DE2827932A1 - BIPHENYLSULFONYLIMINO COMPOUNDS - Google Patents

Description

Biphenylsulfonylimino compounds

The invention relates to biphenylsulfonylimino compounds which are medicaments and in particular are characterized by a distinguish complement-inhibiting effectiveness.

Complement is a complex group of proteins in body fluids that work in conjunction with antibodies and other factors play an important role as mediators in immune, allergic, immunochemical and / or immunophatological Play reactions. The reactions in which a complement takes part run in the blood serum or in other body fluids and they are therefore referred to as humorous reactions.

According to the current state of knowledge, there are more than 11 proteins in the complement system in human blood. These complement proteins are denoted by the letter C and a corresponding number as follows: C 1, C 2, C 3 and so on further up to C 9. The complement protein C 1 is practically a complex of subunits, which are known as C 1 q, C 1 r and C 1 s designated. The numbers given for the complement proteins

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indicate the order in which these complement protexes act The only exception to this is the complement protein C 4, which follows the complement protein C 1 and before the complement protein C 2 unfolds its effect. This different behavior is due to the fact that the number assignment for the individual proteins in the complement system has already been made before complete clarity about the reaction sequence duration. For an in-depth discussion of the complement system and its role in the body Processes, for example, reference is made to the following literature: Bull. World Health Org. 39, 935-938 (1968); Ann. Rev. Medicine 19: 1-24 (1968); The John Hopkins Med. J. 128: 57-74 (1971); Harvey Lectures, 66: 75-104 (1972); The New England Journal of Medicine 287, 452-454, 489-495, 545-549, 592-596, 642-646 (1972); Scientific American 229, (No. 5), 54-66 (1973); Federation Proceedings 32: 134-137 (1973); Medical World News, Oct. 11, 1974, pp. 53-58 and 64-66; J. Allergy Clin. Immunol. 53: 298-302 (1974); Cold Spring Harbor Conf. Cell. Proliferation 2 / Proteases Biol. Control / 229-241 (1975); Annals of Internal Medicine 84: 580-593 (1976); "Complement: Mechanisms and Functions", Prentice-Hall, Englewood Cliffs, N. J. (1976), Pathology Biology, 25 (1), 33-36 (1977).

The complement system can be made up of three sub-systems view consisting of:

(1) a recognition unit (C 1 q), which enables a combination with antibody molecules that have a have detected a foreign intruder,

(2) an activation unit (C 1 r, C 1 s, C2, C4, C3) that has a corresponding Place prepared, and

(3) an attack unit (C 5, C6, C7, C8 and C 9), the forms a so-called hole in the membrane.

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The unit of attack of the membrane is not specific. You destroyed Intruders only because they are formed in their environment. To minimize damage to the host's own Cells, the activity of the attack unit must therefore be limited in time. This limitation arises in part through the spontaneous breakdown of activated complement and partly through the interaction between inhibitors and destructive enzymes. However, the control by the complement is not perfect, so that the host cells are also damaged can suffer. An immunity is therefore a double-edged sword.

Activation of the complement system also accelerates blood clotting. This effect comes from the vom Complement-mediated release of a coagulation factor from the platelets. Fragments and complexes of the biologically active complement can participate in reactions that damage the host cells, and these pathogenic responses can lead to the development of immune complex diseases. In some forms of nephritis, for example, the complement causes damage to the basement membrane of the Kidney, which allows protein to enter urine from the blood. This category includes, for example, disseminated lupus disease called erythematosus. Her symptoms include Nephritis, visceral damage and skin eruptions. Treatment of diphtheria or tetanus by large injection Levels of antitoxin occasionally lead to serum sickness, which is an immune complex disease. Even Immune complexes are involved in rheumotoid arthritis. Similar to disseminated lupus erythematosus, see above This is also an autoimmune disease, the symptoms of which are caused by pathological effects of the immune system in the host tissue. Overall, the complement system therefore plays a role in inflammation, coagulation, fibrinolysis, antibody-antigen reactions and other metabolic processes play a role.

