FI82833C - XUBENSTITUERADE XANTEN- OCH XANTONDERIVAT OCH ANVAENDNING AV DESSA FOER UPPRAETTHAOLLANDE AV SYRETILLFOERSELFOERMAOGAN HOS UPPLAGRADE HUMANERETROCYTER OCH FOERLAENGNING AV DEN ANVAENDBARA UPPLAGRINGSTIDEN F - Google Patents

Description

1 82833

Disubstituted xanthene and xanthone derivatives and their use to maintain the oxygen supply capacity of stored human erythrocytes and to extend the useful storage life 5

By division separated from application 831420.

The invention relates to novel disubstituted xanthene and xanthone derivatives of formula (I): wherein X is carboxyl or 5-tetrazolyl; X is carbonyl or methylene; X is hydroxyl or a group 4 5 4 5 -X (CnH2n) X, where X is oxygen or sulfur and X is hydrogen or the group -OX **, where X ** is hydrogen, alkanoyl having 7 7 20 1-4 carbon atoms, or the group - (C H 9) X, where X is hydrogen 8 gm or a group -OX, where X is hydrogen or acetyl, and m and n are each independently an integer from 1 to 4, provided that when X 1 is a group -ΟΧ **, then n is always greater than 1 4 5 and X and X are attached to different carbon atoms, and that 7 8 25 when X is a group -OX, then m is always greater than 1 and no carbon atom in the radical - (C H_) - is attached-now to two oxygen atoms, and their salts.

These compounds provide an increase in the release of oxygen from oxyhemoglobin and are therefore useful for maintaining the oxygen supply capacity of human erythrocytes in stored blood.

Human hemoglobins consist of four polypeptide (globin) chains that together form a hemoglobin tetramer; each chain surrounds a porphyrin-35 molecule (heme) that contains a central iron atom to which oxygen reversibly binds. Plotting the percentage saturation of hemoglobin with oxygen (ordinate) against the partial pressure of oxygen, sometimes called the oxygen voltage (abscissa), in coordinate system 2 82833, a characteristic s-shaped curve, the oxygen dissociation curve, is obtained.

5 Shifting the curve to the left from its "normal" position would indicate an increase in the affinity of hemoglobin for oxygen, requiring a lower oxygen voltage to achieve a certain saturation percentage, whereas a reverse shift to the right would indicate a reduced oxygen affinity and thus a higher oxygen demand for a given saturation. It follows that the shift of the curve to the right results in a decrease in the percentage of oxyhemoglobin present at a given oxygen voltage and thus an increased release of oxygen after the voltage has dropped to a given level.

The compounds of formula (I) and their salts cause an in vitro shift of the oxygen dissociation curve: to the right 20 (a) in fresh human whole blood and (b) in human whole blood subjected to a process (overnight incubation at 37 ° C) which causes similar changes other than those observed in blood stored by blood services, etc. for long periods of time (as discussed later).

These compounds thus have use under conditions where it is desired to provide more efficient oxygen release.

The in vitro use of these compounds occurs mainly in the area of blood storage. As is well known, there is a continuing need for human blood in medical service points around the world for use in a variety of life support measures. For most recipients, whole blood is the only acceptable ingredient; Numerous alternatives have been proposed, but none of them have been found to be completely satisfactory. Blood collection, storage and distribution usually take care of a special blood-transfusion services or "blood banks", an example of which Trasfusion National Blood Service in the United Kingdom. However, the efficient and economical operation of such facilities is largely governed by the fact that whole blood, or rather red blood cells (erythrocytes), even when stored as usual at 4 ° C, have a very limited shelf life, which is generally acceptable. lit for 21 days after receipt from donor.

At the end of this period, they are considered unsuitable for transfusion and rejected and a great deal of research has been done to find methods to extend the life of stored erythrocytes and thus reduce the loss due to "aging".

One peculiarity of the red blood cell aging during storage is the continuous leftward shift of the oxygen dissociation curve associated with a decrease in the intracellular amounts of 1,3-diphosphoglycerate (DPG), the natural reductor of red blood cells. As discussed above, a shift to the left is associated with hemoglobin, which has an increased affinity for oxygen, and thus the ability of aging cells to deliver oxygen to peripheral tissues after transfusion decreases steadily. Although this property is gradually restored in the recipient's body as DPG levels recover, the initial deficiency is literally vital, as the main reason for red blood cell transplantation (as opposed to plasma) is usually the immediate prevention or reversal of tissue hypoxia (oxygen depletion) (see above). ). By shifting the oxygen dissociation curve to the right, these compounds are valuable not only in maintaining the oxygen supply capacity of stored erythrocytes, thereby improving their quality and providing improved oxygen supply over a period of 35 immediately after transfusion, but also in prolonging their useful storage life.

4,82833 Here, 5-tetrazolyl means a group having the structural formula:

5 V

1 -J | B

N_ N

thus comprising both tautomeric forms thereof, which are identifiable as 5- (1H) -tetrazolyl and 5- (2H) -tetrazolyl, respectively.

When m and / or n in formula (I) is 3 or 4, the parts - (C H „) - and - (C H-) - may be straight-chain or branched, n 2m J n 2n

In the salts of the compounds of formula (I), the biological activity is in the tricyclic (anionic) moiety and the identity of the cation is less important, but is preferably physiologically acceptable. Suitable salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, and salts formed with organic bases, e.g. amine salts derived from mono-, di- or tri (lower alkyl) or (lower alkanol) amines such as triethanolamine and diethylaminoethylamine, and salts with heterocyclic amines such as piperidine, pyridine, piperazine and morpholine.

As a group of compounds of formula (I) there may be mentioned those compounds in which: X 2 is carboxyl or 5-tetrazolyl, X is carbonyl or methylene, X 1 is hydroxyl or the group -X 2 (C 11 H 2 n) in which X 1 is oxygen or sulfur and X 1 is hydrogen or a group 6 6 -OX, wherein X is hydrogen or alkanoyl having 1 to 4 carbon atoms and n is an integer from 1 to 4, together with salts thereof,

5 G

35 provided that when X is a group -OX, then n is 5,82833. 4 5 always greater than 1 and X and X are attached to different carbon atoms.

As subgroups of the compounds of formula (I), those may be mentioned in which: 5 (i) X 1 is 5-tetrazolyl and its salts 2 (ii) X is carbonyl (iii) X 3 is a group -X 4 (CH 2) X 5 4 n 2n ( iv) X is oxygen (v) is hydrogen 5 6 6 10 (vi) X is a group -OX where X is hydrogen, i.e.

X5 is hydroxyl (vii) n is 2 or 3.

The other two groups of compounds of formula (I) are, respectively, those compounds wherein: 1 2 15 (a) X is 5-tetrazolyl, X is carbonyl and X 3 is -O (C H,) H; and (b) χ1, X and X "3 have the same meaning as above, 3 1

provided that X is other than -O (C H-,) H when X

2 Π ΔΤΪ and X 1 are 5-tetrazolyl and carbonyl, respectively; 20 together with their salts.

Preferred compounds of formula (I) are the following: the chemical name is 2-ethoxy-6- (5-tetrazolyl) xanthone, and its salts, and in particular: 6 82833 H0 (CH2) 20 q:? · Γ3 · *

i '- I I

ij-i having the chemical name 2- (2-hydroxyethoxy) -6 - (- 5-tetrazolyl) xanthone and its salts.

The compounds of formula (I) and their salts may be prepared by methods known in the art for synthesizing compounds having an analogous structure and in this regard are referred, for illustrative purposes only, to the following standard manuals: (i) "Protective Groups in Organic Chemistry" , ed.

J. F. W. McOmie, Plenum Press (1973), ISBN 0-306-30717-0; (ii) Compendium of Organic Synthetic Methods, ed. I.T. Harrison and S. Harrison, Wiley-Interscience,

: 20 Oh. I (1971), ISBN 0-471-3550-X, Vol. II (1974), ISBN

0-471-35551-8 and Vol. Ill (eds. L-S. Hegedus and L. Wade): (1977) ISBN 0-471-36752-4; and (iii) Rodd's "Chemistry of Carbon Compounds", second edition, Elsevier Publishing Company.

25 All of the literature references cited above and below are incorporated herein by reference.

The disubstituted xanthene and xanthone derivatives of the invention can be prepared, for example, by the following methods.

