Pyranoquinolinone derivatives, pharmaceutical compositions containing them, and methods for their preparation

Description

S02 / B / 6V jr. ' i 4 / 60909 volume · ' 1 i | Do00rizione fieli »inv©nzìon having thei4 title* -........-4 Γ ~Ί ' Il Description) COMPOUND ”«J [ \Uri 49 ÀwMj*'\ , S | 8(- ' ν 'ίμ[4\ ·(?*.................... Streot .1 ' » * ! a nomet FISONS DI MITRI) i > a: Flson House, 9 Grosvonor 1 1 '1Donfira *- Great Britain « the ' of British nationality and electively domiciled^iia ,ι·.'· .·. ;,\i 1' , . - ' ,· ii' ta to all intents and purposes of l^ego in Milan - Via Dogana,! i ' H | ' | ' ' I1 ' ' . at the Patent Office representative lng*O.GregofÌ' ! ; ; i ' -1 * " ! (DepoBit. on May 2! 1978 - Ho* fj$ￃﾌ^ 8 #.ￂﾷ7 1ￎﾲ )' \ ] By this invention we refer to new pyranohilinone flower-varieties, to compositions containing them and to methods for their preparation. According to the present invention, compounds of formula I, j are produced. '· 1 ,1 t ! C tr 1 *·* C.> -, CP ! u re 1 ο O .ir; And where an adjacent pair of R^, R^, R^ and Rg forms a -COOH^OE-O- chain, and the roots Rr(II·, IL·! , · iy 6 7 j ! ' and Rg , which may be the same or different, each represent hydrogen, hydroxy, alkyl, halogen, alkenyl, alkoxy or -i?K^Rg in which Rj and R2, which may be the same or different, each represent hydrogen or alkyl O :: >7' i-· Ί -2* Rg represents hydrogen, alkyl, alkyl, or phenylalkyl, and Rg represents -COOH, a 5-tetrazolium group, or a (W-tetrazolium-11) or carboxymethyl group, and 11'; and commonly acceptable derivatives of these compounds, iK I . .1 « . In accordance with the present invention, I also provide a process for the production of a compound of formula I, or a pharmaceutically acceptable derivative thereof, wherein: (a) a compound of formula I is produced wherein ΔE 0*-COOH is hydrolyzed or selectively hydrolyzed to ΔE 0*-COOH, IX where Rg is* as defined above, j ' t R^a, R^a, R^a © R^a have the same meanings as above for R^, Rg» R^ and |d R^, with the difference that an adjacent pair of R^a, R^a, R^a© R^a can represent a chain of formula -COGITO (1>)O-, or one of D and or both represent a hydroxylated or oxidizable group with conversion to -COOH| and the other one can represent a -COOH group, (b) b1 produces a fork reaction I in which Eo» -COOH by means of the reaction of, a compound of formula IH or IV, i IV or a stereotype of one or other of these compounds, . , i 1 where Rg is as defined above, R^b, R^b, Lb and Rgb have the same meanings as above for R^b, Rg, R^ and Rg» 'except that an adjacent pair of R^b, Rgb, R^b and Rgb may represent the pair of groups *H and ~0*C(CO01)®0B«CO0H, ! (o) a compound of formula I in which E ι is -COOH is produced by the addition of a compound of \ I 1 I formula V, V ° : K6\ Γι^Τ J1 1 Ji- ..... OOOH R^o ^ {Λ "ìT —L. • R8° 1 , > ;Rg , . .1 ii,1=1,1 '1,(-1 il 1 * 'Ìi n" 1 ,, > I ,i :*a '' il ' 1 1 il 111 Ìm 1' lì 1 i,1(1 ,i «Ί THE JI ,ι . ! ,· : I i' M il i \ ' lì i 1 or a new ©ether, V ; '··', • .···· ( · 1 ' II . II . · . 1 . .. 1 I, plus which Rg o* as above mentioned finite, R^o, Egb, |R^c èi RgO have, the, ©ignificai ©mentioned above for R^» Rg, R^ and R^, except that an adjacent pair of H^o, RgO* R,^co R^o, invoke to form a Chain -COOII«OjiOOOH)-0- represents: I ' ' · presents the pairs of groups* | 11 'il ' (i) -C00Ho00-O0RM or ~COCH*G(COOH)-RX,,L_, 1 ei ί 12.·' l" 1 1 ' .l'· * il' : » 'Hit ,1 ( or a suitable derivative thereof, and -OM^ or an atom, . of » » Of il I li = « ' I . , halogen, or , . . . 1 ,| '1 : (il) ~H o *0«0(C0R")at0H«00R" -V i 1 i Rn represents ^OM# or a group from the (plane ,ii ·. ; ' ' 1 . I , 1 ' . , 1 | ' ' ' . ' which can be obtained by hydrolysis, : i and L0 which can be the same or different ' le < | * ' * I ' | - the i represent each hydrogen, aryl or alkyl, or ·? i taken together form an alkyl chain ·' ' i , saturated or unsaturated, or , 1 1 | 1M represents hydrogen or an alkaline isomer,1 . i ' 'io © and neo©Donario or dehydrogenated by hydrolyzing the · ! ~COK" group, with conversion to a -'COOM" group, !.. i ' ,i ' · (d) conversion of a compound of formula VI, ' «*>. w / VI >1 1 || ' I 11111 ,1 " or one of its foreign countries,1 : : I . ^ 1 i' i. " j ! I i ' ·. ;·. || || in which Rg g<3 ì; are as defined above, ; 1 . I : '' ' , ' Γ Ί , . 1 11 it , i , ' ' l· · 1 RKfi, B>fl, R, de RQd have the same meanings? © , ( v ··', ,. . i1 1 ; 1 ·ν I . ; defined above for R^, R^» R^, and R^j, except that a pair belonging to R^d, R^d, R^d, and R^d can* ' , represent the chain -0{Η^B^)»θ|κ-Ό*, at least one of the pairs© of groups R^ and R^ together forms a group. »S or àsjlerfle forms > a chain ~S(CH9) S- where n represents a number ci XI <1 < : > ©b- of value 2 or 3, and the other pair R], represent »0, i» i to a corresponding compound, of formula I, (or) are selectively removed^ the groups À and B ' gives a compound of formula VII,, ©d R10 can» .t » VII in which Rg and B are trouble! above defined, R^e, R6e, R^e and R^e have the same signs. ·Ι 1 Η. . ; ,Η ϊ 1Λ:' the above-indicated currents for R^, Rg, Ry and Εβ unless 1' , 1 ·' 1 'that a pair of R-©, Re, Le ©a R0© can1 3 .1 ο ι ; γ o ., − 1 ·. represent a chain of at least one pair of groups À ο B as much as 1 . Glove B represents Hydrogen, or one day A and B - :·ν. i " . : ; : '''"'V·,: represents hydrogen and the other represents halide : u, or a hydroxy group, and the other group A, B can together form a double bond;'; <f) si produce un composto di[formula 1 in cui ,1 · I The £ and COOH cycles have a substituent of formula VIII. I COOK VII! . or its ester, r in which Rg is the above defined, R^f, R^f, R^f or 1 1 I ( Rgf have the same meanings as above for [ R^» Rg» R^ and Rg, except that an adjacent pair of < • · · " ' · . ì : R^f» Rgf» R^f and R^f instead of providing a chain' 1 ~CÓCHssC(C00H)*-0~, represents the pair of groups [ 1 ' ,' II -C00H(S0Rl0)-CK(0H)-C00R" e -0M, | 1 ' ' ' i Rw and M are as defined above, and ' i .1 1 l , * ' ι Rl0 represents a chemical group of 1-10 The carbonium atoms, , I * t 7* (β) oi produce a compound of formula I in which E is a 5-totrazolyl group causing a corresponding compound of formula 1 to react in <j>ui E e* -CN,with an azide in an oil solvent,©' |incorrect in 1 i 1 ! : 1 III ' conditions at the reaction,,or , i '.III ··'* , j , 1 ' ! (h) bì produces a compound of formula X in oui E ! i · . and* a group (N-tetrazol-5*-yl)oecemido doing ; ; ; ;<; ; : : shall react a corresponding compound of formula I in 1 ' 'Vi" containing COOH, or an acyl halide thereof, an ester or mixed anhydride, with 5-aminothotriol, as necessary or desired, hydrolyzing the 1 The king of the compound of formula 3 or / or turning the A compound of formula I to a pharmaceutical derivative thereof 1 I 1 1 ! 1 1 ' ' , 1 1 1 acceptable mountain. 1 , pr°CeB3° <a) ^PUO'i.SBer., .è , j esempio, un gruppo ©stereo, di alogermro acilico, , 1 '' -v i ! '- amidi co o nitrillco che sì può* idrolizzare oon ot ; . ; , ; i . ; . 7 tenimento dì un gruppo -ΟΟΟΗ. 1'idrolisi può* ossorè 1 . '. | ' condotta usando metodi dì tipo tradìz-Loziale, ad esempio '. 1 V I '1 in condizioni blandamente basiche,.corno con l'uso ! 1 i ; ' '1 di carbonato sodico, ìdrossido dì sodio, bicarbonato sodico, oppure in condizioni acide, a|d esempio una ' i miscela di diossano acquoso ed acido (cloridrico oppure ! 1 di acido bromìdrico ed acido noetico. [ L'idrolisi può* A ; « δ·· .1 ! ;'ν· ' i 1 ©Beerò condotta ed una.temperature between 25°0 | · '"vo 120°C depending on the compounds used. Alternatively, the D group may be an alkyl group, for example a lower alkyl such as methyl, a lower hydroxy group such as methyl, an aronic acid group such as methyl, an alkyl group such as methyl, an acetyl group such as methyl, an alkanyl group such as methyl, or a formyl group. The reaction can be carried out using traditional methods. ©they do not motivate others «do not you the mole i , ·* · . * ! the col in such a measure © so © the range of desired product ^ i . to be uneconomical, for example An alkyl group-. I | 1 . t- \co or a hydroxymethyl group can be oxy- * il i used using selenium dioxide, for example under reflux in aqueous dioxane; or by drinking acid i I 11 ,| I chromic, for example under reflux in aqueous acetic acid. X aralchonyl groups can be oxidized I ,P 1 II ' , using, for example, neutral permanganate. i | - I ,1 » or alkaline in aqueous ethanol, and acyl groups can be oxidized using, for example, chloromic acid or an aqueous hypochlorite, for example sodium hypochlorite. The formyl group can be oxidized using, for example, chromic acid or silver oxide. ' I : In process (b) the cyclization can be carried out by treating the compound of formula IH or IV with a cyclizing agent, for example a -9- I nothing dehydrating such as chlorosulfonic acid, sulfuric acid, or polyphosphoric acid. The reaction is preferably carried out under anhydrous conditions or can be carried out at a temperature The temperature is between about 25°C and 100°C, or preferably between 75°C and 100°C. Mchiodonto has found that isomerization of the thallic acid derivative of formula IV to the corresponding derivative of fumaric acid. The recombination of formula HI occurs when polyphosphoric acid is used to synthesize these compounds to obtain a compound of formula I, thus making them it is possible to obtain a satisfactory range of the compound of formula I from a seemingly inconsistent mixture of compounds having formula III. I and IV. Compounds of formula III may also be separated by subjecting the compound to a high temperature, for example between 200°C and 250°C, possibly in the presence of a highly concentrated solvent which is inert under the reaction conditions, for example a solvent consisting of diphenyl ether. When one of the groups is -OH, the cyclization of process (c)(i) can be carried out by heating, or under basic or neutral conditions. It is, however, preferred to carry out the cyclization in the presence of an acid, for example hydrochloric acid, or in a solvent which is inert under the reaction conditions, such as ethanol. The reaction can be carried out at a temperature between about 20°C and 150°C. The -COI group is preferably an oxy group, for example H" may be a lower alkyl group. When one of the groups is -CO CH-C (00011)-111^ the derivative of the -COOH group can be a -COOH^L^ group in which L and L are as defined above. 