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    • 专利摘要:
    There are described compounds of formula I, <IMAGE> I in which an adjacent pair of R5, R6, R7 and R8 form a chain -CZC(G1)=(G2)-Z-, R4, R9 and the remainder of R5, R6, R7 and R8, which may be the same or different, each represent hydrogen, alkyl, halogen, alkenyl, -NO2, -NR1R2, -OR3, -S(O)nR3; or alkyl substituted by hydroxy, amino, alkoxy or carbonyl oxygen, n is 0, 1 or 2, R1 and R2, which may be the same or different, each represent hydrogen, alkyl, -CONHR3, phenyl or phenyl substituted by alkyl or halogen, or R1 and R2 together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring, R3 represents hydrogen, alkyl, alkenyl or phenyl, one of G1 and G2 is hydrogen and the other is a group E, each E, which may be the same or different, is -COOH, a 5-tetrazolyl group, or a carboxamidotetrazole group, each Z, which may be the same or different, is oxygen or sulphur, and one or two of the atoms, a, b, c and d are nitrogen atoms and the remainder are carbon atoms, R9 having no significance when two of a, b, c and d are nitrogen, (with certain exclusions) and pharmaceutically acceptable derivatives thereof. There are also described methods for making the compounds and pharmaceutical, e.g. anti-allergic, compositions and mixtures containing them.
    公开号:SU1014476A3
    申请号:SU792838414
    申请日:1979-10-30
    公开日:1983-04-23
    发明作者:Кокс Дэвид；Кейрнс Хью；Чадвик Найджел；Луис Сушицки Джон
    申请人:Физонз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    where Rjj, Rg, K-, and Rg have the same meanings as the groups R, f, R-, and Rg, except that the two neighboring groups R °, R, R and R mean the chain
    -czco) - conj) -2-.
    where one of the group G and Oa means hydrogen, and the other group D, one or both groups of D and Dp means a group that can be hydrolyzed to the COOH group or oxidized, and the other means a COOH group,
    a ,, b, c, d, have the indicated meanings
    and isolate the desired product in free form or as a salt.
    Priority featured:
    10.31.78 - each R, K, R, R,
    Rj-i Rfe b 9 they contain carbon, contain it up to 8 carbon atoms; -C2C (Su) C (G, 2) -Z chain is attached at the R and R positions, with part of the chain in the Rt position, and the -CZC (G) C (G2.) chain - Z represents -COCH C (COOH) -0-; Rr is hydrogen and Rrt is alkyl; d is nitrogen; group E is in the position adjacent to the nitrogen atom of the ring; group E is the same and represents -COOH, R. is located in the para-position in relation to the single nitrogen atom in the Q; area; R4 is different from OH. I. About. 79 - one of a, b, c and d-nitrogen
    "
    This invention relates to methods for producing novel heterocyclic compounds of general formula I.
    6
    where two adjacent groups, R RT and Rg form a CZC chain (C
    G 2 means in which one of G.
    and
    one
    hydrogen, and the other is group E, each group E being -COOH, each group Z is oxygen or Z in a cycle means sulfur, and the other Z is oxygen;
    R and Rg and a group of R, R, R7 and Ro may be the same or different and each means hydrogen, lower alkyl, halogen, lower alkenyl
     -OR. -S (0), R3, where n is 0.1 or 2;
    R and R-. same or different, and each means hydrogen, lower alkyl, CONHR, phenyl, unsubstituted or substituted by alkyl or halogen, or R and R2, together with the nitrogen atom to which they are attached, means a pyrrolidine group;
    1C is hydrogen, lower alkyl; lower alkenyl or phenyl; one or two of the atoms a, b, c and do are nitrogen atoms, and the rest are
    carbon atoms, and R is irrelevant if two of the groups a, b, c and d mean nitrogen, provided that
    a) if a, b and c are carbon atoms and d is a nitrogen atom,
    b) E is in the ortho-position with respect to the nitrogen atom; c) Rg is hydrogen, d) G is hydrogen, and
    2 means group E, e) R ,. R, -r, and Rg each means hydrogen, hydroxy, lower alkyl, halogen, lower alkenyl, alkoxy, and NR R2, f) if k) each Z means oxygen, then R is not an OH group in the para position with respect to the atom nitrogen,
    or their salts, which have pharmacological activity, and. may. find application in medicine.
    A known method for producing carboxylic acids by hydrolysis of the nitrile group p.
    There is also known a method of oxidation using Jones reagent in acetone G2.
    The aim of the invention is to obtain new compounds of general formula 1, which have pharmacological activity.
    This goal is achieved by the proposed method for the preparation of compounds of formula I, based on a reaction known in organic chemistry, which consists in hydrolyzing NMR spectroscopy to confirm the preparation of the title compound.  (with).  Disodium-6-chloro-oxo-10-propyl-1H-pyrano (3,2-d) quinoline-2,8 dicarboxylate.  6-Chloro-4-oxo-10-propyl-H-pyrano (3,2-d) quinoline-2,8-dicarboxylic acid {0.62 g), suspended in water, treated with bicarbonate on ri (0.292 g) and mix until dissolved.  The solution is filtered and then treated with acetone. The precipitated product is collected by filtration and dried.  0.6 g of the title compound are obtained.  Elemental analysis.  Found,%: C 6.6; H 2.9; N 3,0; 8,2 СН рСее-, Об- y. it IGO Calculated,%: C 46.6; H 3.1; N 3.1 7. 9.  NMR spectroscopy confirmed the preparation of the title compound.  Example 2o Disodium-6-methox-ch-oxo-10-propyl-hH-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  (but).  Ethyl 6-methoxy-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2-carboxylate.  0.053 g of sodium hydride (50% dispersion in oil) are suspended in anhydrous ether and then in anhydrous dimethylformamide (1Q ml) under dry nitrogen atmosphere. Ethyl-8-methoxycarbonyl-4,6-dioxo-10-propyl-4H, bN -pyrano (3,2-d) quinoline-2-carboxylate (0.39 g dissolved in anhydrous dimethylformamide (20 ml) and then added dropwise with stirring to the above sodium hydride suspension.  The whole mixture was stirred at ambient temperature for two hours, iodomethane (0.23 ml) was added dropwise and stirring. Continued at room temperature for another two hours.  The whole mixture is then poured into water, extracted into ethyl acetate, dried with magnesium sulfate, filtered and the volatiles removed under vacuum to give a yellow solid, which is then recrystallized from cyclohexane / dichloroethane to obtain 0.2 g of the title compound.  T. square 180182 S.  (B) 6-Methoxy-4-oxo-10-prepyl-4H-pyrano (3,2-d) quinoline-2,8-dicarboxylic acid.  The product of step C (2.355 g) is suspended in methanol (400 ml) with stirring and under reflux, and a 10 M sodium hydroxide solution (122 ml) is added dropwise.  The solution is heated under reflux for an additional 5 minutes after addition, cooled, then poured into water (500 ml) and acidified.  The precipitated product is collected by filtration, washed with water and dried.  1.7 g (5Uc-acid, which is suspended in water (torus ml) and treated with sodium bicarbonate (0.8 g)) are obtained.  The solution is filtered and the filtrate is freeze dried, to obtain 1.2 g of sodium salt.  The salt is purified by reverse-phase high-pressure liquid chromatography using methanol / aqueous ammonium acetate as eluant.  The product, obtained as a solution of ammonium salt, is treated with hydrochloric acid and the precipitated cTuc acid is collected by filtration, washed with water and dried, yielding 0.488 g of the desired product.  T. square   (with decomposition).  (with).  Disodium-6-methoxy-4-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2, 8-dicarboxylate.  0.4 to 8 g of the product of the step is dissolved in water (80 ml) containing sodium bicarbonate (0.192 g).  The solution is filtered and the filtrate is freeze dried.  This gives 0.425 g of the title product.  Elemental analysis.  Found: With 46.1; H 4.59; N 2.5 N ,, 14.61 H, 0 Calculated,%: C 46.1; H 4.4; N 3,0.  Example 3  6-Methylamin-4-oxo-10-propyl-4H-pyrano (3,2-0) quinoline-2, 8-dicarboxylic acid.  (but).  Dimethyl 1- (4-acetyl-Z-hydroxy-2-propylphenyl) -amino fumarate.  4-amino-2-hydroxy-3-propyl acetophenone (19 g) and dimethyl acetylencarboxylate (14.5 ml, 16.8 g) in ethanol (20 Yu ml) are heated under reflux for 7 hours.  