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In the presence of antibody-antigen complexes take the Complement proteins participate in a number of reactions that can lead to irreversible membrane damage if they occur in the vicinity of biological membranes. The complement thus constitutes part of the defense mechanism of the body against infections, it can be seen in immunopathology However, the process can also lead to inflammation and tissue damage. About the type of certain complement proteins, Suggestions regarding the binding of the complement to biological membranes and the manner in which the complement causes membrane damage is reported in more detail in the Annual Review in Biochemistry 38, 389 (1969).

To inhibit the complement system, namely as complement inhibitors, A wide variety of substances have already been proposed. For example, 3,3'-ureylenebis / 6- (2-amino-S-hydroxy-δ-sulfo-i-naphthylazo ^ / benzenesulfonic acid tetrasodium salt (Chlorazole), heparin and a sulfated dextran are anti-complementary (British Journal of Experimental Pathology 33, 327-339 (1952)). The compound 8- (3-benzamido-4-methylbenzaraxdo) naphthalene-1,3,5-trisulfonic acid (Suramin) is described as a competition inhibitor for the complement system (Clin. Exp. Immunol. 10, 127-138 (1972)). InDE-PS 22 54 893 or ZA-PS 727 923 are certain 1- (diphenylmethyl) -4- (3-phenylallyl) piperazines described, which are said to be suitable as complement inhibitors. Other compounds with anti-complement Effectiveness can be seen, for example, from the following literature: Journal of Medicinal Chemistry 12, 415-419, 902-905, 1049-1052, 1053-1056 (1969); Canadian Journal of Biochemistry 47: 547-552 (1969); The Journal of Immunology 93: 629-640 (1964); The Journal of Immunology, 104: 279-288 (1970); The Journal of Immunology, 106: 241-245 (1971); The Journal of Immunology, 111: 1061-1066 (1973).

It has also been reported that the known complement inhibitors epsilon-aminocaproic acid, suramin and tranexamic acid

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already all with success in the treatment of hereditary angioneurotic Edema has been used, namely a disease that is due to an inherited incomplete or its cause has no function at all of the serum inhibitor of the activated first component component (C 1 inhibitor), and see The New England Journal of Medicine 286, 808-812 (1972) pointed out.

The invention now relates to phenyltetrayltetrakxs (sulfonylimino) tetrabenzenedicarboxylic acid alkali metal salts and dicarboxyphenyl-substituted-bisulfonyliminodibenzodithiazepine-S, S, S ', S'-tetroxide salts and of the formula I.

ROOC

ROOC

COOR

SO SO ₉

I I

COOR

(D

worxn

stands for an alkali metal and

the substituents R. and R "

individually each a remainder of the formula

COOR

COOR

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J5--

or together a radical of the formula

ROOC COOR

mean, and the pharmaceutically acceptable salts of these compounds.

Preferred compounds according to the invention have the formula II: ROOC

ROO (T ROOC

: ooR

ROO

COOR

(II)

Further preferred compounds according to the invention have the Formula III:

ROOC

ROO

HN-O ₂ S

SO ₂ -NH

0OR

COOR

(III)

ROOC

COOR

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The invention also includes the biphenylsulfonylimino compound of the formula IV:

-COH ₂ CH-COOC

(IV)

COOCH ₂ CH ₂ OCH ₃

"COOCH ₂ CH ₂ OCH ₃

COOCH ₂ C!

00CH ₂ CH ₂ OCH ₃

namely the 5,5 ', 5 ", 5"' ~ / 2, 2 ' , 4, 4 ' -Biphenyltetray1tetrakis (sulfonylimincOy tetraisophthalic acid octakis (2-methoxyethyl) ester, and this compound is suitable as an intermediate for the preparation of those described above Complement-inhibiting compounds.

The invention also includes 5, 5 '- | _ / 6- (3, 5-dicarboxyphenyl) -dibenzo / d, f // 1,3,2 / dithiazepine-3,9-diyl / bis (sulfonyliminofdiisophthalic acid hexakis (2- methoxyethyl) ester-S, S, S ', S'-tetroxide, which is also suitable as an intermediate product for the preparation of the above-described complement-inhibiting compounds.

