DE2817840A1 - Naphthalene-tris-sulphonyl:imino:benzene derivs. - useful as complement inhibitors - Google Patents

Abstract

Naphthalenetris(sulphonyliminobenzene) derivs. of formula (I) are new: (where R is H or SO3A; and A is a cation; provided that each Ph ring contains 1 or 2 SO3A gps.). Complement inhibitors and so useful in affecting inflammation, coagulation, fibrinolysis, antibody-antigen reactions and other metabolic processes. Dose is 5-100 mg./lg. daily. In an example, 5,5',5"-(1,3,6-naphthalene-tris(sulphonylimino))tris-1,3-benzened- isulphonic acid Na salt was obtd.

Description

Trisubstituted naphthalene compounds

The invention relates to trisubstituted naphthalene compounds of the formula where R1 is hydrogen or methyl, R2 is hydrogen, carboxyl or COOR4, where R4 is an alkali metal or an alkaline earth metal, and R3 is hydrogen, hydroxy or COOR4, where R4 has the meaning given above, with the proviso that each phenyl ring is at least must contain a group of the formula COOR4, and the non-toxic, pharmaceutically acceptable salts of these compounds.

Those compounds of the above formula are preferred in which each phenyl ring is monosubstituted by the group COOR4, with R4 above Has meaning.

In addition, those compounds of the above formula are also preferred, in which each phenyl ring is disubstituted by the group COOR4, where R4 is the has the meaning given above.

Finally, there are also compounds of the above formula preferred in which each phenyl ring is only three times substituted by the group COOR4 is, in which R4 has the meaning given above.

From the first group, those compounds are preferred, in which each phenyl ring is simply substituted in position 3 or in position 4 and the migrating phenyl ring is in position 6 of the naphthalene ring.

From the second group, those compounds are preferred, in which each phenyl ring is disubstituted in position 3 and 5 and the migrating one Phenyl ring is in position 6 of the naphthalene ring.

Of the third group, those compounds are preferred in which the migratory phenyl ring is in position 6 of the naphthalene ring.

The invention also relates to trisubstituted naphthalene compounds of the formula where R5 is hydrogen or methyl, R6 is hydrogen, methoxycarbonyl, 2-methoxyethoxycarbonyl or phenoxycarbonyl and R7 is hydrogen, hydroxy, methoxycarbonyl or phenoxycarbonyl.

Preferred compounds from this group are those compounds in which each phenyl ring is only trisubstituted.

In particular, those compounds are preferred in which each phenyl ring through either 2-methoxyethoxycarbonyl or phenoxycarbonyl only is trisubstituted and the migrating phenyl ring is in position 6 of the naphthalene ring is located.

The new intermediates according to the invention of the formula in which R6 is hydrogen, methoxycarbonyl, 2-methoxyethoxycarbonyl or phenoxycarbonyl and R7 is hydrogen, hydroxy, methoxycarbonyl or phenoxycarbonyl, can be prepared by adding a compound of the formula where R8 is C1-C6-alkyl and Rg is hydrogen, hydroxy or COOR8, where R8 has the meaning given above, reacted with 1,3,6-naphthalenetrisulfonyl chloride in a suitable diluent with a suitable acid acceptor for about 40 minutes to 18 hours.

Suitable diluents are polar solvents such as pyridine, Acetonitrile or triethylamine.

Organic and inorganic bases can be used as such acceptors such as pyridine, triethylamine, sodium carbonate, sodium acetate, quinoline, calcium oxide, Calcium hydroxide or aluminum hydroxide.

The corresponding methyl derivatives of the above new intermediates are obtained by reacting these compounds in the presence of a strong base, such as sodium hydroxide, with methyl iodide. The novel trisubstituted naphthalene compounds of the formula according to the invention where R1 is hydrogen or methyl, R2 is hydrogen, carboxyl or COOR4, where R4 is an alkali metal or an alkaline earth metal, and R3 is hydrogen, hydroxy or COOR4, where R4 has the meaning given above, with the proviso that each phenyl ring is at least contain a group of the formula COOR4 mu / 3 can be prepared by first reacting a corresponding intermediate of the above formula for about 45 minutes to 16 hours in an alkali metal hydroxide and then reacting the resulting reaction mixture with a suitable weak acid, through which the N-alkali salt can be removed from the sulfamido radical, neutralized.

Sodium hydroxide, for example, is suitable as the alkali hydroxide, and a mineral acid or an alkanecarboxylic acid can be used as the weak acid Use 1 to 4 carbon atoms.

The compounds of the invention are remedies, and they excel are characterized in particular by a complement-inhibiting effect.

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 immunopathological reactions play. The reactions to which a complement participates, run in the blood serum or in other body fluids, and they are therefore referred to as humoral reactions.

According to the current state of knowledge, there is more in human blood than 11 proteins in the complement system. These complement proteins are identified by the letter C and denoted by a corresponding number as follows: C 1, C 2, C 3 and so on up to C 9. The complement protein C 1 is practically a complex of subunits, referred to as C 1 q, C 7 r and C 1 s. The ones given for the complement proteins Numbers indicate the order in which these complement proteins take effect, and the only exception to this is the complement protein C 4, which is produced according to 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 have already been made before full There was clarity about the sequence of reactions. For an in-depth discussion of the complement system and its role in processes taking place in the body Reference is made to the following literature: Bull.-World Health Orb. , 39: 935-938 (1968); Ann. Rev. Medicine 19: 1-24 (1968); The John Hopkins Med. J.

, 128: 57-54 (1971); Harvey Lectures, 66: 75-1-04 (1972); The New England Journal 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, Nov. October 1974, pages 53-58 and 64-66; J. Allergy Clin. Immunol. 53: 298-302 (1974); Cold Jumps Harbot Conf. Cell Proliferation 2 / Proteases Biol. Control / 229-241 (197-5-); Annals of Internal Medicine 84: 580-593 (1976); "Complement: Mechanisms and Functions '', Prentice-Hall, Engleood Cliffs, N.J. (1976).

