CA1120953A - Trisubstituted naphthalene compounds - Google Patents
Trisubstituted naphthalene compoundsInfo
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- CA1120953A CA1120953A CA000301048A CA301048A CA1120953A CA 1120953 A CA1120953 A CA 1120953A CA 000301048 A CA000301048 A CA 000301048A CA 301048 A CA301048 A CA 301048A CA 1120953 A CA1120953 A CA 1120953A
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- acid
- compound
- sulfonylimino
- naphthalenetriyltris
- hydrogen
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Abstract
26,720 ABSTRACT OF THE DISCLOSURE
1,3,5- or 1,3,6-naphthalenetriyltris(sulfonylimino)-aryl acids and salts, useful as complement inhibitors, and 1,3,5- or 1,3,6-naphthalenetriyltris(sulfonylimino)aryl acid esters which are intermediates, and the method for their preparation.
1,3,5- or 1,3,6-naphthalenetriyltris(sulfonylimino)-aryl acids and salts, useful as complement inhibitors, and 1,3,5- or 1,3,6-naphthalenetriyltris(sulfonylimino)aryl acid esters which are intermediates, and the method for their preparation.
Description
.~Z~g;~3 The present invention relates to naphthalenetrlyltris-(sulphonylimino benzene carboxylic~ acid derivatives. The novel derivatives are complement inhibitiny compounds useful in the medicinal field.
According to the invention there are provided new compounds of the formula:
According to the invention there are provided new compounds of the formula:
2 NZ ~ 3 (I) ~ ~ / 2 2 wherein Rl is hydrogen or methyl; R2 is hydrogen, carboxyl or COOR4 wherein R~ is alkali metal or alkaline earth metal; R3 is hydrogen,hydroxy or COOR4, wherein R4 is as previously defined;
with the proviso that each phenyl must contain at least one COOR4.
According to the invention, the compounds of formula I
above are prepared by a process which comprises hydrolyzing a compound of the formula:
R7 ~ 25 ~ ~ ~
wherein R5 is hydrogen or methyl; R6 is hydrogen, methoxycarbonyl, 2-methoxyethoxycarbonyl or phenoxycarbonyl; and R7 is hydrogen, hydroxy, methoxycarbonyl or phenoxycarbonyl; in an alkali metal hydroxide and then neutralizing with a suitable weak acid capable of remo~ing the N-alkali salt of the sulfamido moiety; when required reacting a compound of general formula (I) wherein Rl is hydrogen with methyl iodide in the presence of a strong base to give a compound of the general formula (I) wherein Rl is a methyl group, and when required converting the free acid into an alkali metal or alkaline earth metal salt thereof~
A preferred emkodiment of the invention consists in the preparation of those compounds wherein each phenyl is only mono-sukstituted from the group consisting of OOOR4, wherein R4 is as previously defined.
A second preferred embodiment of the in~ention consists of those compounds wherein each phenyl is only disubstituted from the group consisting of COOR4, wherein R4 is as previously defined.
A third preferred embodimRnt of the invention consists in the preparation of those campounds wherein each phenyl is only tri~substituted from the group consisting of OOOR4, wherein R4 is as pre~iously defined.
A most preferred e~bodiment consists in the preparation of those co~pounds wherein each phenyl is only mono-substituted at the carbon 3-position or carbon 4~position and the floating phenyl is at the carbon 6-position on the naphthalene.
A further most preferred embodinx~l-t consists in the preparakion of those compounds ~herein each phenyl is only disubstituted at the carbon
with the proviso that each phenyl must contain at least one COOR4.
According to the invention, the compounds of formula I
above are prepared by a process which comprises hydrolyzing a compound of the formula:
R7 ~ 25 ~ ~ ~
wherein R5 is hydrogen or methyl; R6 is hydrogen, methoxycarbonyl, 2-methoxyethoxycarbonyl or phenoxycarbonyl; and R7 is hydrogen, hydroxy, methoxycarbonyl or phenoxycarbonyl; in an alkali metal hydroxide and then neutralizing with a suitable weak acid capable of remo~ing the N-alkali salt of the sulfamido moiety; when required reacting a compound of general formula (I) wherein Rl is hydrogen with methyl iodide in the presence of a strong base to give a compound of the general formula (I) wherein Rl is a methyl group, and when required converting the free acid into an alkali metal or alkaline earth metal salt thereof~
A preferred emkodiment of the invention consists in the preparation of those compounds wherein each phenyl is only mono-sukstituted from the group consisting of OOOR4, wherein R4 is as previously defined.