To prepare the compounds according to the invention, one forms also an amine ester of an organic acid of the formula

H ₃ COH ₂ CH ₂ COOC COOCH ₂ CH ₂ OCH ₃

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by reducing the corresponding nitro derivative and then with 2,2 ', 4,4'-tetrachlorosulfonylbiphenyl in a mixture from organic solvents such as acetonitrile and pyridine, reacts for about 18 to 20 hours. Through the following Filter the reaction mixture, concentrate the filtrate, treat with 0.2 normal hydrochloric acid and extract in benzene one obtains the intermediate 5,5'- | / _6- (3 , 5-Dicarboxyphenyl) dibenzo / d, f _ // _ 1, 3, 2 / dithiazepine-3, 9-diyl / -bis (sulfonylimino) 7-diisophthalic acid hexasodium salt-S, S, S ', S 'tetroxide. This intermediate product is then used with. an alkali metal hydroxide implemented, which leads to complement-inhibiting compounds of the formula III mentioned at the outset.

The benzene-soluble material obtained in the above extraction is dried and dissolved in acetone, whereupon the solution is worked up by chromatography in a conventional manner. To this Thus, the intermediate octakismethoxymethyl ester of the formula VI is obtained

H COH ₂ CH ₂ COOC H ₃ COH ₂ CH ₂ COOC

H ₃ COH ₂ CH ₂ COOC

H ₃ COH ₂ CH ₂ COOC

(VI)

COOCH ₂ CIi ₂ OCH ₃

By reacting this intermediate of the formula (VI) with an alkali metal hydroxide, a complementary one is obtained effective octaalkali metal salt of formula (II).

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_COPY

- jr-

The compounds according to the invention can be used in any suitable form for inhibiting complement in body fluids Wise administered, for example, orally, intra-articularly or parenterally, and such an inhibition can then relieve or prevent reactions caused by the Function of the complement are dependent, such as inflammatory processes and cell membrane damage caused by Antigen-antibody complexes are induced. Depending on the type administration, the condition being treated, and the particular compound used, a wide range of doses can be employed. With appropriate intravenous or subcutaneous treatments, the dose of active ingredient is for example about 5 to 50 mg / kg / day, these doses also being given every 6 hours in the case of rapidly excreted salts can be. For the intra-articular treatment of large joints, such as the knee joint, for example, amounts of active substance can be used from about 2 to 20 mg per joint per week can be used, taking at. smaller joints with proportional smaller doses works. The dosage range is to be adjusted in each case so that it is in the case of the to be treated Warm-blooded animals give the respective optimal therapeutic effect. In general, the present active ingredients in Doses of about 5 to 100 mg per kg of body weight of the warm-blooded animal to be treated per day are used. At a For warm-blooded animals weighing 70 kg, the daily dose is usually around 350 mg to around 3.5 g. Unit doses of the acid or des Each salt of the active ingredient can contain about 0.5 to 500 mg thereof.

In general, the sodium salts of the acids according to the invention are particularly suitable for parenteral use, but can can also be used with other salts, for example with salts of primary amines, such as ethylamine, secondary amines, such as Diethylamine or diethanolamine, tertiary amines such as pyridine, triethylamine or 2-dimethylaminomethyldibenzofuran, more aliphatic Diamines such as decamethylene diamine or aromatic diamines. Some of these salts are soluble in water, others dissolve in saline solutions, and still others are

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insoluble, so that they can be used for the preparation of suspensions Injection can be used. Just like the sodium salts, other salts, such as potassium or lithium salts, salts of ammonia or alkaline earth salts, such as Use calcium or magnesium salts. As can be seen, these salts generally include derivatives of salt-forming salts Cations,

For therapeutic use, the inventive Compounds can be administered in the form of conventional pharmaceutical preparations. Such preparations can be so be formulated to be oral or parenteral Let administrations use. The active ingredient can be mixed with a pharmaceutically acceptable carrier, and this carrier may, depending on the form of administration desired, for example if you want a pharmaceutical form suitable for oral or parenteral administration, have a wide variety of shapes. The compounds according to the invention can also be used for preparations suitable for the production of tablets. To do this, mix the respective Active ingredient with ingredients commonly used in tablet production, such as corn starch, lactose, sucrose, sorbitol, talc, Stearic acid, magnesium stearate, dicalcium phosphate, gums or similar materials that are considered to be non-toxic pharmaceutical Safe diluents or carriers are used. Tablets or pills from the new preparations can be laminated or otherwise compounded to give a dosage form by which the active ingredient is extended over a period of time or delayed period of time is released or comes into effect successively in a predetermined manner. So can tablets or pills, for example, an inner and an outer dosage component the latter may be in the form of a coating over the former. Both components can be separated from each other by an enteric layer which resists decomposition in the stomach and allows the inner component still intact enters the duodeum or