The complement system can be seen as consisting of three sub-systems view: (1) a recognition unit (C 1 q), which is a combination with antibody molecules that have detected a foreign intruder, (2) an activation unit (C 1 r, C 1 s, C 2, C 4, C- 3), which on the adjacent membrane has a corresponding Place prepared, and (3) an attack unit (C 5, C 6, C 7, C 8 and C 9) which forms a so-called hole in the membrane.

The unit of attack of the membrane is not specific. You destroyed Intruders only de-halved because they are formed in their surroundings. To keep it minimal damage to the host's own Cells must have the activity of Attack unit must therefore be limited in time. This limitation arises in part through the spontaneous decay of activated complement and to the other part through the interaction between inhibitors and destructive enzymes. The control however, of the complement is not perfect, so that the host cells also suffer damage can. An immunity is therefore a double-edged sword.

Activation of the complement system also accelerates the Blood clotting. This effect comes about through the release transmitted by the complement of a coagulation factor from the platelets. Fragments and complexes of the biological effective complements can participate in reactions that damage the host cells, and these pathogenic reactions can lead to the development of immunocomplex diseases to lead.

For example, it comes through with some forms of nephritis the complement causes damage to the basement membrane of the kidney, causing protein from Blood enters the urine. This category includes, for example, those who are disseminated Disease called lupus erythematosus. - Their symptoms include nephritis, Visceral damage and skin eruptions. Treatment of diphtheria or tetanus injecting large amounts of antitoxin occasionally causes serum sickness, which is an immune complex disease. Even with a rheumatoid Arthritis are immune complexes involved.

Similar to disseminated lupus erythematosus, so acts This is also an autoimmune disease, the symptoms of which are characterized by pathological effects of the immune system in the host tissue. All in all therefore plays the complement system in inflammation, coagulation, fibrinolysis, in antibody-antigen reactions as well as in other metabolic processes Role.

In the presence of antibody-antigen complexes, the complement proteins decrease take part in a series of reactions leading to irreversible membrane damage if they occur in the vicinity of biological membranes. That Complement thus contrasts part of the body's defense mechanism Infections, but inflammation can also occur during the immunopathological process and cause tissue damage. about the nature of certain complement proteins, suggestions regarding the binding of the complement to biological membranes and the way in which the complement causes membrane damage is discussed in Annual Review in Biochemistry 38, 389 (1969) reported in more detail.

To inhibit the complement system, namely as complement inhibitors, A wide variety of substances have already been proposed. So, for example 3,3'-ureylenebis / 6- (2-amino-8-hydroxy-6-sulfo-1-naphtylazo) / benzenesulfonic acid tetrasodium salt (Chlorazole), heparin and a sulfated dextran have anticomplementary effects (British Journal of Experimental Pathology 33, 327-339 (1952)). The compound 8- (3-benzamido-4-methylbenzamido) naphthalene-1 -3, 5-trisulfonic acid (suramin) is used as a competitive inhibitor for the Complement system (Clin. Exp. Immunol. 10, 127-128 (1972)). In DE-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 connections with Complement-inhibiting 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 have all been used successfully Treatment of hereditary angioneurotic edema have been used, namely one Disease caused by an inherited incomplete or absent at all Function of the serum inhibitor of the activated first complement component (C-1 inhibitor) and the New England Journal of Medicine 286, 808-812 (1972) pointed out.

The compounds according to the invention can be used to inhibit complement in Body fluids can be administered in any suitable manner, for example oral, intra-articular or parenteral, and by such inhibition can then relieve or prevent reactions that depend on the function of the complement are, such as inflammatory processes and cell membrane damage, the induced by antigen-antibody complexes. Depending on the type of administration, the condition to be treated and the compound used in each case with a wide dosage range can be worked.

With appropriate intravenous or subcutaneous treatments the dose of active ingredient, for example, about 5 to 50 mg / kg / day, these doses im In the case of rapidly excreted salts can also be given every 6 hours. To the intra-articular treatment of large joints, such as the knee joint, active ingredient amounts of about 2 to 20 mg per joint and per week can be used, with smaller joints working with proportionally smaller doses. Of the Dosage range is to be adjusted in each case in such a way that it corresponds to the to be treated Warm-blooded animals give the respective optimal therapeutic effect. In general can use 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 are used per day. In a warm-blooded animal at 70 kg, the daily dose is usually about 350 mg to about 3.5 g. Unit doses the acid or the respective salt of the active ingredient can be about 0.5 to 500 mg thereof contain.

In general, they are particularly suitable for parenteral use the sodium salts of the acids according to the invention, but can also be used with other salts be worked, 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, aliphatic diamines such as decamethylenediamine, or aromatic diamines.

Some of these salts are soluble in water, others can be dissolved in Saline solutions dissolve and in turn others are insoluble, making them useful for making of suspensions can be used for injection. Just like the sodium salts Other salts, such as sodium or lithium salts, salts of ammonia can also be used or use alkaline earth salts such as calcium or magnesium salts. As can be seen These salts generally include derivatives of salt-forming cations.

The compounds according to the invention can be used for therapeutic purposes can be administered in the form of conventional pharmaceutical preparations. Such preparations can be formulated to suit oral or parenteral administrations let use. The active ingredient can be mixed with a pharmaceutically acceptable carrier be mixed, and this carrier can, depending on the form of administration desired, for example if one is suitable for oral or parenteral administration pharmaceutical form would like to have a wide variety of forms. The according to the invention Compounds can also be used for the manufacture of tablets.

