JPS58194879A - Tricyclic compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to tricyclic compounds useful as pharmaceuticals, the manufacture of such compounds, pharmaceutical formulations and other forms of articles containing such compounds and their manufacture; It relates to the use as a medicine and to novel intermediates of this compound and their production.

More particularly, the present invention relates to novel tricyclic compounds of formula (I) as defined below. These compounds have value in both human and veterinary medicine where they can increase oxygen release from oxyhemoglobin.

Human hemoglobin consists of four polypeptide (globin) chains that together contain hemoglobin tetramers; each chain surrounds a porphyrin molecule (heme) containing a central iron ion atom to which oxygen is reversibly bound. . When the saturation percentage of hemoglobin with oxygen (vertical axis) is plotted against the partial pressure of oxygen, the oxygen tension (tens
on ), i.e., the characteristic sigmoidal curve sometimes referred to as
A dissociation curve is obtained. A shift of this curve to the left of the "normal" position means that the affinity of hemoglobin for oxygen increases, and a lower oxygen tension is required to achieve a constant percentage of saturation. means. Conversely, shifting to the right indicates a decrease in oxygen affinity, meaning that higher oxygen tensions are required to obtain a certain saturation percentage.

After this curve shifts to the right, there is a decrease in the percentage of oxyhemoglobin present at any given oxygen tension, whereas as the tension decreases to any given level, oxygen liberation increases. .

Compounds of formula (I), as defined below, have been tested in vitro (overnight at 37°C) to produce changes similar to those seen in fresh human whole blood and blood stored for extended periods, such as for transfusion. Incubation over time induces a rightward shift in the oxygen-dissociation curve of human whole blood (described below).

The compounds of the invention therefore have both in vitro and in vivo applications where it is desired to more effectively transport oxygen to the tissues of a (potential) recipient.

In vivo uses of the compounds of the invention include the following, many of which can be categorized with respect to the alleviation or amelioration of conditions in which the transport of oxygen to tissues is impaired, i.e., in which tissue hypoxia is present: of shock; Treatment; treatment of cardiac ischemia, e.g. myocardial infarction (coronary thrombosis)
Reduction of subsequent treatment and its sequelae such as angina pectoris; Treatment of cerebrovascular accidents and cerebral ischemia in general; Reduction of intermittent bifurcation; Treatment of placental insufficiency in pregnant women; Treatment of anemia symptoms, especially pathological anemia in preterm infants; Treatment of capillary complications of diabetes mellitus; Hypovolemic anemia due to trauma [“blood loss syndrome” (miss
as an adjunct to cardiac bypass surgery, especially anesthesia in patients with critical breathing; to treat diseased tissue or noxious organisms by increasing the partial pressure of oxygen around them; radiosensitization of tumors, for example as an adjunct to deep x-ray therapy with or without hyperbaric oxygen treatment; use of drugs to make the tumor more susceptible to oxygen-sensitive parasites, e.g. aerobic bacterial infections; treatment.

The main in vitro application of the compounds of the invention is in the blood storage field. As is well known, there is a constant demand for human blood by medical services worldwide for use in a wide variety of life support procedures. Although many blood substitutes have been proposed for many blood recipients, a completely satisfactory blood substitute has not yet been found, so whole blood is an acceptable p/l-. blood sampling;
Storage and supply is generally carried out by specialist blood transfusion services or by National B100a Transf in the UK.
This is done using a "blood steel girder" as typified by USION 5 services. However, the effective and economic activity of such institutions depends on whole blood or, more precisely, the red blood cells (erythrocytes) contained therein.
) has a generally accepted and very limited "shelf life" of 21 days after blood collection from a donor, even when stored at 4°C as is customary. There is. At the end of this period, these blood are considered unsuitable for transfusion and are discarded. Accordingly, there has been significant research into ways to extend the useful life of stored red blood cells and thus reduce their "expiration" depletion.

A special feature of aging of red blood cells during storage is a concomitant decrease in the intracellular levels of 2,3-diphosphoglycerate (DPG), a red blood cell natural right-direction-relocating agent, accompanied by a decrease in oxygen-
An incremental left-shifting of the dissociation curve. As mentioned above, leftward repositioning is associated with hemoglobin having an increased affinity for oxygen, and thus aging red blood cells may enhance their ability to transport oxygen to peripheral tissues after transfusion. This property decreases DP in the recipient's body.
Although gradually reversed as G levels are restored, initial deficiencies are literally vital, as the primary purpose of red blood cell transfusions (unlike plasma) is generally to immediately prevent or reverse tissue hypoxia. have meaning (see below). The compounds of the present invention, which shift the oxygen-dissociation curve to the right, not only maintain the oxygen transport capacity of stored red blood cells, but also maintain their quality, improve their oxygen transport properties immediately after the transfusion period, and improve their It has value in extending the useful shelf life of.

In the above formula (I), Xi is carboxyl or 5-tetrazolyl group; x2 is carbonyl or methylene; X5 is hydrogen or the group -0X6; where X6 is hydrogen, alkanoyl having 1 to 4 carbon atoms or the group -(OmH+am)X7; where X7 is hydrogen or the group - ox'; where X8 is hydrogen or 1-
alkanoyl having 4 carbon atoms; and m and n are each independently an integer from 1 to 4; and includes salts thereof; provided that when X5 is a group -ox', n is always 1 and X4 and x5 are bonded to different carbon atoms; and when x7 is the group -0x8, m is always more than 1 and one of the groups -(OmH2m)- 2 carbon atoms
It has the condition that it does not bond to two carbon atoms.

As understood herein, a 5-tetrazolyl group has the structural formula thus 5-(IH)-tetrazolyl and 5-tetrazolyl.
(2H) It includes both tautomeric forms, each of which can be identified as tetrazolyl.

When m and/or n are 3 or 4, the group -
(CmHzm)- and -(OnH2n)- can be straight or branched.

In the salts of the compounds of formula (I), the biological activity is due to the bicyclic (
The type of cation is not critical, although it is preferred for pharmaceutical use that it be pharmacologically acceptable to the intended recipient. Suitable salts include ammonium salts, sodium salts, alkali metal salts such as potassium salts, alkaline earth metal salts such as magnesium and calcium salts, and monomers such as triethanolamine and diethylaminoethylamine. Formed with organic bases such as amine salts derived from -, di- or tri(lower alkyl) or -(lower alkanol) amines and salts with heterocyclic amines such as piperidine, pyridine, piperazine and morpholine. This includes salts such as

A group of compounds included in formula (I), wherein xl is carzaxyl or 5-tetrazolyl group; x2 is carbonyl or methylene; X3 is hydroxyl or the group -X'(CnH2n)X5; where x4 is oxygen or sulfur; X5 is hydrogen or the group -ox6; where X6 is hydrogen or alkanoyl having 1 to 4 carbon atoms; and n is an integer from 1 to 4; and its salts; with the proviso that when X5 is a group -ox6, n is always more dog than 1, and x4 and X5 are bonded to different carbon atoms. I can do it.

The subgroup of compounds included in formula (I) can include the following compounds: (1) Compounds in which XI is 5-tetrazolyl and salts thereof; (II) Compounds in which X2 is carbonyl; G11)
A compound in which X3 is a group -X'(OnHzn)X'';
(lv) Compounds in which X' is oxygen; (V) Compounds in which X5 is hydrogen; (vi) x'' is the group -OM', where x6 is hydrogen, i.e., X5 is hydroxy; Compound;(
Vli) Compounds where n is 2 or 6.

Two further groups of compounds included in formula (I) each have: (a) Xl is 5-tetrazolyl, X2 is carbonyl, and X3 is 10(CnH2n)H;
and (b) Xl, x2 and X3 are as defined above, provided that when xl and x2 are respectively 5-tetrazolyl and carbonyl,
n) Having the condition that it is other than H; includes compounds and salts thereof.

Preferred compounds included in formula (I) are compounds of the formula chemically named 2-ethoxy-6-(5-tetrazolyl)xanthone and salts thereof, particularly chemically 2-ethoxy-6-(5-tetrazolyl)xanthone;
-(2-hydroxyethoxy)-6-C5-tetrazolyl)xanthone and its salts.

When a compound of formula (I) as defined above has an asymmetric center, the above formula is to be understood to include all optical isomers and mixtures thereof subsumed therein.

The compounds of formula (I) and their salts can be prepared by methods known in the art for the synthesis of compounds with similar structures; in this regard the following standard documents may be mentioned by way of example: (i) "Protective Group
in Organic (Hhemistry)
Mi, T, F, W (, Mcomie, Plenum P
ress (1973), Engineering SBN O-306-6
0717-0;(ll) ” Compendium
of Organic SyntheticM8th
OdS”, ■, T, Harrison and S, Ha
Author: Wiley-Entersaienc
e, Volume 1 (1971), ■SBN, 0-471-3
5550-X, Volume II (1974), ■SBN O-
471-, ri 5551-8 and volume ■ (L, S, Hθ
gθdull and I., Wade), (1977
), ]: 5BN-0-471-36752-4+ and GiD ROdd's Ohem1stry of 0a
rbon compounds”, 2nd edition, Elsev
ier Put) lishing OOmpany.

All references cited above or below are herein incorporated by reference.

(11 One method applicable to both xanthene (X2=methylene) and xanthene (X2-carbonyl) contained in formula I is as defined, and one of zl and z2 is hydroxy or an ester thereof and the other one is a leaving atom or group) in the presence of a base. .

Suitable leaving atoms/groups include halo (eg chloro), nitro and sulfinyl; suitable bases include alkali metal alkoxides such as sodium methoxide and sodium ethoxide.

(2) The xanthone compound also has the formula (m) (in the formula x1
and X3 are as defined for formula (I),
and z3 is a carboxyl group, a derivative thereof, or a formyl group) with a Lewis acid or a protic acid (
protonic acid).