(1) The xanthone derivatives of the invention can be prepared by cyclization in the presence of a Lewis or proton-donating acid, a compound of the formula (III): wherein X 1 and are the same as in the formula (I), and is a carboxyl or chlorocarbonyl group.

Suitable Lewis acids include aluminum trichloride, ferric chloride, phosphorus oxychloride and boron trifluoride, while suitable proton donating acids include polyphosphoric (tetraphosphoric) acid and sulfuric acids. The reaction is preferably carried out at a temperature of 20 ° to 160 ° C.

(2) The xanthene derivatives of the invention can be prepared by selectively reducing the corresponding xan-Toni of formula (I).

Suitable selective reducing agents are zinc and an acid, e.g. acetic or hydrochloric acid, zinc amalgam and concentrated hydrochloric acid (Clemmensen reduction).

(3) Compounds of formula (I) wherein X 1 is 5-tetrazolyl may be prepared by reacting a compound of formula (IV): "-

CN

2 3 30 wherein X and X have the same meaning as in formula (I), to react with nitric acid or a salt thereof. The reaction is preferably carried out in a polar aprotic liquid medium, e.g. dimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide, dimethylacetamide, N-methyl-2-pyrrolidone, sulfolane and acetonitrile and mixtures thereof; and preferably 8,82833 with a salt of nitric acid such as sodium or ammonium azide.

(4) Compounds of formula (I) having a carboxyl can be prepared by hydrolyzing a compound of formula (V): 2 3 7

wherein X and X have the same meaning as in formula (I) and Z

8 8 is cyano or the group -CO-Z, wherein Z is alkoxy of 1 to 6 carbon atoms or hydroxyalkoxy of 2 to 4 carbon atoms.

The hydrolysis can be carried out by heating with either a dilute aqueous mineral acid, e.g. sulfuric acid or hydrochloric acid, optionally in the presence of an organic acid, such as acetic acid, or a base, such as an alkali metal hydroxide or alkoxide, e.g. aqueous sodium or potassium hydroxide, sodium methoxide and sodium methoxide. with.

(5) Another synthetic method comprises the formula; 25 (IX), 'Τ§ΟρΧ.ι1. 1. 2 wherein X and X have the same meaning as in formula (I) and Z 1 is a group which can be converted into the group X defined in connection with formula (I).

9 82833 3

Compounds in which X is hydroxyl are prepared by hydrolysis of a suitable precursor, e.g., by the reaction of water and the corresponding diazonium salt (Z 1 is -N + w 'where W ~ is an anion such as chloride, bromide or hydrogen sulphate), the latter being prepared by administering nitric acid. affects the amine (Z 2 is amino).

The diazonium salts can also be converted to the corresponding allylthio end products (where X is sulfur and X is hydrogen) by reaction with the appropriate potassium alkyl xanthate 10 and sequentially decomposing the diazoxanthate and aromatic xanthate formed successively by heating in a slightly acidic copper-containing medium. Alkylthio compounds can also be prepared by alkylation of the corresponding thiol (Z 2 is mer-15 capto) obtained, for example, by alkaline hydrolysis of the above-mentioned aromatic xanthates.

Hydroxyl compounds can also be prepared from 11 to 12 precursors having the group -OZ as the Z group, which can be converted to hydroxyl. Suitable meanings for Z to Z are alkyl, e.g. alkyl having 1 to 4 carbon atoms and especially methyl, ethyl, isopropyl and t-butyl; aralkyl such as benzyl; acyl, such as alkanoyl, especially alkanoyl having 1 to 6 carbon atoms, e.g. acetyl; and tetrahydropyranyl.

25 Such groups can be removed, i.e., replaced with hydrogen, by methods common in the art. Thus, removal of the alkyl group can be accomplished using, e.g., magnesium iodide or sodium thiocresolate, heating with aluminum trichloride in xylene, or using (at reduced temperatures) e.g., boron trichloride or tribromide in a medium such as dichloromethane; the acyl group can be removed by base hydrolysis; the alkyl group and the tetrahydropyranyl group can be removed by acid hydrolysis, using e.g. hydrogen bromide in acetic acid; and hydrogenation (using e.g. a palladium / carbon catalyst) can be used to remove the aralkyl group.

1 ° 82833

It is clear / that some of the conditions described above for the removal of the alkyl group are also suitable for cyclization, as described in (1) above, and thus the hydroxylxanthones of formula (I) can be prepared of formula (III) (where X is oxygen). and X5 is hydrogen) by "one vessel" cyclization / dealkylation of alkoxy compounds.

Alkoxy compounds can be prepared by alkylating the corresponding hydroxyl compound, e.g., using an alkyl halide or dialkyl sulfate and an alkali such as an alkali metal hydride or carbonate.

The hydroxyl compounds can be converted to the corresponding hydroxyalkoxy compounds (where X is oxygen and X 1 is hydroxyl), e.g. by reaction with a suitable alkylene oxide or carbonate, and the hydroxyalkylthio compounds (where X is sulfur and X is hydroxyl) can be prepared in a similar manner from the corresponding thiol (Z 2 is mercapto); when X 1 in the starting materials is carboxyl, the latter group can be simultaneously esterified by this process, whereby the desired final product is obtained by its selective hydrolysis (see (6) above). The final products in which X 1 is alkanoyloxy (i.e., X 6 is alkanoyl) are prepared from the corresponding hydroxyalkoxy or hydroxyalkylthio compounds, as desired, by conventional alkanoylation methods, and the latter is obtained by hydrolysis of the former.

When preparing compounds of formula (I) by the methods described above, it is to be understood that when groups X and X are formed before complete formation of the desired final product 3Q, it may in some cases: be desirable to protect this group (s) from the reaction at the end of the synthesis. , and then regenerate them by suitable deprotection methods using methods well known in the art; alternatively, the formation of X 1 / X 2 may advantageously constitute the last step of the synthetic sequence.

n 82833

The compounds of formula (I) are isolated as acids or their salts and it is clear that these acids can be converted into their salts and vice versa and that the salts can be converted into salts formed with other cations by methods well known and conventional in the art. Thus, those salts which are not themselves physiologically acceptable are useful in the preparation of the corresponding carboxylic and 5-tetrazolyl acids and their physiologically acceptable salts.

When the methods of preparation described herein give a mixture of optical or other isomers of a compound of formula (I) or an intermediate thereof, the individual isomers may be separated by conventional methods.

When these compounds are used as described above for the storage of erythrocytes in vitro, they are preferably mixed with the cells in a container in which the cells are collected and stored; this is usually a bottle or bag large enough to hold a standard whole blood unit (about 450 ml) together with an equal volume of 20 anticoagulants. The compound is contacted with the cells at an appropriate stage after the cells have been taken from the blood donor. Thus, as an alternative, the compound is present together with the anticoagulant in the bottle or bag when it is "ready to use", where mixing takes place after filling with blood, while in an alternative way the compound is added to cells already in the bottle / bag, e.g. after delivery. These compounds can be used in this way whether the cells are stored in the form of whole blood or sealed cell mass (when the plasma is kept separate) and in the latter case, whether they are re-transferred to plasma suspended or in a plasma substitute.

The effective concentration of the compound in the whole blood volume of the flask or bag, as described above, is generally 0.1 mM to 50 mM, more usually 0.5 mM to 25 mM, and i2 82833 most usually 1 mM to 10 mM, with an optimum concentration of 3 mM. Although the exact weight of compound required will vary from compound to compound, a standard size vial / bag (see above) will require about 0.5 g (calculated as acid) to give an optimal concentration (3 mM).

Compounds of formulas (III), (IV), (V) and (IX) as defined hereinabove may be prepared by methods known in the art for the synthesis of compounds having an analogous structure, and in particular e.g. by methods consistent with the methods set forth herein for the compounds of formula (I) using appropriate starting materials and conditions as described above.

A large number of tri-15 cyclic compounds have been described in the literature as active substances in mammals and in vitro in mammalian preparations as inhibitors of allergic reactions involving reactive antibodies responsible for asthma in humans, cf. e.g. GB Patent Publications 1,414,621; 1,447,031; 1447 032; 1,452,891; 20 1,458,185 and 1,458,186; such compounds have thus been proposed for use in the treatment or prevention of allergic conditions in mammals, such as asthma and other allergic breast diseases, hay fever (allergic rhinitis), conjunctivitis, urticaria and eczema.

The compounds of formula (I) as defined above are excluded from all these representations.