Use preparations. To do this, the respective active ingredient is mixed with the usual ingredients for tablet production, such as corn starch, lactose, sucrose, Sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums or the like Materials to be used as non-toxic pharmaceutically acceptable diluents or serve as a carrier. Tablets or pills from the new preparations can be laminated or compounded in some other way making it a dosage form results through which the active ingredient over an extended or delayed period of time is released or comes into effect successively in a predetermined manner. For example, tablets or pills can have an inner and an outer dosage component included, the latter may have the form of a train over the former. Both components can be separated from each other by an enteric layer, which resists decomposition in the stomach and allows the internal component enters the duodenum intact or is released with a delay. For education A wide variety of materials can be used for such enteric layers or coatings use, and this includes, 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 consists of a styrene-maleic acid copolymer along with known materials necessary for the particular enteric desired The properties of the coating. The respective tablets or pills can be used with be colored with an appropriate non-toxic dye so that they are compliant look.

To liquid forms in which the preparations according to the invention may be included for administration, include appropriately flavored Edible oil emulsions 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 injections Isotonic preparations can be made using suitable preservatives contain.

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 having a such predetermined amount of active ingredient contains that in conjunction with the particular pharmaceutical required Diluent, carrier, or vehicle, the particular therapeutic effect desired results. The composition of the new dosage forms according to the invention is specified by the properties of the active ingredient and dO each desired therapeutic Effect or by limits, such as those of the compounding technology of such active ingredients to be determined. Individual examples of suitable oral dosage forms according to the invention are tablets, capsules, pills, powder packets, granulates, cachets, cachets, Teaspoons, drops, ampoules, vials, or divided multiples of the above Shapes or other shapes described herein.

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) - At. this test will activate the ability of human complement protein C 1 to destroy what is present in the liquid phase human complement protein C 2 in the presence of complement protein C 4 appropriate dilutions of the respective active ingredient are determined. An effective inhibitor protects the complement proteins C 2, C 1 and C 4.

(il) Test, Code 035 (C-3 to C-9 Inhibitor) - This test is used for the Ability of the late components of human complement (C 3 - C 9) to lyse of EAC 142 in the presence of appropriate dilutions of the respective test compound measured. An active inhibitor protects EAC 142 from human lysis Complement proteins C 3 - C 9.

(iii) Test, Code 036 (C-Deflection Inhibitor) - Subject to this test brittle human erythrocytes are lysed in autologous serum a deflection activated by Cobra-Venom factor in the presence of appropriate dilutions of the respective active ingredient. An inhibition of the deflection leads to a failure of the Lysis.

(iv) Forssman's Vasculitis Test - This test is educated in guinea pigs by intradermal injection of rabbit anti-Forssman antiserum die well-known complement-dependent damage, namely the so-called Forrsman vasculitis. For this determination, one measures the diameter, edema and hemorrhagia accordingly and indicates the extent to which a combined index of the values obtained here by a previous intraperitoneal injection of the active substance to be examined in each case is inhibited at an amount of 200 mg / kg, unless otherwise stated.

(v) Forssman Shock Test - By intravenous injection of anti-Forssman antiserum a lethal shock is produced in guinea pigs and compared with those treated Guinea pigs obtained values up to the mean time of death with those values how to obtain them using control animals examined at the same time.

(vi) Complement Height Reduction Test - In this test, leaves the guinea pigs treated in the above manner with active ingredient or others the treated animals bleed out to obtain the serum and determined the complement concentration in undiluted serum according to the capillary tube method described in US Pat. No. 3,876,376, comparing the values obtained with the values of control animals, who have not received any active ingredient.

(vii) Chapter 50 test - for this test, collected serum is added of guinea pigs in vitro with corresponding ~ amounts of each to be examined Active ingredient 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% inhibition.

The results obtained in the above investigations are as follows Table I. For this purpose guinea pigs with a weight of about 300 are used g, which are given either intravenously (i.v.) or intraperitoneally (i.p.) 200 mg / kg of the compound to be examined in each case, dissolved in saline solution -and adjusted to pH 7-8.

One hour after administration of the active ingredient, the guinea pigs are cut heads off, collects their blood and separates off the serum one the total complement of this serum by the so-called capillary tube method.

The results obtained in connection with the above experiments can- be taken, -that the compounds according to the invention in warm-blooded animals have a particularly strong complement-inhibiting effect both in vitro and in vivo.

T a b e l l e I Biological Activities In Vivo Activity Compound C1 C-late reversal inhibition (guinea pig) O26 * O35 * O36 * intraperitoneal tubes Tube tube cap. 50 * time (minutes) 30 60 120 5.5 ', 5 "- [1,3,6-naphthalene triyltrissulfonylimino)] tris [2-hydroxyiso- + 5 ** +1 +4 29 -69 -59 -58 phthalic acid] 5,5 ', 5 "- [1,3,6-naphthalenetriyltris- +4 N N 5-67-79 -84 (sulfonylimino)] triisophthalic acid- +6 N +2 hexasodium salt 3,3 ', 3 "- [1,3,6-naphthalenetriyltris- (sulfonylimino)] tris [6-hydroxy- +1 N N benzoic acid] 4,4 ', 4 "- [1,3,6-naphthalenetriyltris- +3 N N 411 (sulfonylimino)] tribenzoic acid- +4 N N trisodium salt 5,5 ', 5 "- [1,3,6-naphthalenetriyltris- +8 +1 +4 43 -63 -71 -71 (sulfonylimino)] - tris-1,2,3-benzenetri- +8 N +5 carboxylic acid sodium salt 3,3 ', 3 "- [1,3,6-naphthalenetriyltris- (sulfonylimino)] tribenzenic acid +3 N N # 500 trisodium salt T a b e l l e I (continued) Biological Activities in vivo activity compound C1 C-late reversal inhibition (guinea pigs) O26 * O35 * O36 * intraperitoneal tube tube tube cap. 50 * time (minutes) 30 60 120 5.5 ', 5 "- [1,3,6-naphthalenetriyltris- +6 N +2 22-84-88-96 sulfonylimino)] triisophthalic acid 5,5 ', 5 "- [1,3,6-naphthalenetriyltris- (sulfonylmethylimino)] triisophthal- +3 N N # 500 acid hexasodium salt N = negative * = code designation for the tests used ** = activity in tubes, serial dilution experiment. A larger number means higher activity. The serial dilutions are twofold.