31 prefers that L or L represent hydrogen, phenyl, carbon atoms of 1-6 carbon atoms, or together form a 4-membered alkylene chain; for example, axioms with a nitrogen atom form a pirodial inoyl. When one of the groups is halogen, the cyclization THE The reaction can be carried out in a solvent that is inert under the reaction conditions, preferably a high-boiling polar solvent of which pyridine is present, dimethyl sulfoxide, or methyl sulfoxide. The reaction is preferably carried out with the aid of THE of a strong base, such as an alkali metal hydride, such as sodium hydride. The reaction is preferably carried out at a temperature of about 80°C to 200°C in the absence of free oxygen. Boron, for example, in an inert atmosphere such as a nitrogen atmosphere. The cyclization of process (c)(ii) can be carried out by treating the compound of formula V with a cyclizing agent, for example a di- t The hydrants such as chlorosulfuric, polyphosphoric or sulfuric acid* reaction is preferably carried out under anhydrous conditions and can be carried out at a temperature between 0°C and 100°C. In Alternatively, the cyclization can be carried out by converting the free carboxylic acid groups of the compound of formula V to acrylic halide groups or by subjecting the resulting acyl halide to an intracellular reaction (Crofto). The processes (d)f when Ηή or li., taken together form a chain — ìj—(CH ) —il—, the conver- - The union can include hydrolloi oatiidatìva and can* I be carried out in a, polar organic oolvonto I aqueous, for example ethanol, acetone or tetra- Aqueous hydrofuran. Oxidative hydrolysis can be carried out in the presence of an oxidizing agent, such as mercuric chloride, an N-halogenated amine such as N-tromosuccinimide or α-chloro-oiodomimide, a p-toluenesulfonyl chloromide or its salt. When mercuric chloride is used the reaction can be carried out in the presence of a base, -12- e.g. mercuric oxide, or cadmium oxide. I or calcium carbonate. N-alkyl succinates may be a ut and in the presence of ί a silver ion, such as silver porchlorate or THE Silver nitrate* The reaction can conveniently be carried out at a temperature between about 1°C and 10°C. When and i.:, together form a group *=S, the conversion may include (oxidative) hydrolysis, and may also be conducted in the presence of a metal compound, for example a compound of a notary from Group Ib, IIb, or IIIb of the Periodic Table of Mandoleef, acting as a catalyst. Suitable compounds include components of norephthalate, thallium I and silver, for example mercury acetate or chloride-(II)», thallium trifluoroacetate(II), or silver oxide. The reaction can also be carried out in the presence of an acetone or a similar organic solvent such as acetone-acetic acid, halogen, trichlorofluoromethanol, or thiadifuran. Alternatively, the reaction can be carried out by solubilization followed by hydrolysis. In such cases the reaction may be carried out by (i) an alkyl sulfonate chloride (e.g., sodium iodide) in a wet solvent, e.g., acetone, (ii) a -13' alkyl sulfonate chloride or sodium iodide in aqueous solution, or (iii) a trifluoroisobutyl iodide followed by aqueous solution. When A and B do not contain hydrogen, the process (e) is a hydrochloric acid process. It can be carried out by oxidation using a mild oxidizing agent, such as selenium dioxide, palladium black, chloranyl, lead triacetate, or triphenyl methyl peripherate. In addition, the dehydrobromolysis of a compound of formula VII in which both A and B are hydrogen can be carried out indirectly by halogenation or followed by dehydrohalogenation, for example by treatment with N-bromo(3)uccinite or pyridine bromide to give a compound of formula VII in which A is halogen and B is hydrogen, which is subsequently dehydrobrominated. When one of the A groups is a hydroxy group, hydrogen synthesis can be catalyzed by an acid, such as sulfuric acid or oxalic acid, or a base such as potassium hydroxide, or a salt such as potassium hydrogen sulfate or N-bromosuccinimide.The reaction can be carried out in a solvent that is inert under the reaction conditions, for example a slated hydrocarbon, xylene, or glacial acetic acid. The reaction can also be carried out at an elevated temperature, for example a rapid reaction or a temperature between 20°C and 150°C. » I -Iju cìcliszntionc del proccaoo >(f) pu' eonere ' I conducted myself in a nolvcnte who is inept in the condi- The reaction products, for example diethyl ether (οχ>), also do not. The reaction can, if desired, be carried out in the presence of a light acid, for example trifluoride, or preferably at a temperature between 10°C and 120°C in the presence of an organic base, for example trifluoride. Solvents which are inert under the reaction conditions of process (g) include chloroethylene, in which both reagents are soluble, such as acetic acid, ΙΊ-dimethylformamide. Other solvents which may be inert include dimethylformamide, tetrahydroxybenzoate, diethylene glycol, or diethylene glycol. The reaction is generally carried out at a temperature ranging from 20°C to 130°C for a time ranging from about 1 to 20 hours. The starch (azothydrate) of which one is made is a component in the reaction and is reversible by adding C1 to amines or a methylformamide. alkali, for example azides of lithium or sodium, but if desired one can also make azides, nitro amides, for example aluminum azides or the azides of nitrogen-containing bases, for example mono-, di-, tri-, and tetra-amine azides, such as aninium, anilinium, phospholinium, and piperidium. In those cases where an azide other than an alkali metal azide is used, this azide can be used.vere prepared in the mixture of rea-. In addition to the double component, the reaction can, if desired, be carried out in the presence of an electron acceptor, such as aluminum chloride, boron trichloride, ethyl sulfonic acid, or benzene sulfonic acid. As an alternative to the reaction conditions mentioned above, the reaction can be carried out using hydrogen azide (hydrochloric acid) at a temperature of about 20°C to 150°C in a suitable solvent, under pressure above atmospheric pressure. When an azide other than hydrogen azide is used, for example disodium azide, the reaction product will be the corresponding tetrazolium salt. This salt can be easily converted to the acid by treatment with a strong acid, for example chloride. In process (h.) the anhydride is preferably a mixed anhydride of a type that splits preferentially to give the desired chromium. Darri idotetrazo which product more important than The doped acids will react with 5-aminototrazole. The types of suitable acids from which the mixed anhydride can be derived are: gulfonic acids, e.g., benzene or Glycerol, dicarboxylic acids, and hindered acids such as pivalic acid, cyclovalcrinic acid, diethylacotic acid, or trimethylacotic acid. I and alcoholic formic acids, such as ethoxyformic acid or isobutyric acid, may be used. When used, an acyl halide may be used instead of an acyl chloride. The reaction is preferably carried out under anhydrous conditions in a solvent which is not capable of reacting with the ramine tetrazolium or the acyl anhydride or the acyl halide, e.g., pyridine or dimethylformic acid. However, when the reaction is carried out in a non-aqueous solvent, e.g., dimethylformic acid, The reaction is preferably carried out at a temperature between about -15°C and +20°C. When mixing an ether, it is preferable to use an alcohol gas (lower alkali) and carry out the reaction in a solvent that is inert under the reaction conditions, such as ordinary acetic acid, operating at a temperature between about 100°C and 100°C. When a compound of formula I is used as the starting material in which .SO₂ and —CO₂ are present, the reaction can be carried out by heating the compound of formula Ϊ and the 5-aminotetrasol in a solvent of the same type as the reaction conditions, for example dimethylacetamide, operating at a temperature between 100°C and 200°C. Alternatively, the reaction can also be carried out in the presence of a condensing agent, such as 1-carbonyl-imides.isoalkyl or dicycloalkylcarbodii-tnide, in an aprotic solvent, for example dimethylformaldehyde, at a temperature between about 10°C and 40°C. L * The starting materials for the procedure (b) are clay prepared by reacting a compound of formula IX, where H&, Kp.li, K ,li, R„b or H(,b are as aboveb 6 ( or defined, with a compound of formula X, ba-CC-Da X where Da is a euthereal group, -18- to produce a mixture of compounds having the formulas XI or XII, where Rg, Da, R^'b, Rgb, R^b and Rgb are not as defined above. The compounds of formula XI and formula XII may be hydrolyzed to give compounds having the formulas IV and III. Alternatively, the Da groups in the compounds having the formulas XI and XII may be combined, using traditional methods now known, with other D groups and the resulting compounds may be separated, using the same conditions as above for process (b), to give a compound I of formula II. As a further and preferred alternative, the compounds of formulas XI and XII can be cycled, using the same conditions as in the above process (b), to give a compound of formula II in which I) is a hexane group, and the resulting compound of formula II is itself used in process (a), or the group I) is converted 8 XI XII, for example, a halogen group to another acyl group, an amide group, or a nitrile group, using methods known per se. The fumaric isomer of formula XII (i.e., the corresponding isomer where Da has been converted to) is the only isomer that can be cyclicized in I to give the required compounds of formula II. The proportion of the two isomers can be easily determined by nuclear magnetic resonance spectroscopy, and the applicant has found that, in general, the desired fumaric acid derivative constitutes only a minor proportion of the mixture of isomers obtained by cyclication. Compounds of formula V, in which an adjacent pair of H e, ttgC, R^c and ìi^o represents the groups -GOCH CO COR" and ~Ot>I or the halogen, can be produced by reacting a compound of formula XIII, CO OH XIII in which Rg is 'as defined above, , and R,.g, R,g. IlrtF, and Knq have the same meanings as indicated above by Ry R^, R^ and Rg, except that an adjacent pair of R^g, Ryfi and llQg forms a chain. halide, where M is the definite function, with a compound of formula XIV,' R'CZ-CZR" XIV I wherein Kw is as defined above, Z is a suitable monomer group, e.g., an alcohol, halogen, amino, alkyl, amino-substituted group (e.g., an amino group, a halogen amino group), or a monomer-substituted group, reactive with the amino group of the -COCH^ group of the compound of formula XIII, and each Z is a carbonyl atom, or a Z may be either a carbonyl atom or another carbonyl atom, or, as the name suggests, a hydroxylation of the compound to form a compound of formula VI. Preferred compounds of formula XIV are diethyl atoms, e.g., diethyl atoms. Compounds of i'o rmul a V ;r'oc unti a "OOCH-'C(COOH) group, or a ou.o derivative, can be obtained from known compounds in one or more'atadl using processes, say por* known* The compounds in the 1'ormi! ο [ζθ al proaea so ( c ) ( ri ) Alternatively, phorate compounds XI» with ammonia, amido, or nitroyl can be produced from the phorate compounds I using traditional methods, such as reacting an ester of the compound of formula I with ammonia to yield starch, followed by dehydration from the ester to yield the nitrate. Compounds of formula V bearing H substituents (C0 R)=0.1-C01) can be obtained by reacting a compound of formula XV, where % is citral, defined as B h, Rgh, R^h and Iranno &Li the same are vilified as above for Rg, R,.^ and R,,, ; it is. known that a pair of 1-hydroxy groups, R^h or Buh instead of forming a chain -OGCH=C!