A second preferred embodiment of the in~ention consists of those compounds wherein each phenyl is only disubstituted from the group consisting of COOR4, wherein R4 is as previously defined.
A third preferred embodimRnt of the invention consists in the preparation of those campounds wherein each phenyl is only tri~substituted from the group consisting of OOOR4, wherein R4 is as pre~iously defined.
A most preferred e~bodiment consists in the preparation of those co~pounds wherein each phenyl is only mono-substituted at the carbon 3-position or carbon 4~position and the floating phenyl is at the carbon 6-position on the naphthalene.
A further most preferred embodinx~l-t consists in the preparakion of those compounds ~herein each phenyl is only disubstituted at the carbon
3,5 position and the floating phenyl is at the carbon 6-position on the naphthalene.
A third most preferred embodiment consists in the preparation o-f those compounds wherein the floating phenyl is at the carbon 6-position on the naphthalene.
The intermediates for preparing the compounds of formula (Il are the compounds of the for~ula:
~ I
~Zq~ i3 ~ 5 R6 S2 _ N
R5 \ ~ ~ ~ ~ R
wherein R5 is selected from the gxoup consisting of hy~rogen and methyl; R6 is selected from the group consisting of hydrcgen, methoxycarbonyl, 2-methoxyethoxycarbonyl and phenoxycarbonyl; and ~ is selected from the group consisting of hydrogen, hydro~y, methoxycarbonyl and phenoxycar~onyl.
A preferred embodiment of these intermediates consists of those ccmpounds wherein each ph nyl is only trisubsti-tuted.
A most pre~rred embodlment of the intermediates consists of those compGunds wherein said phenyl is only trisubstituted with ei-ther 2~
methoxyethoxycarbonyl or pheno~y carbonyl and the floating phenyl is at the carbon 6-position of the napthalene.
-2a-~' The novel intermediates of this invention may be prepared as set forth immediately below. A compound of the formula:
~Z l R7~ o2 wherein R6 is selected from the group consisting of hydrogen, methoxycarbonyl, 2-methoxyethoxycarbonyl and phenoxycarbonyl.;
and R7 is selected from the group consisting of hydrogen, hydroxy, methoxycarbonyl and phenoxycarbonyli is made by reacting a compound o~ the formula: ' ~O~
R8OOC ~ COORg Rg wherein R8 is selected from the group consisting of Cl-C6 alkyli and Rg is selected from the group consis-ting of hydrogen, hydroxy and COOR8, wherein R8 is as previously 5 , defined; with 1!3,6-naphthalenetrisulfonyl chloride in a suita~le diluent ~ith a suita~le acceptor for a~out 40 minutes to about 18 hours. The suitable diluent is selected from the group of polar solvents such as pyridine t acetonitrile t triethylamine and the like ~3L2~ ~3 The suitable acid acceptor is selected from the group of organic and inorganic bases such as pyridinel triethylamine, sodium carbonatel sodium acetate, quinoline r calcium oxide, calcium hydroxide and aluminum hydroxide. The methylated form of the novel intermediates is obtained by - 3a ~
LZ~i3 reacting them with methyl iodide in the presence of a strong base such as sodium hydroxide.
The novel complement inhlbitin~ compounds of thi~
invention clr~ as set forth immedi~tely below. A compound of the formula:
R
~ 1 ~ 2 R~ R~ 2 10 1~3?~N 2 SO_N~
~2 ~ R2 !
wherein Rl is selected from the group consisting of hydrogen and methyl; R2 is selected from the group consisting of hydrogen, carboxyl and COOR4, wherein R4 is selected from the group consisting of alkali metal and alkaline earth metal;
R2 is selected from the group consisting of hydrogen, hydroxy and C~OR4, wherein R4 is as previoùsly defined; with the proviso that each phenyl,must contain at least one COOR4i ZO is made by reacting the appropriate novel intermediates, as -shown and described above, in an alkali metal ~.ydroxide for about 45 minutes to about 16 hours and then neutralizing with a suitable weak acid capable of removing the N-alkali salt of the sulfamido moiety. The alkali metal hydroxide may be sodium hydroxide or the like~ and the weak acid may he a,mineral aci,d of Cl-C4 alkanoic acid.