EXAMPLE 1 5,5 ', 5 "- / 1,3,6-naphthalene triyltris (sulfonylimino) / tris / 2-hydroxyisophthalic acid / hexamethyl ester A mixture of 40 ml of concentrated sulfuric acid and 33 ml of concentrated nitric acid is slowly stirred with 10 ml of glacial acetic acid over a period of 10 minutes and a suspension of 10 g of 2-hydroxyisophthalic acid (manufactured according to Organic Synthesis Coll., Volume V, 617) added to 20 ml of glacial acetic acid. The reaction mixture is cooled, whereupon a further 10 ml of acetic acid is added. The resulting solid is dissolved in water and extracted with diethyl ether. The ether extract is made with washed saturated sodium chloride, dried over anhydrous sodium sulfate and then evaporated to give 2-hydroxy-5-nitroisophthalic acid in the form of a orange oil.

The above product is concentrated with 250 ml of methyl alcohol and 10 ml Treated sulfuric acid, whereupon the whole thing is heated to reflux temperature for 5 days. The reaction mixture is cooled and concentrated under vacuum, which leads to a solid. The solid is filtered off, with water and ether washed and finally air dried. By recrystallizing the thereby The material obtained from ethyl acetate leads to 2.84 g of 2-hydroxy-5-nitroiosphthalic acid dimethyl ester.

A mixture of 2.0 g of the above compound and 200 mg of a 10 percent Palladium-on-carbon catalyst in 200 ml of ethyl acetate is hydrogenated in a while Parr hydrogenator until no more hydrogen is absorbed. The reaction mixture is then filtered through diatomaceous earth, whereupon the filtrate turns to a yellow Solid evaporates.

The solid is recrystallized from ethyl acetate-hexane, whereby one arrives at 1.04 g of 2-hydroxy-5-aminoisophthalic acid dimethyl ester.

A mixture of 60.0 g of 1,3,6-naphthalenetrisulfonic acid sodium salt, 250 ml of thionyl chloride and 5 drops of dimethylformamide are refluxed for 16 hours heated. The resulting solid is filtered off and the filtrate is evaporated. The residue is treated with chloroform, filtered and washed with chloroform and dried to give 25.4 g of 1,3,6-naphthalenetrisulfonyl chloride in the form of a white solid is obtained. A solution of. 695 mg 2-Hydroxv-5-aminoisophthalic acid dimethyl ester, 10 ml of acetonitrile and. 270 mg of pyridine is mixed with 428 mg of 1,3,6-naphthalenetrisulfonyl chloride while stirring offset. The reaction mixture is stirred for 16 hours under an argon atmosphere, whereupon acidify with dilute hydrochloric acid and the acetonitrile under vacuum distilled off. The aqueous mixture is extracted twice with ether. The ether extract is evaporated, resulting in a brown oil, from which on treatment brown crystals are formed with ether.

The crystals are collected, washed with ether and under vacuum dried, whereby 780 mg of 5,5 ', 5 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / tris / 2-hydroxyisophthalic acid / hexamethyl ester in the form of a tan powder receives.

EXAMPLE 2 5,5 ', 5 "- / 1,3,6-suture-triyltris (sulfonylimino) / tris- / 2-hydroxyisophthalic acid / A solution of 680 mg of the product obtained according to Example 1 in 10 ml of 1N sodium hydroxide is stirred for 5 hours and then acidified with dilute hydrochloric acid. The gummy mass obtained in this way is separated, whereupon it is used twice Water and ethanol and then washed once with water. In this way a light brown powder is obtained. The filtrate obtained in this way is evaporated, on what the residue obtained several times with water and then washes with ether. In this way a brown crystalline powder is obtained. the both powders are combined, recrystallized from ethanol and dried under vacuum, resulting in 428 mg of the compound named in the title in the form of orange-brown crystals got.

EXAMPLE 3 5,5 ', 5 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / triisophthalic acid hexakis (2-methoxyethyl) ester A mixture of 500 g of 5-nitroisophthalic acid, 3500 g of thionyl chloride and 6.0 ml of dimethylformamide is slowly heated until the evolution of gas stops. After this, stirring is continued until a solution is formed Heating is continued for about 2 hours, after which the whole is refluxed for 30 minutes heated. The clear solution obtained is then left to stand and finally evaporated under vacuum to an oil. The oil solidifies and becomes carbon tetrachloride twice recrystallized, resulting in 501 g of 5-nitroisophthaloyl chloride.

A mixture of 100 g of the product obtained above and 100 g of 2-methoxyethanol (dried over molecular sieves) in 400 ml of acetonitrile (also dried over molecular sieves) is heated to reflux temperature in a water bath.

This is followed by a further 15 minutes of heating, after which the The mixture is cooled to room temperature and poured into 2 liters of cold while stirring vigorously Water there. The resulting product is filtered off and air-dried, resulting in 129 grams of material. By extracting the filtrate with benzene another product is obtained (5.7 g). The products are combined and poured into 580 ml dissolved in hot ethyl alcohol.

The solution is neutralized with 5.0 ml of 5N sodium hydroxide and then diluted with 450 ml of water. The solution is left until crystals form first stand at room temperature, whereupon the mixture is placed in a cold room overnight (5th OC). The colorless needles obtained in this way are the end a solution of 450 ml of ethanol and 350 ml of water, whereby one to 92.1 g of 5-nitroisophthalic acid bis (2-methoxyethyl) ester.