Suitable groups of 23 when Cal is a xyl group derivative include cyan, carbamyl and chlorocarbonyl.

Suitable Lewis acids include aluminum trichloride, ferrous chloride, phosphorous oxychloride and boron trifluoride, and suitable protic acids include polyphosphoric acid (tetraphosphoric acid) and sulfuric acid. Preferably, the reaction is carried out at a temperature in the range from 20 to 160° C. (3) Another method for producing xanthone compounds involves selective oxidation of the corresponding xanthine compounds also included in formula (I).

Suitable selective oxidizing agents include Triton B (tetramethylammonium hydroxide) and oxygen in the presence of pyridine.

(4) On the contrary, xanthine compounds have the formula (I)
It can be produced by selective reduction of the corresponding xanthone compound contained in

Suitable selective reducing agents include zinc and acids such as acetic acid or hydrochloric acid, and zinc amalgam and concentrated hydrochloric acid (Flemensen reduction).

(5) A compound of formula (I) wherein Xl is 5-tetrazolyl is a compound of formula (IV) in which X2 and X3 are as defined for formula (I) and z4 is 5 as defined herein. -tetrazolyl precursor group) with hydrazidic acid or a salt thereof, or optionally with nitrous acid.

When using hydrazoic acid or a salt thereof, the 5-tetrazolyl group precursor group has the formula [wherein 25 and z6 together represent a bond or tolyl], or z6 is hydrogen or 1 to 4 alkyl having 1 to 6 carbon atoms (imidoester), alkylthio having 1 to 6 carbon atoms (imiP thioester),
hyPradino (amithracine), or amino (amidine), or z5 is hydroxy and z6
represents an amine (amidoxime). The reaction is preferably carried out in a polar aprotic liquid medium such as dimethyl sulfoxide, N-methyl-2-pyrrolidone, sulfolane and acetonitrile and mixtures thereof, preferably using a hydroazide salt such as sodium or ammonium azide P. .

When nitrous acid is used, the 5-tetrazolyl precursor group is of the formula z5 is hydrogen and z6 is an amine (amidine).

In the latter case, the initially formed nitration product is either isolated beforehand or, without isolation, selectively reduced to 5 using a reactant such as sodium amalgam.
-tetrazolyl It is necessary to obtain the desired product.

(6) A compound of formula (I) in which Xl is carboxyl is a compound of formula (V) in which X2 and x3 are as defined for formula (I) and z7 is a carboxyl group as defined herein. It can be produced by hydrolysis of a compound (which is a precursor group).

Suitable examples for z7 include cyanide, trichloromethyl and the group -coz' (where 28 is a leaving, preferably nucleophilic atom or group, for example), trichloromethyl, 1 to 6 carbon atoms. and optionally substituted amino).

Hydrolysis can be carried out using aqueous mineral acids such as sulfuric acid or hydrochloric acid, optionally in the presence of organic acids such as acetic acid, or with aqueous mineral acids such as aqueous sodium or potassium hydroxide, sodium
This can be done by heating with either methoxide and a base such as sodium ethoxide.

This cyclization synthesis requires that the basic conditions suitable for the cyclization of the compound of formula (n) (method (1) above) result in the hydrolysis of the group z7 as defined in formula (V); In some cases, the combined cyclization/hydrolysis product [one-step process]
It will be obvious that it could be expanded to include -pot) Therefore, the starting compound of method (11) is more generally a compound of formula (IIa), where X2 and X3 are of formula (I
), and 1 of zl and z2
one is hydroxy or its ester, and the other one is a leaving atom or group, and Yl is of formula (I
) or a carboxylic group precursor group as defined herein)
It can be shown as

(7) The carboxyl compound of formula (I) also has the formula (VI
) in which x2 and x3 are as defined for formula (I) and z9 is alkyl or alkanoyl having 1 to 6 carbon atoms.

The alkyl group according to z9 is an acidic or alkaline aqueous potassium permanganate, or an aqueous chromate such as sodium or potassium dichromate in the presence of acetic acid, or the presence of a catalyst such as a cobalt, manganese or vanadium salt or oxide. The oxidation of the alkanoyl group can be carried out by nitric acid, or an aqueous dichromate such as sodium or potassium dichromate in the presence of nitric acid, or chromium trioxide and a reactant such as acetic acid or sulfuric acid. , or hypohydrobromic acid or an aqueous salt of hypohydrochloric acid in the presence of a base,
Alternatively, it can be carried out using chromium trioxide and a reactant such as acetic acid or sulfuric acid.

It will be clear that the formation of the carboxyl group of XI by this method can optionally be carried out in combination with the conversion of the xanthine precursor compound to the xanthone target product (method (3) above). In this case, the two treatment reactions can be carried out sequentially or simultaneously (one-step process), depending on the type of selective oxidizing agent used. Therefore, the starting compound for the oxidative production method of the compound of formula (I) is generally of the formula (■), where x2 and X3 are as defined for formula (I), and Y2 is as defined for formula (I). It can be a group XI as defined or alkyl or alkanoyl having 1 to 6 carbon atoms, provided that when X2 is carbonyl 72 is always alkyl or alkanoyl).

(81 Carboxyl xanthine compounds of formula (I), i.e., compounds in which XI is carboxyl and pl and X2 is methylene, have the formula (■), where X3 is as defined for formula (I), and zlo is halo, preferably bromo or iodo).

This reaction involves, for example, reacting a compound of formula (■) in an ethereal solution with lithium or magnesium (in the case of magnesium the corresponding Grignard reagent is formed) and then contacting the mixture with gaseous or solid carbon dioxide. It can be implemented by

(9) Another synthesis method is 2○X) where x1 and x2 are as defined for formula (I) and zll is the group
(which is a group that can be converted into).

Compounds in which X11 is hydroxy can be prepared by hydrolysis of suitable precursor compounds, such as the corresponding diazonium salt (Zll is -N2''W-, W- is an anion such as chloride, bromide and hydrogen sulfate). ) with water.This diazonium salt compound can be produced by reacting an amine compound (z11=amine) with nitrous acid.This diazonium salt compound can also be produced by reaction with an appropriate potassium alkali xanthate. and the sequentially formed diazoxanthate and aromatic xanthate compounds can be converted to the corresponding alkylthio target products (x4 = sulfur and X5 = hydrogen) by subsequent decomposition by heating in a weakly acidic cuprous medium [ LeuOhart synthesis
). This alkali thio compound can also be prepared by alkylation of the corresponding thiol (z11=mercazoto),
This thiol compound can be obtained, for example, by alkaline hydrolysis of the aromatic xanthate compound.

Hydroxy compounds can also be prepared from precursor compounds having a group -0212, which can be converted to a hydroxy group, as zll. Suitable examples of radicals z12 include alkyl, such as alkyl having 1 to 4 carbon atoms, especially methyl, ethyl, isopropyl and t-butyl; aralkyl, such as benzyl; alkanoyl, especially having 1 to 6 carbon atoms. acyl such as acetyl; and tetrahydrogyranyl. Such groups can be removed by methods standard in the art.
In other words, it can be replaced with hydrogen. Removal of the alkyl group can therefore be performed, for example, with magnesium iodide or sodium thiocresolate, by heating with aluminum trichloride in xylene, or (at a reduced temperature).
This can be carried out using reactants such as boron trichloride or tribromide in a medium such as dichloromethane. Acyl groups can be removed by basic hydrolysis; alkyl groups and tetrahydropyranyl can be removed by acidic hydrolysis, e.g. using hydrogen bromide in acetic acid; and aralkyl groups can be removed by hydrogenolysis (e.g. palladium - using a charcoal catalyst) can be used.

The conditions for removing the alkyl group described above also apply to the method described above (
2) and thus convert hydroxy xanthone compounds of formula (I) into alkoxy compounds of formula (UD (X'=oxygen and X5-hydrogen) by a one-step process cyclization/dealkylation. It is clear that it can be manufactured.

Alkoxy compounds can also be prepared by alkylation of the corresponding hydroxy compounds, for example with alkyl halides or dialkyl sulfates and alkalis such as alkali metal hydrides or carbonates.

Hydroxy compounds can also be converted into corresponding hydroxy-alkoxy compounds (X4-oxygen and X5=
hydroxy), and the same 4M hydroxy-alkylthio compounds (X4-sulfur and x5=hydroxy) can be prepared from the corresponding thiol compounds (z11=mercapto): when XI is carboxyl in the above starting compound, This carboxyl group can be simultaneously esterified by this method and its selective hydrolysis (
The desired target product is obtained by the above method (6)).

The desired products in which X5 is alkanoyloxy (i.e. It can be obtained by

In the preparation of compounds of formula (I) by the above method, the group X
If 1 and X3 are formed prior to the complete formation of the desired end product, these groups may
It will be appreciated that it may be desirable to protect them from reaction (one or more) and then remove them by appropriate deprotection methods using techniques known in the art; Alternatively, it may be advantageous to form X 1/X 3 in the final step of the synthetic route.

Compounds of formula (I) can be isolated as acids or salts thereof; these acids can be converted into their salts, and salts can be converted into acids, and the salts can be converted into acids, by conventional techniques well known in the art. It will be clear that the salt can be converted to a salt formed with another cation. Therefore, salts that are themselves pharmacologically unacceptable salts are also useful in the preparation of the parent carboxyl or 5-tetrazolylic acid and its pharmacologically acceptable salts.

Where the above process provides a mixture of optical or other isomers of a compound of formula (I), or an intermediate thereof, the individual isomers may be separated by any suitable conventional technique.