(COOJI)-O- represents the groups -il c —OH, with a trialkyl acetylene of citric acid, bonded in the traditional way, followed, if necessary, by hydrolysis of the reaction product. I >2- Compounds of formula VIII can be produced by reacting a compound of formula XVI. COOH XVI 0 one of its foreign bodies, in which Hg is * as defined above, Hp.i, ligi» It i. or H^i have the same significance as above because R, R,, H' and li except that an adjacent pair of R, i, ligi» and R i instead of forming a -COCH®O(COOH)-O- chain, represents the pair of -OH or -COO-alkyl groups, with a methylalkylolfoxydino anion, for example the dimethyl sulfoxide anion, and the resulting β-hydroxy-2-alkylolfoxydino compound is reacted with glyosalic acid or an ester thereof. The compounds of formula I in which c, ' -CU can be produced by the dehydration of the corresponding pyruvate-2-hydroxy-2-alkylolfoxydinonic starch using, for example, phosphorus oxide as the dehydrating agent. The reaction is preferably carried out with the use of at least one molar equivalent of the pyrano-3-ohinolinone starch dehydrating agent.In those cases where the dehydrating agent reacts with one of Hg, It^ or R^ (for example, a substituent comprising an -OH group), there must be an amount of the dehydrating agent sufficient to allow the secondary reaction to occur as the main reaction. The reaction may, if desired, be carried out in the presence of an acidic binding agent, for example triethylamine. The reaction may also be carried out in the presence of a solvent, for example, N, N-, dimethyl ether, pyridine, benzene, or hexamethasone. dehydrating agent. The action can be carried out at a temperature between approximately 0°C and 200°C depending on the dehydrating agent used. When using phosphorus oxychloride, a temperature between 0°C and 100°C is preferred. Chromon-amide starting materials can be obtained by reacting a corresponding pyranochrome-linone ester with ammonia using traditional methods in the production of ester amides, for example using an aleninol as the solvent at a temperature between 0°C and 120°C. Compounds of formulas VI, VII, IX, XIII, XIV, XV, and XVI are either known compounds or can be produced from known compounds using traditional methods of preparation. The processes described above can produce the compound of formula I or a derivative thereof. It falls within the scope of the pre-eminent Invosion I treat any derivative thus produced so as to release the free compound of formula I, or to convert one derivative into another derivative. The compounds of formula I and the intermediates for these compounds can be isolated from their reaction mixtures using conventional methods. Suitable derivatives of the compounds of formula X include ammonium salts, alkali metals (e.g., sodium, potassium, or lithium), and alkali metals (e.g., calcium or magnesium), and other organic compounds, such as salts containing 1-amino, 1-methylamine, or 1-ol, with diethylamine or 1-ol, with diethylamine or 1-ol, with hydroxy-substituted tricyclics (e.g., hydroxy-substituted tricyclics, e ... monocyclic cyclohexane, such as morpholine or pyrithione. Suitable cyclohexane esters include cyclohexane esters. THE inferior, for example ethyl alcohol, and alcohol-derived oils! containing alkyl groups, for example di-alkyl(lower)-amino-substituted amino-alkyls such as for example β-(diethylacine)-ethyl ether, and alkyl compounds, for example a β-(lower)-alkyl(lower)-ether derived from a biohydric compound, such as a di(hydroalkyl(lower))-ether, for example β-2-oxal-propan-1,3-diyl cathar. Pharmaceutically acceptable additions of the alkyl compounds can also be found, or even of those compounds in which one of the ){y od IAB e » a -ÌUl^ group, such as hydrochlorides, bromides, or equivalents, The malut iof umarati · The odors can be produced by traditional methods, by trans-esterification or trans-esterification. The starches can be used, for example, by rapid reaction, not by thio, or pure can be di-alkyl(0' -G,) starches, which can be produced by trans-, trans-, or trans-, tonal methods, for example by reaction of one or more of the corresponding acid with ammonia or a Appropriate amines. 1 X Compounds of formula I and their pharmaceutically acceptable derivatives are useful because they exhibit pharmacological activity in animals; in particular, they are useful because they inhibit the release and / or action of pharmacological mediators that result from the in vivo combination of certain The types of antibody or specific antigen: ·', for example the combination of reaginic antibody with specific antigen (see Example 27 of British Patent No. 1,222,601). It has been found that the new compounds also interfere with the reflexes in perimental animals and in man and in particular those reflexes which are associated with the joint of the edoip or the hand. In IT: 'uè io, e:r the objective or objective reactions which result from the inhalation of specific antigen from hayfever subjects. The bilized agents are inhibited by a subsequent administration of two new compounds. Therefore, the new compounds are indicated for use in the treatment of reversible airway obstruction and / or to prevent the secretion of excessive amounts of mucus. The new compounds are thus indicated for the Treatment of allergic asthma (so-called "intrinsic" asthma (in which sensitivity to extrinsic antigen cannot be demonstrated), bronchitis, cough, and nasal or bronchial obstructions associated with common colds. The new compounds may also be useful in the treatment of other conditions in which antigen-mediated reactions or excessive mucus secretion are associated with a disease or illness. I to an illness, such as hay fever; certain eye conditions such as trachoma; food allergies such as hives or atopic eczema; and gastrointestinal conditions, such as >eagranulocytosis | I already have gastro-intustinaie especially in children, THE I like milk allergy, or ulcerative colitis. For the above mentioned hearings, the dose Gommini 4M* is mentioned The effect will naturally vary with the compound employed, the mode of administration, and the treatment used. However, in general, satisfactory results are obtained when compounds are administered at a dose of 0.001-30 mg / kg body weight of the animal in the test. I described in example 27 of British patent No. 1,292,601. In the human body the total daily dose indicated is between 0.01 and 1000 mg; rib ì Hymeni is between 0.01 and 200 mg and more specifically between 1 and 60 mg, a dose which can be given in divided doses in the form of 1-6 times a day, or it can be administered in a prolonged release form. This form of dose suitable for administration (by means of THE Inhalation or by mouth; · o ) ranging from 0.01 mg to 10 mg, preferably from 0.01 mg to 20 mg or more, preferably from 0.01 mg to 10 mg of the body. The pharmaceutically acceptable vehicle or adjuvant is a liquid or fluid. The compounds of formula 1, and their pharmaceutically acceptable derivatives, offer the advantage that they are more effective in short-term doses than compounds having a structure similar to that of the compounds of formula 1. Furthermore, the compounds of formula X, and their pharmaceutically acceptable derivatives, are more advantageous in that they are more effective in interacting with the swine flukes or weeds. They inhibit mucus secretion than the compounds of formula 1. The Applicant claims that in each of Rg, .1 A....., li, . ih, and ;...., shades or leathers contain carbon, alkane, pro-acetyl, up to 0 carbon atoms, preferably up to 4 carbon atoms. The Applicant also states that Η, jk, K and Rr,cyano kill hydrogen, methacrylate, propyl, allyl, methyl, ethyl, chlorine, bromine and hydroxide. The .-00011=013-0- chain can be linked to the benzene ring in any sense and in any of the positions. 11 group 13 has a group -COOII. According to the present invention, a process for the production of an acetate I is provided, which comprises the treatment of a compound of formula I, , indicated above for Kg* Pg or Kg* at 1000 C where an adjacent pair of Rg,.l, K^j and K^J can form a chain -O-C(X )=0.1100-, where X is a 5-tetrazolyl group, a (li¬tetrazol-5-yl)carbazolyl group, an arbo or acylic acid group (or a small ester or another group thereof), a nitrile group, an acyl dihydrogen group or Ic where Kg is* which is defined as even a Pico group, . with a compound that contains a pharmaceutically acceptable cation!:) ilo is capable of converting the X group to a pharmaceutically acceptable cation of an E group* Compounds capable of converting the X group to a pharyngeal-aceutically acceptable salt of an E group include compounds, for example, ion-exchange compounds, which contain pharyngeal and ammonium cations, for example, sodium, potassium, calcium, and ammonium cations, as well as appropriate organic cations containing sodium. In general, the chemical composition of the X group is derived from the free acid of formula I. The pharyngeal-aceutical salt is formed by treating the free acid of formula I with an appropriate base, for example, with a hydrogen, carbonate, or bicarbonate of a metal-turbo or alkali metal in aqueous solution, or by a double exchange process with an appropriate salt. When a strongly basic compound is used, care must be taken, for example, to keep the temperature low enough to ensure that the compound of formula I is not hydrolyzed or otherwise degraded.The acceptable salt can be recovered from the mixture in the following direction, for example, by the action of the solvent ο / o rii η ozi ο ned < j ! 1 u ο 1 vent or ον; ι by if -. You know the garden, and in the leading day it is covered with freezing (iloLiizzasiuno). According to the winter forecast, a pharmaceutical composition is also made which comprises a mono-propylene glycol of 80% and more than 1%, or slightly less than 1%, of a formula of formula I, or a pharmaceutically acceptable derivative thereof, in combination with a pharmaceutically acceptable adjuvant, diluent, or vehicle. Suitable adjuvants, diluents, or vehicles are the following: microcrystalline cellulose, calcium phosphate, fossil fibrinogen, a sugar such as lactose, dextrose, or mannitol, talc, stearic acid, starch, sodium carbonate, and / or gelatin in the case of tablets, capsules, and hardened or natural ointment, or in the case of suppositories; or coarse lactose in the case of inhalation compounds. The compound of formula I or its pharmaceutically acceptable derivative is present in a form having an average diameter Particles of 0.01-10 microns*; compositions may also contain suitable preservatives, stabilizers and wetting agents, solubilizing agents, softening agents and coloring agents I -,32- or aro but ti / .santi. The compositions can, if desired, and dare to be formulated in a form of prolonged liberation. The applicant prefers compositions which are intended to be taken via the esophagus and to release their contents into the gastrointestinal tract. | , The S-tetrazolyl or (N-tetrazol-5-*ìl)carboxylamino groups in the amide have the formula XVII or XVIII respectively, -K ,ΓΓ " uV'·' h fi ......CONII-C ' 1' ·- p-Pi Ni--μ 1 1 H i π XVII XVIII The groups of formula XVII or XVIII can be eel¬athers in tautomeric forms and these tautomeric forms are included in the definition of the pumps of formula I» l The foregoing invention is illustrated, but not limited in any way, by the following additional documents. I fiscaapio 1 ì 4,6-Dico-αο-10-propyl-4Η, 611-pyran (.3.2-g] quinolin-2,8-dicarboxylic acid) (a) 4-acetate-2-alkyl acetate (19.3 g) > diethyl bromide (12.1 ml); anhydrous potassium carbonate (33.1 ml) were incubated in dry dimethyl formamide (2.50 ml) at room temperature for 24 hours. The reaction mixture was dissolved in water and the product was extracted with ethyl acetate. The organic solution was washed with water, added with magnesium sulfate and evaporated to dryness. The product indicated in the subtitle was obtained in the form of a brown colored bolide (20.5 g). The quality of the product was confirmed by fluorescence or mass spectroscopy. (b) 4 - acetate; a 1 do - 3 - a 1 i 1 1-2 -hydroxy acetate. The above allied ether (18.4 g) was calcined at 200-210 °C for 4 hours. 17.1 g of the product of the subtitle was obtained thermally, in the form of a brown solid. Also in this case the above mentioned structure was conformed I by KI5N and mass spectrometry. | ( c ) 4-acot amido-2-hydrosoj-3-proportionate etofe η o no The product of step (b) (17 g) was dissolved in glacial acetic acid and hydrogenated in the presence of Adam's catalyst until hydrogen absorption was achieved. The catalyst was separated by filtration through a Kiehlguhr filter and the filtrate was made I * --34- evaporate until 13»0 g of an almost colourless solid is obtained. The maona or HMN spectra have conformed the structure of the product. (d) Ethyl T-acotamido-^-Cd^i'S-propyl-1H-1-hcenzopyran-a*- carboxellate 1 —------1..——........ ................i .........