The solvent is removed by evaporation to obtain a PCb, 4 g of product as an oil.  The structure was confirmed by NMR-mass spectrometry.  (€)  Methyl-6-acetyl-7-hydroxy-8-propyl-4-oxo-4n-quinoline-2-carboxylate.  30 g of product stages O.  was added to diphenyl ether (300 ml), heated under reflux for another 5 minutes after the addition, cooled and poured into a large volume of petroleum ether in C-BO. .  The precipitated product is collected by filtration, washed with petroleum ether and dried, to obtain 20 g of a brown solid.  Recrystallization from a large volume of cyclohexane gives a pv mat; al having t 1b9 170С, (с).  Methyl-6-acetyl - "- chloro-7 hydroxy-8-propyl-quinolin-2-carboxyl" To 3 g, 0.0099 mol of the product of the step is dissolved in anhydrous benzene (50 ml), treated with phosphoryl chloride (2.5 ml ) and heated under reflux for 1 h.  The reaction mixture is cooled, poured into water and extracted with ether, which is then washed with water and dried over magnesium sulfate.  The solvent is evaporated; 2.8 g of a tan solid remains.  Recrystallization from cyclohexane gives yellow needles having m. square  163.  (sl).  6-Acetyl-7 hydroxy-α-methylamino-8-propylquinolin-2-carboxylic acid 8.9 g of the product of the stage are treated (w / w) with a solution of methylamine in ethanol (100 ml) and heated in an autoclave for 17 h.  The reaction mixture is cooled and poured into a mixture of water and ethylacetate.  The organic layer is separated, washed with water and dried over magnesium sulfate.  Rast the evaporator is evaporated.  9.0 g of H-methyl-7 hydroxy-4-methylamino-6- (1-methylimino) -ethylZ-8-propylquinolin-2-car oxamide are obtained.  Amide (7.0 g) is treated with 70% sulfuric acid (350 ml) and heated under reflux for 3 / h.  The reaction mixture is cooled and aqueous ammonia is added at. ice cooling to pti 7.  The gelatinous product is collected by filtration, washed well with water and dried.  6 g of the title compound are obtained.  (e)  Ethyl 6-acetyl-7 hydroxy-5 methylamino-8-propylquinolin-2-carboxylate.  6, g of the crude product of art. Adium d in ethanol (500 ml), which is pre-saturated with gaseous hydrogen chloride, is heated under reflux for 1 hour.  The reaction mixture is cooled, basified with ammonia and extracted with ethyl acetate, after which it is washed with water and dried over magnesium sulfate.  The solvent is removed by evaporation.  8.0 g of residual yellow solid5 are obtained, which is recrystallized from ethanol.  3.8 g of yellow needles are obtained having t. square  219-220 ° C.  (f).  Diethyl-6-methylamino-4-oxo-1 O-propyl-i H-pi early (3,2-d) quinoline-2, 8-dicarboxylate.  3.6 g of the product of stage e and diethyl oxalate (1.4 g) dissolved in anhydrous dimethylformamide (150 ml) are added with stirring under a nitrogen atmosphere to 50% sodium hydride washed with ether (2.3 g), suspended in anhydrous dimethylformamide (120 ml).  The reaction mixture is stirred for 2 hours and then poured into water, acidified with glacial acetic acid and extracted with ethyl acetate, which is then washed with water and dried.  The solvent is evaporated to give an oil, which is dissolved in ethanol (300 ml), previously saturated with gaseous hydrogen chloride, and then heated under reflux for 15 minutes.  The reaction mixture is cooled, basified with aqueous ammonia and the precipitated solid is collected by filtration, washed with water and dried.  Get it.  , 1 g of the product.  Recrystallization from ethanol gives 2.9 g of crystalline product having m. pl, 235-237C.  .  (BG) Disodium-6-methylamino-4-oxo-10-propyl-H-pyrano (3,2-d) quinoline-2, 8-dicarboxylate.  1.932 g of the product of step f is stirred in methanol (200 ml) under reflux when a 1 M solution of sodium hydroxide solution (9.38 ml) is added dropwise.  The reaction mixture is stirred under reflux for another 2 hours, cooled, filtered and the filtrate is evaporated to dryness.  The residue was dissolved in water (100 ml), filtered and the filtrate was treated with a large volume of acetone on completion of the precipitation, the duLC sodium salt was collected by filtration and dried.  1.55 g of product is obtained.  Elemental analysis.  Found /: C 9.7; H k, 5; N b, 8, O- HjO Calculated, /: C + 9-7; And, 1; N 6, + Example C, 6-Ethylthio-oxo-10-propyl-4H-pyran (3,2-d) quinoline-2, 8-dicarboxylic acid, (o).  Methyl-6-acetyl-ethylthio-7-hydroxy-8-propylquinolin-2-carboxylate Methyl-b-acetyl-chloro-Uoxy-B-propylquinolin-2-carboxylate (1.0 g) in anhydrous dimethylformamide (50 ml ) is added dropwise to a stirred solution of sodium thioethyl prepared by adding ethanethiol (0.773 g) to sodium hydride in oil (0.6 g) in anhydrous dimethylformamide (30 ml) under a nitrogen atmosphere.  The purple solution is stirred for 2 hours, poured into this acetate and acidified with dilute hydrochloric acid.  The organic layer is separated, washed with water, sodium bicarbonate solution, and then dried.  Evaporation of the solvent gave 0.8 g of the expected product, which was recrystallized from cyclohexane, to obtain 0.52 g of yellow needles having m. plo 1UZ-195 S.  (B)  Ethyl 6-ethylthio-8-methoxycarbonyl-4-oxo-10-propyl-H-pyrano (3,2-ig) quinoline-2-carboxylate.  2.7 g of the product of step a is converted into the title compound, a pale yellow solid (2.35 g) by the method of Example 3 f.  The structure was confirmed by NMR and mass spectrometry (s).  Disodium-7-ethylthio-4-oxo-10-propyl-H-pyrano (3,2-d) quinoline-2, 8-dicarboxylate.  1.958 g of the product of stage b is converted into a compound (1.3 g) by the method of example 3 q.  . - Elemental analysis.   Found: C 51.1; H 4.1; N2.9; S 6.9 C, H, Calculated,%: C 50.8; H, 8; N 3,1 S 7,1P r and me 5.  Diethyl-6-chloro-4-oxo-10-propyl-4H-pyrano (3,2-d) quinalin-2, 8-dicarboxylate.  Methyl-6-acetyl-4-chloro-7-hydroxy-3-propylquinolin-2-carboxylate (1.0 g) and diethyl oxalate (ml) in anhydrous dimethylformamide (25 ml) are added to ether 50-sodium hydroxide ( 0.65 g) suspended in anhydrous dimethylformamide (25 ml) in the atmosphere of the lot when re-mastered.  The reaction mixture is stirred for S hour at room temperature, poured into ethyl acetate, aqueous acetic acid is added and the organic layer is separated, which is washed well with water and dried.  The solvent is evaporated, the residue is dissolved in anhydrous dioxane (100 ml).  Then, anhydrous hydrogen chloride gas is passed through the solution for 20 minutes.  The reaction mixture is poured into ethyl acetate, washed well with water, saturated sodium bicarbonate solution, and then again with water and dried.  The solvent is evaporated, and the residue is dissolved with petroleum ether heated to AO-COO.  Obtain 0.9 g of the title product.  The structure is confirmed by NMR and mass spectra.  The product is converted to the free acid and disodium salt using the methods of examples 11e and C EXAMPLE 6.  6-Bromo-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2, 8-dicarboxylic acid.  The acid is obtained by the method.  with example 2c Found:% from 9.1; And 3.15; N 3.37, H &amp; gt- 0 Calculated: С, 0; H 3 ,, N 3.05 Example 7.  Disodium-6-methyl- - oxo-10-propyl-H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  (but).  2- (4-Acetyl-3 hydroxy-2-propyl) -phenylamino-4-oxo-pentanoic acid.  A-Amino-4-hydroxy-3 Propyl-phenylethanone (37.2 g) was melted on a steam bath and E-oxopent-2-enoic acid (20.0 g) was added to it.  The mixture is then heated on the steam bath for 15 minutes.  A crude title compound (53 g) was isolated, a 1 g sample of which was recrystallized from. ethyl acetate and dried under reduced pressure and 70 ° C for five hours.  0.2 g of the title compound are isolated, having t. square  1A6-148C.  (t).  6-Acetyl-7-hydroxy- -methyl-8- | fopilhinolin-2-carboxy ki slot.  Polyphosphoric acid (500 ml) is added with vigorous stirring to 50.0 g of the finely ground product of the "stage".  The mixture is heated on the steam bath for fifteen minutes, then poured into a mixture of ice water / ethyl acetate and stirred for one hour.  The resulting mixture is extracted with ethyl acetate and then washed with a saturated solution of sodium carbonate bi111.  