A compound of formula (I) as defined above is a recipient (subject)
It can be used in both human and veterinary medicine in situations such as those described above where it is desired to more effectively transport oxygen to the tissues of the body. When administered in vivo, these compounds are administered on a regular retention basis.
When used in vivo, the compounds of the invention can be administered orally, parenterally (subcutaneously, intradermally, intramuscularly) to a human or non-human recipient. [including intravenous and intravenous] and rectal administration.The effective dosage of the compound depends on the type of recipient, the precise condition being treated and its severity, and the route of administration, and ultimately is at the discretion of the caring physician or veterinarian. Effective doses generally range from 1 to 5001 g/
Recipient body weight ranges from 1 to 9 per day, more commonly 10
~2501 ng/kg body weight/day, in most cases 25-100 ng/kg body weight/day; a particularly suitable dose is 50 ng/kg body weight/day. /day (all doses calculated as carboxyl or 5-tetrazolylic acid of formula (I); amounts for salts are adjusted proportionately). It is preferable to administer it at appropriate intervals during the day. Thus, when two divided doses are used, each dose will generally be between 0.5 and 250, more typically between 5 and 125, and in most cases between 12.5 and 12.5.
~50 ■ (acid)/1 kg body weight, and the optimal amount is 25 ■
(acid)/body weight 1 kg.

The daily dosage for humans weighing around 50 kg generally ranges from 50 to 25 & (F!), more generally from 5001n9 to 12.5 g (acid), in most cases 1.゜25 to 5 g (acid), divided into two equal units, 25 ■ to 12.5 g (acid), more generally 250 ■ to 6.25, !i' (acid), large It may be advantageous to administer 0.625 N to 2.5. .25 g
(acid) is preferably administered in two separate units. For veterinary use, for example in the treatment of non-human mammals such as cats, dogs, cows, sheep, pigs and horses, the above dosages may be increased at the discretion of the veterinarian in relation to the type and weight of the recipient. or decrease.

While it is possible for the compounds of formula (I) to be administered as the neat chemical, it is preferable to present them as a pharmaceutical composition. Formulations of the invention for human or veterinary use contain a compound of formula (I) as defined above, together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients in the formulation and not deleterious to its recipient.

Formulations include those suitable for oral, parenteral (including subcutaneous, subcutaneous, intramuscular and intravenous) and rectal administration; the optimal route of administration may vary depending on, for example, the condition and type of recipient. can.

The formulations are preferably presented in unit dosage form and may be manufactured by any of the methods well known in the pharmaceutical arts.

All methods include the step of bringing into association a compound of formula (I) (active ingredient) with the carrier which contains one or more accessory ingredients. In general, the formulations are prepared by homogeneously and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and, if necessary, shaping the product into the desired formulation.

Formulations of the invention suitable for oral administration may be administered as discrete units such as capsules, capsules or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or oil-in-water liquid emulsion or water-in-oil liquid emulsion/
It can be provided as The active ingredient may also be presented as a lozenge, tongue spread or paste.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are made by compressing the active ingredient in free-flowing form, such as a powder or granules, in a suitable machine, optionally mixed with binders, lubricants, inert diluents, lubricating surfactants or dispersants. It can be manufactured by Molded tablets are moistened with an inert liquid diluent,
It can be manufactured by molding a mixture of powdered compounds in a suitable machine. The tablets may optionally be coated or scored and may be formulated to give slow or controlled release of the active ingredient therein.Preparations for parenteral administration may be supplemented with antioxidants, buffers, etc. Aqueous and non-aqueous sterile injection baths containing agents, bacteriostatic agents and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile injection baths that may contain suspending and thickening agents. The formulations, including suspensions, can be presented in sealed unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be mixed with a sterile liquid carrier, eg, water for injection, immediately before use. It can be stored in a freeze-dried (vacuum freeze-dry) state. Ready-to-use injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

Formulations for rectal administration may be presented as a dispensing agent using conventional carriers such as cocoa butter and polyethylene glycols.

Preferred unit dosage formulations are those containing a daily dose or divided daily doses, or appropriate fractions thereof, of a compound of formula (I) as described above.

In addition to the ingredients mentioned above in particular, the formulations according to the invention can contain other auxiliaries customary in the art in relation to the type of formulation in question, for example formulations suitable for oral administration can contain flavoring agents. The compound of I) can also be presented as a depot formulation of the type known in the art from which the active ingredient is released over an extended period of time once it has been placed in the body of the recipient.

Another use for compounds of formula (I) is in the extracorporeal treatment of blood from patients (generally humans). One possible such treatment can be carried out in a patch fashion by drawing an appropriate amount of blood, mixing it with a compound of the invention, and then returning the treated blood to the patient. Another possible treatment can be carried out in a continuous manner, similar to well-known techniques for hemodialysis, in which blood is continuously drawn for a period of time, mixed with the compound, and then returned to the patient. Both methods should be carried out under sterile conditions and may be repeated as often as necessary.The effective blood concentration of the compound of formula (I) is generally 0. In the range of LmM to 50mM, more commonly in the range of O,EIM to 25mM, in most cases 1771. ranges from M to 11077L, with an optimal concentration of 3yn)J.

For in vitro applications in the storage of red blood cells as described above, it is preferred to collect the red blood cells and mix them in a storage container;
/) is conveniently in the form of a bottle or bag of sufficient size to hold the anticoagulant in an appropriate amount. This compound is used when blood is collected from blood donors and then transfused (along with this compound) into recipients. Contact with red blood cells can be made at any suitable point during the process. Thus, in one possible method, the compound is present in a bottle or bag together with an anticoagulant, and the container is ready for immediate use, and the introduction of blood causes υ mixing; It can also be added to the red blood cells already contained in the bag, for example immediately after blood collection or just before use (transfusion). The compounds of the invention can be used in this manner regardless of whether the red blood cells are stored in the form of whole blood or as backed red blood clots (if plasma is separated); the latter resuspended in plasma or plasma substitute.

The effective concentration of the compounds of the invention in the whole blood volume in the bottles or bags described above generally ranges from 0.17'LM to 5071LM.
□ Range, δ generally ranges from 0.5%M to 25mM, in most cases 1%M to 10? ? 'In the range of M υ, the optimal concentration is 3? It is 7LM. The exact weight of compound required will vary depending on the type, but a standard sized bottle/bag (above) will contain approximately 0.000 mg to obtain an optimal 6mM concentration.
5. ! 17 (calculated as acid) is required.

Compounds of formula (n) to (IX) as defined above can be prepared by methods known in the art for the synthesis of compounds of similar structure, in particular those of formula (I) using suitable starting compounds and conditions as defined above. They can be prepared by methods similar to those taught herein for the compounds.

It will be appreciated from the foregoing description that the invention may include any novel features described herein; non-exclusive examples may include, for example, the following features: (a) Compounds of formula (I) and salts thereof as defined above.

('bJ above Hr2 The method described above for the preparation of the compound according to (a) and the compound thus prepared.

(C) Compounds of formula (I) and pharmacologically acceptable salts thereof as defined above for use in the medical treatment of mammals, especially humans; (d) achieving more effective transport of oxygen to tissues; Compounds of formula (I) and pharmacologically acceptable salts thereof as defined above for use in mammals, especially humans.

(e) IliIi Compounds of formula (I) and pharmacologically acceptable salts thereof as defined above for use in reducing tissue hypoxia in mammals, especially humans.

(f) Treatment with a compound of formula (I) or a pharmacologically acceptable salt thereof as defined above - a pharmaceutical preparation containing an effective amount together with an acceptable carrier for pharmaceutical preparation O (g) As defined above A method for manufacturing a formulation according to (f) above, comprising mixing the active ingredient of with a pharmaceutical carrier.

(h) administering to a mammal in need thereof a non-toxic and therapeutically effective amount of a compound of formula (I) or a pharmacologically acceptable salt thereof, as defined above; A new way to more effectively transport oxygen to humans.

(1) A mammal that desires to administer to a mammal in need thereof a non-toxic and therapeutically effective amount of a compound of formula (I) or a pharmacologically acceptable salt thereof, as defined above. , especially methods to reduce tissue hypoxia in humans.

(j) The stored mammalian red blood cells are treated with formula (I) as defined above prior to their transfusion into a recipient mammal.
or a pharmacologically acceptable salt thereof.

(k) The stored mammalian red blood cells are treated with formula (I) as defined above before transfusing them into a recipient mammal.
or a pharmaceutically acceptable salt thereof.

(1) The above (, +) where the red blood cells are derived from humans.
or the method described in (k).

(→ A sterile, sealed container containing an anticoagulant and a non-toxic amount of a compound of formula (I) or a pharmacologically acceptable salt thereof as defined above.

(n) red blood cells of mammals, especially humans, in a sterile and sealed container containing an effective amount of an anticoagulant and a non-toxic amount of a compound of formula (I) or a pharmacologically acceptable salt thereof as defined above; container.

(0) Novel compounds of formulas (n) to (IX) as defined above, methods for their production as above and compounds thus produced.

A number of tricyclic structures have been disclosed in the literature as active in mammals and as inhibitors of allergic reactions in combination with reagin antibodies that can mildly respond to human asthma in in vitro mammalian formulations. , for example British Patent Specification Letter No. 1.414.621;
No. 47.031; No. 1.447.032; No. 1.
452.891; 1.458,185 and 1,458,186; i.e., such compounds may be used to treat allergic conditions in mammals such as asthma and other allergic chest conditions. It has been proposed for use in the treatment or prevention of hay fever (allergic rhinitis), conjunctivitis, urticaria and eczema.

In particular, it is believed that formula (I) as defined is outside the description of all this prior art.

Japanese Published Patent Application No. 16 & 21/82 (published on January 28, 1982) discloses the use of active substances for the treatment of immunodeficiency diseases in mammals, e.g. humans, of the general formula (wherein R is a hydrogen atom or a lower alkoxy group). represents,
and A represents an oxygen atom or a sulfonyl group) or a salt thereof.

The immunodeficiency diseases specifically mentioned here include cancer, rheumatism,
autoimmune diseases, hepatitis, nephritis and infectious diseases.