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delayed release. A wide variety of materials can be used to form such enteric layers or coatings, and these include, for example, polymeric acids or mixtures of polymeric acids and materials such as shellac, shellac and cetyl alcohol or cellulose acetate. A particularly suitable enteric coating comprises a styrene maleic acid copolymer together with known materials that _t provide for the respectively desired enteric properties of the coating, the respective tablets or pills may be colored with an appropriate non-toxic dye, so that they look pleasing.

Liquid forms in which the preparations according to the invention can be contained for administration include corresponding flavored emulsions of edible oils, such as cottonseed oil, Sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. For parenteral administration sterile suspensions or solutions can be produced. For injection purposes, isotonic preparations can be used which contain suitable preservatives.

Under a dosage form there are physically separate entities understood that can be used as unit dosage forms for warm-blooded animals, each of these units being one contains such a predetermined amount of active ingredient that in connection with the particular pharmaceutical diluent, carrier or vehicle required, the particular desired gives therapeutic effect. The composition of the new dosage forms according to the invention is determined by the Properties of the active ingredient and the therapeutic effect desired in each case or by limits such as those from compounding technology such active ingredients are determined. Individual examples of suitable oral dosage forms according to the invention are tablets, capsules, pills, powder packets, granules, Cachets, cachets, teaspoons, drops, ampoules, vials, or divided multiples of the above shapes or other forms described herein.

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The complement-inhibiting effect of the compounds according to the invention has been determined by one or more of the following tests:

(i) Test / Code 026 (C 1 inhibitor) - This test is the ability of activated human complement protein C1 to destroy what is present in the liquid phase human complement protein C 2 in the presence of complement protein C 4 by corresponding Dilutions of the respective active ingredient determined. An effective inhibitor protects the complement protein C. before the complement proteins C 1 and C 4.

(ii) Test, Code 0.35 (C3 to C9 Inhibitor) - For this test the ability of the late components of human complement (C 3 -C 9) to lyse EAC 142 in Measured presence of appropriate dilutions of the respective test compound. An active inhibitor protects EAC 142 prior to lysis by human complement proteins C 3 - C 9.

(iii) Test, Code 036 (C-Deflection Inhibitor) - In this test subjecting brittle human erythrocytes in autologous serum to a lysis by a deflection activated by Cobra-Venom factor in the presence of appropriate dilutions of the respective Active ingredient. An inhibition of the diversion leads to a failure of the lysis.

(iv) Forssman Vasculitis Test - In this test, one forms in guinea pigs by intradermal injection of rabbit-derived anti-Forssman antiserum the well-known complement-dependent damage, namely the so-called Forssman vasculitis. To this determination if the diameter, edema and hemorrhage are measured,

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speaking and indicates the extent to which a combined index of the values obtained here is replaced by a prior intraperitoneal injection of the active ingredient to be examined in each case in an amount of 200 mg / kg is inhibited, unless otherwise stated.

(v) Forssman Shock Test - By intravenous injection of Anti-Forssman antiserum is produced in guinea pigs with a lethal shock and compared to those in treated ones Guinea pigs obtained values up to mean time of death with the values as one using them simultaneously examined control animals receives.

(vi) Complement Height Reduction Test - In this test the guinea pigs or other treated animals treated in the above manner with active ingredient are allowed to be obtained of the serum and determines the complement concentration in the undiluted serum according to the method described in US-PS 3 876 37 6 described capillary tube method, whereby the values obtained are compared with the values of control animals compares those who have not received any active ingredient.

(vii) Chapter 50 test - For this test, what has been collected is added Serum from guinea pigs in vitro with corresponding amounts of the respective active substance to be investigated and then examines the whole thing according to the capillary tube test described above. Here one determines the one Active ingredient concentration that results in 50 percent inhibition.