Japanese Patent Application Kokai No. 16821/82 (published January 28, 1982) describes a medicament for the treatment of immunodeficiency diseases in mammals, e.g., humans, which contains as an active ingredient a compound having the general formula:

O

"Ui JQ-u

A H

i3 82833 wherein R is a hydrogen atom or lower alkoxy and A is an oxygen atom or a sulfonyl, or a salt thereof; specifically listed immunodeficiency diseases include cancer, rheumatism, autoimmune disease, hepatitis, nephritis, and infectious disease.

5 This Japanese application identifies Only three specific compounds of this general formula, each of which has been previously described in the literature and proposed for use in the treatment or prevention of asthma and related allergic conditions. These three compounds are: (A): 3- (1H-tetrazol-5-yl) thioxanthone-10,10-dioxide (B): 7-methoxy-2- (1H-tetrazol-6-yl) xanthone (C) : 2- (1H-tetrazol-5-yl) xanthone Thus, this Japanese application does not identify any particular compound not previously specifically described in the literature, and said invention is disclosed as a novel invention for known compounds.

None of the compounds identified in said Japanese Application as (A), (B) and (C) fall within the scope of formula (I) as defined herein.

The utility and advantage of the compounds of the invention in blood storage are apparent from the following Examples I, II and III.

25 Example I

Activity in human whole blood in vitro

Human blood was collected from volunteer donors in CPD anticoagulant * medium at a ratio of 100 ml blood / 15 ml medium; 1 ml aliquots were dispensed into 2 ml polycarbonate 30 ampoules and kept for 3 hours at 4 ° C to allow cells to settle from the plasma. The samples were then kept at room temperature while the test compounds, one per ampoule, were added according to the following procedure to give a concentration of 6 mM in whole blood: 35 A small amount of plasma was removed from each ampoule: sodium salts were dissolved directly (see

i4 82833 these), while acids (see these) were added to warm aqueous sodium bicarbonate (300 mM, 2 drops), which was then mixed with plasma; in either case, the compound-loaded plasma Palau-5 was then placed in the original ampoule, the ampoule was capped, and the contents were mixed thoroughly.

Three reference ampoules were also prepared for each set of experiments, respectively, containing: a) blood alone 10 b) blood + hydrochloric acid (0.1 M, 150 microliters) c) blood + aqueous sodium hydroxide (0.1 M, 150 microliters).

After a total of two hours at room temperature, all samples were left at 37 ° C for 16 hours and the pH of each was then measured at this temperature. The vials were then stored on ice and the oxygen dissociation curve was determined for each sample using a whole blood spectrophotometer (Hem-O-Scan, trade name). Finally, after reheating at 37 ° C, the pH of each sample was remeasured.

The shift of the P 2 Q point (oxygen voltage at which hemoglobin is 50% saturated with oxygen) to the right of the oxygen dissociation curve was observed for each sample relative to the P 50 value for the appropriate sample pH. The results are given below.

* CPD anticoagulant is an aqueous solution containing per 100 ml: sodium citrate 2.63 g anhydrous dextrose 2.32 g 30 citric acid monohydrate 0.327 g acid sodium phosphate 0.251 g

Compound Right shift (mm Hg) Sodium salt of 7-methoxyxanthone-3-carboxylic acid 35 13.0 7-Ethoxycanthone-3-carboxylic acid 16.2 is 82833

Compound Right shift (mm Hq) 7-propoxixanthone-3-carboxylic acid 13.0 Sodium salt of 7- (methylthio) xanthone-3-carboxylic acid 15.6 5 Sodium salt of 7-isopropoxyxanthone-3-carboxylic acid 9.7 7-hydroxyxanthone-3 Sodium salt of carboxylic acid 5,3 Sodium salt of 7- (3-hydroxypropoxy) xanthone-3-carboxylic acid 25,8 10 7-Butoxycanthone-3-carboxylic acid 6,9 Sodium salt of 7- (2-hydroxyethoxy) xanthone-3-carboxylic acid 25.0 7- (2-hydroxypropoxy) xanthone-3-carboxylic acid 23.1 7- (3-acetoxypropoxy) xanthone-3-carboxylic acid 19.9 2-methoxy-6- (5-tetrazolyl) xanthone Sodium salt 18.8 2-Ethoxy-6- (5-tetrazolyl) xanthone Sodium salt 27.4 2-Propoxy-6- (5-tetrazolyl) xanthone-20 Sodium salt 23.2 2-Butoxy-6- (5-tetrazolyl) ) xanthone 14.6 2-Isopropoxy-6- (5-tetrazolyl) xanthone sodium salt 12.6 2-Methylthio-6- (5-tetrazolyl) xanthone sodium salt 9.5 25 2- (3-hydroxypropoxy) -6- (5-Tetrazolyl) -xanthone sodium salt 23.5 2- (2-hydroxypropoxy) -6- (5-tetrazolyl) -xanthone sodium salt 28.7 7-Methoxyxanthene-3-carboxylic acid 17.3 7- (2-acetoxyethoxy) xanthone-3-carboxylic acid 19.0 2- (2-acetoxyethoxy) -6- (5-tetrazolyl) -xanthone 20.0 2- (2-hydroxyethoxy) -6- (5-tetrazolyl) -xanthone sodium salt 32.6 2- [2- (2-hydroxyethoxy) ethoxy / xanthone-6-35 carboxylic acid sodium salt 25.6 16 82833

Compound Right shift (mm Hq) 2- (2-butyryloxyethoxy) xanthone-6-carboxylic acid sodium salt 25.5 2- [2- (2-acetoxyethoxy) ethoxy] xanthone-6-5 carboxylic acid sodium salt 26.1 2- ( 2-Butyryloxyethoxy) -6- (5-tetrazolyl) xanthone sodium salt 22.2 2- (ethylthio) xanthone-6-carboxylic acid sodium salt 20.0 2-ethylthio-6- (5-tetrazolyl) xanthone-10 sodium salt 16 , 6 2- (methylthio) xanthene-6-carboxylic acid sodium salt 16.2 2- (2-hydroxyethylthio) -6- (5-tetrazolyl) xanthone 17.7 15 (A) * 7.6 (B) * -1 , 6 * (O * 3.5

Japanese patent Kokai no. 16821/82: (A): 3- (1H-tetrazol-5-yl) thioxanthone-10,10-dioxide 20 (B): 7-methoxy-2- (1H-tetrazol-6-yl) xanthone (C) : 2- (1H-tetrazol-6-yl) xanthone ** means a shift to the left

Example II Toxicity Values The disclosed compounds were administered intravenously to female CDI mice (Charles River U.K. Ltd).

For example, for 15a, the LD5Q was found to be between 140 mg / kg and 200 mg / kg (calculated as free acid).

For example, the LD50 of 25a was found to be greater than 600 mg / kg.

Example III Blood Storage A sterile, sealed bag (Fenwal, Travenol Laboratories Ltd., Therford, Norfolk, England) was used which was suitable for collecting 420 ml of blood and containing 63 ml of CPD anticoagulant solution. Under sterile conditions, the anticoagulant was removed, mixed with an effective, non-toxic amount (see above) of a compound of formula (I) 1782833 and returned to the bag and the bag was then resealed and stored at room temperature.

Blood from human volunteer donors was then collected in a bag by conventional methods and the filled bag was then stored at 4-6 ° C.

The following examples are provided to illustrate this invention. All temperatures are in degrees Celsius.

Example 1 7-Methoxyxanthone-3-carboxylic acid 10 A. 2- (4-methoxyphenoxy) terephthalic acid

Sodium metal (11.5 g) was dissolved in methanol (250 ml), and to this solution was added 4-methoxyphenol (62.1 g). The methanol was thoroughly removed on a rotary evaporator and the remaining sodium salt was dissolved in dimethyl sulfoxide. Dimethyl 2-nitroterephthalate (107.6 g) was added and the mixture was stirred and heated at 120 ° C for 2.5 hours. The resulting dark solution was hydrolyzed by refluxing with a solution of sodium hydroxide pellets (70 g) in water (500 ml) and ethanol (800 ml) for 2.5 hours.

The solution was acidified by pouring excess hydrochloric acid on ice and the precipitated 2- (4-methoxyphenoxy) terephthalic acid was filtered off, washed with water and dried at 90 ° C under vacuum to give 125.0 g, 25 m.p. 280-283 °.