This Japanese published patent identifies only three specific compounds within the general formula described therein; each of these compounds has been previously recognized as a compound described in the literature, including asthma, asthma, and Use in the treatment or prevention of other related allergic conditions is suggested. These six compounds are: (A): 3-(IH-tetrazol-5-yl)thioxanthone-10,10-dioxide (B) nia-methoxy-2-(IH-tetrazol-5
-yl)xanthone (0): 2-(IH-tetrazol-5-yl)xanthone.

Therefore, this Japanese patent application does not describe a special compound that has not been specifically described in prior literature, but is provided as a discovery of a new use for a known compound.

Among the compounds identified as (A), (B) and (0) in the above-mentioned Japanese published patent, there is no compound included in formula (I) as defined herein.

The following is illustrative of the invention and is not intended to limit it in any way. All temperatures are given in degrees Celsius.

Example 1 7-Medoxyxanthone-ro-carboxylic acid 1 Sodium metal (11,5 g) was dissolved in methanol (250,
d) and add 4-methoxyphenol (6
Add 2.1g). The methanol is thoroughly removed by rotary evaporation and the remaining sodium salt is dissolved in dimethyl sulfoxide. Dimethyl 2-nitroterephthalate (
107.6 g) are added and the mixture is stirred and heated at 120° for 2.5 hours. Dilute the resulting dark residue with water (500i)
and sodium hydroxide pellets (70 g) in ethanol (800, d) and boiling under reflux for 2.5 hours. This solution was acidified by pouring it into excess water-cooled hydrochloric acid, and the precipitated 2-
One portion of (4-methoxyphenoxy)terephthalic acid was taken, washed with water and then dried under reduced pressure at 90° to give the product 1.
2. Obtain OF; melting point 280-286°.

Similarly, the following compound is prepared: 2-(4-ethoxyphenoxycotellental acid; melting point 2
80~281°: McI! ! 1va1n and Eng
lehardt's method (J, Amer, chem,
soc, (1944), 66.1080).

2-(4-propoxyphenoxy)terephthalic member; melting point 279-281°: Klarmann, Gatya
sO and 5hternov's method [J, Amer,
□hem, Boc,.

(1932), 54, 2981).
Manufactured from zorophoxyphenol.

2-(4-Impropoxyphenoxy) Teref! ; Melting point 261-266° (acetic acid): Klarma
nn.

The method of Gatyas and 5hternov (,T,
Amer, Oh, am.

soc, (1932), 54.298] 2-(4-methylthiophenoxy)terephthal 1
; melting point 294-296° (from methanol) = prepared from 4-(methylthio)phenol.

B, 7-nodoxyxanthone-6-carboxylic acid 2-
(4-methoxyphenoxy)terephthalic acid (90,0,
! i7) with phosphorus oxychloride (900,d) 2
Boil under reflux for an hour. The cooled reaction mixture is added to water and carefully decomposed by adjusting the temperature to 40-500 °C by adding ice.

The precipitated 7-nodoxyxanthone-6-carboxylic acid is collected, washed with water and recrystallized from dimethylformamide (melting point 601-3 after drying under reduced pressure at 80°).
020).

Elemental analysis: Calculated value for 015H1005: 0
66.67 section; H3, 73% actual value: 066.73%
; H3, 70% The following compound is prepared in the same manner: Example 2: 7-ethoxyxanthone-6-carboxylic acid; melting point 286-289° (non-recrystallized).

Example 6: 7-bropoxyxanthone-6-carboy-
; melting point 261-264° (from dimethylformamide).

Elemental analysis: -017H1,405, calculated value 2068.46%; H4,70% actual value: 068.8
4% i H4, 91% rubonic acid; melting point 272-275° (from acetic acid) 0 Elemental analysis: Calculated for C115HlQO4S:
062.94%; H3, 49%; 811.19% Actual value: 062.69%i H3, 48% 1s11.
Section 15〇Example 5 7-Impropoxyxanthone-6-carboxylic acid 2-(4-impropoxyphenoxy)terephthalic acid (
13,59) is boiled under reflux with thionyl chloride for 0.5 h, ferric chloride (1,0, V) is then added and reflux is continued for a further 4.5 h. Evaporate the excess thionyl chloride and pour the residue into water. The precipitated product was poured into a sieve, washed with water, and then washed with excess bicarbonate).
Stir with IJum aqueous solution at 80-90° for 1.5 hours. The solution is made acidic and one portion of the precipitated 7-itzoropoxyxanthone-6-carboxylic acid is taken, washed with water and then dried. Recrystallized first from dimethylformamide and then from acetic acid; mp 261-263°.

Elemental analysis: Calculated value for 01tHxtO5: 0
68.46%; H4, 70% actual value: 068.12chi; H4, 60%.

Example 6 Two-hydroxyxanthone-6-carboxylic acid 7-Nodoxyxanthone-6-carboxylic acid (8.0 g) is boiled under reflux with a solution of 12-thihydrobromide in acetic acid (500 mJ) for 28 hours. Pour the reaction mixture into ice water and incubate at 100°.
7-bitroxyxanthone-6-
Carboxylic acid is obtained; melting point 649-350'.

Elemental analysis: For 014H805, calculated value: O6
5,63%; Hfiltration, 12% Actual value: O65, 59%;
H3, 14th.

Example 7 (+) 7-HyP-roxyxanthone-6-carboxylic acid ('5.0.!li') was dissolved in dimethylformamide (15
Stir with a mixture of anhydrous potassium carbonate C509) and diethyl sulphate (10.25 ml; 12.0 g) in 0.0, d) for 5 hours and then leave to stand at room temperature for 16 hours. Pour the reaction mixture into water, take one portion of the remaining ethyl ester of 7-ethoxyxanthone-6-carboxylic acid, and add water (
200 mJ) and a solution of sodium hydroxide (2,0,!i') in ethanol (507) and boiling for 2 hours. The cooled reaction mixture is acidified with excess hydrochloric acid and the precipitated acid is taken off, washed with water and then recrystallized from dimethylformamide; mp 287-289°.

Elemental analysis: Calculated value for 01eH1,zOδ: 0
67.60%; H4, 26 cm Actual value: O'67.72 cm H4, 40%.

7-bitroxyxanthone-6-carboxylic acid (10,0
,9) in methanol (1,5/ ) and concentrated sulfuric acid (15
, d) for 6 hours at reflux.

The hot solution is filtered once and upon cooling, methyl 7-bitroxyxanthone-6-carboxylate crystallizes out. Take the product and dry it; 6.5. ! i'; melting point 268
~2700° Methyl 7-bitroxyxanthone-6-carpoxylate (6,9 g) was boiled under reflux with ethyl iodide (9,75 g), potassium carbonate (75 g) and acetone (11) for 4 hours with stirring. Make me sleepy.

The mixture is filtered hot and the residue is washed with acetone. The collected f-fluid and washing liquid are evaporated to dryness and the residue is dissolved in dichloromethane and then washed with water. The solution was dried, evaporated and methyl 7-ethoxyxanthone-
6-carpoxylate 3.65 F is obtained; melting point 169
~171°.

This ester (3,6 g) was dissolved in sodium hydroxide (2,0,9 g) in water (250 ml) and ethanol (50 ml).
) and boiling for 2 hours. Acidifying the resulting solution with excess dilute hydrochloric acid and taking a portion of the precipitated product gives 7-ethoxyxanthone-6-carboxylic acid; mp 290-291° after recrystallization from dimethylformamide.

Similarly, the following compounds are produced: (from acetic acid): prepared from 6-promo-1-propanol (methyl ester, melting point 161-162°, from methanol).

Elemental analysis: Calculated value for C1fu H1406: 06
4.97%; H4,49q6 actual value: 065.15%
;H4,56 person in charge.

Example 9: 7-ptoxyxanthone-6-carboxylic acid; melting point 225-227°; elemental analysis: calculated value for C1aH1aO5: 069
．． 22%iH5, 11% actual value: 069.09%iH
5.16%.

Example 1 oney 7z nolopoxyxanthone-5-personμmu1;
Melting point 262-263° (from n-zolopyl iodite); (methyl ester, melting point 151-152°).

Example 11 7-hydroxyxanthone-6-carboxylic acid (3,0 g
), ethyl carbonate (13,0g) and tetramethylammonium iodite (0,07,!9) together, 1
Heat at 700 for 4 hours. The cooled reaction mixture was diluted with chloroform, one portion of the solid residue was taken and diluted with ethanol (4
0 m) and a solution of hydroxide (C2,0 g) in water (60 mA) and boil for 5 hours. The reaction mixture was then diluted with water, filtered once, acidified with dilute hydrochloric acid, and the solid product was then collected and recrystallized from boiling dimethylformamide to give 7-(2-hydroxyethoxy)xanthone-6-carboxylic acid. Obtain acid; melting point 265-267°0
Elemental analysis: Calculated value for 016H1206: 0
64.00%; H4,03chi actual value', 066.46
%; H4, 11 section.

Example 12 Methyl 7-bitroxyxanthone-6-carboxylate (2,08), zolopyrene carbonate (10,
0,! i') and tetramethylammonium iodite (0,2'Og) are heated together at 170° for 4 hours. The cooled reaction mixture was then diluted with sodium hydroxide C6,
0 g) and boil under reflux for 30 minutes. The solution is cooled, filtered, and then acidified with excess dilute hydrochloric acid.

The precipitated product was collected with P, washed with water, and then 95% 2
-Butanone-5T was recrystallized twice from a water mixture and 7-(
2-hydroxy-zolopoxy)xanthone-6-calf
m.p. 252-254° (structure confirmed by proton magnetic resonance spectroscopy).

Elemental analysis = 01F H1406, calculated value: 06
4.96%; H4, 49% actual value: 065.06 coefficient i
H4, 54%.

Example 16 7-(3-Hydroxyethoxy)xanthone-6-carboxylic acid (8.8 g) is boiled under reflux for 2 hours with 200 mL of acetic anhydride. The resulting solution is filtered once and then the excess anhydride The remaining solid is washed with water, dried and recrystallized from acetic acid to give 7-(3-acetoxy-propoxy)xanthone-6-carboxylic acid;
Melting point 266-267°.