The term "complement" refers to a complex group of proteins in body fluids that, working together with antibodies or other factors ! play an important role as mediators of immune, immunochemical and~or immunopathological ~ 4 reaction$. The react~ons ~n whi~ch complement pa~t~c~p~tes take place ln ~lood serum or ~n other body ~lu~ds ! and hence are considered to ~e ~umoral reactions, - 4a ;~' ~2~ i3 With regard to human blood, there are at present more than 11 proteins in the complement system. These com-plement proteins are designated by the letter C and by number;
Cl, C2, C3 and so on up to C9. ~he complement protein Cl is actually an assembly of subunits designa~ed Clq~ Clr and C15.
The numbers assigned to the complement proteins reflect the sequence in which they become active~ with the exception of complement protein C4, which reacts after Cl and before C2.
The numerical assignments ~or the proteins in the complement system were made before the reaction sequence was fully under-stood. A more detailed discussion of the comp]ement system and its role in body processes can be found in, for example, Bull. World Health Org., 39, 935-938 (1968); Ann. Rev. Medicin~
19, 1-24 (1968); The John Hopkins Med. J., 128, 57-74 (1971);
Harvey Lectures, 66, 75-~04 ~1972); The New England Journal of Medicine, 287, 452~454; 489-495; 545-549; 592-5~6; 642-646 (1972); Scientific American, 229, (No. 5), 54-66 (1973);
~ederation Proceedings, 32, 134-137 (1973); Medical World News, October 11, 1974, pp. 53-58; 64-66; J~ Allergy Clin. Immunol., 53, 298-302 (1974); Cold Spring Harbor Conf. Cell Proliferatior 2/Proteases Biol. Control/229-241 (1975); Annals of Internal Medicine, _ , 580-593 11976); "Complement: Mechanisms and Functions", Prentice-llall, Englewood Cliffs, N. J. (1976).
The complement system can be considered to consist of three sub-systems: (1) a recognition unit (Clq) which en-ables it to combine with antibody molecules that have detected a foreign invader; (2) an activation unit (Clr, Cls, C2, C4, C3) which prepares a site on the neighboring membrane; and (3) and attack unit (C5, C6, C7, C8 and C9) which cr~ates a "hole" in the membrane. The membrane attack unit is non--specific; it destroys in~aders only because it is ge}lerated in their neighborhood. In order to minimi2e damage to the host's own cells, its activity must be limited in time. This ~2~ii3 limitation is accomplished partly by the spontaneous decay of activated complement and partly by interference ~y inhibitors and destructive enzymes. The control of complement, however, is not perfect, and there are time~ when damage is done to the host's cells. Immunity is therefore a double-2dged sword.
Activation of the complement system also accelerates blood clotting. This action comes about by way of the comple-ment-mediated release of a clotting ~actor from platelets.
The biologically active complement fragments and complexes can become involved in reactions th~t damage the hostls cells, and these pathogenic reactions can result in the development of irnmune-complex diseases. For example, in some forms of nephri-tis, complement damages the basal membrane of the kiclney, re-sulting in the escape of protein from -the blood into the urine The disease disseminated lupus erythematosus belongs in this category; its symptoms include nephritis, visceral lesions and skin eruptions. The treatment of diphtheria or tetanus with the injection oE large amounts of antitoxin sometimes results i~ serum sickness, an immune-complex disease. Rheuma-toid arthritis also involves i~nune complexes. Like dissemin-ated lupu5 erythematosus, it is an autoimmune disease in which the disease symptoms are caused by pathological effects of the irnmune system in the host's tissues. In summary, the comple-rnent system has been shown to be involved with inflammation, coag~lation, fibrinolysis, antibody-antigen reactions and other metabolic processes.
In the presence of antibody-antigen complexes the complement proteins arei in~olved in a series of reactLons which may lead to irreversible membrane damage if they occur in the vicinity of biological membranes. Thus, while complement constitutes a part of the body's defense mechanism against infection it also results in inflammat~on and tlssue damage in the immunopathological process. The nature of the com-- 6a -~L~2~
plement proteins, suggestions regarding the mode of complement bindin~ to biological membranes and the manner ln which com-plement effects membrane damage are discussed in Annual Review in Biochemistry, 38, 389 (1969~.
A vari.ety of substances have been disclosed as in-hibiting the complement system, i.e., as complement inhibitors.