The bicarbonate solution is acidified and extracted into ethyl acetate, dried over magnesium sulfate, filtered and the volatile material is removed under vacuum to isolate 16.5 g of the crude title compound, and the 1 gram sample is recrystallized from ethanol.  0.7 g of the pure title compound are obtained in the form of orange needles having t. square  125 127 ° С "(С).  Ethyl 6-acetyl-7 hydroxy-4-methyl-8-propylquinolin-2-carboxylate.  6.5 g of product of stage b are dissolved in anhydrous ethanol (500 ml).  Anhydrous hydrogen chloride gas is then bubbled into this solution until the solution is saturated. .  This solution is heated on a steam bath for 1.5 h. The mixture is poured into water and extracted into ether.  The ether layer is washed with water. saturated sodium bicarbonate solution, dried with magnesium sulfate and filtered.  When the solvent is partially removed, a yellow solid crystallizes out of solution, which is filtered off.  1.1 g of the title compound are obtained, having t. square  150-151C (d).  Diethyl-6-methyl-4-oxo-10-Pro pil-4H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  Metallic sodium (40.8 g) is added to anhydrous ethanol (100 ml) and then heated on the steam bath until the reaction is complete.  A suspension of 4.9 g of the product of the stage and diethyloxylate (8.5 ml) in anhydrous ethanol (250 ml) was quickly added to the resulting sodium ethylate solution.  Heating is continued for 15 minutes, then the mixture is poured into water, acidified with dilute hydrochloric acid, dried with magnesium sulfate, filtered and the volatile material removed under vacuum to obtain an oil.  A saturated solution of ethanolic hydrogen chloride (250 ml) is added to the oil and the mixture is heated under reflux for thirty minutes, then it is poured into water, extracted into ethyl acetate, dried with magnesium sulfate, filtered and the volatile material is removed by vacuum.  An orange-brown solid is obtained, which is purified by chromatography using silica gel as the stationary phase and a 7612 mixture of 1: 1 heated to 0-60 ° C. of the net line and diethyl ethers as eluent.  The product thus obtained is recrystallized from petroleum ether heated to 80-100 ° C.  0.8 g of the title compound is obtained, having t. square  1b5 1b8S.  (e)  6-Methyl-4-oxo-10-propyl-4I-pyrano (3,2-d) quinoline-2,8-dicarboxylic acid.  To a stirred solution of the 0, product of stage c in ethanol (200 ml) on a steam bath was added 0.105 M NaOH (8.8 ml).  Heating is continued for 1.5 hours.  The mixture is then filtered and the volatile material is removed under reduced pressure.  The resulting oil was dissolved in distilled water (50 ml) and an excess of acetylene was added, which resulted in precipitation (51 sodium salt).  The salt is dissolved in water, acidified and extracted into ethyl acetate, dried with magnesium sulfate, filtered and the volatiles removed under reduced pressure.  0.3 g of the pure title compound is obtained, having t. square  252-25 ° С ().  Disodium-6-methyl- -oxo-10-propyl + H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  1.0 g of the product from step c is converted to 0.75 g of the title compound by the method of Example 3.  Found,%: C- 52.4; H 3.9; N З,. Ofe 1.5 mol (6.6%) Calculated: С 52.4; H 3.9; N, 3.4 The NMR spectrum confirmed the formation of the title compound.  I Example 8.  4,6-dioxo-10-propyl-4n, 6H-pyrano (3,2-d) quinoline-2.7 dicarboxylic acid.  (but).  Diethyl 4,6-dioxo-propyl-4H, 6H-pyrano (3,2-d) quinoline-2,7-dicarboxylate.  A mixture of ethyl 7-amino-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate (1.5 g. , 0.00545 mol), diethyl ethoxymethylenemalonate (1.17 g, 1.1 ml, 0.00545 mol) and anhydrous toluene (20 ml) are stirred and heated on the steam bath for 16 h.  A further equal portion of diethyl ethoxymethylenemalonate (0.5 ml) is then added and the mixture is heated under reflux for 20 h.  The volatile components were removed by evaporation and the residue was added to the pre-heated diphenyl ether (0 ml) for 5 minutes. The mixture was heated under reflux for 1 hour, allowed to cool and poured into 4 ° -60 ° C petroleum ether.  The insoluble material is filtered off, washed with petroleum ether, boiled with ether and crystallized from ethanol.  The title compound is obtained as a pale brown solid (0.38 g) having m. square  232-23 0.   (B)  , 6-dioxo-10-propyl-H, 6H pyrano (3,2-d) quinoline-2. , 7-Dicarboxylic acid.  2.95 g, 0.007 mol of a solution of the product of stage a and 7% aqueous hydrobromic acid (25 ml) in glacial acetic acid (100 ml) are heated under reflux for 6 hours and then left to cool to obtain the desired product in two portions as a tan solid (2.29 g which is dried under vacuum to remove the remaining acetic acid.  NMR and mass spectroscopy confirm the structure of the product.  (with ).  Disodium, 6-dioxo-Yu-propi, 6H-pyrano (3,2-d) chiloline-2,7-Dicarboxylate, 1.5 g, 0, mol of the diacid product of the stage b are converted into the disodium salt as yellowish brown powder , 22 g by the method of example 1c.  Elemental analysis.  Found,%: C 50.0; And 3.7 ;, N, 3.2 H 5.1%; Calculated,%: C 50.0; H 3.3; N G, Example 9.  Disodium-6-chloro-t-OKCO-7, 10-dipropyl-H-pyrano (3.2 Quinoline-2, 8-dicarboxylate.  ( about).  Diethyl, 6-dioxo-10-propyl-4H, 6H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  k, 6-dioxo-10-propyl-4H, bH-pyrano (3,2-d) quinoline-2,8-dicarboxylic acid (3.9 g) is converted into g of the title compound as a yellow powder (t. square  211-213 c) according to the method of Example 6a, using ethanol.  (B)  Diethyl-4-oxo-6- (prop-2-enyl hydroxy) -1O-propyl-H-pyrano (3,2-d) quinoline-2, 8-dicarboxylicate.   1 product of stage c (3.0 g), anhydrous potassium carbonate (T, 6. d) and allyl bromide (1.26 g, 0.902 ml) in anhydrous dimethylformamide is stirred for 17 h.  The reaction mixture is poured into water, the precipitated product is collected by filtration and dried to obtain 3.0 g of a pale yellow product having t. square  151-153s.  (WITH).  Diethyl-4,6-dioxo-7- (2-propenyl) -10-propyl-4H, 6H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  The product of stage b (0.5 g) in diethylaniline (5 ml) is heated under reflux for 1 1/2 hours.  The reaction mixture is cooled, poured into 60-80C petroleum ether, the precipitated product is collected by filtration, washed well with petroleum ether and dried.  Recrystallization from ethanol gives O, g of yellow crystals having m. pl, 137 139 ° C, (d) Diethyl-, 6-dioxo-7,10-dipropyl-H, 6H, pyrano (3,2-d) quinoline-2, 8-dicarboxylate.  The product of stage C (0.5 g) is dissolved.  in ethanol (50 ml) is treated with R3 / C (0.1 g) and hydrogenated at a pressure of 3 atm until the uptake of hydrogen has stopped.  The reaction mixture is filtered, the filtrate is evaporated to dryness.  0.4 g of the expected product is obtained.  Recrystallization from aqueous ethanol gives a material having m. square  127130 ° C.  (b)  Diethyl-6-chloro-A-oxo-7,10-dipropyl-4H-pyrano (3,2-g) quinoline 2, 8-dicarboxylate, the product of stage c (1.8 g) in anhydrous benzene (100 ml) is treated with chlorine oxide phosphorus (1.12 ml) and heated under reflux for 6 hours  The reaction mixture is cooled, treated with ethyl acetate and washed well with water.  The organic layer is separated, dried and the solvent is evaporated, yielding 1.7 g of residue.  Recrystallization from 60-80 ° C petroleum ether gives 1.16 g of the desired product, having m. square  .  ()  6-Chloro-oxo-7,10-dipropyl-4H-pyrano (3,2-g) quinolin-2,8-diconic acid.  A 0.1 g solution of nati hydroxide (28.9 ml) is added while stirring for 15 minutes over the diester product of step (0, g) in boiling water with reflux metaol (100 ml).  The reaction mixture is heated under reflux and stirred for an additional 3 hours, the solution is filtered and evaporated.  The residue is dissolved in water. (100.  ml) and acidified.  The precipitated acid is collected by filtration, washed with water and dried.  Get 0, + g of the target product.  Recrystallization from ethyl acetate gives 0.2 g.  T. square  20 (with decomposition).
