7 , R 8 , and the provisos are as defined above; (d) producing a compound of Formula Ia or an ester thereof in which R 6 , R 8  and the provisos are as defined above; R 5 <SP>x</SP> is hydrogen, or -OR<SP>1</SP> 5  as defined above; R 7 <SP>x</SP> has the same significances as R 7  above; and one or R 5 <SP>x</SP> and R 7 <SP>x</SP> is -OR<SP>1</SP> 5  or lower alkoxy-lower alkoxy respectively, by reacting a corresponding compound of Formula V or an ester thereof in which R 6 , R 8  and the provisos are as defined above; R 5 <SP>y</SP> is hydrogen or hydroxy; R 7 <SP>y</SP> is hydrogen, hydroxy, hydroxylower-alkoxy, or lower alkoxy substituted by an anion forming group; and one of R 5 <SP>y</SP> and R 7 <SP>y</SP> is hydroxy, hydroxy-lower-alkoxy, or lower alkoxy substituted by an anion forming group, with, when R 5 <SP>y</SP> is a hydroxy group, an appropriate alkylene oxide, or a compound of Formula XIV in which R<SP>1</SP> 5  is as defined above; and X represents an anion forming group; when R 7 <SP>y</SP> is hydroxy lower alkoxy, a lower alkane substituted by an anion forming group; or when R 7 <SP>y</SP> is lower alkoxy substituted by an anion forming group; a lower alkanol; or when R 7 <SP>y</SP> is hydroxy, lower alkoxy-lower alkane substituted by an anion forming group; (e) producing a compound of Formula Ib or an ester thereof in which the provisos are as defined above; R 6 <SP>e</SP> and R 8 <SP>e</SP> have the same significances as R 6  and R 8  above, save that at least one of R 6 <SP>e</SP> and R 8 <SP>e</SP> represent a group R 11 ; and R 11  represents an allyl group or an allyl group substituted by alkyl in the position adjacent to the benzene ring, said group containing up to 6 carbon atoms, by subjecting a compound of Formula XII or an ester thereof in which the provisos are as defined above; R<SP>1</SP> 11  represents an allyl group or an alkyl substituted allyl group containing up to 6 carbon atoms; and R 6 <SP>f</SP> and R 8 <SP>f</SP> have the same significance as R 6 , and R 8  above, save that at least one of R 6 f and R 8 <SP>f</SP> represents hydrogen, to an elevated temperature; (f) producing a compound of Formula If  or an ester thereof in which R 6 , R 8  and the provisos are as defined above, by replacing an R<SP>9</SP> group with a hydrogen atom in a compound of Formula XIII or an ester thereof, in which R 6 , R 8  and the provisos are as defined above, and R 9  represents alkyl, aralkyl or acyl, or (g) producing a compound of Formula Ig or an ester thereof in which R 7  and the provisos as defined above; and R 6 g, R<SP>1</SP> 5 g and R 8 <SP>g</SP> have the same significance as R 6 , R<SP>1</SP> 5  and R 8  respectively, save that at least one of R 6 g, R<SP>1</SP> 5 g and R 8 g represent alkyl containing from 2 to 8 carbon atoms, by hydrogenating a corresponding compound of Formula XV or an ester thereof in which R 7  and the provisos are as defined above; and R 6 <SP>h</SP>, R 8 <SP>h</SP> and R<SP>1</SP> 5 <SP>h</SP> have the same significance as R 6 , R 8  and R<SP>1</SP> 5  above, save that at least one of R 6 <SP>h</SP>, R 8 <SP>h</SP> and R<SP>1</SP> 5 <SP>h</SP> represent an alkenyl group containing from 2 to 8 carbon atoms as appropriate, and if necessary or desired hydrolysing the ester of the compound of Formula I to a compound of Formula I and/or converting the compound of Formula I to a pharmaceutically acceptable derivative thereof. The term "lower" hereinbefore means up to C 6 . Specified intermediates (but see also application 3735/74, Serial No. 1,368,244) are Therapeutic compositions which inhibit antigen-activity reactions comprise compounds of the above Formula I, and may be administered orally, rectally or by inhalation, but preferably in the form of compositions designed to be taken oesophageally and to release their contents in the gastrointestinal tract. Reference has been directed by the Comptroller to Specifications 1,297,264 and 1,340,512.