In a similar manner the following compounds were prepared: 2- (4-ethoxyphenoxy) terephthalic acid, m.p. 280-281 °, prepared from 4-ethoxyphenol, by the method of McElvain and Englehardt1, J. Amer. Chem. Soc., (1944), 66, 1080.

2- (4-propoxyphenoxy) terephthalic acid, m.p. 279-281 ° C, prepared from 4-propoxyphenol by the method of Klarmann, Gatyas and Shternov, J. Amer. Chem. Soc. (1932), 54, 298.

2- (4-isopropoxyphenoxy) terephthalic acid, m.p. 261-35 263 °, from acetic acid, made from 4-isopropoxyphenol

Klarmann, Gatyas, and Shternov, J. Amer. Chem. Soc. (1932), 54, 298.

18,82833 2- (4-methylthiophenoxy) terephthalic acid, m.p. 294-296 ° from methanol, prepared from 4- (methylthio) phenol.

B. 7-Methoxyxanthone-3-carboxylic acid 2- (4-methoxyphenoxy) terephthalic acid (90.0 g) was refluxed with phosphorus oxychloride (900 ml) for 2 hours. The cooled reaction mixture was carefully decomposed by adding water and adjusting the temperature to 40-50 ° C by adding ice. The precipitated 7-methoxycanthone-3-carboxylic acid was filtered off, washed with water and recrystallized from dimethylformamide (after concentration at 80 ° in vacuo, m.p. 301-302 °), Found: C, 66.73%; H, 3.70%, C 18 H 24 N 2 O 2 requires C, 66.67%; H, 3.73%.

The following compounds were prepared in a similar manner: Example 2: 7-ethoxycanthone-3-carboxylic acid, m.p. 286-289 ° (without recrystallization).

Example 3: 7-propoxixanthone-3-carboxylic acid, m.p. 261-264 ° from dimethylformamide.

Found: C, 68.84%; H, 4.91%.

Calcd for C17H14O5: C, 68.46%; H, 4.70%.

Example 4: 7- (methylthio) xanthone-3-carboxylic acid, m.p. 272-275 ° from acetic acid.

Found: C, 62.69%; H, 3.48%; S, 11.15%.

Calcd for c 15 H 10 (O 4 S): C, 62.94%; H, 3.49%; S, 11.19%. Example 5 7-Isopropoxyxanthone-3-carboxylic acid 2- (4-isopropoxyphenoxy) terephthalic acid (13.5 g) was refluxed with thionyl chloride (150 ml) for 0.5 h, then ferric chloride (1.0 g) was added and boiling water was added. from which reflux was continued for a further 4.5 h. Excess thionyl chloride was evaporated off and the residue was poured into water. The precipitated product was filtered off, washed with water and mixed with the excess aqueous sodium bicarbonate solution at 80-90 ° for 1.5 h. Solution 35 was acidified to precipitate 7-isopropoxyxanthone-3-carboxylic acid, which was filtered off, washed with water and dried. It was recrystallized first from I9 82833 dimethylformamide and then from acetic acid, m.p. 261-263 ° C. Found: C, 68.12%? H, 4.60%.

Calculated for C 17 H 14 O 5: C, 68.46%; H, 4.70%.

Example 6 7-Hydroxycanthantone-3-carboxylic acid 7-Methoxyxanthone-3-carboxylic acid (8.0 g) was refluxed with a 12% solution of hydrogen bromide in acetic acid (500 ml) for 28 h. The reaction mixture was poured into ice water and the precipitated product was filtered off. 10 l, washed well with water and dried at 100 ° under vacuum to give 7-hydroxycanthone-3-carboxylic acid, m.p. 349-350 °.

Found: C, 65.59%? H, 3.14%.

Calculated for C 12 H 9 O 2: C, 65.63%; H, 3.12%.

Example 7 7-Ethoxycanthone-3-carboxylic acid (i) 7-Hydroxycanthone-3-carboxylic acid (5.0 g) was mixed with a mixture of anhydrous potassium carbonate (50 g) and diethyl sulfate (10.25 ml). .0 g) in dimethylformamide (150 ml) for 5 h and then allowed to stand at room temperature for 16 h. .0 g) in water (200 ml) and ethanol (50 ml), 2 h. The cooled reaction mixture was acidified with excess hydrochloric acid and the precipitated acid was filtered off, washed with water and recrystallized from dimethylformamide, m.p. 287-289 °.

Found: C, 67.72%; H, 4.40%.

Calcd for C 16 H 12 O 5: C, 67.60%; H, 4.26%.

(iii) (A) Methyl 7-hydroxycanthone-3-carboxylate 7-Hydroxycanthone-3-carboxylic acid (10.0 g) was refluxed with methanol (1.5 L) and concentrated sulfuric acid (15 mL) for 3 h. The hot solution was filtered and on cooling methyl 7-hydroxycanthone-3-carboxylate crystallized and filtered off and dried, 6.4 g, m.p. 268-270 °.

(ii) (B) 7-Ethoxycanthone-3-carboxylic acid Methyl 7-hydroxycanthone-3-carboxylate (6.9 g) was refluxed with stirring with ethyl iodide (9.75 g), potassium carbonate (75 g) and acetone (1 1) with 4 h. The mixture was filtered hot and the residue was washed with acetone. The combined filtrate and washings were evaporated to dryness and the residue was dissolved in dichloromethane and washed with water. The solution was dried and evaporated to give methyl 7-ethoxycanthone-3-carboxylate, 3.65 g, m.p. 169-171 °.

The ester (3.6 g) was hydrolyzed by boiling with a solution of sodium hydroxide (2.0 g) in water (250 ml) and ethanol (50 ml) for 2 h. The resulting solution was acidified with excess dilute hydrochloric acid and the precipitated product filtered off to give 7-ethoxycanthone-3-carboxylic acid (after recrystallization from dimethylformamide, m.p. 290-291 °).

In a similar manner were prepared:

Example 8: 7- (3-hydroxypropoxy) xanthone-3-carboxylic acid, m.p. 245-246 ° recrystallized from acetic acid.

From 3-bromo-1-propanol (intermediate methyl ester of 7- (3-25 hydroxypropoxy) xanthone-3-carboxylic acid, m.p. 161-162 ° from methanol).

Found: C, 65.15%; H, 4.56%.

Calcd for C 18 H 18 N 2 O 2: C, 64.97%; H, 4.49%.

Example 9: 7-butoxycanthone-3-carboxylic acid, m.p. 225-30 227 °.

Found: C, 69.09%; H, 5.16%.

Calculated for C 18 H 28 N 2 O 2: C, 69.22%; H, 5.11%.

Example 10: 7-propoxixanthone-3-carboxylic acid, m.p. 262-263 °, from n-propyl iodide (methyl ester, m.p.

35 151-152 °).

21 82833

Example 11 7- (2-Hydroxyethoxy) xanthone-3-carboxylic acid 7-Hydroxycanthone-3-carboxylic acid (3.0 g), ethylene carbonate (13.0 g) and tetramethylammonium iodine-5 dia (0.07 g) were heated together to 135- At 140 ° C for 4 h.

The cooled reaction mixture was diluted with chloroform and the solid residue was filtered off and boiled with a solution of sodium hydroxide (2.0 g) in ethanol (40 ml) and water (60 ml) for 5 h. The reaction mixture was then diluted with water, filtered and acidified with dilute hydrochloric acid and the solid product was filtered off and recrystallized from boiling dimethylformamide to give 7- (2-hydroxyethoxy) -xanthone-3-carboxylic acid, m.p. 265-267 °.

Found: C, 63.43%; H, 4.11%.

Calculated: lie: C, 64.00%; H, 4.03%.

Example 12 7- (2-Hydroxypropoxy) xanthone-3-carboxylic acid Methyl 7-hydroxycanthone-3-carboxylate 20 (2.0 g), propylene carbonate (10.0 g) and tetramethylammonium iodide (0.20 g) were heated together. At 170 ° for 4 h. The cooled reaction mixture was then refluxed with a solution of sodium hydroxide (6.0 g) in water (200 ml) and ethanol (200 ml) for 30 min. The solution was cooled, filtered and acidified with excess dilute hydrochloric acid. The precipitated product was filtered, washed with water and recrystallized twice from a mixture of 95% 2-butanone and 5% water to give 7- (2-hydroxypropoxy) -30 xanthone-3-carboxylic acid, m.p. 252-254 ° (structure confirmed by proton magnetic resonance spectroscopy).

Found: C, 65.06%; H, 4.54%.