The results obtained in the above investigations are shown in Tables I and II below. There are guinea pigs for this weighing about 300 g used those

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either intravenously (i. ν.) or intraperitoneally (i. p.) 200 mg / kg of the particular compound to be examined, dissolved in saline and adjusted to pH 7 to 8. One hour after the administration of the active substance has taken place, one cuts the Guinea pigs' heads off, collect their blood and separate the serum. The total complement is then determined this serum using the so-called capillary tube method. The percent inhibition values are given by Comparison with the results of corresponding control experiments calculated. The test results can be seen in Tables I and II can be taken. They show that the compounds according to the invention both in vitro and in vivo in warm-blooded Animals have a particularly strong complement-inhibiting effect.

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Tabel Biological activities link

C1

026 *
tube

C-late

035 *
tube

Reverse escapement

036 *
tube

Cape. 50 *

O (O OO CO

O CD O

5.5 x, 5 ", 5 '" - / 2.2', 4,4'-biphenyltetrayltetrakis (sulfonylimino ^ / octasodium tetraisophthalic acid

= Code designation for the tests used

= Activity in tubes, serial dilution experiment. A larger number means a higher activity, The serial dilutions are twofold.

N = negative

89 139

Tabel

II

Biological activities

link

5,5 '- </ 6 ~ (3,5-dicarboxyphenyl) di-

CD benzo / d, f // l, 3.2 / dithiazepin-3 / 9- ⁰⁰

1 diyl / bis (sulfonylimino) f phthalic acid hexasodium salt-S, S, S ', S'-tetroxide

Deflection

C1 C late inhibition 026 * 035 * 036 * tubes tubes tubes

.N

Cape. 50 *

159

in vivo activity (guinea pigs)

percent inhibition intraperitoneal intravenous time (in minutes) time (in minutes)

30 60 120 2 30 120

-23 -57

-42

* = Code designation for the tests used

** ^ = activity in tubes, serial dilution experiment. A larger number means more activity. The serial dilutions are twofold.

N = negative - y

- vr -

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example 1

5,5 ', 5 ", 5"' ~ / 2 , 2 ', 4,4'-Biphenyltetrayltetrakis (sulfonylimine O / - tetraxsophthalic acid octacxs (2-methoxyethyl) ester

A mixture of 500 g of 5-nitroisophthalic acid, 3500 g of thionyl chloride and 6.0 ml of dimethylformamide is gradually heated until the evolution of gas subsides. Then under Stirring heated for about 2 hours until a solution has formed, whereupon the mixture is refluxed for a further 30 minutes heated. The clear solution obtained is left to stand and then evaporated to an oil in vacuo. The oil solidifies and is recrystallized twice from carbon tetrachloride. This is how you get to 501 grams of 5-nitroisophthaloyl chloride.

A mixture of 100 g of the above product and 100 g of 2-methoxyethanol (dried over molecular sieves) in 400 ml of acetonitrile (dried over molecular sieves) is heated to reflux temperature on a water bath. Heating is then continued for 15 minutes, after which the mixture is cooled to room temperature and poured into 2 liters of cold water with vigorous stirring. The product is filtered off and air dried, yielding 129 grams of material. The above filtrate is extracted with benzene to give more product (5.7 g). All of the product is combined and dissolved in 580 ml of hot ethanol. The solution is neutralized with 5.0 ml of 5 normal sodium hydroxide and then diluted with 450 ml of water. The solution is then left at room temperature until crystals separate out, whereupon the mixture is placed in a cold room (5 ^° C.) overnight. The resulting colorless needles are recrystallized from a solution of 450 ml of ethanol and 350 ml of water, giving 92.1 g of bis (2-methoxyethyl) 5-nitroisophthalate.

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86.0 g of the above product are added to 300 ml of ethyl acetate Use of 2.0 g of 10 percent palladium-on-carbon catalyst hydrogenated in a Parr apparatus. The mixture is filtered and the filtrate evaporated to dryness, whereby one receives whitish crystals. The crystals are dissolved in 350 ml of hot benzene and the solution is mixed with 140 ml of hexane diluted. The solution is then allowed to crystallize overnight at room temperature, yielding 72.0 g of bis (2-methoxyethyl) 5-aminoisophthalate got.

A solution of 31.4 g of 4,4'-diamino-2,2'-bxphenyldisulfonic acid in 150 ml of water and 7.7 g of sodium hydroxide is filtered and then diluted with 300 ml of absolute ethanol. The product obtained is collected, washed with ethanol and ether and rocked, resulting in 31.9 g of 4,4'-diamino-2,2'-biphenyldisulfonic acid disodium salt got.