——~ ' ......................... THE A mixture of diethyl osculate (0.9 g), 17.9 ml, and the above product of step (c) (12.4 g) in dry ethanol (100 ml) was added to a stirred solution of sodium oxime in ether (prepared with sodium oxime (6.1 g) in dry ethanol (200 ml). The reaction mixture was heated to reflux and then dilute hydrochloric acid or chloroform was poured in. The chloroform layer was separated, washed with water, and dried. The solvent was evaporated to leave a coloured solid which was dissolved in ethanol (300 ml) containing concentrated hydrochloric acid (3 ml) or the whole was heated to reflux for 1 hour. The reaction mixture was poured into water and the product was trapped in ethyl acetate which was washed with water and dried. The solvent was evaporated to yield 10 g of a sticky solid, which exhibited mass or RI spectra.IM in accordance with the previously foreseen procedure (or) useful T-iisn ! - pr ο ρ i 1 - 41I- Ί -b υ η · / , ο ρ 1 r lui.-2-cnfboaailat ο _ ____ __________________'__ U α ;a so ·, and ο m > d. c ; I !..1 a . io·.' and ο 11 ο : ; tadium ( d ) ( 10 a )inctirinol (300 ini), which contains concentrated hydrochloric acid (b such), which is kicked into the fluid for an hour. the reaction mixture was di-. I luitn with water and treated with ethyl aoctute. The o-truth was washed with water, oiled or oiled and evaporated elsewhere an oomie oil material of dark brown colour. ment of 4-, 0 ., of the required product Ire Whose structure was coined and reborn from ghosts of nasa and ghosts there there the; p.:f. 84" ο70ϋ. ( f ) 8-eto a aie ; iri)onyl~2-trioto a sic r irb o nyl-4,6-diox so-10¬ ρη opyl-4H , (ui-pyrano [ 3 » . quinoline L * amino -bensopylane of. step ( 2 ) ( 2.0 q )odi rno ti 1 acetyl indic aro oa silate ( 1.2 4 r, 1.01 tal ) were heated to reflux in ethanol (30 ml) for 26 hours. The reaction mixture was cooled to 0°G od. The insoluble solid of the brownish-white color was collected by filtration and washed with a small amount of water; ; ; tit à ti; L et ano 1 or ι ndorisicc ί 11 or per rdare 2.0 p of a product which was a mixture of ο or tori inalo ic or fumaric oc obtained by additionMichael do111 amin a to the ae ethylene. A / ; This mixture(s) (2.0 g) was treated with polyphosphoric acid (30 ml) or heated on a steam bath with heat for 20 minutes. The reaction mixture was poured onto ice and stirred with ethyl acetate. The organic layer was separated, washed with water, or dried. The solvent was evaporated, leaving 1.0 g of a yellow-orange solid. Freezing of this solid from ethyl acetate gave the required product only in the form of fluffy needles of the same color. I arimeion, mp 187-108°C. ! the Analysis: 1 THE Find it: C, 62.0^ II 5.1^5 H 3.7^ Hi chic· I'm about to 0 II JO.i G 62f3^i Η 4,9#ί H 3, A Acid ìj { ; (g) / 4-, 6 - dio ea o-10~;pr o pi 1- 4H i 6H-pyrano[3» 2-g] quinolin-2,8- cì leardosailic o _ 1.............................. i The above M-ostar (2.5 g) was heated under reflux with sodium bicarbonate (1.64 g) in ethanol (100 ml) and water (50 ml) for 1.5 hours. The mixture was poured off and acidified to precipitate a gelatinous solid. This was collected by filtration, heated under reflux with ethanol, and the product was separated by centrifugation (1,4 β); at 303-304°C with decomposition. The structure of the product was conformal to ΚΜΗ mass spectroscopy. I (li) IHdodìo 4,6 -dìoaso- 10-pcopyl-411 *6H-pyrimo[3, 2-g]quino 1 in-2,8-di c ari)ο osi 1 a to____________|_____. . The bio-acid obtained from step (g) (1.35 β) and sodium bicarbonate (0.661 g) in water (150 ml) were added to the solution and stirred until the solution was I ο 11o nut a clear solution. This solution was filtered or the filtrate was freeze-dried to give 1.43 β clol of the required biofilm. THE Analysis: i 17 1 17 Found; C, 46.1^; H, 4.0 / '? N, 2.1 1 12»5# HO: c, 46.1 / ίϊ II, 3.8^5 H, 3j ' I use rnpio Acid 4 » 6-di oa so-1 -ot il-10-pro pyl-4H, 611-pyrone [ 3 > 2-g ) quinoline 2,8-day ar b ο saìIleo ___________\______,_ ( a ) Ho-4- t (ce anino-2-allyloxyacotophenonec The 4-(K-ace til-Ke til) amino-2-hydrouciac ethophenone I (S)2.6 g ), alyl brownide (51 μM) and anhydrous potassium urbonate (1)0.4 β) were, stirred in di- The methylene chloride was left to dry (500 ml) for 17 hours. The mixture was poured into water and the product was poured with ether. The organic saturation was then washed thoroughly with water, dried over magnesium sulfate, and evaporated to dryness. The product was obtained in the form of an oil (102.5 g). The structure of the product was confirmed by spectroscopy, KMN, and Glassa. (b) 4-(H-acetyl Hc tll) .alkyl-3-propyl-2-hydroxy-ascotophonone The product consisting of the allylic ether of stage (a) (100.5 g) was heated by reflux of the flax threads (300 m) for 3 hours. The last extract was washed with dilute hydrochloric acid or water. The organic solution is tainted with 11.0 ± 10 lfi> sodium oxide which has then been acidified. The proximate product was extracted with ο ο ι:ieto ro, extracted with helium or *stalli or then dried over magno halo sulphate. The resulting etheric solution was evaporated to dryness to obtain a yellow-brown oil (78.7 g). I di / 1 -* ( The - ac01 ì 1 -Nc ti 1 ) jμìn0-3-π.11 i 1 -2 iCìrο is 10f cnono and 6-(N-acotil-K-ctyl)nmino-3'-r*lljL-2-hydrophenone 3ai. This mixture was added to acetic acid in the presence of * acetate dissolved in ethanol (500 ml) or 1 ethanol (20 ml) or has been hydrolyzed. Adam's chambers were used until hydrophobic absorption was achieved. The catalyst was separated by filtration through a Kioelguhr and the filtrate was evaporated to leave 79% of brown oil. This brown oil was a mixture of the two and was separated by mechanical means. I high pressure liquid phase using ether / other of Petroleum (1*1) as an oil with the result of obtaining 44.2 g of the subtitle compound and 23» 0 g of 6 - ( IJ - ace 111- K - oti 1} ì ì' ni α o - ' 1 - prop α 1 -2 - hydroxyacotophenone · ( c ) 4 -II - eti 1 am 1 η o - 3 - pr ο p 13- 2 - ic ί r ο rosi 1 acetof ο η η oi 4 - ( W-aco 11 lH»o L i 1 ) nm:i no~ 3--prop α 2-hydroxyacotophenone (44 g) was heated under reflux in a 4 8 / <' solution of acid hydrobromide in acetic acid (ICC) ml), glacial acetic acid (90 ml) and water (20 ml) for 6 hours. The reaction mixture was poured onto ethyl acetate and extracted with ethyl acetate, the extract was washed with water, sodium bicarbonate solution, then again with water, after which the extract was dried over magnesium sulfate. The organic solvent was evaporated until dryness, obtaining the compound of the subtitle in the form of a red (34 β) coloured oil * la -40- The structure is confirmed by RMTT optical coherence tomography I and molecular spectroscopy. (d) Me ìli 6-aootìl*-l-etlJ -7'-idi'oa3lr4.-oono-8-prop:ll-4-H~eh in olili-8- carbosali la t o___________; ( The aininìc product of the stage: {o ) (17 g) odime taeetilendicuvrbo sailato (11 »3. di') nono alati The reaction oil was heated to infinity in ethanol (300 ml) for 17 minutes. The reaction oil was left intact, cooled and evaporated to a fine silica-colored oil. This oil was subjected to silica gel column chromatography using petroleum ether (1:1) as a byproduct to yield 19.1 g of dimethyl 1-(4-acotyl-3-hydroxy-1-2-propylphoryl)-N-ylutaino-oloate, m.p., 83-87°C. The malolactic ether (3 g) was heated and stirred in polyisothiazolinone (100 ml) on a steam bath for 10 minutes. The reaction mixture was cooled and poured onto an ice-water or ethyl acetate mixture. The organic solution was It was separated, washed with water, and heated on magnesium fume. The solvent was evaporated to a silicate, leaving a pale yellow color. This product was purified by high-pressure liquid chromatography with I obtained 2.6 g of the compound of the subtitle, 41 pf 121-123°C. ti Analyses Found: H; 6.6 / 5 II; 4.2 / 5 liiohiosto for O^H^Kry 0,:65.35¾ II; 6,345¾ N; 4.33^ Methyl 6-acGtii-· ]...otil-*!>-iàrossi-'4-i"ODsO”4H-quinolin~ S-dicarbonsàl g' was obtained by purification, cooked form of a pale yellow solid (100 g), (0) Diotil 4,6-di00Dc-1-qtyl-10-propyl-4H-6H-pyrano[3,2-g]- eh inolia*-2, S-dicarbonsàl ntn The hydrouci-ketone product of step (d) (1.0 g) and diotyloxalate (3.3 ml) in dimethylformamide (25 t) were added to 50 / 5 sodium hydride washed with ether (0.531 g) and dried dimethylformamide (20 t) and the reaction mixture was stirred for 4 hours. The reaction mixture was then poured into The water was acidified, or extracted with ethyl acetate, the extract was then washed with water and dried over magnesium sulfate. The solvent was evaporated to dryness to give; I have an oil that has been: Ito in ethanol (100 ral) 0 yes ' I 0' added concentrated hydrochloric acid (a few drops). The solution was heated or refluxed for muz- I %1 now, it has been cooled, or it has been placed in water. The solution was extracted with ethyl acetate, the extract -42- was washed with water and dried over magnesium sulfate. The solvent was evaporated. I up to if oche z sa,so as to give an oil cho si c* I solidified by grinding with petroleum ether 40-60° (1.2 g). The structure of the compound is * I conformed by KMN. ' 1 (f) 4,6-diODso-1-ethyl"10-propyl-4H,6H-pyrono[3»2-g]quinoline-2. 8—dicarboalì.I ic acid ----1---------------------------------1..................... ....~" The above bis-ostere (1.0 g) G sodium bicarbonate (0.767 g) in ethanol (0.5 ml) and water (32 ml) were heated under reflux for 4 hours. The reaction mixture was cooled in water, acidified and the The precipitate was collected by filtration or drying. The product was purified by trituration with boiling ethanol, then twice with boiling acetone. After each trituration, the mixture was centrifuged and the supernatant liquid was removed by decantation. The residual solid was evaporated to give 0.547 g of the required diacid. I in the form of a yellow powder, pf298-300°C, cori de c. i Analysis: Tcovatotc:·6ì, 3 / δ; H:5.0' / >; H:3.6# Required for 0 H^NO^ C: 61.5#; H: 4.6#; li : 3.79# (β) Lysodium 4,6-diosao-1-ethyl-10-propyl-4H,6H-pyrano[3.2-g] quino:!.in~2,8-dicarboase!nto The above mentioned Placido (4.098 g) was suspended -43- In. water (100 tl) and was treated with sodium bicarbonate (1.82 g). The resulting solution was filtered or the filtrate was treated with cotton until complete precipitation of the product occurred. The required disodium bicarbonate was separated by filtration and dried to give 3.39 β of a pale yellow powder. Analyses : Found: C:51*1^;U: 4.3 / ^ϊ N*3>0^ li1 chic: I'm about to C.ir 1. from 11019122 / (6.9 / " of. water) Ibi empio 3 By the processes described above, the following compounds can be prepared: (i) 9-ethyl-4(8-dioxo-1O-propyl-4H,8H-pyrano[2,3-h]-quinolin-2,6-diacetic acid (ii) 4,10-dioxo-4H-1O-pyrano[2,3-h]-pyrano[2,3-h]-2,8-diacetic acid (iii) 10-bromo-4,6-dioxo-4H-6H-pyrano[3-2-g]-quinolin-2,8-diacetic acid (iv) 11-hydroxy-4,6-dioxo-10-propyl-4H,6H-pyrano[3,2-g]-2,8-diacetic acid 1 in~ 2,8- d ì c arb od si Ileo [ (v) 4,S-diox0-411,9H-p±rano[2, 1-g]quinone 1 in-2,7- dicarboxylic acid ' (vi) 4 f 10— cJ:ro : ; : ;o - 4 il,! C i.!- ,· i :i i.. no / 2, 3"-f7quinolin-2,8-di / N- ( tetraKOl-·' !.>··· ;i.1 ) / a box.imides de( vi i ) 10- 'brorao- 4,6- d ì ox so - 2 „ 8- di -(tetrazol- 5- ϊ 1. ) - 4 Η, 6Epiran / 3, 2-g / chi noli naExample 4 The following compounds can also be prepared by the processes of the present invention: ( i ) ae ;ì ϋ or 7~ ( 3 - meters 1 )-4,10 - dioxide-4 Η, 10 H- pi r 3-··:Γ7~θ·ϊιίηο1ά,ϊ!···2 f 8-di carboxyl co pf 24 6- 24 8 0 0 ( two, ) {i;l ) we do 9- ( 3-methyl buty 1 )-4,6-3-H >pi dioa (iiì ) of sodium 7-e ti 1-4.10.....di... ozone, OH-pyrane / * 2,3-18-silato-quinodiiin. Found: G 4 4.17, Il 3.37 , H Ki chi bone for C1(-ll Μη20γ.14 .4 11^0: 0 44.17, H 3.77, h Example 5 According to the process of the present invention, the following compounds may also be prepared: (a) 5-methoxy~4,7-dioxo-411.71pyranoic acid / ~ 3,8-h7~quinoin-2,9-dicarosali co, pf 294-bdeacetone.6°C bone-10- (prop-2.....cnyl)-4H, 6I-pyrano- 7 3, ohin ol i n-2,8- di e: residual, tiny,'tura< / j>