Calcd for C 18 H 18 N 2 O 2: C, 64.96%; H, 4.49%.

22 82833

Example 13 7- (3-Acetoxypropoxy) xanthone-3-carboxylic acid 7- (3-Hydroxypropoxy) xanthone-3-carboxylic acid (8.8 g) was refluxed with acetic anhydride (200 ml) for 2 h. The resulting solution was filtered. and the excess anhydride was evaporated. The residual solid was washed with water, dried and then recrystallized from acetic acid to give 7- (3-acetoxy-propoxy) xanthone-3-carboxylic acid, 10 m.p. 236-237 °.

Found: C, 63.94%? H, 4.51%.

Calcd for C 18 H 18 N 2 O 2: C, 64.04%; H, 4.53%.

Example 14 7-Methoxy-3- (5-tetrazolyl) xanthone 15 (A) 7-Methoxyxanthone-3-carboxamide 7-Methoxyxanthone-3-carboxylic acid (20.0 g) was refluxed with thionyl chloride (200 ml) for 2 hours. Excess thionyl chloride was evaporated thoroughly from solution and the remaining acid chloride was added to 0.880 ammonia (200 ml) with stirring.

The solid 7-methoxycanthone-3-carboxamide was filtered off, washed with water and dried at 80 ° under vacuum to give 19.6 g, m.p. 285-287 °.

The following amides were prepared in a similar manner: 7-ethoxycanthone-3-carboxamide, m.p. 311-314 °.

7-butoxycanthone-3-carboxamide, m.p. 222-225 °.

7- (3-acetoxypropoxy) xanthone-3-carboxamide, m.p. 205-209 °.

7- (2-acetoxypropoxy) xanthone-3-carboxamide, 30 m.p. 196-198 ° from acetic acid.

7-propoxyxanthone-3-carboxamide, m.p. 272-274 °. 7-isopropoxyxanthone-3-carboxamide, m.p. 234-239 °. 7- (methylthio) xanthone-3-carboxamide, m.p. 228-234 °.

35 (B) 6-Cyano-2-roethoxycantone 23,82833 7-Methoxyxanthone-3-carboxamide (1.15 g) was added to a stirred solution of thionyl chloride (5.0 ml) in dimethylformamide (25 ml), 0-5 ° in about 5 minutes. The reaction mixture was stirred at 0-5 ° for 5 h and then poured onto ice. The precipitated solid product was filtered off, washed with water and recrystallized from dimethylformamide to give 6-cyano-2-methoxyxanthone, 0.60 g, m.p. 254-255 °.

The following nitriles were prepared in a similar manner: 6-cyano-2-ethoxyxanthone, m.p. 204-205 °, dime from style formamide.

2-butoxy-6-cyanoanthantone, m.p. 156-157 ° from acetic acid.

2- (3-acetoxypropoxy) -6-cyanoanthantone, m.p. 158-15 ° C from ethanol.

2- (2-acetoxypropoxy) -6-cyanoanthantone, m.p. 139-140 ° from methanol.

6-cyano-2-propoxyxanthone, m.p. 166-167 ° from dimethylformamide.

6-cyano-2-isopropoxyxanthone, m.p. 145-146 ° from aqueous dimethylformamide.

6-cyano-2- (methylthio) xanthone, m.p. 209-210 ° from aqueous dimethylformamide.

(C) 2-Methoxy-6- (5-tetrazolyl) xanthone 6 6-Cyano-2-methoxyxanthone (12.6 g) was heated with sodium azide (3.41 g) and ammonium chloride (2.95 g) in dimethylformamide (100 ml) at 125 ° for 6 h. The reaction mixture was diluted with water and acidified with excess hydrochloric acid. The precipitated 2-methoxy-6- (5-30 tetrazolyl) xanthone was filtered off, washed with water and recrystallized from dimethylformamide, decomposing above about 300 °.

Found: C, 60.82%; H, 3.45%; N, 18.91%.

Calculated for c 15 H 10 N 4 O 3: C, 61.22%; H, 3.42% N, 19.04%.

35 In a similar manner prepared: 24 82833

Eg 15; 2-ethoxy-6- (5-tetrazolyl) xanthone

Decomposed at 272-274 °, from dimethylformamide.

Found: C, 62.01%; H, 3.94%; N, 18.20%.

Calculated for C 16 H 12 N 4 O 3: C, 62.33%, ♦ H, 3.92%; N, 18.17%.

Example 16: 2-Propoxy-6- (5-tetrazolyl) xanthone

Decomposed at 272-273 °, from dimethylformamide.

Found: C, 63.93%? H, 4.37%; N, 17.15%.

Calculated for c17H14N4O3: C, 63.35%; H, 4.38%; N, 17.38%. Example 17: 2-Butoxy-6- (5-tetrazolyl) xanthone 10 Decomposed at 249-250 °, from dimethylformamide.

Found: C, 64.37%; H, 4.71%; N, 16.54%.

Calculated for c 18 H 16 N 4 O 3: C, 64.28%; H, 4.79%; N, 16.66%. Example 18: 2-Isopropoxy-6- (5-tetrazolyl) xanthone Decomposed at 263-265 °, from 2-methoxyethanol.

Found: C, 63.27%; H, 4.37%; N, 17.25%.

Calcd for C37H34N4O3: C, 63.35%; H, 4.35%; N, 17.39%.

Example 19: 2- (methylthio) -6- (5-tetrazolyl) xanthone

Sp. 253-255 °, from aqueous 2-methoxyethanol. Found: C, 58.34%; H, 3.23%; N, 17.97%; S, 10.29%.

Calcd for C 15 H 10 N 4 O 2 S: C, 58.06%; H, 3.22%; N, 18.06% and S, 10.32%.

Example 20 2- (3-Hydroxypropoxy) -6- (5-tetrazolyl) xanthone 2- (3-acetoxypropoxy) -6-cyanoanthantone (3.25 g), sodium azide (0.66 g), ammonium chloride (0.57 g) g) and dimethylformamide (50 ml) were heated together at 125 ° C for 5 h. The reaction mixture was poured into water and basified with sodium hydroxide solution. The solution was extracted twice with chloroform to remove the unchanged nitrile and then acidified with hydrochloric acid to precipitate crude -2- (3-acetoxypropoxy) -6- (5-tetrazolyl) xanthone, 2.85 g, m.p. 240 ° (decomposed).

The acetoxy compound (1.5 g) was refluxed with sodium hydroxide (3.0 g) in water 35 (30 ml) for 1.5 h and the solution was acidified with hydrogen chloride. The precipitated precipitate was filtered and recrystallized from dimethylformamide to give 2- (3-hydroxypropoxy) -6- (5-tetrazolyl) xanthone, m.p. 270 ° (decomposed). Found: C, 60.37%; H, 4.27%; N, 16.72%.

Calculated for 01? 1414404: C, 60.35%, ♦ H, 4.17%, N, 16.56%. 5 In the same way:

Example 21: 2- (2-hydroxypropoxy) -6- (5-tetrazolyl) xanthone M.p. 250 ° (decomposed).

Found: C, 60.08%; H, 4.21%; N, 16.62%.

Calculated for c17H14N4O4: C, 60.35%; H, 4.17%; N, 16.56%. Example 22 7-Methoxyxanthene-3-carboxylic acid 7-Methoxyxanthone-3-carboxylic acid (10.0 g) was reduced by the Clemmensen method using zinc amalgam prepared from zinc powder (100 g) and mercuric chloride (8.0 g). in acetic acid at ambient temperature. The product, 7-methoxyxanthene-3-carboxylic acid, was obtained by chromatography on silica gel eluting with 5% methanol in chloroform and had a melting point of 259-261 °.

Found: C, 70.41%; H, 4.78%.

Calculated: lie: C, 70.30%; H, 4.72%.

Preparation of sodium salts Sodium salt of 7-methoxyxanthone-3-carboxylic acid (e.g., 1a) 25-Methoxyxanthone-3-carboxylic acid (32.9 g) was heated with a solution of sodium bicarbonate (10.08 g) in water (1 L), the solution was filtered and evaporated to dryness. The remaining precipitate was ground to a powder and dried in vacuo with calcium chloride to give the sodium salt of 30 mg, which was analyzed to contain 0.25 moles of water of crystallization.

Found: C, 60.61%; H, 3.22%.

Calculated for C 15 H 9 NaO 5.0.25 H 2 O: C, 60.72%; H, 3.23%.