For example, the compounds 3,3'-ureylenebis-l6-(2-amino-8--hydroxy-6-sulfo-1-naphthylazo)]benzenesulfonic acid, -tetra-sodium salt (chlorazol fast pink), heparin and a sulphated dex~ran have been reported to have an anticomplementary effect, British Journal of Experimental Pathology, 33, 327-33g (1952)~
The compound 8-(3-benzamido-4-methylhenzamido)naphthalene-1,-3,5-trisulfonic acid (Suramin) is described as a competitive inhibitor of the complement system, Clin. Exp. Immunol., 10, 127-138 ~1972). German Patent No. 2,254,893 or South African Patent No. 727,923 discloses certain 1-(di~henylmethyl)-4--(3-phenylallyl)piperaæines useful as complement inhibitors.
Other chemical compounds having complement inhibiting activity are disclosed in, for example, 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, 1041 279-288 (1970); The Journal of Immunology, 106, 241-245 (1971~; and The Journal of Immunology, 111, 1061-1066 (1973).
It has been reported that the known complement in-hibitors epsilon-aminocaproic acid, Suramin and tranexamic acid all have been used with success in the treatment of her-editary angioneurotic edema, a disease state resulting from an inheri.ted defici.ency or lack of Eunction of the serum in-hibitor oE the activated first component of complement (Cl inhibitor), The New En~land Journal of Medicine, 286, 808-812 (1972).
~ 3 3 The compounds of the present invention may be admin-istered internallyr e.g., orally, intra-articularly or paren-terally~ e.g., intra-articular, to a warm blooded animal to inhibit complement in the body fluid of the animal, such in-hibition being useful in the amelioratioll or pr~vention of those reactions dependent upon the fullction of complement, such as inflammatory process and c~ll membrane dama~e induced by anti~en-antibody complexes. A range of doses may be em-ployed depending on the mo~e of administration 7 the condition being treated and the particular compound being used. For example, for intravenous or subcutaneous use from about 5 to about 50 mg/kg/day, or every six hours ~or more rapidly ex-creted salts, may be used. For intra-articular use for large joints such as the knee, rom about 2 to about 20 mg~joint pex week may be used, with proportionally smaller doses for smal-ler joints. The dosage ran~e is to be adjusted to provide optimum therapeutic response in the warm-bloodéd animal being treated. In general, the amount of compound administered can vary over a wide range to provide from about 5 mg/kg to about 100 mg/kg of body weigh~ of animal per day. The usual daily dosage for a 70 kg subject may vary from about 350 mq to about 3.5 g. Unit doses of the acid or salt can contain from about 0.5 mg to about 500 mg.
While in general the sodium salts of the acids of ~he invention are suitable for parenteral use, other salts may also ~e prepared, such as those of prirnary amines, e.g., ethylamine; secondary amines, e.g., diethylamine or diethanol amine; tertiary amines, e.g., pyridine or triethylamine or 2 dimethylaminomethyl-dibenzofuran; aliphatic diamines, e.~., decamethylenediamine; and aromatic diamines, can be prepared.
Some of these are soluble in water, others are soluble in saline solution, and still others are insoluble and can be used Eor purposes of preparing suspensions for injectionO
Furthermore as well as the sodium salt, those of the alkali metals, such as potassium and lithium; of ammonia; and of the alkaline earth metals, such as calci~n or magnesium, may be employed~ It will be apparent, therefore, that these salts embrace, in c3eneral derivatives of salt-forming cations.
In therapeutic use, the compounds of this invention may be administered in the form of conventional pharmaceutical compositions. Such compositions may be formulated so as to be suitable for oral or parenteral administration. The active ingredient may be combined in admixture with a pharmaceutic-ally acceptable carrier, whlch carrier may take a wide variety of forms depending on the fo~n of preparation desired for administration, i.e., oral or parenteral. The compounds can be used in compositions such as tablets. Here, -the principal active ingredient is mixed with conventional tabletting ingre-dients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesi~n stearate, dicalcium phosphate, gums, or similar materials as non-toxic pharmaceutically acceptable diluents or carriers. The tablets or pills of the novel com positions ca~ be laminated or otherwise compounded to provide 2~ a dosage form affording the advantage of prolonged or delayed action or predetermined successive action of the enclosed medi cation. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist dis-integration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or coatings, such materials including a number of polymcric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate and the like.
particularly advantageous enteric coating comprises a styrene maleic acid copolymer to~3ether with known materia:Ls contribu-~3 ting to the enteric properties of the coatinq. The tablet or pill may be colored through the use of an appropriate non--toxic dye, so as to provide a pleasing appearance.