A total of 86.0.g of the product obtained in the above manner was hydrogenated one in 300 ml of ethyl acetate using 2.0 g of 10 percent palladium-on-carbon catalyst in a Parr shaker. The reaction mixture obtained in this way is filtered off and the filtrate was then evaporated. The whitish crystals obtained in this way -be dissolved in 350 ml of hot benzene, whereupon the solution is diluted with 140 ml of hexane. The solution is then left to crystallize overnight at room temperature, whereby 72.0 g of 5-aminoisophthalic acid bis (2-methoxy-ethyl) ester are obtained.

A solution of 15.16 g of the above product and 6.18 g of dimethylaniline 7.2 g of 1,3,6-naphthalenetrisulfonyl chloride are added to 75 ml of acetonitrile. The solution is refluxed on a water bath for 2 hours, whereupon pour it into 250 ml of cold water and stir to form a solid product. The product is filtered off, washed with water and then in 150 ml of a 2: 1 mixture dissolved from methylene chloride and methanol. The solution obtained is over anhydrous Sodium sulfate dried and evaporated to dryness in vacuo, whereupon the this resulting solid dissolves in 100 ml of methylene chloride. The solution turns 16 Dried over sodium sulfate for hours, filtered and while adding methanol concentrated on a water bath until two thirds of the methylene chloride are removed and a viscous colorless paste has formed. The mixture is increased to 250 with methanol ml and then filtered. The product is on the filter with methanol and Washed ether, whereupon it is air-dried for 16 hours. The material obtained is dissolved in 500 ml of refluxing acetonitrile, whereupon the solution is filtered and allowed to crystallize for 16 hours. The product will filtered off and dried, whereby 16.35 g of 5,5 ', 5 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / triisophthalic acid hexakis (2-methoxyethyl) ester in the form of a colorless powder receives.

EXAMPLE 4 5,5 ', 5 "- / 1,3,6-naphthalene-triyltris (sulfonylimino) / -triisophthalene acid hexasodium salt z A mixture of 9.05 g of the product obtained according to Example 3 and 45 ml of 2N sodium hydroxide is stirred for 45 minutes at room temperature. The solution is filtered, whereupon the filtrate is neutralized with 2.5 ml of glacial acetic acid and then diluted with 250 ml of ethanol. The product obtained is filtered off with ethanol and washed with ether and then dried to give 7.85 g of the title compound comes in the form of a yellow powder.

EXAMPLE 5 3,3 ', 3 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) -tris / 6-hydroxybenzoic acid / trimethyl ester A solution of 20.0 g of 5-aminosalicylic acid, 250 ml of methanol and 10 ml of concentrated Sulfuric acid is refluxed overnight. The reaction mixture it is cooled and made alkaline with dilute aqueous sodium carbonate solution and focused. The solid obtained is separated off and washed with water. The solid is then washed with ether, whereupon the ether is formed of a brown solid evaporated. The aqueous filtrate obtained above is with Ether extracted, whereupon the ether extract is dried over anhydrous sodium sulfate and evaporated to a brown solid. The solids are combined and taken out Recrystallized ether, resulting in 10.7 g of 5-aminosalicylic acid methyl ester.

A solution of 2.1 g of the compound 994 obtained above mg of pyridine and 10 ml of acetonitrile is mixed with 1.7 g of 1, - 3, 6-naphthalene trisulfonyl chloride offset. The reaction mixture is stirred for 16 hours with dilute hydrochloric acid acidified, concentrated and extracted with ether. The ether extract is saturated with Washed sodium chloride, dried over anhydrous sodium sulfate and evaporated, which gives -2.91 g of the compound mentioned in the title in the form of a pink Solid received.

EXAMPLE 6 3,3 ', 3 "- / 1,3,6-Napthalintrivltris (sulfonylimino) / - tris / 6-hydroxybenzoic acid / A solution of 1.5 g of the product obtained according to Example 5 in 25.0 ml of 1N sodium hydroxide is stirred for 48 hours at room temperature. The solution is then diluted with Acidified hydrochloric acid. The solid obtained is filtered off, with Washed with water and dried, resulting in 920 mg of the title compound comes in the form of a brown powder.

EXAMPLE 7 4,4 ', 4 "- [1,3,6-naphthalene triyltris (sulfonylimino / tribenzoic acid trimethyl ester A mixture of 10.7 g of p-aminobenzoate, 200 ml of acetonitrile and 5.59 g of pyridine is made 10.0 g of 1,3,6-naphthalenetrisulfonyl chloride were added while heating and stirring. The mixture is stirred further and heated to reflux temperature for 16 hours, - whereupon it is cooled and filtered off. The filtrate is poured into ice-cold water, whereby after stirring and leaving to stand at room temperature, a solid is formed. The solid is disconnected, washed with water, in 60 ml of 30 percent Acetone dissolved in benzene and filtered through anhydrous magnesium silicate. The the Magnesium silicate containing desired product is mixed with 30 percent acetone in Washed benzene and then treated with acetone to dissolve the product. The acetone eluates are combined and evaporated to a residue, which is then dissolved in 200 ml of acetonitrile solves. The whole thing is then left to stand in a cold room (5 "C) for 16 hours. The The white solid obtained is separated off and washed with acetonitrile and petroleum ether and finally dried at 70 "C, resulting in 12.0 g of 4,4 ', 4" - / 1, 3,6-naphthalenetriyltris (sulfonylimino) / trimethyl tribenzoate arrives.