Elemental analysis: Calculated value for 01gJ60fu: 064
．． 04%; H4-56% actual value: 063.94%;
H4,51 section.

Example 14 7-methoxyxanthone-6-carboxylic acid (20,0,
9) is boiled under reflux with thionyl chloride (200i) for 2 hours. The excess thionyl chloride was thoroughly evaporated from the solution and the remaining acid chloride was dissolved in 0.880 ammonia (2
00+d) with stirring. The solid 7-nodoxyxanthone-6-carpoxyamide was collected, washed with water and dried under reduced pressure at 80°, 19.6. ! i'; melting point 286-287°.

Similarly, the following AmiP compound is obtained: nia-ethoxyxanthone-6-carpoxyamide; melting point 611-614°.

7-Butoxyxanthone-6-carboxamide; melting point 222-2250° (from acetic acid).

7-Propoxyxanthone-6-carboxamide; melting point 272-274°.

7-Inzoloboxyxanthone-6-carpoxyamide; melting point 264-269°.

7-(Methylthio)xanthone-6-carboxamide; melting point 228-264°.

(B) 6-Dia-2-methoxyxanthone 7-methoxydixanthone-6-carpoxyamide (1,15 g) was dissolved in thionyl chloride (25, d) in dimethylformamide (25, d).
5, Od) over a period of approximately 5 minutes at 0-5°. The reaction mixture is stirred at 0-5° for 1 hour and poured onto ice. The precipitated solid product was collected, washed with water, and then recrystallized from dimethylformamide for 6 hours.
- Obtain 0.60 g of diatu-2-methoxyxanthone; melting point 254-255°.

Similarly, the following 2) IJ compound is prepared: 6-cyano-2-ethoxyxanthone; melting point 204-205°
(from dimethylformamide).

2-Butoxy-6-cyanoxanthone; melting point 156-1
57° (from acetic acid).

2-(6-acetoxypropoxy)-6-diatuxanthone; melting point 158-160° (from ethanol).

from).

6-dia2-propoxyxanthone; melting point 166~
167° (from dimethylformamide).

6-dia2-isopropoxyxanthone; melting point 14
5-146° (from aqueous dimethylformamide).

6-dia2-(methylthio)xanthone; melting point 20
9-210° (from aqueous dimethylformamide P).

(C) 2-Methoxy-6-(5-tetrazolyl)xanthone 6-dia-2-methoxyxanthone (12,6 g) was dissolved in sodium azide (3,41 g) and ammonium chloride (2,95 g) in dimethylformamide (100 ml).
g) and heat at 125° for 6 hours. The reaction mixture is diluted with water and acidified with excess hydrochloric acid.

The precipitated 2-methoxy-6-(5-tetrazolyl]xanthone is separated, washed with water and then recrystallized from dimethylformamide; decomposed above 600°.

Elemental analysis: Calculated values for 015H1ON403:
C61,22; H3, 42% 1N19.04% Actual value: 060.82%; H3, 45%; N1B, 91%
.

Similarly, the following compound is manufactured. from formamide).

Elemental analysis: Calculated value for 016H12N4Or3:
062.33 Chi H, 1S, 92 Chi; N 18.
17% actual value: 062.01%; H39-4%; N
18.20%.

from chillformamide).

Elemental analysis: Calculated values for 017H14N403:
o63.35%; H4, 38%; N17.38% Actual value: c65.69% iH4,37% 1N17.15%.

from formamide).

Elemental analysis: Calculated values for 018H16N403:
064.28chi; H4, 79%; N 16.66%
Actual value: a64.37%; H4,71chi; N16°5
4%.

(2-methoxyethanol cara).

Elemental analysis = C1fu H14N403, calculated value = 0
63.65%; H4, 35 + N 17.39 Actual measurement: o63.27%; H4, 37% 1N17.25%
.

(from 2-methoxyethanol).

Elemental analysis: Calculated value for a15H10"4o2s: 058.06%iH3, 22%; N18.06%; 8
10.32chi actual value: C58, 34%; H3, 23%; N 17
．． 97%; S 10.29% Example 20 2-(3-acetoxypropoxy)-6-diatuxanthone (3,25,9), sodium azide C0,66
9) Ammonium chloride (0.57 g) and dimethylformamide (50 d) are heated together at 125° for 5 hours. The reaction mixture is poured into water and made alkaline with sodium hydroxide solution. The solution was extracted twice with chloroform to remove the unchanged nitrile and then acidified with hydrochloric acid to give the crude 2-(6-acetoxypropoxy)-6
-(5-tetrazolyl]xantho 72.85 N is precipitated; melting point 240° (decomposed).

The acetoxy compound is boiled under reflux with sodium hydroxide (3.0 g) in water (30 m/) and the solution is then acidified with hydrochloric acid. The precipitated solid is removed and reconstituted from dimethylformamide. Crystallization gives 2-(3-hydroxyzoloboxy)-6-(5-tetrazolyl)xanthone; melting point 270° (decomposition).

Elemental analysis: Calculated values for 017H14N404:
060.35%; H4, 17; N 16.56% Actual value: 060.37%; H4, 27%; N16.72
Person in charge.

The following compounds are produced in the same way: (Disassembly).

Elemental analysis: Calculated value for C17H14N404: 0
60.35%; H4, 17%i N 16.56% Actual value: 060.08%; H4, 21ch; N 16.62
Person in charge.

Example 22 7-Nodoxyxanthene-6-carboxylic acid 7-nodoxyxanthone-6-carboxylic acid (10,0,9) was prepared by Flemensen's method using p1 zinc powder (100 g) and mercury chloride (8,0,!). i+) in acetic acid at room temperature. Product, 7-
Medoxyxanthene 6-carboxylic acid is obtained by chromatography on silica sol using 5% methanol in chloroform as eluent; melting point 259-261°0 Elemental analysis: C! Calculated value for 15H1204: 0
70.30 coefficient i H4, 72 coefficient actual measurement value: 070.41
%; H4, 78%.

7-nodoxyxanthone-6-carboxylic acid (32,9,
! 17) in water (11) with sodium bicarbonate (10,0
8 g) of the solution, the solution is filtered once and evaporated to dryness. The remaining solid is ground to a powder and dried under reduced pressure over calcium chloride to obtain the sodium salt. It is analyzed to contain 0.25 mol of water of crystallization.

Elemental analysis: 015H9Na05 ・0.25 H20
Calculated value for: 060.72%; H3, 23% actual value: 060.61ch; H3, 22%.

The following sodium salts are prepared analogously using well-defined free carboxylic acids or tetrazoles.

The number of moles of water of crystallization depends on drying conditions and exposure to the atmosphere.
Even the same sodium salt may vary depending on the individual production.

Lyophilized monohydrate.

Elemental analysis: Regarding C16H1lNa○5・H20,
Calculated value: 059.26%; H4.04% actual value:
059.43%; H3, 52%.

Lyophilized monohydrate.

Elemental analysis; Regarding 017H13NaO, -H20,
Calculated value: 060.35%; H4, 47% actual value;
a 60.49%; H4, 12%.

Lyophilized monohydrate.

Elemental analysis: Regarding 017H13Na05/H20,
Calculated value: C60, 65%; H4, 47%: H205
, 33% Actual value: 059.72%; H4,00%; 1
4.94% lyophilized monohydrate lost on 200f drying.

Elemental analysis: Regarding 015H9NaO4S-H20,
Calculated value: a 55.20%; H3, 40%; S
9.82%; H205, 52% Actual value: a 55.63%; H3, 21%;
s 9.70%; 4,78% lost when drying at 1200°C Japanese item.

Elemental Analysis" Calculated value for C14H17Na05-2H20: 053.50chiiH3,53% Actual value:
a 53.67%; H2, 79%.

-Calginate sodium salt (Example 11a) mono,pentahydrate dried at room temperature.

Elemental analysis: Calculated values for C16HxINaOa・1.5H20: C55, Cl3 attack; u 4.04chi actual value: 054.93%; H3, 92%.

7-(3-Hydroxypropoxy)xanthone - 0,5 hydrate dried at 80° under reduced pressure.

Elemental analysis: 017H13N, Na04・0.5H20
Calculated value: a 55.29%; H3, 82 CH Actual value: C 55,68 arrogant; H3, 64.

The tetrahydrate was dried under vacuum at 800 °C and exposed to air at room temperature.

Elemental analysis: Tweet on 015HgN4Na03・4H20, calculated value: 046.40%; H4, 41%; N14
．． 43% actual value: 046.44; H4, 34%; N1
4.58%.

Monohydrate dried under reduced pressure at 800 °C and exposed to air at room temperature.

Elemental analysis: Calculated value for 016H11N4Na03.H,40: C! 55.17%; H3, 76%1N1
6.08% Actual value: 055.34%; H4,00%i
N 16.11%.

2,25-hydrate dried at room temperature.

Elemental analysis: c17H14N4”ao3’ 2.257
(Tweet on 20, calculated value: C53.05%i H4.5
8%; N14.56% actual value: C53, 15%HH4,
36%iN 14.65%.

Lyophilized hexa, pentahydrate.

Elemental analysis: 017Hz3N41JaOs・3.5H2
Tweet on o, calculated value: 050.12%; H4, 95chi; N 13.75%; H2015, 48% Actual value: 050.13%; H4, 58%; N 13
．． 36%; lost on drying at 120°, 14.77T2-(methylthio)-6-C5-tetrazolyl) lyophilized trihydrate Elemental analysis: Calculated for 015H9N, Na02S-3H20: 04 '6.63 Chi H3,9'1 Section;
N 14.50%; S 8.30%; H, 013
, 99% actual value: C46,69chiiH3,74chiiN
14.31 q; S8.11% lost on drying at 120°, 13.81 q6° monohydrate dried at 80° under reduced pressure.