Claims

1. and ο inferred through them, (e) 4 ,lO-di0330“4H,20ìI-pyraro / 2,3-h7quinolin·"2 , 8- dicar ho to cy 1 ico, pf 20 0 0 C(d) l-pyri-oxyoxy acid 3,2-.^quinoline, carboxylic acid, sodium chloride 6.11 Found : C 4 5.74 H 2.1 U 3.8#14 la 2 (c found: C 4.6754 N H 2 4,10-dioxo-4H,10H~pyrane / 2.3, 3.10-2,8-d carbose with Analysis to Found: 0 44.367 H 2.

10. W 3.547 Required 27 2 C 44.17 H 2.387 N 3.6?7( i' ) for 10-moles 1-4.6- for 1-4.2- for / 3.2- for 10-moles for cario asyl co, pf <302; VETOIGATIONS 1. Process for the production of a compound of formula 1, in which an adjacent pair of R, , R^, R.and Rg forms a chain -0000-0K--0, and the residues of R^, -4 6- R^, R or lig, which may be equal to each other. to 1 such , or -WR where R^ or R,J( which are equal or of inherent, represent each hydrogen or to the kilo,Rg represents hydrogen, to the helios,, to the helions or phon i 1 - to the one ; The trace or a group ο ( 31- te t. r cui- · -;ji}~o ar 1Jo ss ; imi do,op [ai· and a derivative ο f ; i ;rc ( : utically accessed) by the process composed 1 e, I produce a phonal compound I in which E represents -COOH by hydrolyzing or oxidizing so-]. » r ; defined, ;a have / il i! or .. st they mean- Li above the inclusions for E1, , R7 ' and ii.,, except that an adjacent pair of R^a, R^-a, R^a and ii.,;,:; can represent a pair of formula -00011= 0()0-, one, or cnLramtd, of E and ]lj represent either a hydrolysable or osadible group, with conversion to a -COOH group, and I* can represent a -00011 group, Cb) a compound of formula I is produced in which E represents -COOH by nanocycles of a compound of formula III or IV, R,b. b K6b ... IIOOC ''NE CO OH III R,bb fi bt 1 eoo II EE Eg C001I IV or an ester of one or other of these compounds where Eg is as defined above, Rrb. Rrb, Ifib and R0b will have the same meanings as indicated above for I^, La, ìì.j or except that an adjacent pair of Ut, Ln, Xì^b and L^'b can represent the pair of groups -H and ~0“C(COCli)-CH-CO0lI,(c) a compound of formula I is produced in which E represents -COOH by means of the addition of a compound of formula V,, 48 - γ or one of its derivatives, in which Jg is as defined above, R^c, R^c, R^c and Ii^c have the same meanings as indicated above for K^, and Rg except that an adjacent pair gives B*.c, R and R^c can form a chain -COCH=C(COOii')......, represents the pairs of groups: (:i ) “COCIj^GO COR" or -COOII C(COOH)-U1^I»2, or a suitable hydrogen atom thereof, or -OHi or a halogen atom, or (ii) -OHi - O-O(COihO-hH-COJ;1,1 RM represents -OHi, or a group from which it can be obtained by hydrolysis, 1- and 10 which may be the same or of :.CfDrentiJL. £}'·) or crentari or each hydrogen, aryl or alkyl, or taken together they form a 1-kilometer chain. 1- is saturated or saturated, and 1- represents hydroxyl.a ο or pp; re a rne ί;to it a. the ali no, and, if necessary or desired, the gvupρ or -CO!;", and the gvupρ or -CO!;", and the gvupρ is added to a group! finished., R,d a, ci, ] b ο •là or IV; other uses of the above indicate l for f- ,· V or jV 1 bald that a couple can run the robbers; ,-0-, at least one of the < :0p})1 and p} f ί Γί forms a group =G or forms together a chain -3(011^) 3- in which a represents a number of values ​​2 or 3* where then = I-0,1'. to a corresponding compound of formula I (e) yes the groups Λ and Bda selectively remove a compound of formula VII, li.AI » Ho and Bg B8 are a duo-ether, VII where Bg and E are as defined above, Rg, Rgc, Hrjo or RgO have the above-mentioned ignitable states for Rg, Rg Rg, and RgO, except that an adjacent pair (hi, Rg, Rg and RgO) may represent a double bond, where at least one of the pairs of groups A and B both represent hydrogen, or one of A and B represents hydrogen and the other represents halogen or hydrogen, and the other pair A, B may together form a double bond, (f) which produces a compound of formula I where K represents -COOH by the removal of a third-place ion of VITA, .......COOH In which Rg is defined as a dark one, Rrf, R,f, R„l' boi and Ifgf have the same finite swans as above for Ry Rg, IΙίγ and Rg, except that an adjacent pair of R,f, R,lh R., f and R;:. Γ, I invoke of this but a chain -000::=0(00011)-0- represents the pair of nodes -C0CH(S0ì.^0)-(:iI(0H)~C00R" and -0ΤΛ,lì" or II are as above from; the nàti, c .! ; ^ raj)p:r esents a group of chi l:i. co '-p " (;jq » (g) a compound of formula I is produced wherein E is a 5-tetrazolyl group by reacting a corresponding compound of formula I wherein E is ~CH, with an azide in a solvent which is inert under the reaction conditions, or (h) a compound of formula I is produced wherein E is a (h-tetrazolyl--ii-'-yl) group,'.irÌ,x;)Ssamiào by reacting a corresponding compound of formula J wherein E represents -000H, or a syl ogenide, an ester or an anhydride thereof, with b-aminotetrazolyl, and, if necessary or desired, hydrolyzing the compound of formula I and / or converting the compound of formula I to a -coilli derivative thereof. comment and acceptable.'bile,.