EXAMPLE 8 4,4 ', 4 "- / 1, 3,6-naphthalenetriyltris (sulfonylimino) / - tribenzoic acid sodium salt 9.0 g of the product obtained according to Example 7 are dissolved in 46.5 ml of 2N sodium hydroxide and stir the whole for 45 minutes. The solution is neutralized with 2.7 ml of glacial acetic acid and then diluted with 200 ml of ethanol. The solid that forms is filtered off, washed with ethanol and ether and then dried, resulting in 8.7 g of the connection named in the title.

EXAMPLE 9 5,5 ', 5 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / - tri-1,23-benzenetricarboxylic acid nonaphenyl ester A mixture of 125 g of 1,2,3-benzenetricarboxylic acid and 900 ml of concentrated sulfuric acid is stirred at a temperature of 60 to 70 OC for a period of Slowly added 312 g of potassium nitrate for 2 hours. The mixture is on for 16 hours 135 to 140 OC heated, cooled and with Ice water treats. A certain amount of solid precipitates out and is dissolved in water. All of the aqueous The mixture is extracted with ether, whereupon the extract is washed with water and dries over magnesium sulfate. The ether is concentrated to a small volume, whereupon the whole thing is mixed with petroleum ether. The white solid obtained in this way is filtered off and dried, resulting in 76.5 g of 5-nitro-1,2,3-benzenetricarboxylic acid got.

A mixture of 50.0 g of the product obtained above, 300 ml of thionyl chloride and 2.0 ml of dimethylformamide are refluxed for 16 hours heated. The solvent is evaporated in vacuo and the residue in chloroform solved.

The chloroform is concentrated to a small volume and the residue dissolved in carbon tetrachloride. The yellow solid that forms on standing is collected and dried to give 30.0 g of material. A mixture of this Material with 100 ml of thionyl chloride and 2.0 ml of dimethylformamide is 16 hours heated to reflux temperature. The solvent is evaporated and the thereby resulting yellow solid recrystallized from chloroform and carbon tetrachloride, whereby 23.0 g of 5-nitro-1,2,3-benzenetricarbonyl chloride are obtained.

A solution of 30.6 g of phenol in 100 ml of pyridine (using molecular sieves dried) is stirred with 22.7 g of the product obtained above offset. The solution is heated on a water bath for 1 hour, cooled and taken under vigorous stirring poured into 500 ml of cold water. The reaction mixture is filtered and the resulting solid washed with water, resulting in a brown Powder arrives. This product is dissolved in 100 ml of methylene chloride, whereupon the whole filtered. The filtrate is heated to boiling on a water bath, whereupon the boiling solution is added in portions with a total of 250 ml of ethanol, until all of the methylene chloride is removed. That Mixture becomes cooled to room temperature, whereupon the product obtained is separated off with ethanol and ether washes and then dissolved in 75.0 ml of methylene chloride. By subsequent Recrystallize the resulting material from 200 ml of ethanol in the above described manner, separation and drying leads to 30.8 g of 5-nitro-1,2,3-benzenetricarboxylic acid triphenyl ester.

A solution of 29.0 g of the nitro compound obtained above in dimethylformamide is in the presence of 10 percent palladium-on-carbon catalyst hydrogenated in a Parr shaker. The reaction mixture is replaced by diatomaceous earth , filtered, whereupon the filtrate is diluted with water and extracted with methylene chloride. The extract is dried over anhydrous sodium sulfate and then added evaporated to an oil. The oil is crystallized from ether, whereupon the product is obtained recrystallized from benzene and three times from ethanol.

In this way, 15.0 g of 5-amino-1,2,3-benzenetricarboxylic acid triphenyl ester are obtained in the form of tan crystals.

A solution of 13.6 g of the product obtained above in 50 ml of pyridine (dried over molecular sieves 4A) is mixed with 4.24 g of 1,3,6-naphthalenetrisulfonyl chloride with stirring offset. The reaction mixture is stirred for 10 minutes and then left for 30 minutes heated on a water bath, cooled and dissolved in 300 ml of ice cold 2.5N hydrochloric acid pours. The mixture is stirred until the product solidifies. The material is filtered off, washed neutral with water and dried, resulting in 19.3 g crude product arrives. The crude product is chromatographed in the usual way, whereby a fraction containing 14.9 g of material is obtained. This material will be used twice recrystallized from a 2: 3 mixture of methylene chloride and ether and then dried, whereby 9.8 g of the compound mentioned in the title are obtained in the form of colorless crystals receives.

EXAMPLE 10 5,5 ', 5 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / tri-1,2,3-benzenetricarboxylic acid sodium salt 6.7 g of the product obtained according to Example 9 become 50 ml of 2N sodium hydroxide given, whereupon the whole thing is stirred for 30 minutes and then with 3.68 ml of glacial acetic acid offset. The solution is poured into 500 ml of absolute ethanol with vigorous stirring. The resulting fine-grained precipitate is filtered off, with ethanol as well Washed ether and then dissolved in 35.0 ml of water, the 1.0 g of sodium acetate trihydrate contains. The solution is filtered through diatomaceous earth and poured into 350 ml of absolute ethanol poured. By filtering and then drying the resulting material 5.3 g of the title compound are obtained in the form of a yellow powder.

EXAMPLE 11 3,3 ', 3 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / trimethyl tribenzoate A mixture of 10.7 g of methyl m-aminobenzoate, 80 ml of acetonitrile and 6-, 1 ml of pyridine 10.8 g of 1,3,6-naphthalenetrisulfonyl chloride are added with stirring. The mixture is heated to reflux temperature for 2 hours with further stirring and then cooled. The solution is poured into water, creating an oil that when standing and Stir becomes firm. The solid is dried, dissolved in acetonitrile and filtered. The solvent is removed in vacuo and the residue obtained is removed dries. In this way 16.0 g of the compound mentioned in the title are obtained in the form of a beige solid.

EXAMPLE 12 3,3 ', 3 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / tribenzoic acid trisodium salt A mixture of 12.0 g of the product obtained according to Example 11 and 62.0 ml of 2N sodium hydroxide is stirred for 45 minutes.