A mixture of 25.6 g of the above product in 10.0 ml of water is mixed with 9.8 g of sodium nitrite, whereby a paste is formed. The paste is added to a cooled solution (0 to 5 ^° C.) of 45.0 ml of concentrated hydrochloric acid and 16.3 ml of water in such a way that the temperature remains ^{at 0 °} C. to 5 ^{° C.} A milk-like mixture is obtained.

A solution of 3.0 g of copper (I) chloride in 3.0 ml of water is added to 130 ml of glacial acetic acid and saturated with sulfur dioxide gas. The mixture obtained is then added to the above milky mixture in such a way that the temperature remains ^{at 5 to 7 ° C.} After the addition has ended, the mixture is stirred at room temperature for 2 hours. The solvent is then removed by evaporation at 24 ^° C. in a water bath and the residue obtained is dissolved in water. The solution is adjusted to pH 8.0 with anhydrous sodium carbonate and filtered to remove the solid.

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The filtrate is diluted with absolute ethanol and stirred, whereby an oil separates out. The oil is separated and used Allowed to solidify to give a white solid. The solid is collected at 85 percent Aqueous ethanol, ethanol and ether and dried, giving 36.0 g of 2,2 ', 4,4'-biphenyltetrasulfonic acid tetrasodium salt receives.

A mixture of 39.0 g of the product prepared above, 500 g of thionyl chloride and 3.0 ml of dimethylformamide is Heated to reflux temperature for 18 hours. The mixture will cooled and then filtered. The filtrate is evaporated and the residue is treated with hot chloroform. The mixture will cooled, the solid collected, washed with chloroform and dried. The solid is made up with methylene chloride and acetonitrile treated, collected and dried, yielding 13.0 g of 2,2 ', 4,4'-tetrachlorosulfonylbiphenyl «.

A solution of 23.8 g of 5-aminoisophthalic acid bis (2-methoxyethyl) ester and 7.0 ml of pyridine in 200 ml of acetonitrile are admixed with 12.0 g of the above product with stirring at room temperature. The mixture is then stirred for a further 3 hours, whereupon the mixture Let stand overnight at room temperature. The solution is filtered, the filtrate concentrated to 100 ml and the concentrate poured into 500 ml of 0.2 normal hydrochloric acid, creating an oily precipitate. The mixture is extracted three times with a total of 500 ml of benzene. The extract is washed twice with 250 ml of dilute sodium chloride solution and then dried over sodium sulfate. The mixture it is filtered and the filtrate is evaporated to give an orange glass-like mass. The solid is in 250 ml dissolved in warm benzene, whereupon the whole thing is left to crystallize overnight. The solid is filtered off and the filtrate (A) saved. The solid is washed with benzene and ether and then dried. The received pink Powder is dissolved in 75.0 ml of methylene chloride. the

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Solution is treated with activated charcoal and filtered through diatomaceous earth. The filtrate is combined with 350 ml of benzene and heated to the boil until all the methylene chloride has been removed. The mixture is cooled to room temperature, the the resulting product was filtered off and the filtrate (B) obtained was saved. The product is washed with benzene and ether and recrystallized again from methylene chloride-benzene (1; 7)., The solid is filtered off and the filtrate (C) obtained in this way is combined with the above Filraten (A) and (B), whereupon the whole is evaporated and so 8.5 g of an orange-red glass-like mass is obtained. 5.0 g of this material are in 250 ml Dissolved acetone, whereupon the solution is added to 60.0 g of silica gel (suitable for dry column chromatography), evaporated and on there is a dry column containing 1500 g of silica gel, which has previously been mixed with 150 ml of a mixture of acetone and hexane (1r1) has equilibrated. The column is eluted with a mixture of acetone and hexane (1: 1), giving the desired fractions selectively removed from the column packing and extracted with acetone. The vitreous mass obtained in this way is treated with diethyl ether to give a solid. The solid is dissolved in methylene chloride and ethanol dissolved, whereupon the solution is treated with activated charcoal, filtered and evaporated and the material obtained is removed Ethanol recrystallizes and dries. In this way, 900 mg of the title compound are obtained in the form of cream-colored crystals.