    (g) Disodium 6-chloro-oxo-7,10-dipropyl-H-pyrano (3,2-d) quinoline-2, 8-dicarboxylate
    The product of step f is converted to 0.668 g of the desired product by the method of Example Bg.
    Elemental analysis.
    Found: C 9.08; H 4.27; N 2.9b se 7.2
    С2оНнбСРММа2.0б 8.53%
    Calculated: With 9.03; H 4.22; N 2.86; every 7.25
    The products of stages b, c and d can be hydrolyzed to free acids.
    Example 10.7-Chloro-5 methoxy-4-oxo-4H-pyrano (3 2-d) quinoline-2,9-dicarboxylic acid.
    Named acid and its disodium SALT receive by the method of example 1.
    Elemental analysis.
    Found: C, 43.3; H 2.04; M 3.2;
    ce 8,4
     that se 5.26
    Calculated: C 43.3; H 2.1; N 3.4; All 8.5.
    NMR spectroscopy confirmed the preparation of the title compound.
    Example 11. 6-Chloro-4-oxo-10- (prop-2-enyl) 4H-pyrano (3,2-d) quin6lin-2,8-dicarboxylic acid.
    Named acid and its disodium salt receive the method of example 1.
    Elemental analysis.
    Found,%: C 48.53; H 2.44; N 3.04
    ce 8, h, 99%
    Calculated: C 48,53; H 2.34; N 3.3; ce 8,7 ..
    NMR spectroscopy confirmed the presence of the title compound.
    Example 12. 4-Chloro-10-oxo-1OH-pyrano (2,3-I) quinoline-2,8-dicarboxylic acid.
    This acid and its disodium salt are prepared according to the method of Example 1.
    Theoretically for 9.75
    Found,%: C 40.4; H 2.75; N 2.7;
    ce 7.2
    Calculated D: 40,8; H 2.48; N 2.75; Cr 7,3Example 13. M- (2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethyl) -1,1-dimethylethylammonium sodium-6-chloro-4-oxo-10-propyl-4H-pyrano ( 3,2-d) quinoline-2-, 8-dicarboxylate.
    N- (2-OXY-2- / 4-hydroxy-3-hydroxymethylphenylAethyl) -1, 1-dimethylamine (o, 284 g) pure sodium bicarbonate (0.0997 g) and 6-chloro-4-oxo-10- Propyl-4H-pyrano (3,2-d) quinoline-2,8-dicarboxylic acid containing 5.2% water (0.452 g) is mixed in pharmaceutically pure water (20 ml) and stirred until complete dissolution is obtained. The solution is filtered and freeze dried to isolate the title compound as a yellow solid (0.6 g).
    Elemental analysis.
    Found: C 54.27; H 5.72; N 4.63; CP 6.0
    WITH-. 6,4 NgO
    Calculated, o: C 54.3; H 5.27; N 4.22; CE 5.4 Example 14. Calcium 6-chloro-4-OXO-10-propyl-4H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.
    Disodium-6-chloro-4-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2,8-dicarboxylate (0.5 g) is dissolved in water (1 ml) and anhydrous solution is added. calcium nitrate (0.05 g) in methanol (5 ml). After stirring for one hour, the precipitate is collected and washed well with water. Drying in vacuo gives the title compound (0.27 g) as a yellow solid. I
    Elemental analysis.
    Found: C, 41.57; H 4.03; N 3.13
    All 7,1-.
    s, n sasemo -5
    Calculated,%: C 41.57; And 4.12; N 2.85; every 7.2.
    Example 15. 6-Ethylsulfonyl (and 6-ethylsulfonyl) -4-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2,8-dicarboxylic acid.
    (but).  Ethyl 6-ethylthio-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2-carboxylate (0.9 g) was extracted into dichloromethane (50 ml). and treated with methachlorobenzoic acid (2.5 g).  After mixing. at room temperature for 3 days, the suspended solids are removed by filtration and the solution is washed well with a saturated solution of sodium bisulfite, dried and evaporated to obtain a brown residue (0.68 g), which is divided into components by high pressure liquid chromatography.  Two major fractions were recovered: (i) sulfoxide (0.38 g); (-I-i) sulfone (0.22 g).  Two materials were identified by NMR and mass spectrometry.  (B)  Disodium-. b-ethylsulfinyl-oxo-10-propyl-4H-pyrano (3, -d) quinoline-2,8-dicarboxylate.  The product of Stage 1 O (0.3b g) is hydrolyzed by the method of Example 3c to yield the title compound (0.18 g).  The structure was confirmed by NMR and IR spectroscopy, (c).  Disodium-6-ethylsulfonyl-oxo-10-propyl-4H-pyrano (3, -2-d) quinoline-2,8-dicarboxylate.  Product 1-1 of the indicated suit of hydrolysis is carried out in the same manner as iv) to isolate the title compound (0.12 g).  The structure is represented by NMR and IR spectroscopy.  Example 16  2-OXY-9-OXO-5-propio-9H-pyrano (3, 2-d) quinoxaline-3, 7-dicarboxylic acid.  (h)  1 - (- Acetylamino-2-hydroxy-5-nitro-3-propylphenyl-) -ethanol.  1 - (- Acetylamino-2-hydroxy-3-propi-Lphenyl) -ethanol (58.75 g) is suspended in glacial acetic acid (750 ml) and the suspension is treated with an ice-cold mixture. acetic acid (250 ml), acetic anhydride (8 ml) and concentrated nitric acid (19.2 ml) with vigorous stirring.  After 18 hours, the insoluble material was collected and dried under vacuum to isolate the title compound (29.1 g. Structure confirmed by NMR and mass spectrometry.  (B)  Methyl-7-amino-6-nitro-4-oxo-8-propyl-H-1-benzopyran-2-carboxy lat.  Sodium (11.5 g) is dissolved in ethanol (500 ml).  The product of this stage a (28 g) is added to it, and then, after stirring for 5 minutes, diethyl oxalate (31.5 g) is introduced.  The reaction mixture is heated for 3 hours with reverse ho / divination, then cooled and poured into a vigorously stirred mixture of chloroform (2 liters of water CtOO ml) and concentrated hydrochloric acid (100 ml).  The organic solution is dried and evaporated, and the residue is extracted into ethanol (00 ml) containing concentrated hydrochloric acid (k ml).  The solution is heated under reflux for an hour, and then 100 ml of glacial acetic acid and 10 ml of concentrated hydrochloric acid are added and boiled for a further period.  18 hours. The ethanol is removed under vacuum and the residue is heated in a mixture of glacial acetic acid (150 ml), concentrated hydrochloric acid (200 ml) and water (150 ml) under reflux for 3 hours.  After cooling, the precipitate is taken up and dried, then suspended in anhydrous methanol (500 ml).  This suspension is heated under reflux for one hour while gaseous hydrogen chloride is passed through.  The solvent is removed in vacuo, the residue is extracted into ethyl acetate and dried over potassium carbonate.  Removal of the solvent gives the target material (15.1 g).  Crystallization from methanol gives a yellow solid, tgpLo 160-161 ° C, (c).  Methyl-6,7-Diamino-oxo-8-propyl-H-1-benzopyran 2-carboxylate, the product of this stage (0.5 g) is dissolved in ethyl acetate (150 ml) containing glacial acetic acid (5 ml) The mixture is hydrogenated over 5% Pd / C (0.1 g) at a pressure of 3 atm.  The catalyst is removed by filtration through glass fiber paper under a nitrogen atmosphere.  The solvent is removed first at and then at.  The residue is dissolved with methylene chloride, the insoluble solid is collected and dried.  A brown solid is obtained (0.125 g), having m. NMR and mass spectrometry pLo -21222 confirmed the preparation of the title compound.  (AND).  Ethyl 2-hydroxy-7-methoxycarbonyl-9-oxo-5-propyl-9H-pyrano (3,2-d) quinoxaline-8-carboxylate.  The product from this step C (0.6 g) is suspended in ethanol (25 ml) and diethyl ketonemalonate (0.328 g) is added.  The mixture was heated under reflux for 18 hours. The resulting precipitate was collected (0.29 g) and identified as the title compound by NMR and mass spectrometry.   : 1.0 (3H, t); 1, (3H.  t); 1.6 (2H, m); 3.0 (2H, t); 4.0 (3H, S); k, k (2H, g); 6.95 (1H, S); 8.2 {1H, S); 386, BP 283.  (fc).  Disodium-2-hydroxy-9-oxo-5-propyl-9H-pyranb (3,2-d) quinoline-3,7-dicarboxylate.  The product of this stage d (0.98 g is suspended in stirred methanol (200 ml), heated under reflux), to which 11/10 Mera is added dropwise. target NaOH (25) 8 ml).  After 18 hours, the methanol is removed in vacuo and the aqueous residue is cooled in ice.  The precipitate is removed.  The aqueous solution is diluted with acetone (200 ml), the precipitate is collected and dried.  