Elemental analysis: Calculated value for 017H13N4NaO, .H3'O: 053.97%; H4,07CH; N
14.81chi Actual value: a 56.96%; H4.0
0%; N 14.58 excellent.

Technical hydrate dried at 800 °C under reduced pressure.

Elemental analysis: 017J 3N4Na04 ・Q, 3
3 Tweeted in H20, calculated value: a 55.7'4%;
H3, 76%; H15, '25'% actual value: 058.
68%; H3, 64%; N 15.14ch.

Example 26 7-(2-hydroxyethoxy)xanthone-6-carboxylic acid (4,09) is boiled under reflux with acetic anhydride (200 mz) for 6 hours. The solution is evaporated to dryness and the residue is recrystallized from acetic acid to give 7-(2-acetoxyethoxy)xanthone-6-carboxylic acid; mp 248-2
49°C0 elemental analysis: Calculated value for 018H140F: C63,16ch; H4,12% Actual value: 063
．． 08th; H4, 18th.

Example 24 7-(2-acetoxyethoxycuxanthone-6-carboxylic acid (3,4 g) is boiled with thionyl chloride (50-) under reflux for 2 hours. The resulting solution is evaporated to dryness and the remaining acid The chloride is added to the ice-cold concentrated ammonia solution with stirring. After 2 hours, one portion of the amide is taken and dried to give 3.3F; mp 260-262°C.

(B) 2-(2-acetoxyethoxy)-6-cyanoxanthone The amide (3,3,!i') from step (A) is converted to thionyl chloride (7-) in dimethylformamide (50,d).
solution at -10°C. The mixture is stirred at water bath temperature for 6 hours and then poured into ice water. Precipitated 2) I
Take 1 portion of J.L., wash with water and dry to obtain 2.99; melting point 194-196 °c0 cyanoxanthone (2.9 g) from step (B), sodium azide (0.61,
F), ammonium chloride (0.53 g) and dimethylformamide (50) are heated together at 125° for 8 hours. The reaction mixture is poured into a water-cooled aqueous hydrochloric acid solution (excess) and the product is taken out and dried. Recrystallization from dimethylformamide gives the title compound; mp 216
~218°C.

Calculated value for elemental analysis 2018H14N405: C
59.02chi; H3-85%; N 15.29% Actual value: 058.96%; H3, 84%; N15.01
%.

Example 25 2-(2-acetoxyethoxy)-6-C5-tetrazolyl)xanthone (1,0g) was treated with a solution of sodium hydroxide (2,0,9) in water (20-) for 2.5 hours. Boil under reflux. The solution is cooled and poured into excess aqueous hydrochloric acid, and the precipitated product is taken out, washed with water and dried. Recrystallization from dimethylformamide gives the title compound; mp 270°C (decomposed).

Sodium salt (Example 25a) Free tetrazole (13,45,9) was dissolved in water (150-
) of sodium bicarbonate (3.48 g) by heating. The cooled solution is filtered, extracted once with chloroform and evaporated to dryness. The residue was dried over phosphorus pentoxide under reduced pressure at room temperature and 2-(2-hydroxyethoxy)-6-(5-tetrazolyl)xanthone
The sodium salt dihydrate is obtained.

Elemental analysis: Calculated for 016H15N4NaO6: 050.26%; H3,95; N 14.
66% actual value: 050.4 (5%; N3.79chi; N1
452 chi.

Example 26 Two-hydroxyxanthone-6-carboxylic acid (75,O
g), ethylene carbonate (325g) and tetrabutylammonium iodite (1,75,!i')
Heat with stirring for 5 hours. The cooled reaction mixture is diluted with methanol to remove the solid residue and boiled for 4 hours with sodium hydroxide (175,!ii') in ethanol (1,0/) and water (1,07). .

The mixture is diluted with water (2,07) and acidified with dilute hydrochloric acid. The solid product was collected by fP, washed with water,
Then recrystallized from 2-methoxyethanol; melting point 188°C0 Elemental analysis: Calculated value: 062.78%; H4,68% Actual value: 0
62.52chi; H4, 73%.

Example 2Sa The above product acid (1 g) is boiled with sodium bicarbonate (0,2449) in water (200,d); the cooled solution is filtered and lyophilized to give the sodium salt as a pale yellow solid. ; Melting point: 650°C or higher 0 Example 27 2-(2-hydroxyethoxy)xanthone-6-carboxylic acid (10 g) is refluxed with butyric anhydride (250 m/) for 2 hours. The resulting solution is evaporated and the residue is triturated with ether. Recrystallization from dimethylformamide/water gives the title carboxylic acid; mp 267-2
41°C0 elemental analysis: Calculated value: c 64.86%; H4,89 coefficient actual value:
O(S 5.05H; H4.87H Example 27a The corresponding sodium salt is obtained as a pale yellow solid; melting point >650°C.

Example 28 2-(2-(2-hydroxyethoxy)ethoxyfoxanthone-6-carboxylic acid (10 g) was mixed with acetic anhydride (150 g).
-) and reflux for 2 hours. The resulting solution is evaporated and the residue is triturated with ether.

Recrystallization from methanol gives the product as yellow crystals; melting point 199-200° C0 Elemental analysis: Calculated: C62, 17%; H4, 69% Found: 06
2.08%; H4, 63 section.

Example 28a The corresponding sodium salt is obtained as a pale yellow solid: melting point >650°C.

Example 29 2-(2-butyryloxyethoxy)xanthone-6-
Carboxylic acid (8,0g) to thionyl chloride (100m/)
and reflux for 1 hour. The resulting solution is evaporated to dryness and the remaining acid chloride is added in portions to the water-cooled 0.880 ammonia solution with stirring.

After 2 hours, take one portion of the solid and wash with water. Recrystallization from 2-methoxyethanol gives the title product; mp 205-207° CO Cumulative analysis: Calculated: 065.03H; a 5.19%; N 3.79%
Actual value: 065.35%; H5,18S; N3.67%
To a stirred suspension of carboxyamyl' (5,229) from step (A) in dimethylformamide (100 td) is added thionyl chloride (10 mt, ) dropwise at -10<0>C. The mixture is kept at water bath temperature for 1 hour and then poured into ice water. The solid precipitate is separated and recrystallized from glacial acetic acid to give the title cyanoxanthone; melting point 145.
~147℃.

Cyanoxanthone (4,179), sodium azide (0,82,9), ammonium chloride (
0,70g) and dimethylformamide (100-)
Stir together at 120°C for 8 hours.

The cooled mixture is poured into water-cooled 2N hydrochloric acid, warmed to 50° C. for 10 minutes, cooled and filtered. The resulting solid is recrystallized from dimethylformamide/water to give the title compound; melting point 207-209°C. Elemental analysis: Calculated: 060.90H; H4, 61%; N14
．． 22chi actual measurement value: 060.93%; H4, 55%; N1
4.12%.

Example 29a The corresponding sodium salt is obtained as a pale yellow solid; melting point 275-280°G (decomposed).

Example 60 Sodium metal (3,4,!ii') is added to a stirred solution of 2-(4-ethylthiophenoxy)terephthalic acid (IOg) in hexamethylphosphoramide (100 ml) over 20 minutes. After 2 hours, the mixture is cooled and then treated with ethyl iodide (20 mL), maintaining the temperature below 450 C using a water bath. After a further 60 minutes, the mixture is poured into water and extracted with ether. The organic extracts are washed with brine, dried over magnesium sulphate and evaporated. The remaining oil is eluted on silica with chloroform/6o-80 petroleum (2:6
C8 Zobartux (Zo
rbax) chromatography using reverse phase HPLO with methanol/water (7:6 cap/vol°) as eluent gives the product as an oil.

(B) 2-(4-ethylthiophenoxy)terephthalic acid The diester (1,9&) from step (A) is dissolved in water (70+
and a solution of sodium hydroxide (5.6 g) in ethanol (30 m/l) and boiled under reflux.

After 2 hours, the mixture was allowed to cool and then added with water (100 ml
). Acidify with concentrated hydrochloric acid and remove the product acid formed and dry; melting point 282-284°C.

(0) 2-(Ethylthio)xanthone-6-carboxylic acid Terephthalic acid (1.5 g) from step (B) is boiled under reflux with phosphorous oxychloride (50y) for 8 hours. The cooled reaction mixture is added to water and carefully decomposed by adjusting the temperature below 80°C by adding ice. One portion of the precipitated solid is washed with water and recrystallized from dimethylformamide/water to give the title carboxylic acid; melting point 264-266°C8 Elemental analysis: Calculated: 063.99%; H4.03 % Actual value: 0
63.98 Coordination i H4, 10%.

Example 30a The corresponding sodium salt is obtained as a yellow powder; melting point >350°C.

Example 61 Xanthonexamide 2-(ethylthio)xanthone-6-carboxylic acid (0,
65 &) is boiled under reflux with thionyl chloride (50 ml) for 1 hour. The resulting solution is evaporated to dryness and the remaining acid chloride is added in portions to the water-cooled 0.880 ammonia solution with stirring. After 2 hours, take 1 piece of solid food,
Wash with water to give the product carboxamide (0.62 g)
(B) Thionyl chloride (1 , 5-) little by little at 5°C.

The mixture is kept at water bath temperature for 1 hour and then poured into ice water. The solid precipitate was taken off, dried and then plated on silica with methylene chloride/60-80 petroleum (1:1) as eluent.
Chromatography using (vol/vol) gives the title cyanoxanthone (0,44 g); mp 159
~161°C0(C) 2-Ethylthio-6-(5-tetrazolyl)xanthone Cyanoxanthone (0,42F), sodium azide (0,102,9), ammonium chloride (0,088g) from step (B) and dimethylformamide (25+
++1. ) were stirred together at 120°C for 10 hours.