The following sodium salts were prepared in the same manner from fully characterized free carboxylic acids or tetrazoles. The molar amount of crystal water can vary from 26 to 82833

For various preparations of Scima's sodium salt under drying conditions and exposure to atmospheric humidity, I included the sodium salt of 7-ethoxycanthone-3-carboxylic acid (e.g. 2a) 5 Freeze-dried monohydrate.

Found: C, 59.43%; H, 3.52%.

Calculated for C 16 H 11 NaO 5 · Found: C, 59.26%; H, 4.04%.

Sodium salt of 7-propoxyxanthone-3-carboxylic acid (Ex. 3a) 10 Freeze-dried monohydrate.

Found: C, 60.49%; H, 4.12%.

Calcd for C 12 H 12 N 2 O 2 • H 2 O: C, 60.35%; H, 4.47%.

Sodium salt of 7-isopropoxyxanthone-3-carboxylic acid (Ex. 5a) 15 Freeze-dried monohydrate.

Found: C, 59.72%; H, 4.00%; drying loss at 120 °, 4.94%.

Calculated for C17H13Na05. for T 0 O: C, 60.35%; H, 4.47%; H 2 O, 5.33%.

Sodium salt of 7- (methylthio) xanthone-3-carboxylic acid (Example 4a)

Freeze-dried, monohydrate Found: C, 55.63%; H, 3.21%; S, 9.70%; drying loss at 120 °, 4.78%.

25 Calculated for C15HgNaO4S. Found: C, 55.20%; H, 3.40%; S, 9.82%; H 2 O, 5.52%. Sodium salt of 7-hydroxycanthone-3-carboxylic acid (Ex. 6a)

Dried at room temperature under vacuum; dihydrate. Found: C, 53.67%; H, 2.79%.

Calculated for C 12 H 12 N 2 O 2 • 2 H 2 O: C, 53.50%; H, 3.53%.

Sodium salt of 7- (2-hydroxyethoxy) xanthone-3-carboxylic acid (Ex. 11a)

Dried at room temperature; sesquihydrate.

Found: C, 54.93%; H, 3.92%.

Calculated for C 16 H 11 NaO 6 1.5 D: C, 55.02%; H, 4.04%.

27 82833 Sodium salt of 7- (3-hydroxypropoxy) xanthone-3-carboxylic acid (Ex. 8a)

Dried at 80 ° under vacuum, hemihydrate.

Found: C, 55.68%; H, 3.64%.

Calcd for C 17 H 13 N 4 NaO 4 .0.5 H 2 O: C, 55.29%; H, 3.82%.

2-Methoxy-6- (5-tetrazolyl) xanthone sodium salt (Ex. 14a)

Dried at 80 ° in vacuo, exposed to air at room temperature. Tetrahydrate.

Found: C, 46.44%; H, 4.34%; N, 14.58%.

Calculated for C 15 H 9 N 4 NaO 3 .4 H 2 O: C, 46.40%; H, 4.41%; N, 14.43%.

2-Ethoxy-6- (5-tetrazolyl) xanthone sodium salt (Ex. 15a) Dried at 80 ° in vacuo, exposed to air at room temperature. The monohydrate.

Found: C, 55.34%; H, 4.00%; N, 16.11%.

Calculated for C 16 H 11 N 4 NaO 3 .H 2 O: C, 55.17%; H, 3.76%, N, 16.08%.

2-Propoxy-6- (5-tetrazolyl) xanthone sodium salt (Ex. 16a)

Dried at room temperature, 2,25-hydrate. Found: C, 53.15 *; H, 4.36%; N, 14.65%.

Calculated for ci7Hi4N4NaO3. 2.25 for H 2 O: C, 53.05%; H, 4.58%; 25 N, 14.56%.

2-Isopropoxy-6- (5-tetrazolyl) xanthone sodium salt (Ex. 18a)

Freeze-dried, 3,5-hydrate.

Found: C, 50.13%; H, 4.58%; N, 13.36%; drying time at 120 ° 14.77%.

Calculated for c17H13N4NaO3.3.5 H2O: C, 50.12%; H, 4.95%; N, 13.75%; H 2 O, 15.48%.

28 82833 2- (Methylthio) -6- (5-tetrazolyl) xanthone sodium salt (Ex. 19a)

Freeze-dried, trihydrate.

Found: C, 46.69%; H, 3.74%; N, 14.31%; S, 8.11%; 5 Loss on drying at 120 ° 13.81%.

Calculated for c 15 H 9 N 4 NaO 2 S 3 H 2 O: C, 46.63%; H, 3.91%; N, 14.50%; S, 8.30%; H 2 O, 13.99%.

2- (2-Hydroxypropoxy) -6- (5-tetrazolyl) xanthone sodium salt (Ex. 21a) 10 Dried at 80 ° under vacuum, monohydrate.

Found: C, 53.96%; H, 4.00%; N, 14.58%.

Calcd for C 17 H 13 N 4 NaO 4 .H 2 O: C, 53.97%; H, 4.07%; N, 14.81%.

2- (3-hydroxypropoxy) -6- (5-tetrazolyl) xanto-15 sodium salt (Ex. 20a)

Dried at 80 ° under vacuum, one-third hydrate. Found: C, 58.68%; H, 3.64%; N, 15.14%.

Calculated for c37H33N4NaO4.0.33 H2O: C, 55.74%; H, 3.76%; N, 15.29%.

Example 23 7- (2-Acetoxyethoxy) xanthone-3-carboxylic acid 7- (2-Hydroxyethoxy) xanthone-3-carboxylic acid (4.0 g) was refluxed with acetic anhydride (200 ml) for 3 hours. The solution was evaporated to dryness and the residue recrystallized from acetic acid to give 7- (2-acetoxyethoxy) xanthone-3-carboxylic acid, m.p. 248-249 ° C.

Found: C, 63.08%; H, 4.18%.

Calculated for c 18 H 14 O 7: C, 63.16%; H, 4.12%.

Example 24 2- (2-Acetoxyethoxy) -6- (5-tetrazolyl) xanthone (A) 7- (2-acetoxyethoxy) xanthone-3-carboxamide 7- (2-acetoxyethoxy) xanthone-3-carboxylic acid 4.4 g) was refluxed with thionyl chloride (50 ml) for 2 h. The resulting solution was evaporated to dryness and the residual acid chloride was added to ice-cold concentrated ammonia solution with stirring. After 2 hours, the amide was filtered off and dried to give 3.3 g, m.p. 230-232 ° C.

5 (B) 2- (2-acetoxyethoxy) -6-cyanoanthantone

The amide from step (A) (3.3 g) was added to a solution of thionyl chloride (7 ml) in dimethylformamide (50 ml) at -10 ° C. The mixture was stirred at ice bath temperature for 3 h and then poured into ice water. The precipitated nitrile was filtered, washed with water and dried to give 2.9 g, m.p. 194-196 ° C.

(C) 2- (2-acetoxyethoxy) -6- (5-tetrazolyl) xanthone

Cyanoanthantone from step (B) (2.9 g), sodium azide (0.61 g), ammonium chloride (0.53 g) and dimethylformamide (50 ml) were heated together at 125 ° for 8 hours. The reaction mixture was poured into an ice-cold solution of hydrochloric acid (excess) and the product was filtered off and dried. Recrystallization from dimethylformamide gave the title compound, m.p. 216-218 ° C.

Found: C, 58.96%; H, 3.84%; N, 15.01%.

Calculated for c 18 H 14 N 4 O 5: C, 59.02%; H, 3.85%; N, 15.29%.

Example 25 2- (2-Hydroxyethoxy) -6- (5-tetrazolyl) xanthone 2- (2-Acetoxyethoxy) -6- (5-tetrazolyl) xanthone (1.0 g) was refluxed with a solution of sodium hydroxide ( 2.0 g) in water (20 ml), 2.5 h. The solution was cooled and poured into excess aqueous hydrochloric acid and the precipitated product was filtered, washed with water and dried. Recrystallization from dime-style formamide gave the title compound, m.p. 270 ° C (decomposes).

30 82833

Sodium salt (Ex. 25a)

The free tetrazole (13.45 g) was dissolved with heating in a solution of sodium bicarbonate (3.48 g) in water (150 ml). The cooled solution was filtered, extracted once with chloroform and evaporated to dryness.

The residue was dried at room temperature in vacuo over phosphorus pentoxide to give 2- (2-hydroxyethoxy) -6- (5-tetrazolyl) xanthone sodium salt dihydrate.