The liquid forms in which the novel compositions of the present invention may be incorporated for administra-tion include suitable flavored emulsions with edible oils, such as, cottonseed oil, sesame oil, coconut oil, peanut oil, and the like, as well as elixirs and similar pharmaceutical vehicles. Sterile suspensions or solutions can be prepared for parenteral use~ Isotonic preparations containing suitable preservatives are also desirable for injeCtiQn use~
The term dosa~e form, as described herein, refers to physically discrete units suitable as unitary dosaqe for warm-blooded animal subjects, each unit containing a predeter-mined quantity of active component calculated to produce the desired therapeutic effect in as~ociation with the re~uired pharmaceutica~ diluent, carrier or vehicle. The specification for the novel dosage forms of this invention are indicated by characteristics of the active component and the particular therapeutic effect to be achieved or the limitations inherent in the art of compounding such an active component ior thera-peutic use in warm-blooded animals as disclosed in this speci-fication. Examples of suitable oral dosage forms in accord with this invention are tablets, capsules, pills, powder pack-ets, qranules, wafers, cachets, teaspoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foreqoing and other forms as herein described.
The complement inhibiting activity of the compounds of this invention has been demonstrated by one or more of the followinq identified tests: (i) Test, Code 026 tC1 inhibitor) This test measures the ability of activated human C1 to destro fluid phase human C2 in the presence of C4 and appropriate di-lutions of the test compound. An active inhibitor protects C2 from Cl and C4; (ii) Test, Code 035 (C3-C9 inhibitor) -This test determines the ability of the late components of human complement (C3-C9) to lyse EAC 142 in the presence of appropriate dilutions of the tes-t compound. An active inhibi-tor protects EAC 142 from lysis by human C3-C9; (iii) Test, S Code 036 ~C-Shunt inhibitor) - In this test human erythrocytes rendered fragile are lysed in autologous serum via the shunt pathway activated by cobra venom factor in the presence of appropriate dilutions of the test compound. Inhibition of the shunt pathway results in failure of lysis; (iv) Forssman Vas-culitis Test - Here~ the well known complement dependent les-ion, Forssman vasculitis, is produced in guinea pigs by intra-dermal injection of rabbit anti-Forssman antiserumO rrhe les-ion is measured in terms of diameter, edema and hemorrhage and the extent to which a combined index of these is inhibited by prior intraperitoneal injection of the tsst compound at 200 mg is then reported, unless otherwise stated; (v) Forssman Shock Test - Lethal shock is produced in guinea pigs by an i.v. in-jection of anti-Forssman antiserum and the harmonic mean death time of treated guinea pigs is compared with that of simul-taneous controls; (vi) Complement Level Reduction Test - In this test, the above dosed guinea pigs, or others, are bled for serum and the complement level is determined in undiluted serum by the capillary tube method of U.S. Patent No. 3,876,37 and compared to undosed control guinea pigs; and (vii) Cap 50 2S Test - Here, appropriate amounts of the test compound are addec to a pool of guinea pig serum in vitro, ~fter which the undi-luted serum capillary tube assay referred to above is run. Th~
concentration vf compound inhibiting 50% is reported.
With reference to Table I, guinea pigs weighing about 300 g were dosed intravenously (i.v.) or intraperito-neally (i.p.) with 200 mg/kg of the test compound dissolved in saline and adjusted to pl~ 7-8. One hour after dosing, the -- l 1 --guinea pigs were decapitated, blood was collected and the serum separated. The serum was tested for whole complement using the capilla~y tube assay~ Percent inhibition was cal-culated by comparison with simultaneous controls. The results appear in Table I together with results of tests, code 026, 035, 036, Cap 50, % inhibition and Forssman shock. Table I
shows that the compounds of the invention possess highly sig-nificant in _tro and ln vivo, complement inhibiting activity in warm-blooded animals.