2. Process according to part (a) of claim 1, characterized in that the group D is a sterol, araldic or nitrile group and the hydrolysis is carried out under mildly basic conditions and / or in the presence of nitric oxide.

3. A process according to part (a) of claim 1, characterized in that group I is an alkyl, anionic, or formyl group and the process comprises oxidation.

4. Process according to part (a) of the claim - ϊι .1 ο η e I ο s ο c ο η δ ο 1 a ri ν ( ή ά ica district 3, ear a. 11 and riz -zated by the fact that group 1) is a local group and the supply is carried out to nauti or there. Oh yes, I give myself selenium.

5. A process according to part (h) or (c) (ii) of claim 1 characterized in that the reaction is carried out under anhydrous conditions and in the presence of a dehydrated gas! 1.

0.

6. Process according to part (h) of claim 1, characterized in that a compound of formula III is cyclically cycled by placing it at a high temperature.

7. Process according to part (e) (i) of case 1, characterized by the fact that Λ'~ is a -OH group or the cyclization is carried out under acid conditions at a time between 70°C and 100°C.

8. Process and ο and ο I, ; part (0(i) of the verification of indication 1, characterize the data, the fact that A is halogen and the reaction is carried out in a high-temperature solvent and in the presence of a strong base1.

13. Process for the production of a salt Parmaceirti ο im ο η ΐ e ; ic: c et' la là Ile of a foxmul compound as defined in claim 1, characterized in that it is a compound of formula 1, wherein Rg is as defined in claim 1, Rg, Eg, Rg, or Rg have the same meanings as indicated in claim 1 for Rg, Eg, Rg, except that an adjacent pair of Rg, Rg, Rg, or Rg may form a -0--O(1)-Ci ICO- carboxylate, and X is a tetrazolic acid group, a (li-totrazolic acid -1>-i 1 )-carboxylic acid group, a docardoxylic acid group (or an ester or other salt thereof), a nitritic group],!c, an acyl halide group or a halide group, with a compound1 containing a pharmaceutically acceptable salt of group E. 10.

11. A process according to claim 10, characterized in that in each of Rt, Rg, and Rg, when they contain up to 8 carbon atoms, there are up to 4 carbon atoms.

12. A process according to claim 10, characterized in that in each of Rt, Rg, and Rg, when they contain carbon, there are up to 4 carbon atoms.

13. A process according to claim 10, characterized in that in each of Rt, Rg, and Rg, when they contain carbon, there are up to 4 carbon atoms.

13. A process according to any of the preceding claims, characterized in that E represents -C001I.

14. Process according to claim 1, characterised in that it is substantially as described above.

15. Process according to claim 1, characterized by being substantially as described above in each of the examples* 16. Compound according to formula 1, as defined in claim 1, or its alternatively acceptable formaldehyde derivative, and characterized by being prepared by a process as claimed in any of the preceding claims.

17. Compound according to claim 17, characterized by the fact that in the first 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 22-, 23-, 24-, 25-, 26-, 27-, 28-, 30-, 31-, 32-, 33-, 34-, 35-, 36-, 37-, 38-, 39-, 40-, 41-, 42-, 43-, 44-, 45-, 46-, 47-, 48-, 49-, 50-, 51-, 52-, 53-, 54-, 55-, 56-, 57-, 58-, 60-, 61-, 62-, 63-, 64-, 65-, 66-, 67-, 68-, 69-, 70-, 71-, 72-, 73-, 74-, 75-, 76-, 77-, 78-, 80-, 81-, 82-, 83-, 84-, 85-, 86-, 87-, 88-, 90-, 91-, 92-, 93-, 94-, 95-, 96-, 97-, 98-, 99-, 10 ...

19. Compound according to 1: , rj vendi, cassione 18, charac- terized by the fact that it 1 each of IV, IV, IVa 0 (cd Tip, when they con ni cip ' 0 n 0 c ; .1 j-1 h 0 ni 0, s 0 n 0 present up to A atoms of, or :i.;r Itory, 20. Compound according to any of the claims 17-19, characterized by the fact that the -C0CH=CE~O~ chain is in the positions R and R, the -O- part of the R^ chain being in the position R^.

21. Compound according to any of the claims 17-20, characterized by the fact that R^, Η^, R^ and R^ are chosen: the hydroxyl group, ra^ and 10 3 sil, propyl, methyl, <sile. .itile, cloro, dromo e Idros- 22. Composto secondo u;i la qualsiasi delle riven- di cn zi oni 17-21, cara 11 or:presenta un gruppo -COOH. [zzato dal fatto che Emp- 3. Aci do 4,6-dios so -.10~propil-4H, f> H~pi rimo / " 3, 2-g7 24 » Ac;ì do 4,6-dio» ao-1-ethyl-10.....propyl-4H, 6H- pyran / ~3,2-^7quinoline-2,8-dicarboxylic acid.

5. 5~ethyl”4 » 8-dioxo-10......propyl-4H, 8H~pyran f~2, 3-h7cM,nolin-2,6-di carboxyl and o.

26. Acid 4 ,I0~di oxo-4n,10H-pci rono / ~ 2,3-07 eh ri. n oils π 2,8-di ear bo s si 1 ic o.

27. 10- bromo™ acid 4 , 6.....dios.00--411, 6ll~pierano / " 3,2-t<*7 ehi ηoli n- 2,8- di earho s si 11 eo * 28. A ci give 5~hydro s si -4 » 6- of or. so -10-1)001:)11-411, 6.Π- pirs.no / 3, ff / cMnolirw0, 3.....di carboxyl co.

29. 4,9-Dioxo acid~4h, 9h~pyran0 / 2,3-*c7nhinolin- 2,7- eli cario a- si lì e 0.

30. 4 ,10-di 0 ss0 -4Jί,10} 1 -])2 r; 1 n0 / 2,3-ί'7chi η01 iri -2,8-di / ~~2-~ ( 1 a ira. sol- '3-yl ) / ~ cardosauri de.

31. 10- brom.o-4,6-dioxo-2,8-di - ( t oberano 1-5-yl )~ 4 II, 61ί-ni r·an 0 f 3,2-^7obi. ne 1 i na.

32. Extort and there 13, co of compound as claimed in any of claims 17-31* 3. Sai or so of co of a co mcp 0a 10 as claimed in any of the re claims 17-31.

34. Cora.··) os-According to any of the claims 17-33 in. a form, having a value of 0.01 to 10 microns, the average of the day of the other of the parts and at the 1st degree between 0.01 and 10 microns. The composition consists of farro:.! coated meats. 'Locri casata from 35. fact of comprising a compound such as claimed in Ca¬io in any of the claims 17-34 incor- porated with an adjuvant, diluent or vehicle phanaceous earths.

36. Composition according to claim 35, characterized by the fact that it comprises less than 1 803 ml of a compound per 50 ml of a compound as claimed in any one of claims 17-34, as the active ingredient, in a unitary form.

38. Composition suitable for 1 item indicated in 37* carriers, characterised by the fact that it comprises from 0.01 m² to 20 kg of active ingredient.

39. Composition according to claim 38, characterised in that it comprises from 0.01 mp to 10 mp of active ingredient.

40. Zicne compositions according to claim 35, characterized by the fact that they are made of the same material as described above.

41. Composed of fonts II, 311, XV, V, VI, VII or Vili as defined in claim one. ν<ο / ο'Ό : c.] ;, ί 1 < - ( Ο < 3 (·'ϊ U t | Vi 10οί. - riii no- 7.7 Q— 0 ) i Gold.....S / '-'i'1 Chloe,ri.......A , 3,83(33,η);: < »33 (13,s); co:) we 5 n~-2 , ?.....0 :ir or! > cori1 i co 0 δ 33 0 0: 6.33(171.0): y,0 (i 3 3:,) : a , C (:Ui,o ) (t (..-1 rare!.......3-......3 - 7). )......0,3-05..... ( ιfo·· A·-''·> 1........03 -}! ί' r\::no[3,2..... g lobes. us 5 η--~2 ,3- ( ' , ..'t 1.Ό 0 .0,:(*,3,-1,o ,iv); 7 o- ) : 3, 3(03.0,);· ) ; 73(0)! ,ir, ) ί 3.3 (13,'::); 7 0 1 13.0) ; a, 3(−13.0 ); 8 .7(13.0); / -)0,3(1.0-) * 00 .....1-::1 1 0.....;)!(; ·;. 0 1-3,3........di —1 ( ir 0,::01.- .......i 1.......3; J33 i 3., ο !f. '{ / :" · !,0. )......d one - ' · f * ;, t - , 1 do (3 db ) ; 1 ,3 (33 t. ) ; 3 (oh 0) ; Ί(ί,3(3ΐ: sf ! the M \ J " ϊ ο, ani ο {1 A and 3 do ί;—f'-t O.^rk- ί ί 'ί.