The solution is neutralized with 3.6 ml of glacial acetic acid, whereupon the Whole diluted with 400 ml of ethanol. The solvent is under vacuum except for one small volume removed. Then one dilutes the whole thing again with ethanol, whereby an oil separates. The solvent is decanted and the oil with fresh Treated ethanol to give a yellow solid. The solid will separated off, washed with ethanol and ether and then dried at 70 OC, whereby 7.3 g of the compound mentioned in the title are obtained.

EXAMPLE 13 5,5 ', 5 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / tritrii sophthalic acid A mixture of 12.06 g of the product obtained in Example 3 and 60 ml of 2N sodium hydroxide is stirred for 1 hour.

The yellow solution obtained is mixed with 65 ml of 2N hydrochloric acid acidified, which leads to a colorless, rubbery mass, which in the Will stand firm. The mixture is filtered off and the separated product with water washed neutral. The material is dried under vacuum, then pulverized and dried again, resulting in 8.36 g of the title compound in In the form of a colorless powder.

EXAMPLE 14 5,5 ', 5 "- / 1,3,6-naphthalene triyltris (sulfonylmethylimino) / triisophthalic acid hexakis (2-methoxyethyl) ester A solution of 6.03 g of the product obtained according to Example 3 in 25 ml of dimethylformamide is added dropwise with 3.25 ml with stirring and with cooling in a water bath 5N sodium hydroxide and then 3.75 ml of methaliodide are added. The mixture is stirred in a closed flask for a total of 3 hours at room temperature. The reaction mixture is then filtered off and the product obtained with a small amount of dimethylformamide washed on the filter. Then stir the whole thing with 100 ml of water, whereupon the product is separated off and dried. The product is dissolved in 30 ml of methylene chloride, whereupon the solution is replaced by diatomaceous earth filtered. The filtrate is heated to boiling with the addition of methanol until until the methylene chloride is removed. The mixture is then allowed to cool and crystallize.

The product is collected and dried, giving 5.7 g of colorless Crystals of the title compound arrives.

EXAMPLE 15 5,5 ', 5 "- / 1,3,6-naphthalene-triyltris (sulfonylmethylimino) / -triisophthalic acid hexasodium salt A solution of 5.0 g of the product obtained according to Example 14 in 40 ml of dioxane is 20 ml of 2N sodium hydroxide are added while heating and stirring. The reaction mixture is stirred vigorously for 10 minutes, after which it is mixed with 10 ml of water and a total of Continue stirring for 1 hour. The resulting solution is poured into 300 ml of absolute ethanol. The mixture is filtered and the product obtained in this way with ethanol and ether washed. The product is mixed with 1.0 g of sodium acetate trihydrate in 20 ml of water dissolved, whereupon the solution is poured into 250 ml of absolute ethanol. As obtained mixture is stirred for 1 hour and then filtered. The product is made with ethanol as well as ether washed and then dried, resulting in 4.22 g of those mentioned in the title Compound in the form of a beige powder.

EXAMPLE 16 Compressed Tablet Preparation Ingredients mg / tablet Active ingredient 0.5 - 500 Dibasic calcium phosphate N.F. qs Starch USP 40 Modified Starch 10 Magnesium Stearate USP 1-5 EXAMPLE 17 Preparation 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) dibasic calcium phosphate N. F. qs Alginic acid 20 Starch USP 35 Magnesium stearate USP 1 - 10 *) Complement inhibitor plus aluminum sulfate gives aluminum complement inhibitor. The complement inhibitor content in the aluminum sulphate preparation is 5 - 30%.

EXAMPLE 18 Preparation of Hard Shell Capsules Ingredients mg / tablet - Active ingredient 0.5 - 500 lactose, spray-dried - qs Magnesium stearate 1 - 10 EXAMPLE 19 Preparation of an orally administrable liquid (syrup) Ingredients by weight / volume Active ingredient 0.05 - 5 liquid sugar 75.0 methyl paraben USP 0.18 propyl paraben USP -0.02 Aroma qs Purified water qs ad 100.0 EXAMPLE 20 Preparation of an orally administrable Liquid (Elixir) Ingredients% by weight / volume of active ingredient 0.05 - 5 Alcohol US-P 12.5 glycerin USP 45.5 Ingredients% by weight / volume of syrup USP 20.0 Aroma qs Purified water qs ad 100.0 EXAMPLE 21 Preparation of an orally administrable Suspension (syrup) components weight / volume active ingredient in the form of a preparation 0.5 - 5 with aluminum sulfate, micronized (acid equivalent) Polysorbate 80 USP 0.1 Magnesium Aluminum Silicate, Colloidal 0.3 Flavor qs Methyl Paraben USP 0.18 Propyl Paraben USP 0.02 Liquid sugar 75.0 Purified water qs ad 100.0 EXAMPLE 22 Production an injectable suspension components wt .-% / volume active ingredient 0.05-5 benzyl alcohol N.F. 0.9 water for injection 100.0 EXAMPLE 23 Preparation of a Injectable oil components% by weight / volume of active ingredient 0.05-5 benzyl alcohol 1.5 Sesame oil qs ad 100.0 EXAMPLE 24 Production of an intraarticularly administrable Product Ingredients Amount of active ingredient 2 - 20 mg NaCl (physiological table salt) 0.9% benzyl alcohol 0.9% sodium carboxymethyl cellulose 1 - 5% pH adjusted to 5.0 - 7.5 water for injection qs ad 100% EXAMPLE 25 Preparation of an injectable Depot suspension components% by weight / volume of active ingredient 0.05 - 5 (acid equivalent) Components Weight% / Volume Polysorbate 80 USP 0.2 Polyethylene Glycol 4000 USP 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