The lero is then redissolved in a small amount of water and freeze dried to isolate a red-brown powder (0.25 g).  Elemental analysis, Found: C 42.85; H 3.65; N 5, NaaOV j3, |.  N2O Calculated: С 42.85; H 3.74; N b; 25.  The NMR spectrum confirmed the structure of the title compound.  Note 17.  10-Chloro-1-oxo-1H-pyrano (3,2-f) quinoline-3.8-dicarbic acid.  (Decomposition 253c), NMR (d, DMS (G, 8.48; 8.13; (AB quartet, J 9H) 8.33, (S, 1H), 7.2 (S, 1H).  Obtained by the method of example 1.  Example 18: 10-Chloro-4-oxo-4H-pyrano (2,3-f) quinoline-2,8-dicarbic acid and its disodium salt were prepared by the method of Example 1.  The structure was confirmed by NMR and elemental analysis.  Found: C, 8.57; C 41.12; H 2.46; N 3.19. CPNNa, j06-21 / 2 Calculated, 5g: Ce 8.67; C 41.14; H 2.22; N 3.43.  Example 19  Disodium-4-oxo-10-propyl-4H7-Pyrano (3,2-d) quinoline-2, 8-dicarboxylate.  (but).  Methyl-6-acetyl-7-hydroxy-8-pro pilhinolin-2-carboxylate.  Methyl-6-acetyl-4-ethylthio-7-hydroxy-8-propylquinolin-2-carboxylate (1.0 g) is added to Rene Nickel (16 g net weight, pre-washed with ethanol) in anhydrous ethanol (100 ml) and refluxed for 1 1/2 m.  The catalyst is filtered off and the filtrate is evaporated to dryness.  The residue is triturated with + 0-60 ° C petroleum ether and the yellow solid is collected by filtration to obtain 0.6 g of the title product.  Recrystallization from ethanol gives 0.2 g of the compound with m. square  110-111 ° C.  (B) Diethyl-oxo-1 0-propyl-Npirano (3,2-d) quinoline-2,8-carboxylate.  The product of stage a (1.75 g) and diethyl oxalate C +. The SV of d), dissolved in anhydrous ethanol (50 ml), is added with stirring to a solution of sodium ethylate, obtained by adding sodium (0.35 g) to anhydrous ethanol (50 ml).  The reaction mixture is stirred at heating, refluxed for 1 h, cooled.  poured into ethyl acetate and dilute hydrochloric acid.  The organic layer is separated, washed well with water and dried.  The solvent is evaporated, the residue is worked up with ethanol, saturated with gaseous hydrogen chloride (100 ml), and heated under reflux for-10 min.  The reaction mixture is cooled, poured into water and the precipitated product is collected by filtration, rinsing well. water and dry to yield 2.5 g of product.  Recrystallization from ethanol gives 1.25 g, t. square  1b8-171 ° C.  (WITH).  4-Oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2,8-dicarboxylic acid.  The product of stage b (1.118 g) is suspended in methanol (100 ml) and heated with stirring under reflux while adding dropwise a 10/10 solution of sodium hydroxide (58.37 ml). .  The reaction mixture is stirred and heated under reflux for an additional 15 minutes, cooled, filtered and acidified.  The precipitated product is collected by filtration, washed with water and dried, yielding 0.852 g, t. square  252 ° С (with decomposition), (d).  Disodium-4-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  The product of stage c (, semi hydrate 0.629 g) and sodium bicarbonate VO, g) is stirred in water (.  70 ml) until completely dissolved.  The solution is filtered and the filtrate. freeze dried to get 0. 658 g of target salt.  Elemental analysis.  FoundD: With Av. H; H it, 1; N 3.05 C, t H NNa, Ofe-3 Calculated: C H, 0; N 3.2 Example 20.  ii-Oxo-b-phenoxy-10-propyl-H-pyrano (3,2-d) quinoline-2, 8-dicarboxylic acid.  (o) M tyl-6-acetyl-7 hydroxy-4-phenoxy-8-propyl-quinoline-2-carboxylate Phenol (. 10.0 g), ground in a mortar and pestle, is added to the ground potassium hydrate (0.3 b g) in a flask that is immersed in an oil bath.  The mixture was stirred at 6065 ° C for 5 minutes prior to the addition of methyl 6-acetyl-4-chloro-7 hydroxy-8-propyl-quinoline-2-carboxylate (1.0 g).  The whole mixture was stirred at 60 ° C for 1.5 hours and then the phenol was removed by steam distillation.  The desired product is isolated from the remaining mixture by filtration and dried.  0.81 g of the title compound are obtained as yellow crystals with m. square  195-19b ° C.  (B)  Diethyl 4-oxo-6-phenoxy-10-propyl-H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  Sodium (0.25 g) is dissolved with stirring in anhydrous ethanol (50 cm) and when a solution is obtained, the product of step q (1.0 g) is added, along with diethyl oxalate (2.69 g) and anhydrous ethanol (30 cm).  The whole mixture is stirred at room temperature for 1 hour and then heated under reflux for 1.5 hours.  The reaction mixture is poured into ice water and acidified with glacial acetic acid to pH 5. The product is extracted into ethyl acetate, which is washed and dried.  The solvent is removed by evaporation, yielding a red oil, which is a solution; t in dioxane (50 ml).  Anhydrous hydrogen chloride is bubbled through it for 15 minutes.  The entire mixture is poured into. Ethyl acetate, washed with water and sodium bicarbonate solution and dried.  The solvent was removed by evaporation, leaving a dark red oil.  It is recrystallized from CO-60 ° C of a petrol ester and dried, yielding 0.6 g of a crude title compound.  It is recrystallized from ethanol to obtain 0.2 g of the title compound, (partially melted at).  (c), Disodium- -oxo-6-phenoxy-10-prog1yl-H-pyrano (3,2-d) quinoline-2, 8-dicarboxylate.  The product of stage b (0.41 g) is stirred in methanol (50 cm) under reflux and in a drop wise.  bathe with 0.1. Sodium hydroxide solution (17.5 cm).  The whole mixture is stirred and heated under reflux for 15 minutes after addition, cooled, filtered and the filtrate is evaporated until the mixture.  Water (30 cm) is added.  The solution is treated with acetone to obtain complete precipitation.  Etc. The product is collected by filtration and dried.  0.22 g of the title compound are obtained.  Elemental analysis.  Found: C 55.85; H 3.8; N-2.69 С nN-ММвз О-, 6, 3 Calculated: С 55.85; And 3.7; N 2.8.  NMR spectroscopy confirmed the presence of the title compound.  Example 21  M, M-Diphenyl-6-chloro-oxo-T O-propyl-H-pyrano (3,2-d) quinoline-2,8-dicarboxamide.  A suspension of disodium-6-chloro-oxo-1 O-propyl-4H- (3,2-d) -pyranoquinolin-2, 8-dicarboxylat (З g) in 1,2-dichloroethane (80 g) is mixed and processed according to drops of concentrated sulfuric acid (0.5 ml).  Thionyl chloride (15 ml) is then added, followed by N, N-dimethylformamide (2 drops).  This mixture is heated under reflux for 3.5 hours, then the solution is separated from the sulphate salt and evaporated.  The residue was redissolved in 1,2-dichloroethane (30 ml) and added to a stirred solution of aniline (20 g) in 1,2-dichloroethane (80 ml).  This mixture is left to stand for 0.5 h, then the precipitated material is filtered and washed with petroleum ether.  Traces of the solvent are removed under vacuum at 50 ° C and the remaining powder is thoroughly dissolved with water, then dried again under vacuum at 50 ° C, so that the title compound remains as a yellow powder (2, b5 g), t. square  over 1515c.  Satisfactory nuclear magnetic resonance and mass spectrometry data are obtained.  Example 27 .  1, 1i-dioxo-1H, 1OH-thiopirano (3,2-f) quinoline-3,8-wild p () onic acid ”(a).  Ethyl b-amino-t-OKCo-H-l-benzothiopyran-2-carboxylate hydrochloride.  4-Acetamidothiophenol (16.7 g) is added to a solution of potassium hydroxide (16.8 g) and mono potassium acetylenecarboxylic acid (16.7 g) in water (200 ml).  The mixture is heated under reflux for 2 hours, then cooled and the solution is washed twice with ethyl acetate.  The mixture was treated with concentrated hydrochloric acid (35 ml) and extracted into ethyl acetate.  Drying and evaporation gives a yellow solid (7 g), which is intensively suspended in stirred tetraphosphoric acid (50 ml) heated on a steam bath.  After one hour, the reaction mixture was poured into a large volume of ice water and the precipitate was collected.  