1. shot- / J) T C.....-di 000-] rdio] 1-...... .r (a) Acino 3 -a.ee t :i 1.......1-rtil-l T4---di ì diro-?.......-ideo:: ssi--0........ OC. ίν',μ,-Ο-η.: ;tree s yes 3 1 with K.oi the 3 - crosses n-,?~ ee; rìx> ' ? ì 1 (; > 0 e) C* (you heat.v' )j Go (:i SS ni) with the noise ; 0 3. u :, i 0 n e1 ae qi j 0 sa ί Q. CG of JJPr ( ·!ί· i .3! ) . At :jpo 18 o'clock the mass was e* si a. ta ;r alTresido [ to pour in acr sue» If it is 'api unta knots (>ca *'·: no a. : heads unpero an equal, a 3. 11 proci pi 1 ,·.> 1 0 e:1 YES ..the harvest and drying it and the fì e fì e f. 0 ? 1., '· i < ·.111 and KìiK C mirrors for (di. ) ,,· : .- O 0 C ; <c il eoosoMo 5 noi calo ne 1. sotto- titolo { '' ··· ; : ;i 3 ) # (b) a ci do 3-et oc si carboni 1.......3.....-(d:i l~f> ^p.-sb i dr day (...)< SO 3 0·· 1 y.: ·' '33-jsi:i's us 3 TP—qje Vii us in......3 — C OSI.'C: SS .11 r'nod. et 1.0 or. In '"3i. ad ri. 0 (a) ( 1 1 to <J ) e* si a t u ;i unto nò n.'P"- f.f.'T n .[io.1'·', O-j · .oi i o ( S ,.? o ) j yj etanolo ( io „i C / ϊ !. 1 ) , c: poi .<" :Ì. f: 11 « . : ; c ! 1 ί j vi lo c > ( !} # ? L i I. I ii .. 1 ' ' l. t ì ( ' ^ '{ E ' t. 1' J ' i ' I ( ' [' 'i ! tj 5 t L i - .1 1 . i : ' . ' -O p ·τ |jc .· -c , ,'·. .and t. * '.A cA and, r ; 0, ccv · t r. 3o (1 ο 0.Γ0 re :.i O (l 1 2 t .· -o ) « il.., ): 1 Ir. in * the house. There are < ; · 1 J: ; ,1 to <;] or 1 rice cf j olives the fixed M)tp here * yes . .1.. a ,f< Λ ta is ' IcCrSC 0(3 SO poses. 0' Γ,ΐ ('uo C* r,t alo ; that is. <. - va- ο i1no cf ct < .· 1 r > ri - ct 2 sΐ £~ 1 !..

1. >· i <>: mentioned here. to 0 o the vυ........ pofito 5 ηt' :ic fi\ o ìi(,; 1 so 11 c> 1... :i canvas ( j , ;: g ) ·, I, a < tj 1 ia 1 11or1 ae1 s 1... ί -1 or i £i £i ;> " ;i ! i F c- ] : 3 ·· eoj > and shoot rupees to cn but dare- (c) Acci CÌO p-~ . (;>; j !- , p......( ' ; e ( ΓΓ11 YES 11 with J 1 part slot t 0 eie .1.10 rt £> c:io (li) e» .0 ΐ f lo 1. of SO·— 1 :ioz to the jj'i c-ci 'i ; in the j;i >0·1 · ί'> and i : < 1 or (a) with or 11 (' nine ring edges there is a p ΚΓ*. "> (!0tJt"0 ( 1. ,1 g) that is 1 6 aeo; 1. the r si or cott :i 1 ec?» r 1 is contiguous with which 10 ci·' 1. * cycle O 2. * so 02 0 1. / .cycle g~- et 1 - d / J-di. '"ΊΟ.....] so;>i 3.......Zjj...o)1:ra - us 3 .....i: JcM ? joi i s......;> jS ·.- or:i. exotic . >r. .i / . 'ì .1 ;5 *:ίο («) ......Ì'~ V-^| 1 o .....1 il......1 jp" .-Ο io 'O").......3 0— s six ] ,, <1 Job i no Ί is - :--:1 ; ·τ·ί r ιΓ "I - '.·: γ. . the.....-7-3 <!<'osci...... / j (] ] ).......osso....... propi l i-h·] ! o .....c 'Ό .rossi 1 :ioo (3,13 <() o* rA eto so - r-:i 1 n : η h.'. >j '·.. . . i .> ("!. ptp o) or then Cin' rode! ·[ or f. io fi i. ia j'iot te si <·'** rat to pass it· eoi — 0 oe 'ì c»:t" :i clr ic;c' ( ί oo· <··r > poreeO 3 fi m se and 1 a ccy nr· ciITr < .· dc] vj to of ì, i.ìc ; ι * v,i one * h ami ree 1 ee * et ; : eoe and the eoi.?t<: to do οορο.,ιοί to believe that he was burning on the ground. ia ( C.io,. / e.-1. i 1 ace t. <:Io ) with otte:r:ijϊier) 1.o dc11 combination st o 1 ii di c : to re: " 1 so11 οI ί t f a t 1 o (0 .8 g). ·, <a t ; i rn : d :i a c ΐ«·ίϊ? e s p>1: t ;rc ; s ο of > 5. here the Sii:s. ( b} oido d.....' > b 1 - f f......<' :5 5 d :i Ό........d T fi - di ο n ; :o :......Ί 0.....pr-c ) pi 1-......d 11- pir<t no [ 3 f ; > .....and the entities a......Ο , Π or I,:ds: a ; if 1. :i. ο o...... 1 ì j >.r : : ' c ' 1. t: c :i tì ed : ]. or stay at 5o ( ) ( 0.7 bf ) and stay, or heated to reflux with solar dioxide (1.3 <j)i ri < i c i 11 o i:: c c 1: i e o t ; ?l. a ( : :i a 1 c : ( i re 1 ) ρ· : r 4 8 o r c· 1Γ1 ì. t. :i a - / ione al t re se .reso "del .ite·" ha dato un fil tirato 3 ispi¬do elio o1 :.. t ' ί t o tua ti sto con esodo cl oso dui oo cori j'1 'i, / ' lo ^3 11 1) -a a , Ϊ : ,. 1 o :.r 1 1 c , Il <J t 1 ’ 1 o e. .Γ j Π v <, 1 o par 1 2 C,a 'a * ,1 J'j. ,i'; ' pai 1 o r r fi":; rV'fc". a, ai 1 i ΐ o ( v ] rf o 5 y, a e p·.) a ' ' ,i ; f ; Vi ! 1 a v pHP ,. ; 1 o (f ,3 ,;) o ), · i la. i « 1 - ,· t :i C cJ 1 . " i" ' '1 1 c, Il il ( : a a1'1 C f (. ' (. ì ,:njv t 1 e ..... .1 ] > < ' o ; , ' ; 1 ·.ai af" : a : ; Λ O...... 0 χ· iSi am atr 1 : t. o 'a.ali i. ì c, f rj o 8 / . C .i fa l ,'ti I..... c [ --0 1 ic iP Pi:à. !. Λ, · .......Ί 3j;> ο jcM r ο 1 i; a-:.:1 rro. he was a ; ri '(aaa: i 'J :i. with f -,V ) ..AC ido rict ·· a!;aaa :ì < three J fa :~ p-:: proci il — f'Ο a 1 >· a-et there 3 -aaiao~ lai -·< nr: 1 , / -f 5 e : \ C(f -...... Ft i 1 a::. i ni 0...... j ai , ' A·: a al o ( i / » p ; "l ) ti Ì O 1. i 11 tP' O et i lo XiCi .1 C Oli" ÌX'> .'ai 1(li; o (lic)' ) '>a ai jO i< g ) , aro ua (30 κ,Ι ) the aa al : o (:i (frai) r, r:o et a_ 1 i riso al foti i !- ri i 1 us'aO for P4 ur V..' *, 'there :i 1 :r ;(. "IO ifi 11. O i V '1 ] -dJ1' Γ: 'Ί ' , 11 kings of the horses CC ♦ 1, river aa t. [Vi. 1, O t'Vr ·.··.) (3 t 6 n) . The air is attached to the eye. <b) . fa : co p •-et i 1......f , f .-o: i ò:’"'a - -Λ p H.....ri ‘Ì C) « ?.....:i 0—] ':.r'a .3 1......4L- )’ii a ?;> .)[ f τ 2.....a JcLi i tol 1 a......af?,........a ori.io a ai 1 ico ij :i V··· 0 O ( d ί 0 di'" ilo -.1 :e"1o (a) 1 { ?> 1 i ,'i VU \ ''-'J0 > 1"l to those who are ardent Od { ' Si] ) will say 1 11 O i r.lO ​​S3 JiO to ......Vd (:'C;, for risk; ii; J and S; > ta ri e:: <0 da..» , 1. ( : 'Jj-p - r Ì UO '1 1 a teaps.rs the contents of the aa;il si ani 0 ss.a; - ep >: YES (a * f ; 1 you know the ' ..

1. *' j 1 : you ' do not PI PII ]> ;<f,u ehi accio (.1 ì ri tro ) od v * stati·'* e.s Leat t a in età 1aeot rio. l> If the other shot was resistant, it would evaporate and the residue would be separated into crystals or arcades at the bottom of the cone. .1:0 0 nd i t: 0 in the three -.- 10 1 0 d- : ! dp} > 1 5' vi t< 'X O'a i / .t.i al'. ;το0 p A c ;i do P—et .il-r. - 1 i 1 3-......0 ;-Gp 1 rapi, the Vii— ] IO 1 ri 0 - ^ Jl f'N ^ say-s" E" ; p 11 with - / ; C * i v ' 0 r 1; ;i lf ,d.....tj ;! 5 ì 'v d......d , 6.....r dos: r;>— 1 0-. j.daily 1 do! -Easy:around! .0 ΐ " * p] air .1 Where ~ir * > c;· — ί ij (' with Ί 1 i 00 (1 <J) e d i ( -15 1 c,'i Sia ( d Ri ) .soric s ai c ti y al eh sii r.is Si r;,sr :ì n un drivi. ossi a f p ,-p 12 ore a 1. (. 0 SJ 0 de po < li che .1 iììcPl e ri ί: 1 ì voi ; fi Ί :i, ose'. stai i ,f r 1 t; i ove por, i re? ci 00 °C , 3 Ϊ :r1 f:1 a 1 de 0 0 ' st : t O t r.i 1. vso lo 0 tm c taro (a oc > n 011. sa :i ir ss t 0 I / ( f ·] co:;.: ·Ό ', 1' 0 1 C, li ( ; jt ÌR .ί ο Ί only 1 η 1 01 C (C t Vi i,0 * from •Vi.J'-.Γ. >Ci ,j 1 Of ,j iC'i 1 idi a ) ; ir" ; ii . OR, and Ri K t: Γ,]'-et tro- S i„ ' ì . '5 t : < 'i :ij;; ? e : * (h) / .cm-c Rare] :i r Riches and oils with tedium (C 5' / i (j) o ' ».t atheist suspended :i ! fixed or: gold .Ί The co ed: eli.; 1 ' so (ao idi ) from e» rti. 1 0 the stairs, the river: I know how to go. ore 1 v immediately if; 1 painful bone .solved rtC' 3' a from 0 a Reei duo that is 'st this separate j / t ;ΐ cnt. and believe,·.;· to 3 rr Yes Ì !J ir. y bone to pvst o<.: ae; high pisci- yes oils.1 heart; Dite king in a; ite Ci'ri a co, posted in the title (: , o) was <?’ ri sì il 1 al ) e π ‘oo cita;; r al i e 01.