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~Z~)9~3 5,5~,5"-l1,3,6-Naphthalenetriyltris(sulfonylimino)]-ester To a mixture of 40 ml of concentrated sulfuric acid and 33 ml of concentrated nitric acid stirrecl for 10 minutes is slowly added 10 ml of glacial acetic acid and a suspension of 10 g of 2-hydroxyisophthalic acid (prepared as described in Organic Synthesis Coll., Vol. V, 617) in 20 ml of glacial acetic acid. The reaction mixture is cooled and an additional 10 ml of acetic acid is added. The solid formed is dissolved in water, and is extracted with diethyl ether. The ether extract is washed with saturated sodium chloride, dried over anhydrous sodium sulEate ancl evaporated to an orange oil identifiecd as 2-hydroxy-5-nitroisophthalic acid.
The product is treated with 250 ml of methyl alcohol and 10 ml of concentrated sulfuric acid, and is reflux~
for 5 days. The reaction mixture is cooled and concentrated in vacuo to afford a solid. The solid is collected by fil-tration, washed with water, followed by ether, then is air dried. The material is recrystallized from ethyl acetate~
-hexane to afford 2.84 g of 2-hydroxy-5-nitroisophthalic acid dimethyl ester.
A 2.0 g portion of the preceding compound and 200 mg of 10% palladium on carbon catalyst in 200 ml of ethyl acetate is hydrogenated on a Parr shaker until no additional hydrogen is absorbed. The reaction mixture is then filtered through diatomaceous earth. The Eiltrate is evaporated to afford a ycllow soli~1. 'I`he ~olicl is rccryst~]li~c(l ~rom cthyl acetate--hexane to yield 1.04 g of 2-hydroxy-S-aminoisophthalic acid dimethyl ester.
A mixture of 60.0 g of 1,3,6-naphthalenetrisulfonic acid trisodium salt, 250 ml of thionyl chloride and 5 drops Q~5i3 of dimethyl~ormamide is refluxed for 16 hours. The solid is removed by filtration and the filtrate is evaporated.
The residue is triturated with chloroform, and filtered, washed with chloroform, and dried to yield 25.4 g of l,3,6-naphthalenetrisulfonyl chloride as a whi-te solid.
To a stirred solution of 695 mg of 2 hydroxy--5-aminoisophthalic acid dimethyl ester~ l~ ml of acetonitrile and 270 mg of pyridine is added 428-mg of 1,3,6-naphthalenetrisulfonyl chloride. The reaction mixture is stirred for 16 hours under an atmosphere of argon, then is acidified with dilute hydrochloric acid~
and the acetonitrile is removed by distillation ln vacuo.
The aqueous mixture is extracted twlce with ether. The ether extract is evaporated to yield a brown oil which affords brown crystals on being worked with ether. The crystals are collected, washed with ether, and dried in vacuo to give 780 mg of 5,5',5'-[1,3,6-naph*halenetriyl~
tris(sulfonylimino]tris[2-hydroxyisophthalic acid~hexa-methyl ester as a tan powder.
Example 2 5,5l,5"-[1,3,6-Naphthalenetriyltris(sulfonylimino)]-tris[2-hydroxyisophthalic acid]
A solution of 680 mg of the product of Example l in lO ml of l_ sodium hydroxide is stirred for 5 hours, then is acidified with dilute hydrochloric acid to afford a~ hxo~n ~um. The gum is separated and washed twice with bokh water and ethanol, then once with ether affording a light brown powder. The filtrate above is evaporated and the resulting residue is washed several times with water, then ether, affording a brown crystalline powder. The ~ ;.,~, fractions are combinedf recrystaill~i`zed from ethanol~
and dired ~ va~uo to yield 428 mg of the product of :~
the Example as orange-~ro~n crystals.
- 16a --~2~9~ii3 Example 3 5,5',5"-il,3,6-Naphthalenetr yltris(sulfonylimino)]-triisophthalic acid hexakis(2-n!ethoxyethyl~ester A mixture of 500 g of 5-nitroisophthalic acid, 3500 g of thionyl chloride and 6.0 ml of dimethylformamide is heated gradually until the evolution of gases subsides. Heat-ing is continued for approximately 2 hours with stirring until solution is achieved, then reflux is continued for an addi-tional 30 minutes. The resulting clear solution is allowed to stand, then is evaporated in acuG to afford an oil. The oil solidifies and is recrystallized twice from carbon tetra-chloride to give 501 g of 5-nitroisophthaloyl chloride.