The precipitate is dissolved in saturated sodium bicarbonate solution and filtered and re-acidified. The resulting suspension is filtered and the solid product is dried under vacuum and then suspended in anhydrous ethanol (100 ml).  The suspension is saturated with gaseous hydrogen chloride with simultaneous heating under reflux for 1 hour.  Upon cooling, a precipitate is obtained which is collected and air-dried to isolate the title compound (1.2 g) as a gray powder.  The structure is confirmed by the NMR spectrum.  (B)  1,10-Dioxo-1H-, 10H-thiolirano (3,2-f) quinine-3,8-dicarboxylic acid, methyl ethyl and diethyl esters.  The amine hydrochloride product of step a (0.71 g) is suspended in ethanol (25 ml) and treated with sodium bicarbonate (21 mg), dimethyl acetylenedicarb oxylate (0.355 g) and triethylamine (2 drops).  The mixture was heated under reflux for 18 hours, and then another 0.2 ml of Dimethylacetylene dicarboxylate was added.  After another 3 hours at reflux, the mixture is cooled, poured into chloroform (100 ml) and washed well with water.  The organic layer is dried and evaporated. Repeat extraction of the residue with hot lOO / IZO C with petroleum ether gives a yellow-orange oil (1.3 g).  A part of this oil (1 g) is dissolved in a small amount of diphenyl ether and this solution is added to the reflux ether (20 ml) heated under reflux. After five minutes, the mixture is cooled rapidly and diluted with a large volume of 60/80 ° C petroleum the ether.  The precipitate, which is distilled, is collected and boiled at 100/120 ° C petroleum ether.  The solid residue is recrystallized from acetonitrile to produce a fuzzy yellow solid (0.23 g).  : The data of NMR and mass spectrometry confirmed the receipt of a material that is a mixture of methyl ethyl and diethyl complex EFI-, in a ratio of 7: 2.  (with).  Disodium-1,10-DIOXO-7H, 10H-thiopyrano (3,2-f) quinoline-3,8-dicarboxylate.  Mixed. The esters obtained in stage b are suspended in anhydrous methanol (50 ml) and heated under reflux with intensive stirring and N / 10 NaOH solution is added dropwise.  Heating is continued for another 30 minutes after the addition, then the mixture is cooled, filtered and evaporated.  Water (20 ml) is added to dissolve the residue, and then a large volume of acetone is added to form a precipitate. The solid is collected by filtration through a glass fiber filter, immediately re-dissolved in a minimal amount of water and dried by freezing.  Thus, the title compound (150 mg) is obtained. .  Elemental analysis.  Found,%: C 1.05; H 2, 3.77 C. HcNaj NOft 11.9% HiO Calculated: С ibOl; And 2.6; N 1 Example 23.   -Oxo-U-propyl-6- (1-pyrrolidino) - H-pyrano (3,2-d) - quinoline-2,8-dicarboxylic. acid.  The title compound and its disodium salt were prepared according to the method of Example 3 (c). The structure was confirmed by NMR and mass spectrometry.  SGD / ICO: 0, E (3N, t); 1.6 (, m); T, 8 (2H, m); 2.8 (, m); 3 6 (2H, t); 7.3 (1H, S); 7.5 (1H, S); 8.7 (IH, S).  Example 10-Chloro-1-oxo-1H-thiopyrano (3,2-f) quinoline-3,8-dicarboxylic acid.  This compound and its disodium salt are prepared according to the method of Example 1.  Elemental analysis.  Found: C 37.6; H 2.72; N2.0 СN СРМНа2 0, g 15, NaO Calculated,%: С 37, «б; H 2.12; N2 Example 25.  6-Chloro-10-methyl-4-oxo-N-pyrano (3,2-d) quinoline-2,8-dicarboxylic acid.  Brown solid, t. square   (with decomposition).  Prepared according to the method of example 1,  This acid and its disodium salt are obtained according to the method of the example of ZO NMR GAMSO: 1.0 (3N, t); 1.3 (3H, t 1.85 (2H, m); 3.7 (2H, t); 4.6 (2H, g 7.15 (7H, 6); 8.2 (7H, S); 9.1 (7H, S).  PRI am 27.  6-Dimethylamino-4-oxo-10-propyl-H-pyrio {3, 2-d) quinoline-2,8-dicarboxylic acid.  The above acid and its disodium salt are prepared; using the aid of Example 3: 1.0 (3N, t); 1.8 (2H, t); 3.1 (6H, S); 3.5 (2H, t); 7.1 (1H, S) 7.5 (1H, S); 8.8 (1H, S).  Example 28  4,6-dioxo-4H, 6H -pyrano (3,2-d) quinazoline-2,8-dicarboxylic acid, (a).  Ethyl-6-acetyl-3, Dihydro-7-hydroxy-α-oxo-quinazolin-2-carboxylate A mixture of methyl 3-acetyl-β-oxy-6-aminobenzoate (5 g, 23.9 mmol), ethyl cyanoformate (2, g , 24.2 mmol) of concentrated hydrochloric acid (2, ml) and glacial acetic acid (31.9 ml) are heated in a preheated oil bath (120 ° C) for 3 hours.  The mixture is cooled.  A white solid is obtained, which is filtered off, washed with ice-cold cooled water, and then dried under vacuum at above P ,, 0 for 2A h.  The NMR spectrum and mass spectrum confirmed the receipt of the desired structure.  Elemental analysis.  Found,%: C 56.5; H, 52; N 9.98 Calculated: C 56.52; H, 38; N 10, T (b), Diethyl-, 6-dioxo-H, bH7Pig early (3,2-d) quinazoline-2,8-dicarboxylate.  A mixture of diethyl oxalate (4 ml) and the product of step a (1.1 g, 3.98 mmol) in ethanol (50 ml) is slowly added to a freshly prepared solution of ethyl sodium (0.68 g, 9.9 mmol) in ethanol (80 ml), a yellow suspension is quickly formed.  After the addition, the mixture is heated under reflux on the steam bath for half an hour to obtain a brown suspension.  The mixture is cooled and neutralized with dilute hydrochloric acid to give a bright orange precipitate.  This precipitate is extracted into chloroform, dried and evaporated.  A bright orange solid is obtained which is redissolved in ethanolic hydrogen chloride.  The solution is heated under reflux on a steam bath for 3 hours.  The mixture is cooled and treated with water.  After concentration, the mixture is extracted into chloroform.  The organic extract is washed with water, dried and evaporated to give a brown solid (0.95 g, 73%), the structure of which is confirmed by an NMR spectrum and a mass spectrum.  (c), Disodium-4,6-dioxo-4H, 6H-g-pyrano (3,2-d) quinazoline-2,8-dicarboxydate.  The product of stage b is converted to the title compound by the method of example 3c: 1.0 (3H, t); 1.6 (2H, t); 3 2 (2H, t); 6.9 (F, S); 8.5 (1H, S), Example 29, -Oxo-6-phenylamino-10-propyl-H-pyrano (3,2-d) quinoline-2,8-dicarboxylic acid and its disodium salt.  (AMCO: 0.95 (3N, t); 1.75 (2H, t); 3.7 (2H, t); 6.95 (1H, S); 7 ,. 8 (5H, t); 3 3 (1H, S); 8.75 (1H, S), Example 30.  5-Oxo-6-phenylthio-10-propyl-4H-pyrano (3,2-d) quinoline2, 8-dicarboxylic acid and its disodium salt, (dlino: 1.0 (3N, t); 1.82 (2H , t); 3.7 (2H, t); 7.05 (1H, S); 7.6 (5H, t); 8, i "(1H, S); 8.9 (1H, S).  Example 31  Disodium-M-carbamoyl-6-amino-oxo-10-propyl-H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  (a), N-Carbamoyl-b-amino-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2, 8-dicarboxylic acid.  Diethyl-6-chloro-4-oxo-10-propyl-H-pyrano (3,2-d) quinoline-2,8-dicarboxylate (1 g) and urea (50 g) are fused together for 6 hours.  After cooling, the solid is added to 70% sulfuric acid (200 ml) and heated on the steam bath for 8 hours.  The mixture was poured into ice water (2L) and the precipitate was collected and washed well with water to isolate the title compound (0.15 g), which was identified by NMR.  (B)  Disodium-Ncarbamoyl-6-amino - -oxo-10-propyl-H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  The product of step a is converted into the title compound by the method of Example 2C.  flMPtf: 0.9 (3N, t); 1.7 (2H, ha 3. 6 (2H, t); 6.9 (1H, S); 8.3 (1H, S): 9.0 (1H, S); 11.1 (2H, wide).  Example 32  b-Ethoxy-oxo-10-propyl-H-pyrano (3,2-d) quinoline-2, 8-dicarboxylic acid.  (d)  Diethyl-6-ethoxy- | -oxo-10-propyl-H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  Methyl 6-acetyl-chloro-7-hydroxy-8-propylquinolin-2-carboxylate (1.0 g) and diethyl oxalate (3.7 ml) are added to ether washed with sodium hydride (0, b5 g) in anhydrous dimethylformamide ( 20 ml) at room temperature. After stirring for five hours, the whole mixture is poured into ethyl acetate and treated with aqueous acetic acid.  