Pour the cooled mixture into water-cooled 2N hydrochloric acid and heat to 80°C.
Warm for 10 minutes, cool, then filter. The resulting solid is extracted into 5% sodium bicarbonate solution and washed with ether. The basic extract is acidified and the title compound obtained is purified and dried; mp 261-262°.
C○ Elemental analysis: Calculated value: a59.24%; N3-76%; N17.28
Actual measured value: 059.25%; H3, 76%; N17.
32%.

Example 31a The corresponding sodium salt is obtained as a yellow powder; melting point 635-666°C.

Example 62 Boo/borane tetrahydrofuran complex (30 mJ, 1M solution in tetrahydrofuran) was combined with dry tetrahydrofuran (
2-(methylthio)xanthone-6- in 100 mJ)
Add to an ice-cold, stirred solution of the carboxylic acid (6 g) under an atmosphere of dry nitrogen. After 1 hour, the mixture was brought to room temperature and heated to 12
Stir for an hour. Decompose excess borane by adding ice,
The resulting solution is extracted with ethyl acetate. The organic extracts are washed with brine, dried over magnesium sulfate and then evaporated to give the title compound (2.39 g) as a white solid; mp 151-153 °C.

Under a nitrogen atmosphere, dimethyl sulfoxide (5-) is added dropwise to a stirred solution of oxolyl chloride (0,89 v) in methylene chloride (5-) at -60°C. After 2 minutes, a solution of the xanthine compound (2.5 g) from step (A) in dimethyl sulfoxide (35 m) was diluted to 150 g by cooling.
While maintaining the temperature at °C, it is introduced dropwise over a period of 5 minutes. After 15 minutes, triethylamine (6,20+d)
was added and the mixture was allowed to warm to room temperature, then poured into water and the mixture was extracted with acetic acid and the organic phase was extracted.
,.

The title carboxaldehyde (
L97. ! ? ); melting point 122-126°C.

(C) 2-methylthio-6-diatuxanthene process (B
) carboxaldehye P compound (1,75 g),
A mixture of hydroxyamine hydrochloride (0.56 g), sodium fumarate (1 g) and jalic acid (15-) is refluxed for 1 hour. The resulting solution is diluted with water and extracted with ether, the extract is washed with brine, dried over magnesium sulphate and then evaporated. The remaining solid was eluted on silica with chloroform/methanol (98:
2 volume/volume] to prepare the title cyanoxanthy (L
58fl) with a melting point of 142-144°C.

(D) 2-(Methylthio)xanthine-6-carboxylic acid Add cyanoxanthin (0.3 g) from step (0) to water (
10 m) and hydroxide in ethanol (10 mg)
A solution of IJum (6 g) and boiled under reflux for 6 hours. The resulting solution was diluted with water, extracted with ether,
Then, make it acidic with concentrated hananoic acid. One portion of the precipitated carboxylic acid is washed with water and then dried; melting point 266-26
7°c.

Elemental analysis: Calculated value: 066.20%; H4, 45% actual value: a
66.24%; H4-82 Example 32a The corresponding sodium salt is obtained as a white powder; melting point >600°C.

Example 66 Santhone 6-(5-tetrazolyl)thioxanthone-10°10
-Dioxide Sodium Salt (British Patent Specification Letter 1.4
No. 47.031; 45. Og) is stirred with 2N sodium hydroxide solution for 6.5 hours and boiled under reflux. The solution is made υ acidic by pouring it into excess hydrochloric acid solution and one portion of the precipitated product is recrystallized from dimethylformamide to give the title compound (14,95,9); mp 296°G. (Disassembly).

Elemental analysis: Calculated value: 063.64%; H3,054; N21.20
% actual value: 063.77%; H3, 05%; N21.
Dissolve 15% 6-(5-tetrazolyl)xanthone (1,0 g) in concentrated sulfuric acid (10,0 v) and cool the resulting solution at 15 °C.
Cool below. Potassium nitrate (0.50 g) is added in portions over 10 minutes, maintaining the temperature between 10° and 15° C. by cooling, and the reaction mixture is then stirred at 20° C. for 1 hour. The reaction mixture is poured onto ice and one portion of the precipitated product is taken, washed with water and recrystallized from dimethylformamide.

The crystallized product was washed with methanol and heated to 156” O/
Dry at 20 myn Hg to obtain the title compound (0,
78g); melting point approximately 280°C (with decomposition)
0 Elemental analysis = Calculated value for 014H7N504: 0
54.11%; H2, 25%: N22.60chi actual value;
c54.38%; ) (2,28%; N-22,65
%.

(C) 2-amino-6-(5-tetrazolyl)xanthone Nitroxanthone compound from step (B) (1,55 g
) in water (150 mg) with sodium bicarbonate (0,42
Dissolve in the solution of F) by heating. A 10% palladium on carbon catalyst is added to this solution and the solution is hydrogenated at room temperature and atmospheric pressure for 4 hours, during which time the measured hydrogen absorption cap is 440-. Pass the solution 1 time, and 2 times pass the P solution.
Acidify with normal hydrochloric acid solution. The resulting amine compound was removed from the warm mixture, washed with water, and dried to give a concentration of 0.9
Obtain 8 g; melting point 296-297°C (decomposition).

Elemental analysis a Calculated value for 014HgN502/Hg0: 056.38chi; H3, 71%; N23.58%
Actual value: 056.57%; H3, 73%; N23
．． 56%.

(D) Aminoxanthone compound C14,49 from 2-hydroxy-6-(5-tetrazolyl)xanthone step (0)
) was dissolved in concentrated sulfuric acid (250 m), and sodium nitrate (3,6,!i') was added to this stirred solution at 10
Add little by little with C. The solution is then stirred for 1 h at 15°C and poured onto ice C2 &) and water (2,57). The mixture is brought to a slow boil and boiled under reflux for 1 hour. One portion of the yellow product formed is washed thoroughly with water and then dried.

The sample is purified by chromatography on silica sol using chloroform-methanol (5:1 vol/vol) as eluent; melting point elemental analysis: Calculated for 014HBN4Q3: a
so, oo%i H2, 87%; N 20.00chi Actual value: Example 64 2-amino-6-(5-tetrazolyl)
,60,! i') in concentrated sulfuric acid (80-) with stirring at 15 DEG C. and while maintaining the temperature at 15 DEG C. during cooling, sodium nitrite (1.15 g) is added portionwise over 10 minutes. The mixture is stirred for 1 hour at 15°C and then poured onto ice. The solid diazonium sulfate is removed and washed with a small amount of cold water.The solid salt is added in small portions to a hot (50°C) solution of 2-mercaptoethanol (5-) in water (50,d). Severe foaming occurs. The mixture is held at 50° C. for 60 minutes, then the solid product is taken off and washed with water. The dried crude product was flash chromatographed on silica sol using chloroform-acetic acid (4:1 vol/vol) as eluent and then recrystallized once from aqueous dimethylformamide and then twice from 2-methoxyethanol. , the title compound is obtained; melting point 249°C (with decomposition). The structure was supported by n, m, r spectral analysis.

Elemental analysis: Calculated value for 016H12N405B: 056.46%; H3,55%1N16.46% Actual value: 056.09%; H3,69CH1N16.28
%.

Example 65 Human blood from a blood donor is treated with OPD anticoagulant (which is an aqueous solution containing the following ingredients: sodium citrate 2
．． 65g, anhydrous dextrose 2.6291 citric acid 1
0.327 g of hydrate and 0.327 g of sodium acid phosphate.
251 g) Collect in a ratio of 100 parts blood to 15 parts medium; dispense this lme amount into 2-polycarbonate vials and hold at 4°C for 6 hours to allow the red blood cells to sediment from the plasma. The sample is then kept at room temperature, where one test compound per vial is added to 6mM in total blood volume according to the following method: A small amount of plasma is separated from each vial and the sodium salt (adjusted amount ) is dissolved directly therein, and the acid (appropriate amount) is added to a warmed aqueous sodium bicarbonate solution (72 drops of 600 nM), which is mixed with the plasma; in each case, the test compound-containing plasma is transferred to the original vial. Reconstitute, cap the vial, and mix the contents thoroughly.

For each experiment, six control vials are made; each of these contains the following components: a) blood only; b) hematological hydrochloric acid (0.1 M i 150 microliters); C) blood + aqueous hydroxide solution. ) IJum(0,1M;1
After a total time of 2 hours at room temperature, all samples were incubated at 67°C for 1 hour.
Leave for 6 hours and measure each - at this temperature. The vial was then stored on ice and placed in a whole blood spectrophotometer (trade name Hem-
Measure the oxygen-dissociation curve for each sample using the O-5can).Finally, rewarm to 67°C and re-measure the - of each sample.

250 points on the oxygen-dissociation curve (if hemoglobin is 50 points with oxygen)
The rightward position change of the oxygen tension at the time of saturation is evaluated for each sample against the calculated P50 of the appropriate sample. The results are shown in the table below: Test compound Right direction -
Position change (mx Hg) example ia 15.
0 Example 2 16.2 Example 5 13.0 Example 4a 15.6 Example 5a 9.7 Example 6a 5.3 Example 8a 25.8 Example 9a 6.9 Example 11a 25.0 Example 12 ・26.1 Example 13 19 .9 Example 14a 18.8 Example 15a 27.4 Example 16a 23.2 Example 17 "14.6 Example 18a 12.6 Example 19a 9.5 Example 20a 23.5 Example 21a 28.7 Example 22 17.6 Example 23 19.0 Example 24 20.0 Example 25a 62.6 Example 2611L 25.6 Example 27a 25.5 Example 28a 26.1 Example 29a 22.2 Example 3Qa 20.0 Example 31a 16.6 Example 32a 16.2 Example 34 17.7 (A) Nutrition 7.6 (B)
-1,6゜(0) Blue
6.5 Pot Japanese Published Patent No. 16821/82: (Shu: !1-(IH-tetrazol-5-yl)thioxanthone-10,10-dioxide (B) nia-methoxy-2-(IH-tetrazol-5- xanthone (0): 2-(IH-tetrazol-5-yl)xanthone

Example 66 Using male Wistar glazed rats (240-420g) 1
7. Induce anesthesia with halothane/oxygen, α-chloralose and sodium bendoparbitan (i, v,
) to maintain anesthesia. The test compounds (compounds of Examples 15a and 25a) were given as a solution in 5% dextrose at a dose of 9 to 1-0-/ in 5 seconds (i, v,)
, then flushed with 5% dextrose solution (0.1 m/). Administration is 0.001 at intervals of 10-30 minutes
Give in increasing amounts over a range of 9 to 30 mg/.