Claims (18)

Claims 1. Trisubstituted naphthalene compounds of the formula where R1 is hydrogen or methyl, R2 is hydrogen, carboxyl or COOR4, where R4 is an alkali metal or an alkaline earth metal, and R3 is hydrogen, hydroxy or COOR4, where R4 has the meaning given above, with the proviso that each phenyl ring is at least must contain a group of the formula COOR4, and the non-toxic, pharmaceutically acceptable salts of these compounds. 2. Compounds according to claim 1, d a d u r c h g e -k e n n z e i c h n e t that each phenyl ring is only monosubstituted by a group of the formula COOR4 is. 3. Compounds according to claim 1, d a d u r c h g e -k e n n z e i c h n e t that each phenyl ring is only disubstituted by a group of the formula COOR4 is. 4. Compounds according to claim 1, d a d u r c h g e -k e n n z e i c h n e t that each phenyl ring is only trisubstituted by a group of the formula COOR4 is. 5. Compounds according to claim 2, d a d u r c h g e -k e n n z e i c h n e t that each phenyl ring is monosubstituted in the 3 or 4 position only and the variable phenyl ring is in position 6 on the naphthalene ring. 6. Compounds according to claim 3, d a d u r c h g e -k e n n z e i c h ne t that each phenyl ring is only disubstituted in the 3 and 5 positions and the variable phenyl ring is in position 6 of the naphthalene ring. 7. Compounds according to claim 4, d a d u r c h g e -k e n n z e i c h n e t that the variable phenyl ring is in position 6 on the naphthalene ring is located. 8. Compounds according to claim 1, d a d u r c h g e -k e n n z e i c h n e t that these are the following: 5,5 ', 5 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / tris / 2-hydroxyisophthalic acid /, 5,5 ', 5 "- / 1,3,6-naphthalene triyltris (sulfonylimino) / triisophthalic acid hexasodium salt, 3,3 ', 3 "- / 1,3,6-naphthalene triyltris (sulfonylimino) / tris / 6-hydroxybenzoic acid /, 4,4 ', 4 "- [1,3,6-naphthalenetriyltris (sulfonylimino)] tribenzoic acid trisodium salt, 5,5 ', 5 "- [1,3,6-naphthalenetriyltris (sulfonylimino)] tri-1,2,3-benzenetricarboxylic acid, sodium salt, 3,3 ', 3 "- [1,3,6-naphthalenetriyltris (sulfonylimino)] tribenzoic acid trisodium salt, 5,5 ', 5 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / triisophthalic acid, 5,5', 5" - / 1,3,6-naphthalenetriyltris (sulfonylmethylimino) -triisophthalic acid hexasodium salt. 9. Trisubstituted naphthalene compounds of the formula where R5 is hydrogen or methyl, R6 is hydrogen, methoxycarbonyl, 2-methoxyethoxycarbonyl or phenoxycarbonyl and R7 is hydrogen, hydroxy, methoxycarbonyl or phenoxycarbonyl. 10. Compounds according to claim 9, d a d u r c h g e -k e n n z e i Note that each phenyl ring is tri-substituted. 11. Compounds according to claim 10, d a d u r c h g e -k e n n z e i c h e t that each phenyl ring is with either 2-methoxyethoxycarbonyl or phenoxycarbonyl is only trisubstituted and the variable phenyl ring is in position 6 of the Naphthalene ring is located. 12. Compounds according to claim 9, d a d u r c h g e -k e n n z e i c h n e t that these are the following: 5,5 ', 5 "- / 1,3,6-naphthalene triyltris (sulfonylimino) / tris / 2-hydroxyisophthalic acid / hexamethyl ester, 5,5 ', 5 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / triisophthalic acid hexakis) / methoxyethyl) ester, 3,3 ', 3 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) / tris / 6-hydroxybenzoic acid / trimethyl ester, 4,4 ', 4 "- / 1,3,6-naphthalenetriyltris (sulfonylimino) tribenzoic acid trimethyl ester, 5,5 ', 5 "- [1,3,6-naphthalenetriyltris (sulfonylimino)] tri-1,2,3-benzenetricarboxylic acid nonaphenyl ester, 3,3 ', 3 "- [1,3,6-naphthalenetriyltris (sulfonylimino)] tribenzoic acid trimethyl ester, 5,5 ', 5 "- / 1,3,6-naphthalenetriyltris (sulfonylmethylimino) / triisophthalic acid hexakis (2-methoxyethyl) ester. 13. Method of inhibiting the complement system in body fluid of a warm-blooded animal, d u r c h e -k e n n n n z e i c h n e t that one is such Body fluid containing an effective anti-complementary amount of a compound treated according to claim 1 to 8. 14. The method according to claim 13, d a d u r c h g e -k e n n z e i c Doesn't mean that blood serum is treated as a body fluid. 15. Method of inhibiting the complement system in body fluid of a warm-blooded animal, d u r c h e -k e n n n n z e i c h n e t that one is such Warm-blooded animals internally claim an effective complementary inhibiting amount of a compound 1 to 8 administered. 16. A method for producing a trisubstituted naphthalene compound according to claim 1 to 8, d u r c h g e k e n n -z e i c h n e t that one The compound of claim 9 first with an alkali hydroxide for about 45 minutes up to 16 hours treated and the resulting reaction mixture then with a weak acid, through which the N-alkali metal salt of the sulfamido radical can be removed, neutralized. 17. The method according to claim 16, d a d u r c h g e -k e n n z e i c It does not mean that sodium hydroxide is used as the alkali hydroxide and sodium hydroxide as the weak one Acid a mineral acid or an alkanecarboxylic acid with 1 to 4 carbon atoms begins. 18. The method according to claim 17, d a d u r c h g e -k e n n z e i c Do not use glacial acetic acid as a weak acid.