The organic layer is washed with water, dried and evaporated.  The residue is extracted into a saturated ethanolic solution of hydrogen chloride.  (50 ml) and heated under reflux for 15 minutes.  This solution was poured into ethyl acetate and washed with sodium bicarbonate. Drying and evaporation gave a solid, which was triturated with light petroleum ether to obtain a solid (1 g), which was identified with the material by NMR and mass spectra.    (to).  Disodium-6-ethoxy-4-oxo-10-propyl-H-pyrano (3,2-d) quinoline-2, 8-dicarboxylate.  A 0.1 N sodium hydroxide solution (5b, 2 ml) was added dropwise to a refluxing suspension of the product of this stage a (1.2 g) in methanol (50 ml) over 30 minutes.  Heating is continued for 30 minutes after the end of the addition, then the mixture is cooled, filtered and all the solvent is removed under vacuum.  The residue is extracted into water and poured over with acetone.  The precipitate is collected and dried.  Get 1 g of the above material.  Found,%: C, 51.25; H 3.86; N3.02 45, - l, 5 Calculated,; g: C 31.5; H 3.73; N3.16 Example 33.  6-Chloro-oxo-1 O-propyl-4H-pyrano (3,2-d) quinoline 2, 8-dicarboxylic acid.  (but).  6-Chloro-oxo-1 0-propyl-H-pyrano (3,2-d) quinoline-2,8-dicarbonyl chloride (1.31 g) is dissolved in dichloromethane (50 ml) and added dropwise at vigorous stirring in water (100 ml) at.  After the addition was complete, stirring was continued for one hour, dichloromethane was removed by distillation under vacuum, and the title compound (1.1 g) was collected by filtration, t. square  Zos „(b).  6-Chloro-8-formyl-oxo-10-propyl-CH-pyrano (3,2-d) quinoline-2-carboxylic acid (0.23 g) in acetone (20 ml) is treated with Jonas reagent (0.8 ml), left for 20 minutes at, then diluted with a saturated aqueous solution of sodium chloride and extracted with 10% sodium bicarbonate.  Acidification with 2N hydrochloric acid gives the title compound (200 mg), t. square  .  Etc. and meper 3+.  Ethyl-6-chloro-6-methoxycarbonyl-4-oxo-10-propyl-H-pyrano (3,2-d) quinoline-2-carboxyl; Dimethyl- (2-ethoxycarbonyl-3-propyl-4-oxo-4H-1-benzopyran-7-ylamino) trans-butenoate (17 g) is dissolved in anhydrous dichloromethane (40 ml) and freshly distilled, free from HC, phosphoryl chloride (1.5 or 7.  Solution (acne under reflux with NIKOM for one hour to obtain, on cooling, the title compound (1.4 g) as a pale yellow solid, t. square 184186С, Example 35.  Diethyl-6-ethoxy-k-OKCo-10-propyl-H-pyrano (3,2-d) quinoline-2,8-dicarboxylate.  Ethyl-6-chloro-8-methoxycarbonyl-A-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2-carboxylate (k, Qg) is suspended in ethanol (200 ml 7) and a solution is bubbled through gaseous NA, supporting the formation of phlegm.  After 30 minutes the gas transmission is stopped and the whole mixture is heated under reflux for 2 hours.  Ethanol is then removed by distillation under vacuum and the resulting oil is chromatographed to obtain the title compound (1.2 g) during crystallization from ethanol, t. square  190192S.  Pr 36  Ethyl 6-ORO-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2-carboxylate.  Ethyl 6-chloro-2,3 dihydro-8-methox carbonyl-4-oxo-10-propyl-H-pyrano (3,2-d) quinoline-2-carboxylate (O. tOS are suspended in cumene (10 ml) and heated under reflux with Pd / C (5%, 0.0200 g) for 10 hours.  The whole mixture is filtered hot to remove the catalyst, cooled, poured into petroleum Zfir (O-BOS, 40 ml) to obtain a pale yellow-brown solid which is chromatographed on silica gel.  The title compound is obtained (0.027 g), t. square  .  Example 37  Diethyl-6-methylamino-4-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2,8-dicarboxylTo Diethyl-b-amino-oxo-10-propyl-4H-pyrano (3, 2-d) Quinoline-2,8-dicarboxylate (0.4 g) is dissolved in anhydrous dimethylformamide (15 ml) and added dropwise with stirring to a suspension of sodium hydride (50, 0.053 anhydrous ether, in anhydrous dimethylformamide (10 ml) in a dry nitrogen atmosphere After about 30 minutes of stirring at ambient temperature, after the appearance of a saturated red color iodomethane (0.23 ml) is added dropwise and stirring is continued at room temperature. temperature for another five hours.  The mixture is then poured into water and extracted with chloroform.  The organic extracts are mixed, dried over magnesium sulphate, evaporated under vacuum and the resulting oil is chromatographed on alumina. The title compound (0.11 g) is obtained, t. square  235-237C (from ethanol).  Example 38  Ethyl-6-chloro-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2-carboxyl t.  Ethyl-6-chloro-8-methoxycarbonyl-10-propyl-4-thioxo-4H-pyrano (3,2-d) quinoline-2-carboxylate (0.030 g) in acetone (10 ml) containing water (0.2 ml) and methyl iodide (0.1 ml), stirred in the dark at room temperature. The temperature is within 2 days.  Concentration of the reaction mixture yields a light tan solid, which after recrystallization from ethanol gives the title compound (0.015 g), t. square  17b-179 S.  Example 39  Diethyl 4-oxo-10-propyl-4H-pyran o (3,2-d) quinoline-2, 8-dicarboxylate.  Ethyl b-ethylthio-4-oxo-10-propyl-4H-pyrano (3,2-d) quinoline-2,8-dicarboxylate (2.8 sg) was dissolved in ethanol (200 ml) and the washed ethanol Rene nickel (20 g, wet).  The mixture is heated under reflux for 1 1/2 hours, filtered to remove the catalyst, and concentrated.  The title compound is obtained by cooling (1.75 g), t.  square  168-171 0.  I The compounds of the formula I, or their salts thereof, are useful as they possess pharmacological activity (in animal experiments); in particular, they inhibit the release and / or action of pharmacological mediators, which occurs due to the in vivo combination of certain types of antibodies and certain antigens, for example, the combination of a reactive antibody with a specific antigen.  The compounds of formula I inhibit the degranulation of host cells and affect the reflex pathways in experimental animals and humans, in particular, affect those reflexes that are associated with lung function. In humans, after prior administration of new compounds are suppressed as subjective and objective changes resulting from the inhalation of a particular antigen in an allergic person.  Thus, the novel compounds are useful in the treatment of reversible airway disorders and / or in preventing the release of excess mucus.  The compounds of the formula I are thus useful in the treatment of allergic asthma, i. n  internal asthma (when not sensitive to external antigens, such as asthma caused by exercise), birdwalking diseases, bronchitis, cough (including whooping cough), and nasal and bronchial disorders caused by general cooling.  The novel compounds are also useful for treating 11 other conditions in which antigen-antibody reactions or the release of excess mucus are caused or accompanied by disease.
    Thus, the compounds of formula I are useful in the treatment of a wide variety of diseases in humans (and, in appropriate cases, other animals, such as cattle, horses, cats or dogs).
    For these uses, the dosage administered will, of course, depend on the compound used, the type of administration and the treatment required. Satisfactory results are obtained with Bisedenia compounds in doses ranging from 0.001 to 50 mg per kg of live weight. For a human, said total daily dosage is 0.001-2000 mg, preferably from 0.001-1000 mg, more preferably 0.01-200 mg and, most preferably, 0.1-60 mg / kg, which can be administered in separate doses of 1- 6 times a day or in the form of continuous administration. Thus, unit dosage forms suitable for administration by inhalation or glutin contain from 0.001 to 200 mg, preferably from 0.001 to 50 mg, more preferably from 0.01 to 20 mg, and most preferably .0.01 to 10 mg of the compound.