Found: C, 50.46%; H, 3.79%; N, 14.52%.

Calculated for c 16 H 15 N 4 NaO 6: C, 50.26%; H, 3.95%; N, 14.66%.

Example 26 2- [2- (2-Hydroxyethoxy) ethoxy] xanthone-6-carboxylic acid 7-Hydroxycanthone-3-carboxylic acid (75.0 g), ethylene carbonate (325 g) and tetrabutylammonium iodide (1.75 g) were heated. with stirring at 175 ° C for 5 h. The cooled reaction mixture was diluted with methanol and the solid residue was filtered and boiled with sodium hydroxide (175 g) in ethanol (1.0 L) and water (1.0 L) for 4 h. filtered and the filtrate was diluted with water (2.0 L) and acidified with dilute hydrochloric acid. The solid product was filtered, washed with water and recrystallized from 2-methoxyethanol, m.p. 188 ° C.

25 Analysis:

Calculated,%: C, 62.78; H, 4.68 Found,%: C, 62.52; H, 4.73.

Eg 26a

The product acid from above (1 g) was boiled with sodium bicarbonate (0.244 g) in water (200 ml); the cooled solution was filtered and lyophilized to give the sodium salt as a pale yellow solid, mp, greater than 350 ° C.

3i 82833

Example 27 2- (2-Butyloxyethoxy) xanthones-6-carboxylic acid 2- (2-hydroxyethoxy) xanthones-6-carboxylic acid 5-poa (10 g) was refluxed with butyric anhydride (250 ml) for 2 h. the solution was evaporated and the residue triturated with ether. Recrystallization from dimethylformamide / water gave the title carboxylic acid, m.p. 237-241 ° C.

10 Analysis:

Calculated,%: C, 64.86; H, 4.89 Found,%: C, 65.05; H, 4.87.

Example 27 (a)

The corresponding sodium salt was obtained as a pale yellow solid, m.p. above 350 ° C.

Example 28 2- [2- (2-Acetoxyethoxy) ethoxy] xanthone-6-carboxylic acid 2- (2- (2-hydroxyethoxy) ethoxyxanthone-6-carboxylic acid (10 g) was refluxed in acetic anhydride (150 ml). The resulting solution was evaporated and the residue triturated with ether Recrystallization from methanol gave the product as yellow crystals, mp 199-200 ° C.

25 Analysis:

Calculated,%: C, 62.17; H, 4.69 Found,%: C, 62.08; H, 4.63.

Eg 28a

The corresponding sodium salt was obtained as a pale yellow solid, m.p. above 350 ° C.

Example 29 2- (2-Butyryloxyethoxy) -6- (5-tetrazolyl) xanthone (A) 2- (2-butyryloxyethoxy) xanthone-6-carbox-35-amide 2- (2-butyryloxyethoxy) xanthone-6-carboxylic acid 32,82833 poa (8.0 g) was refluxed with thionyl chloride (100 ml) for 1 h. The resulting solution was evaporated to dryness and the remaining acid chloride was added portionwise to ice-cold 0.880 ammonia solution with stirring.

After 2 hours, the precipitate was filtered and washed with water.

Recrystallization from 2-methoxyethanol gave the title product, m.p. 205-207 ° C.

Analysis:

Calculated,%: C, 65.03; H, 5.19; N, 3.79.

10 Found,%; C, 65.35; H, 5.18; N, 3.67.

(B) 2- (2-Butyryloxyethoxy) -6-cyanoanthantone Thionyl chloride (10 ml) was added dropwise to a stirred suspension of carboxamide from step (A) (5.22 g) in dimethylformamide (100 ml) at 15-10 ° C. :in. The mixture was kept at ice bath temperature for 1 h and then poured into ice water. The solid precipitate was filtered off and recrystallized from glacial acetic acid to give the title cyanoanthantone, m.p. 145-147 ° C.

(C) 2- (2-butyryloxyethoxy) -6- (5-tetrazolyl) -20 xanthone

Cyanoanthantone in step (B) (4.17 g), sodium azide (0.82 g), ammonium chloride (0.70 g) and dimethylformamide (100 ml) were stirred together at 120 ° C for 8 h. 2M hydrochloric acid in ice, heated to 50 ° C for 10 minutes, cooled and filtered. The resulting solid was recrystallized from dimethylformamide / water to give the title xanthone, m.p. 207-209 ° C.

Analysis:

30 C H N

Calculated,%; 60.90 4.61 14.22 Found,%: 60.93 4.55 14.12.

Eg 29a

The corresponding sodium salt was obtained as a pale yellow solid, m.p. 275-280 ° C (dec.).

i 33 82833

Example 30 2- (Ethylthio) xanthone-6-carboxylic acid (A) Diethyl 2- (4-ethylthiophenoxy) terephthalate

Sodium metal (3.4 g) was added over 20 minutes to a stirred solution of 2- (4-methylthiophenoxy) terephthalic acid (10 g) in hexamethylphosphoramide (100 ml) at 100 ° C. in a dry nitrogen atmosphere. After 2 hours, the mixture was cooled and treated with ethyl iodide (20 mL) in an ice bath to keep the temperature below 45 ° C. After a further 30 minutes, the mixture was poured into water and extracted with ether. The organic extracts were washed with brine, dried over magnesium sulfate and evaporated. Chromatography of the residual oil on silica gel eluting with chloroform / 60-80 petroleum (2: 3, v / v) and C8 Zorbax reverse phase HPLC eluting with methanol / water (7: 3, v / v) gave the product as an oil.

(B) 2- (4-ethylthiophenoxy) terephthalic acid

The diester from step (A) (1.9 g) was refluxed with a solution of sodium hydroxide (5.6 g) in water (70 ml) and ethanol (30 ml).

After 2 hours, the mixture was cooled and diluted with water (100 mL). Acidification with concentrated hydrochloric acid gave the product acid which was filtered off and dried, m.p. 282-284 ° C.

(C) 2- (ethylthio) xanthone-6-carboxylic acid

The terephthalic acid from step (B) (1.3 g) was refluxed with phosphorus oxychloride (50 ml) for 8 h. The cooled reaction mixture was carefully decomposed by adding water and keeping the temperature below 80 ° C by the addition of ice. The precipitated precipitate was filtered, washed with water and recrystallized from dimethylformamide / water to give the title carboxylic acid, m.p. 234-236 ° C.

34 82833

Analysis:

C H

Calculated,%: 63.99 4.03 Found,%: 63.98 4.10.

5 Eg 30 years

The corresponding sodium salt was obtained as a yellow powder, m.p. above 350 ° C.

Example 31 2-Ethylthio-6- (5-tetrazolyl) xanthone 10 (A) 2- (Ethylthio) xanthone-6-carboxamide 2- (Ethylthio) xanthone-6-carboxylic acid (0.65 g) was refluxed with thionyl chloride (50 ml). ) for 1 h. The resulting solution was evaporated to dryness and the remaining acid chloride was added portionwise to an ice-cold 0.880 ammonia solution with stirring. After 2 hours, the precipitate was filtered and washed with water to give the product carboxamide (0.62 g), m.p. 248-250 ° C.

(B) 2-ethylthio-6-cyanoanthantone; Thionyl chloride (1.5 ml) was added dropwise to a stirred solution of the carboxamide of step (A) (0.55 g) in dimethylformamide (20 ml) at 5 ° C. The mixture was kept at ice bath temperature for 1 h and then poured into ice water. The solid precipitate was filtered, dried and chromatographed on silica gel eluting with methylene chloride / 60-80 petroleum (1: 1, v / v) to give the title cyanoanthantone (0.44 g), m.p. 159-161 ° C.

(C) 2-ethylthio-6- (5-tetrazolyl) xanthone

Cyanoanthantone from step (B) (0.42 g), sodium azide (0.102 g), ammonium chloride (0.088 g) and dimethylformamide (25 ml) were stirred together at 120 ° C for 10 h. The cooled mixture was poured into ice-cold 2M hydrochloric acid, heated at 80 ° C for 10 minutes, cooled and filtered. The resulting precipitate was extracted into 35% sodium bicarbonate solution and washed with ether: 3582833. Acidification of the base extracts gave the title compound which was filtered and dried, m.p. 261-262 ° C. Analysis:

C H N

5 Calculated,%: 59.24 3.73 17.28 Found,%: 59.25 3.76 17.32.

Eg 31 a

The corresponding sodium salt was obtained as a yellow powder, m.p. 335-336 ° C.