Example 2

5,5 ', 5 ", 5 ·' · - / 2,2 ', 4,4' -Biphenyltetrayltetrakis (sulfonyliminoj _ / - tetraisophthalic acid octasodium salt

640 mg of the product from Example 1 are stirred at room temperature 45 minutes with 6.0 ml of 1 normal sodium hydroxide, after which one 2.8 ml 1 normal acetic acid and then 50.0 1 absolute

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Adding ethanol. The mixture is heated to reflux on a water bath and then cooled to room temperature. The solvent is decanted and the gummy mass that remains is solidified by stirring with fresh ethanol. The solid is collected and dissolved in 1.0 ml of water, whereupon the solution is neutralized with 2 drops of glacial acetic acid and diluted with 50 ml of ethanol. The solvent is then decanted and the remaining gummy mass is solidified by stirring with fresh ethanol. After appropriate drying, 564 mg of the title compound are obtained in the form of a cream-colored powder *

Example 3

5,5'- ) / 6- (3,5-dicarboxyphenyl) dibenzo / d, f // 1,3,2 / dithiazepine-3,9-diyl / bis (sulfonylimino) rdiisophthalic acid hexakis (2-methoxy ethyl) ester- S, S, S ', S'-tetroxide

The procedure described in Example 1 is repeated using the product obtained from a mixture of methylene chloride and benzene (1: 7) recrystallized, filtered and dried accordingly. This results in 20.9 g of the title compound in the form of a pale pink powder.

Example 4

5,5 '- {/ 3,5-dicarboxyphenyl) dibenzo / d, f // 1,3,2 / dithiazepine-3,9-diyl / bis (sulfonylimino)? Diisophthalic acid hexasodium salt-S, S, S', S ' tetroxide

6.47 g of the product from Example 3 are admixed with 50.0 ml of normal sodium hydroxide while stirring. The solution will be Stirred for 30 minutes at room temperature and then treated with 5.0 ml of 5 normal sodium hydroxide, whereupon it is 2 hours leaves standing. The solution is neutralized with 2.3 ml of glacial acetic acid

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and then diluted with 400 ml of absolute ethanol. The solvent is decanted and the remaining gummy solid is mixed with 300 ml of fresh ethanol. The mixture is then left stand overnight, whereupon the resulting solid is collected and dried. This results in 4.62 g of the title compound in the form of a cream-colored powder.

Example 5 Production of Compressed Tablets Ingredients mg / tablet

Active ingredient 0.5 - 500

Calcium dibasic phosphate N.F. gs

Strength USP 40

Modified starch 10

Magnesium stearate USP 1-5

Examples

Production of compressed tablets with delayed action Ingredients mg / tablet

Active ingredient in the form of a preparation 0.5 - 500

with aluminum sulfate, micronized *) (acid equivalent)

Calcium dibasic phosphate N.F. qs

Alginic acid 20

Strength USP 35

Magnesium stearate USP 1-10

*) Complement inhibitor plus aluminum sulfate results

Aluminum complement inhibitor. The complement inhibitor content in the aluminum sulfate preparation is 5 - 30 %.

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Example 7 Manufacture of hard-shell capsules Components

mg / capsule

Active ingredient lactose, spray-dried magnesium stearate 0.5-500

qs
1-10

Example 8

Making an orally administrable liquid (syrup) Components Wt% / volume

Active ingredient liquid sugar Methylparaben USP Propylparaben USP Aroma

Purified water qs ad 0.05 - 5 75.0 0.18 0.02 qs
100.0

Example 9

Preparation of an orally administrable liquid (elixir) Components Wt% / volume

Active ingredient Alcohol USP Glycerin USP Syrup USP Aroma

Purified water qs ad 0.05-5 12.5 45.0 20, O qs 100.0

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Example 10

Preparation of an orally administrable suspension (syrup)

Components Wt% / volume Active ingredient in the form of a preparation 0.05-5 with aluminum sulfate, micronized (Acid equivalent) Polysorbate 80 USP 0.1 Magnesium aluminum silicate, colloidal 0.3 Aroma qs Methyl paraben USP 0.18 Propyl Paraben USP 0.02 Liquid sugar 75.0 Purified water qs ad 100.0