    权利要求:
    Claims (1)
    [1]
    A method for producing heterocyclic compounds of the general formula where two adjacent groups Rr, Re, R 7 and R fl form a chain CZC (G ^) = C (G 2 ) -Z ~, in which one of G and Gx means hydrogen and the other - group E wherein each E group is C0OH, each Z group is oxygen, or Z in the cycle is sulfur, and the other Z is oxygen.
    R 4 and R 9 and a group of Rg-, R fe , R 7 and Rg may be the same or different and each means hydrogen, lower alkyl, halogen, lower alkenyl
    NR ^ R 2 , -OKE, -S (0) h R 3 , where η is 0.1 or 2;
    and Rj are the same or different and each means hydrogen, lower alkyl, CONHR ^, phenyl, unsubstituted or substituted by alkyl or halogen, or R 4 and f <2 together with the nitrogen atom to which they are attached mean a pyrrolidine group;
    R 3 is hydrogen, lower alkyl, lower alkenyl or phenyl, one or two of the atoms a, b, end are nitrogen atoms, and the rest are carbon atoms, and R 3 does not matter g if two of the groups a, b, c and d mean nitrogen, provided that a) if a, b and c are carbon atoms, d means nitrogen atom, b) E is in the ortho position relative to the nitrogen atom, c) R ^ means hydrogen, d) G means hydrogen, a G 2 means a group E, e) Rg., R 6 , R and Rg each means hydrogen, hydroxy, lower alkyl, halogen, lower alkenyl, alkoxy and NR ^ R 2 , £) each Z means oxygen, then R 4 not me is OH group in the para position with respect to the nitrogen atom, or their salts, which consists in hydrolyzing or oxidizing with the help of Jones reagent a compound of the general formula (O
    SU, 1014476 where Rjy, R 6 , R-, and R e have the same meanings as the groups R ,, R 7 and R g , except that the two neighboring groups R , R , Rt and R means the chain -CZC (^) - C (3j) -Z-, where one of the group and Oo. means hydrogen, and the other group D <, one or both of D and D o means a group that can be hydrolyzed to a COOH group or oxidized, and the other means a COOH group, a, b, c, d, R ^ and Rg have the indicated meanings and the desired product is isolated in free form or in the form of a salt.
    Priority by signs:
    10.31.78 - each R ^, H 2 , R 3 , R ^, 85-,% "K 7 " and Rg, when they contain carbon, contain up to 8 carbon atoms; is the chain -CZC (Gf) = C (Gj) -Z attached at the positions R fe and R wherein the part of the chain is in the R t position, the chain —CZC (G ^) = C (Ga) —Z is —COCH = C (COOH) —O—; R ^ is hydrogen and Rg is alkyl; d is nitrogen; group E is in the position adjacent to the nitrogen atom of the ring; groups E are the same and are COOH, R ^ is in the para-position with respect to the single nitrogen atom in position ai; R4 is different from OH.
    06/14/79 “one of a, b, c and d is nitrogen”
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    同族专利:
    公开号 | 公开日
    BR7907006A|1980-07-15|
    HK66185A|1985-09-13|
    PL130691B1|1984-08-31|
    NL7907916A|1980-05-02|
    CU21123A|1982-08-28|
    CH643264A5|1984-05-30|
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    GR73861B|1984-05-08|
    PT70392A|1979-11-01|
    FR2440371A1|1980-05-30|
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    SE7908995L|1980-05-01|
    MY8500439A|1985-12-31|
    PH15442A|1983-01-18|
    PL219304A1|1980-12-01|
    AU5228779A|1980-05-08|
    NZ191956A|1984-05-31|
    US4419352A|1983-12-06|
    IE49464B1|1985-10-16|
    SG40885G|1986-05-02|
    MA18631A1|1980-07-01|
    LU81841A1|1980-05-07|
    FI67702B|1985-01-31|
    DD146954A5|1981-03-11|
    AU528648B2|1983-05-05|
    AR230449A1|1984-04-30|
    NO793469L|1980-05-02|
    IL58579D0|1980-01-31|
    AT379811B|1986-03-10|
    DK458679A|1980-05-01|
    IE792074L|1980-04-30|
    CS231166B2|1984-10-15|
    ATA701479A|1985-07-15|
    FI793369A|1980-05-01|
    NO154522B|1986-06-30|
    CS735979A2|1984-02-13|
    SE451071B|1987-08-31|
    DE2943658C2|1991-08-01|
    FR2440371B1|1983-01-28|
    CA1142520A|1983-03-08|
    HU183087B|1984-04-28|
    IL58579A|1985-12-31|
    DE2943658A1|1980-05-14|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1504709A|1974-12-07|1978-03-22|Fisons Ltd|N-substituted quinolinone-2-carboxyl. acid der|
    AU513456B2|1977-03-08|1980-12-04|Takeda Chemical Industries Ltd.|l-Azaxanthone-3-carboxylic acids|
    IL54614A|1977-05-04|1983-07-31|Fisons Ltd|Dihydrodioxo-pyranoquinoline dicarboxylic acid derivatives,their production and pharmaceutical compositions containing them|US5260306A|1981-07-24|1993-11-09|Fisons Plc|Inhalation pharmaceuticals|
    GB8402047D0|1984-01-26|1984-02-29|Fisons Plc|Nitrogen heterocycles|
    EP0162556B1|1984-04-13|1991-11-06|FISONS plc|Novels forms and formulations of nedocromil sodium|
    GB8501015D0|1985-01-16|1985-02-20|Riker Laboratories Inc|Drug|
    GB8607159D0|1986-03-22|1986-04-30|Smith & Nephew Ass|Pharmaceutical composition|
    HU202753B|1986-06-21|1991-04-29|Sandoz Ag|Process for producing retard pharmaceutical compositions containing cetotiphene|
    EP0279121B1|1986-12-23|1993-09-01|FISONS plc|Pharmaceutical compositions comprising an aqueous solution of a pyranoquinoline derivative|
    USRE38628E1|1986-12-23|2004-10-19|Fisons Plc|Pharmaceutical compositions|
    USH672H|1986-12-31|1989-09-05|E. R. Squibb & Sons, Inc.|Stable antifungal capsule formulation|
    US4767612A|1987-01-23|1988-08-30|Rorer Pharmaceutical Corporation|Triamcinolone acetonide for the treatment of allergic rhinitis|
    GB8704089D0|1987-02-21|1987-03-25|Fisons Plc|Method of treatment|
    EP0294914A3|1987-03-17|1990-10-10|FISONS plc|Nedocromil for the treatment of dermatological disorders|
    US5648084A|1990-02-28|1997-07-15|Guttag; Alvin|Multiple dosage medicine drop bottle|
    CA2087423A1|1990-07-25|1992-01-26|Tatsuki Shiota|Benzopyran derivative, process for producing the same and pharmaceutical composition containing the same|
    US5294433A|1992-04-15|1994-03-15|The Procter & Gamble Company|Use of H-2 antagonists for treatment of gingivitis|
    US5453431A|1993-10-29|1995-09-26|Gilman; Andrew L.|Use of hydroxychloroquine for treatment of graft-versus-host disease|
    ZA966579B|1995-08-04|1998-02-02|Wakamoto Pharma Co Ltd|O/W emulsion composition for eye drops.|
    US5891472A|1996-11-19|1999-04-06|Meri Charmyne Russell|Treatment of equine laminitis|
    US5989571A|1997-07-23|1999-11-23|Millenium Pharmaceutical Technologies, Inc.|Contact dermatitis pharmaceutical preparation with anti-histamine and anti-inflammatory|
    US5885550A|1998-07-02|1999-03-23|Vallier; Deandra K.|Ophthalmic whitening solution|
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    AU6461601A|2000-05-17|2001-11-26|Cor Therapeutics Inc|Methods for producing amino substituted chromanes and intermediates therefor|
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    GB0524808D0|2005-12-05|2006-01-11|Novartis Ag|Organic compounds|
    DE102007028095A1|2007-06-19|2009-01-15|Bachmann, Vincent|Preparation for the treatment of laminitis in equidae|
    FR2924344B1|2007-12-04|2010-04-16|Pf Medicament|USE OF MEQUITAZINE IN THE FORM OF RACEMATE OR ENANTIOMERS FOR THE PREPARATION OF A MEDICAMENT FOR THE TREATMENT OR PREVENTION OF PATHOLOGIES INVOLVING HISTAMIC RECEPTORS H4.|
    EP2424527B8|2009-04-29|2019-07-17|Willowcraft Pharm Inc.|Mast cell stabilizers to prevent or treat laminitis|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB7842679|1978-10-31|
    GB7920760|1979-06-14|
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