Both compounds produced dose-related blood pressure reductions in the dose range of 3 to 60 μ/kg.

No significant waveform' abnormalities appeared in the electrocardiograms after administration of both compounds.

Example 67 HarlθeRi data The following test compound was administered to female CDI mice (□harlθeRi
, ver [T, to, Ltd,) by intravenous administration (i, V,
) did.

In the case of the compound of Example 15a, the LD5o is 140 ■/kg
~200 μ/kl (calculated as free acid).

For the compound of Example 25a, the LD5o is 6007 ng/
It was found that it was larger than Yu.

Example 38 Pharmaceutical formulation (A) Capsule compound (acid) 625 mg starch (s
tarch) 1500 250Tng Magnesium Stearate 8■886■ Mix the ingredients with a suitable mixer and fill into capsules with a capsule filling machine.

(B) Tablet compound (acid) 625 ■ Lactose 200 ■ Polyvinylpyrrolidone 50 ■ Starch
100■ Magnesium stearate 10■985■ Dissolve polyvinylpyrrolidone in an appropriate amount of water.

Mix the compound, lactose and starch and add to the polyvinylpyrrolidone solution. Add more water if necessary. Pass through a suitable sieve and dry. Magnesium stearate is added and then compressed in a tablet machine.

(0) Suppository compound acid 1.2! Sodium salt hard fat f17j (Hard fat) pharmacopoeia grade equal to M
Add a portion of hard fat to a maximum of 50℃ to make the total amount 6-
Melt it with A compound is added to this molten base material and dispersed. Add the remaining hard fat to the suspension. Once a smooth homogeneous suspension is obtained, pour it into a 6-mold.

(D) Injectable compound acid 1.2! Sodium salt mannitol (pharmacopoeial grade) equal to M 125.0 ■ Water for injection BP
ZPh Ham Amount to bring the total volume to 2.5-00 The compound and mannitol are dissolved in the final volume of water for injection. Add water for injection to Kira to make a predetermined amount. The solution is sterilized by passing it through a sterilizing grade filter. 2,5-units are filled into appropriate vials under aseptic conditions and lyophilized. Once drying is complete, the vial is sealed under an oxygen-free nitrogen atmosphere and capped with an aluminum collar.

(B) Injection compound (acid) 2.50 & benzyl alcohol 90.01 ng TR engineering S solution (0.05
M) 5y hydrochloric acid (0, IN) 3
．． d Injection BP/Ph/Gm Dissolve the cap compound to make the total amount 10- in TR-S and hydrochloric acid. Add benzyl alcohol, dissolve and then make up to volume with water for injection. The solution is sterilized by passing it through a suitable sterilizing grade filter. 10 - Fill vials under aseptic conditions and seal with rubber stoppers.

In the above, (acid) indicates that the compound of formula (I) is present as free carboxylic acid or 5-tetrazolylic acid, respectively.

Example 69 Blood storage 420 m! ! A sterile sealed bag (Fθnwal) containing cPD anticoagulant solution 66-
.

Travenol Laboratories, Th.
etford, N0rfolk.

UK). The anti-aggregating agent is separated under sterile conditions, mixed with an effective, non-toxic amount of the compound of formula (I) (described above) and returned to the bag, which is then resealed and stored at -C1 room temperature.

Blood from the donor is then collected into the bag in a conventional manner and the entire bag is then stored at 4° to 6°C.

Agent: Haru Asamura Continuing from page 1 Priority claim @ October 21, 1982 ■ United Kingdom (G
B)■8230055 0 Inventor Richard Martin Hyde 85 Croham Road, Leigh Croydon, United Kingdom [Phase] Inventor William Richard King 24 Kent Bitskley Bardham Close, United Kingdom 0 Inventor David・John Livingston 38 06 Matsukenzie Road, Ghent, Bethkenham, United Kingdom Procedural Amendment (Music) June 1983/-I-I-Date Commissioner of the Patent Office 1, Indication of Case Patent Application No. 73688 of 1982 2. Name of the invention Tricyclic compound 3. Relationship with the case of the person making the amendment Patent applicant's address Showa Year/Month/Date 6. Number of inventions increased by amendment 7. Specification subject to Supplement i

Claims (1)

[Claims] (11 Formula (I) [In the formula, X1 is carboxyl or 5-tetrazolyl group; x2 is carbonyl or methylene group; X3 is hydroxy or group -X'(OnH2n)X5 where x4 is oxygen or sulfur; X5 is hydrogen or a group -0x6; where X6 is hydrogen, an alkanoyl having 1 to 4 carbon atoms or a group -
(OmH2m) is an integer of ~4; and includes salts thereof; provided that when X5 is the group -0x6, n is always greater than 1 and x4 and X5 are bonded to different carbon atoms; and when X7 is a group -0X8, m is always greater than 1 and with the condition that one carbon atom in the group -(OmHzm)- is never bonded to two oxygens. ] A tricyclic compound represented by (2) Xl is carboxyl or 5-tetrazolyl group; X2 is carbonyl or methylene group; X3 is hydroxy or group -X'(OnHan)X5; where X' is oxygen or sulfur; is hydrogen or a group -OX'; where X6 is hydrogen or alkanoyl having 1 to 4 carbon atoms; and n is an integer of 1 to 4; and includes salts thereof; provided that x5 is the group -ox6, with the proviso that n is always greater than 1, and X4 and x5 are bonded to different carbon atoms. Compound. Compound 0 of Claim 1 which is (312-(2-hydroxyethoxy)-6-C5-tetrazolyl)xanthone and its salt (4) 2-ethoxy-6-(5-tetrazolyl)xanthone and its salt The compound according to claim 1, which is (5) Compound 0 according to any one of claims 1 to 4 which is a salt thereof (6) Claims 1 to 4 which are a pharmacologically acceptable salt thereof A compound according to any one of clause 4. (7) Claims 1 to 4 which are sodium salts
A compound according to any one of paragraphs. (8) A compound according to any one of claims 1 to 4, or a pharmacologically acceptable salt thereof, for use as a human or veterinary medicine. (9) Use as a supplier of more effective oxygen transport to the tissues of the recipient, as claimed in claim 1~
A compound according to any one of paragraph 4 or a pharmacologically acceptable salt thereof. (10) The compound according to any one of claims 1 to 4, or a pharmacologically acceptable salt thereof, for use in reducing or improving tissue hypoxia. 01) A compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof for use in storing human red blood cells. A pharmaceutical preparation containing the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof together with an acceptable carrier for dispensing. 03) A method for producing the formulation according to claim 12, which comprises mixing the respective components thereof. (1) Any one of claims 1 to 4
A sterile, sealed container containing a non-toxic amount of a compound or a pharmacologically acceptable salt thereof and an anticoagulant. (l!51) Containing a non-toxic amount of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof, an effective amount of an anticoagulant and human red blood cells. (16) A method for producing a compound or a salt thereof according to any one of claims 1 to 4, comprising: (a) formula (IIa) [wherein X2 and X3 are as defined for formula (I), one of Zl and z2 is hydroxy or an ester thereof, and the other is a leaving atom or group, and yl is as defined for formula (I) or a carboxyl group precursor group as defined herein] in the presence of a base; or ('b) X2 is carbonyl; In the case, a compound of formula (III)3 in which x1 and x3 are as defined for formula (I) and z3 is a carboxyl group, a derivative thereof or a formyl group is treated with a Lewis acid or a protic acid. or (C) when X2 is methylene, selectively reducing the corresponding compound of formula (I) in which x2 is carbonyl; or (d) is 5-tetrazolyl, of formula () in which X2 and X3 are as defined for formula (I) and z4 is a 5-tetrazolyl group precursor group as defined herein. timely reacting the compound with hydrazonic acid or its salts or with nitrous acid;
or (e) when xl is carboxygyl, formula (V) [
where X2 and x3 are as defined for formula (I) and z7 is a carboxyl group precursor group as defined herein; (■) [wherein X2 and X3 are as defined for formula (I) and Y2 is a group X1 as defined for formula (I), or an alkyl or alkanoyl having 1 to 6 carbon atoms; or (g) when X2 is carboxyl and X2 is methylene, then 72 is always alkyl or alkanoyl; ■) [In the formula, X3 is as defined for formula (I),
and zlO is halo; or wherein x1 and x2 are υ as defined for formula (I), and zll is a group X3 as also defined for formula (I). and optionally converting the product into the free acid or a salt thereof. αη Produced according to the method of claim 16,
A compound or a salt thereof according to any one of claims 1 to 4. Administering a non-toxic therapeutically effective amount of a compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof to a mammal in need thereof. A method of achieving more effective transport of oxygen to mammalian tissues comprising: (I9) Administering a non-toxic therapeutically effective amount of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof to a mammal in need thereof. A method of reducing or ameliorating tissue hypoxia in a mammal comprising administering. (21) Claim 1 in which the mammal is a human
The method according to either Clause 8 or Clause 19. (Before transfusing the 211 red blood cells to the recipient, the cells are mixed with a non-toxic, retained effective amount of claims 1-4 or a pharmacologically acceptable salt thereof. , a method for preserving the oxygen transport capacity of stored human red blood cells. A method of extending the useful shelf life of stored human red blood cells comprising admixing with a non-toxic prolonging effective amount of a salt.