Example 11 Making an Injectable Solution

Components

Wt% / volume

Active ingredient benzyl alcohol N.F. water for injection

0.05-5

0.9 100.0

Example 12

Making an Injectable Oil

Components

Wt% / volume

Active ingredient benzyl alcohol sesame oil qs ad

O, O5-5

1.5 100.0

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Meng - ever 2 ο, 20 mg ο, 9% _ 9% 1 5%

Example 13

Manufacture of a preparation that can be administered intraarticularly Components

Active ingredient

NaCl (physiological table salt) benzyl alcohol

Sodium carboxymethyl cellulose pH adjusted to 5.0-7.5

Water for injection qs ad 100%

Example 14

Preparation of an injectable depot suspension Ingredients% by weight / volume

Active ingredient 0.05 -

C acid equivalents)

Polysorbate 80 USP 0.2

Polyethylene glycol 4000 ÜSP 3.0

Sodium Chloride USP 0.8

Benzyl alcohol N.F. 0.9

HCl to pH 6-8 qs

Water for injection qs ad 100.0

809883/0807

Claims (10)

Patent to sayings 1 ./ Biphenyltetrayltetrakissulfonyliminoverbindungen of the formula ROOC ROOC ENT worm stands for an alkali metal and COOR COOR the substituents R. and R " individually each a remainder of the formula COOR -NH- COOR or together a radical of the formula ROOC COOR mean, and the pharmaceutically acceptable salts of these compounds. 809883/0807 ORIGINAL INSPECTED -arf- 2. Biphenylsulfonylimino compounds of the formula ROOO COOR : 00R ROO (T ROOC COOR ROO where R is an alkali metal, and the pharmaceutically acceptable salts thereof. 3. Biphenylsulfonylimino compounds of the formula ROOC ROO HN-O ₂ S 0OR COOR ' ROOC COOR 809883/0807 - 2-8 ~ - where R is an alkali metal, and the pharmaceutically acceptable salts thereof. 4. 5,5 ', 5 ", S ¹¹ ' - / 2,2 ', 4,4" -Biphenyltetrayltetrakis (sulfonylimino ^ / tetraisophthalic acid octasodium salt and 5,5'- k / ß- (3,5-dicarboxyphenyl) dibenzo / d, f // 1,3,2 / dithiazepine-3,9-diyl / -bis (sulfonyliminoJdiisophthalic acid hexasodium salt-S, S, S ·, S '~ tetroxide according to claim 1. 5. 5,5 ', 5 ", S ^{1' 1} ~ / 2,2 ', 4,4'-Bipheny1tetray1tetrakis (sulfonylimino _) _ / tetraisophthalsäureoctakis (2-methoxyethyl) ester. 6. 5,5 '- / 6 (3, 5-dicarboxyphenyl) dibenzo / d, f _ // 1, 3, ^ thiazepine-Sfg-diyl ^ / bis (sulfonylimino) diisophthalic acid hexakis- (2-methoxyethyl) ester-S, E, S ', S'-tetroxide. 7. Process for the preparation of BiphenyIsulfonylixninoverbindungen the formula ROOC R00C_A COOR COOR ROOC COOR 809883/0807 wherein R is an alkali metal, characterized in that the compound 5,5 ', 5 ", S ¹¹¹ - / _ 2, 2', 4,4 '-Biphenyltetrayltetrakis (sulfonylimino ^ / tetraisophthalic acid octakis (2-methoxyethyl) ester with a suitable Reacts alkali metal hydroxide. 8. The method according to claim 1, characterized in that there is used as the alkali metal hydroxide sodium hydroxide. 9. Process for the preparation of biphenylsulfonylimino compounds the formula ROOC ROO HN-O ₂ S -SO ₂ -NH 0OR COOR ROOC COOR wherein R represents an alkali metal, characterized in that the compound 5,5'-c / 6- (3,5-dicarboxyphenyl) dibenzo / d, _f // 1,3,2 / dithiazepin-3 ₁ 9-diyl / -bis (sulfonylimino) diisophthalic acid hexakis (2-methoxyethyl) ester-S, S, S ¹ , S ¹ reacts tetroxide with an alkali metal hydroxide. 809883/0807 10. The method according to claim 9, characterized in that that sodium hydroxide is used as the alkali metal hydroxide. 80988 3/0807