Example 32 2- (Methylthio) xanthene-6-carboxylic acid (A) 2-Methylthio-6-hydroxymethylxanthene Borane-tetrahydrofuran complex (30 ml, 1 M solution in tetrahydrofuran) was added under dry nitrogen to an ice-cold stirred solution of 2 - (methylthio) xanthone-6-carboxylic acid (3 g) in dry tetrahydrofuran (100 ml). After one hour, the mixture was allowed to warm to room temperature and stirred for 12 h. The excess borane was decomposed by further addition of ice and the resulting solution was extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulphate and evaporated to give the title compound (2.39 g) as a white solid, m.p. 151-153 ° C.

(B) 2- (methylthio) xanthene-6-carboxaldehyde

Dimethyl sulfoxide (5 mL) was added dropwise under a dry nitrogen atmosphere to a stirred solution of oxalyl chloride (0.89 mL) in methylene chloride (5 mL) at -60 ° C. After 2 minutes, a solution of xanthene from step (A) (2.3 g) in dimethyl sulfoxide (35 mL) was added dropwise over 5 minutes keeping the temperature below -50 ° with cooling. After 15 minutes, triethylamine (6.20 ml) was added, the mixture was allowed to warm to room temperature and then poured into water. The mixture was extracted with ethyl acetate, the organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated to give the title carboxaldehyde (1.97 g), m.p. 122-123 ° C.

(C) 2-Methylthio-6-cyanoanthene 5 A mixture of carboxylaldehyde from step (B) (1.75 g), hydroxylamine hydrochloride (0.56 g), sodium formate (1 g) and formic acid (15 ml) was refluxed. 1 h. The resulting solution was diluted with water and extracted with ether, the extracts washed with brine, dried over magnesium sulfate and evaporated. The residual precipitate was chromatographed on silica gel eluting with chloroform / methanol (98: 2, v / v) to give the title cyanoxanthene (1.58 g), m.p. 142-144 ° C.

(D) 2- (Methylthio) xanthene-6-carboxylic acid Cyanoxanthene from step (C) (0.3 g) was refluxed with a solution of sodium hydroxide (3 g) in water (10 ml) and ethanol (10 ml). .6 h. The resulting solution was diluted with water, extracted with ether and acidified with concentrated hydrochloric acid. The precipitated carboxylic acid was filtered, washed with water and dried, m.p. 266-267 ° C.

Analysis:

C H

Calculated,%: 66.20 4.45 Found,%: 66.24 4.82.

Eg 32 a

The corresponding sodium salt was obtained as a white powder, m.p. above 300 ° C.

Example 33 2-Hydroxy-6- (5-tetrazolyl) xanthone (A) 3- (5-Tetrazolyl) xanthone 3- (5-Tetrazolyl) thioxanthone-10,10-dioxide-sodium salt (UK Patent 1,447,031; 45 .0 g) was stirred and refluxed with 2N sodium hydroxide solution for 6.5 hours. The solution was acidified by pouring into excess hydrochloric acid poly solution and the precipitated product was filtered and recrystallised from dimethylformamide to give the title compound (14.95 g), mp 296 ° C (dec).

Found: C, 63.64%, H, 3.05%, N, 21.20% Found: C, 63.77%, H, 3.05%, N, 21.15%.

(B) 2-Nitro-6- (5-tetrazolyl) xanthone 3- (5-Tetrazolyl) xanthone (1.0 g) was dissolved in concentrated sulfuric acid (10.0 ml) and the resulting solution was cooled to below 15 ° C. Potassium nitrate (0.50 g) was added in small portions over 10 minutes under cooling to maintain the temperature between 10 ° C and 15 ° C and the reaction mixture was then stirred at 20 ° C for 1 h. The reaction mixture was poured onto ice and the precipitated product was filtered, washed with water and recrystallised . The crystallized product was washed with methanol and dried at 156 ° C / 20 mm Hg to give 0.78 g, m.p. about 280 ° C, (decomposed).

Found: C, 54.11%; H, 2.25%; N, 22.60%, 014Η50504: Calculated: C, 54.38%; H, 2.28%; N, 22.65%.

(C) 2-Amino-6- (5-tetrazolyl) xanthone

The nitroxanthone from step (B) (1.55 g) was dissolved in a solution of sodium bicarbonate (0.42 g) in water (150 ml) with heating. To the solution was added 10% palladium / carbon catalyst, and the solution was hydrogenated at room temperature and atmospheric pressure for 4 h, during which time 440 ml of hydrogen was measured. The solution was filtered and the filtrate was acidified with 2N hydrochloric acid solution. The amino compound was filtered from the heated mixture, washed well with water and dried to give 0.98 g, m.p. 296-297 ° C (decomposed) Found: C, 56.38%; H, 3.71%; N, 23.58%; C14H9N5 O 2 · H 2 O: Calcd:

Calculated: C, 56.57%; H, 3.73%; N, 23.56%.

38 82833 (D) 2-Hydroxy-6- (5-tetrazolyl) xanthone

The amino oxanthone from step (C) (14.4 g) was dissolved in concentrated sulfuric acid (250 ml), and to this stirred solution was added sodium nitrite (3.6 g) portionwise at 10-15 ° C. The solution was then stirred at 15 ° C for 1 h, poured onto ice (2 kg) and water (2.5 L). The mixture was brought to a slow boil and refluxed for 1 hour. The resulting yellow product was filtered, washed well with water and dried.

The sample was purified by chromatography on silica gel eluting with chloroform / methanol 3: 1 v / v. mp.

Found: C,%; H,%; N,% for C 14 H 9 N 4 O 3: Calculated: C, 60.00%; H, 2.87%; N, 20.00%.

Example 34 2- (2-Hydroxyethylthio) -6- (5-tetrazolyl) xanthone 2-Amino-6- (5-tetrazolyl) xanthone (4.60 g) was dissolved with stirring in concentrated sulfuric acid (80 ml) at 15 ° C. while sodium nitrite (1.15 g) was added portionwise over 10 minutes with cooling to maintain the temperature at 15 ° C. The mixture was stirred at 15 ° C for 1 hour and then poured onto ice. The solid diazonium sulfate was filtered and washed with a small amount of cold water.

The solid salt was added to a hot (50 ° C) solution of 2-mercaptoethanol (5 ml) in water (50 ml) portionwise. There was a strong turmoil. The mixture was kept at 50 ° C for 30 minutes, the solid product was filtered off and washed with water. Flash chromatography of the dried crude product on silica gel, eluting with chloroform / acetic acid 4: 1 v / v, followed by recrystallization once from aqueous dimethylformamide and twice from 2-methoxyethanol gave the title compound, 35 m.p. 249 ° C (decomposed), structure confirmed by n.m.r. spectroscopy.

39,82833 Found; C, 56.09%; H, 3.69%; N, 16.28%, for C 16 H 12 N 4 O 5 S:

Calculated: C, 56.46%; H, 3.55%; N, 16.46%.

Claims (6)

40 82833 Disubstituted xanthene and xanthone derivatives of formula (I) 1. wherein X is carboxyl or 5-tetrazolyl; X is carbonyl or methylene; X is hydroxyl or a group 4 5 4 5 -X (CH-) X where X is oxygen or sulfur and X is hydrogen ** gg or a group -OX where X is hydrogen, alkanoyl having 7 7 15 1-4 carbon atom, or the group - (CH 2) x, where X is hydrogen 8. m or the group -OX, where X is hydrogen or acetyl, and m and n are each independently an integer from 1 to 4, provided that when X 5 is a group - OX6, then n is always greater than 4 5 1 and X and X are attached to different carbon atoms, and that when X is a group -OX, then m is always greater than 1 and no carbon atom in the radical - (CH „) - is not connected to the two oxygen atoms now, and their salts. Xanthene or xanthone derivatives according to Claim 1, characterized in that X 1 2 25 is carboxyl or 5-tetrazolyl, X is carbonyl or i 4i 82833 Use of a di-substituted xanthene or xanthone derivative or a physiologically acceptable salt thereof according to any one of claims 1 to 4 for maintaining the oxygen supply capacity of stored human erythrocytes. Use of a disubstituted xanthene or xanthone derivative or a physiologically acceptable salt thereof according to any one of claims 1 to 4 for prolonging the useful storage life of stored human erythrocytes. 10 42 82833