0. " rete ;i daat :i.co al può eie! to ir .1.1 * e i or [ ; Λ r a l·· scepsi ο K.) / ,ci ciò S—ot i l.....C i r ro ~4 5 6-di Or 'CO--IO- prò ;si 1--411-1.0100..030- [ 3 12-yJcfcipoii Γ^'λ? -a i e O'I OS si 1 i co (a) Dici il 1 i.PR f ΐ i io ό.......

1. o......ì > king>.i 1 : ? l-Water ::: so--4 ! I— pi / raiio! 3 , IR MOl .... !f ,3......they cardassi 1. a 1: o Ri eri ;i 1 R-Otì 1 ..... r R.....<'i 5 a. so- Λ T C……0 i, os so…..1 0…….oro pi. - 41!· pyranoL ipt-pi jc )n col ia .p......^ eiROR" RI a to (10 d) and pesto..... fire and.CO Ci C'CeCQ IR i re (PO a) at 1 60°C for (gold, iron or other photographs: rare echoes sold in the product) :il , e-et, ao « CO L 'ì to .>, raiiìa (; rii. of R Ί 1 ivoa / oR 1 eoo ta e, '-.j ( )ί·1ο from below! 1 '; ί ic ' :. and eρ -t 1 :te?,ν,.ν- i , ·: two n ;, ra · e) Ac.i (''!ο ' '"".!? *1. ..f1 f'1' -0 je 'ir ' ' s'i-ij f> ' ,T ' " / ' H '...... ; > j1 ;i if e 1 d ;. O 1 (>i L'C :i ) , i:C'i .IO ie"i 1 ;ì et 1' gli ve i. : li, ί rei. ) te.;):'; > r.i'ί ί i <: / : 'a ce ci). king ii' Oi CO Ci ..rtee · ο! :i !" <0 O 5 ··1 ) ì>'-r ·> of v* 13 you >3 will be with the kings :i ti ì ito a.od it 0 ef 0 et C.) .f 1 t: ί o ( ,y ,'ij >OJM; "!'·(' C· C il ne ;ii no e * 1 fi: ·. 0 t irci tv .le C ' O !" 1 and (dO r 1) with jet e·} and avi ee goes and (1 king ) ede' Ole 1 oa 11 i !.. (ito and ίΐΐ'Ίνριϊ te -nre e with the eggs. threads. .μι 1 fi 1 oe " οί. to your pvvi ficai 0 JliO of t V Λ J l. e? ero / .·! to work' ie 5 .r J ì'1. "l et. O ne 3 title ( ' to 1 g) 1 gin le o' i : and 1, .: t The kings.?; ί at ο ij r ;. ... / ? , f- Oc co·... 1 fi ο ver1 ^ 1of OC. ld.OO- :i.

1. .1 co ) .......d e5 * c· ci li 1.....;> .1 '1 ϊ . * -t ?..1'ir d.ro .....1 rd:vo O vi)......lo¬ Ί Ό i >1 1 'Ϊ ì C:C oj. ;i, '...... ' ? V : .! Lithium} V .. ΊΟ jvopil.- - d ! ;……..for r oro [_ 3} d……d Ji )>: 0 : re ? v '.'f ( ." 0-..I Ί :( r mi 1 rite (: ) i ir f >e- :> do o ( Odi CO 1 yesterday , 1 ( ( / 00 jn; 1 ) c« : ri , 1 o (().'; π ) ,rd"cn pr e. | ^ ^ ^ η, ' , / f.* r. ;f\ r : ì (· L ·; . "{ ] 1 1 , |" ι 1 'ir: ,f ; IL ; ' < | 1 'ir: ,f ; IL ; ' < | 1 f , the carriages and / t1 :ig * sheet. rv,tc> e ». Or '0)1 irto hatred in making guidelines to Ita for: '.rione ι 1 ni re li duo L r: pain the heart]: indie pole or in the south << »3 r) The ri.col ; '.· .king. er riot to confc; broken ],·; (b) There (I - ' t ' ì 5 ' brf'-l / i ' " .-di were no :r?S'~y uro uri !_ / ]) The product of helium (( / 1 (0 / 1 by) and CO in] >0^0 in eiemone (10 rrd) is wrong with a chrome colour, or 10 / 1 c ri, red. After stirring for 6 hours, it goes and evaporates; tc-i near gold with kidney cells and rat iodine bodies and 1 title (ο, 1 5 g ) , risj :it (> toe ι oo n 1 or <__ rafje cnc η Ί and :i gold rd :i co) at ^ >..?.(Yesterday).<iol 1 11 > "" o · r >5 op , ):r. ····:·,!]> io 12 of the co.. L.:--ct i Ι.--- ί ,e~di i é'ro-A / '...of one·::…….lO-propii .....eviro.- ' 5 1 [! 1 , (;) hρο.......pi ϊ Γ j i.,1 ÌV rt ί ' 1 1.e ' ri·.· « r"'ic ;i ί C dri co1 ear»click and 'ce / «. te ί.·' m. . . in saying if there is a .C ( " cu / ;S ore 11 , l< :}, ?. '· 1 '' V: - 1: , Γ , ' :bc ; be e, '0' i kings» :ì cin "> ] - i , ', <'aj ih1';' ί …….' ie (.·..' '< j e.1 ; i.' ( <j. ) d e-or ri 3 i co " o olii ; .....j......· ,3......di L r ) (' - f ! ;! ( 1 e 0 die - r u,,d 1.... di: !»l. 3 , i"* d.5 r> « : J Γ> '. * .... , -, e.. J '' ί r3 r . ? , " 1 ud. 0 ( d , 7 yes: ,j ( 'Ci ( 'i • .Ή ·; o fi ,0 7) fi Ì"J ;.c - UUÓ (]0 Ji|l ' cc;ua •ΐ' .VC iu tl < 1 C'Y OpOì' ere 0 ti : i 1 re - ri (your ci¬ ' et (good or 1 π e 1 ; i'rOlO ( d ,0 -1 ) you ' Giti! r to with r,e ;io '0: > oo de i.1 0 1 d 1 0 0 is the value of Et C.MCi ri -Γ¬ :ivv nrd e 11 nej 1 1, 0 1 ìl'J ree i duo r lui. C ' et. 1 opOo IO e ere io, u lo UJC' f;i u. (; - 1 ci ì si li re ) with ot, luci i:. 1 ,t 0 of a 0 :ì < e te ir e (3 * L 0 ) that io i'd-,1. 1 o - ì iO j J 1J r cor u; ,0 so 110 ione? di. Ì G:'Ì 't noi r; 1 eio (0,1 3 ir 9) ir UiC φ!) U i f- ' rn 1. ) » :ir se ju 1 to nel :ì e ον,ione ri. e 1 b Oim n ri 10 a P .ree 1}ri. t otio elio e* ubo or sr1·re il ,-.nociotto to d <o ni t i su Unti rii PKR e ? ci do ' a........(\ ^di ί Pro.......d [ 3 f 2......;; )c 1 ' ì .noi i .y,.·... 3}l [’,*. di ri·,': ] 1 prodel 1 o de- i Io ci. <idi oet ì 1 re-i'i Γor;ri <io e -eco ( 1 (5'.;o31),;, li o no di rocco (l φ( 30 rii.) o 4d|C'C rutto a ter]. o ci :c·' -3 u di co e-, i e,no e duie:r oto ¢0,93 fj) urbi tre scopi a d ί ressa. 6— di 0 s so.....3 O-pri udì 1......«IH· lo.) s si 1 i co (a) (0,7 <0 re i oli to l'i'il) e1 stu:to a idi, unto in direi,i 1 sol. idi.) 'i.rido d„i, fora di i.' / .ot'O * ; . cot i n et ut a vere ut e • ;ΐ;ι.ΐ(':ί (CCC ; cl ) pei • ( Λ VM - 0 / D " . : 1 ·; . ;fj ce \ yc··: / 0vi1' c ; ' js C'1 gold, Γ. < / < / 1 L Ci 00 00 i:0 re CY Y è '' : r ' ; V il C ' 1 ' 1 Vii; 0 > '! / > evie or: ( ' 1 1 O / 0 / ' 0 eh·::· cf ..1 i : ' 1 e :i .·; 1. reo / >:0 ì p ' <.' 1 ì.<.'ì C ; co? 1 CO *Ì •DiU) { I , C i ) )r;.ij l. / / ]. C ί .! 1: C r / ί 11 0 1'0 per I> 0 / D JC IID, f ; -"· J' Ί i. ( · * H − 1 v 1 ' L : .:·,· f'.1 ' / rj ( / ri, 1, , C* C:t < 1. c Vi / ÒSc A a 3 Ti v 13 :i £ (.' · eie<v„ ' ) Ce η* «pois 1 V, t 0 cc> of 1D,·..:! hours D f ' 1 / Vii D ui 1 DAY C" : : n C 1 cr> · ].;.! s(' 11 > :,1 ¢:>nr irj 1:':ic:- e") Ci C 0 (. . 4 ì. (. : t ! 1 ce t sto. OS Sii CCDO / rt 0 < •e ov [ / porr / 0 / !; jO Cj ; ri. 0 OV: a eie croi / ο le οο\' <·.: ,!Vl ( cr: -00 and operate" i 1)3 phase the prayers 0 / high}v oc «vi re heart; 01 1 co / 1 io: rite O Deport the delicate new! i same with the Co 1: to eie : 1 l*o pio 1 * "ll λ À\ \ FLOODED E ] ·: ott i. I ic 11 ea 11 a ci cscr 1 ziong ci c II a ·: J o in an adibie ve;..tc> η. 2291 8 A / 7 8 of 2 May 1978, contained in items 11 to 11, and contained in items 11 of 16 September 1985 -Items 1 ! a 1 ) : on page 1, line 2, the title is intended replaced by the following: "DERI VATI. PI RANOQINOLINOM CI, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND METHOD FOR THEIR PREPARATION. For more information, PEPICIO PATENTS INO / / U. GREGGERS OF K-EM / ii.; Milano, 5 / 11 / 1985 v, E'· A "o; / : b.}.