A mixture of 100 g of the product above and 100 g of 2-methoxyethanol ~dried over molecular sieves) in 400 ml of acetonitrile (dried over molecular sieves) is heatecl to lS reflux on a steam bath~ ~leating is continued for 15 minutes, then the mixture is cooled to room temperature and poured into 2 liters of cold water with vigorous stirring. The pro-duct is collected by filtration and air dried to give 129 g of material. Additional product (5.7 g) is recovered from the filtrate by extraction with benzenev The combined frac-tions are dissolved in 530 ml of hot ethyl alcohol. The solu-tion is neutralized with 5.0 ml of 5N sodium hydroxide, then diluted with 450 ml of water. The solution is kept at room temperature, crystals separate, and then the mixture is placed overnight in a chill room (5C). The colorless needles are recrystallized from a solution of 450 ml of ethanol and 350 ml of water to give 92.1 g of 5-nitroisophthalic acid bis(2--methoxyethyl)ester.
A total of 86.0 g of the preceding product is hydrogenated on a Parr shaker in 300 ml of ethyl acetate using 2.0 g of 10% palladium on carbon catalyst. The mixture is filtered and the filtrate evaporated to give off-white crys-~ 17 -3L~Z~3 tals. The crystals are dissolved in 350 ml of hot benzene and diluted with 140 ml of hexane~ The solution is allowed to crystallize overnigh-t at room temperature to yield 72.0 g of 5-aminoisophthalic acid bis(2-methoxyethyl)ester.
To a solution of 15.16 g of the product above and 6.18 g of dimethylaniline in 75 ml of acetonitrile is added 7 . 2 g of 1, 3 1 6 -naphthalenetrisulfonyl chloride. The solution is refluxed on a steam bath for 2 hours, then is poured into 250 ml of cold water and stirred until a product is solidi-fied. The product is collected and washed with water, then is dissolved in 150 ml of methylene chloride:methanol ~2:1) and the solution is dried over anhydrous sodium sulfate.
Evaporation in vacuo provides a solid which is dissolved in 100 ml of methylene chloride. The solution is dried over sodium sulfate for 16 hours -filtered and is concentrated on a steam bath with the addition of methanol until 2/3 of the methylene chloride has been removed, at which point a thick colorless paste is formed. The mixture is diluted to 250 ml with me~hanol and filtered~ The product is washed on the filter with methanol and eth~r and air dried for 16 hours.
The material is dissolved in 500 ml of reEluxing acetonitrile, filtered and allowed to crystallize 16 hours. The product is filtered and dxied to give 16.35 g of 5,5'l5"-[1,3,6-naphthalenetriyltris(sulfonylimino)]triisophthalic acid hexakis(2-methoxyethyl)ester as a colorless powder.
Example 4 5,S',5"-[1,3,6-~aphthalenetriyltris(sulfonylimino)]-triisophthalic acid hexasodium salt __ .__ ~ mixture of 9.05 g of the product of Example 3 and 45 ml of 2N sodium hydroxide is stirred at room temperature for 45 minutes. The sol~tion is filtered, the filtrate is neutralized with 2.5 ml of glacial acetic acid, ancl diluted wi-th 250 ml of ethanol. The product formed is collected by filtration, washed with ethanol followed by ether and dried to give 7.85 g of the product of the Example as a yellow powder.
~xample 5 3,3',3"-[1 3 6-Na hthalenetri ltris(sulfonylimino)]-S trisl6-hydroxybenzoic acid]trimethyl ester A solution of 20.0 g of 5-aminosalicylic a~id, 250 ml of methanol and 10 ml of concentrated sulfuric acid is refluxed overnight. The reaction mixture is cooled~ made alkali~e with dilute aqueous sodium carbonate solution and concentrated. The resulting solid is separated and washed with water. The solid is then washed with ether, and the ether is evaporated to dryness yielding a brown solidO The aqueous filtrate above is extracted with ether, the extract is dried over anhydrous sodium sulfate, and evaporated yield-ing a brown solid. The solids arè combined and recrystallized from ether to afford 10.7 g of 5-aminosalicylic acid methyl ester.
To a stirred solution of 2.1 g of the above com-pound~ 994 mg of pyridine and 10 ml of acetonitrile is added 1.7 g of 1,3,6 naphthalenetrisulfonyl chloride~ The mixture is stirred for 16 hours, then acid~fied wi-th dilute hydro-chloric acid, concentrated and extracted with ether. The extract is washed with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to give 2.91 g of the product of the Example as a pink solid.
Example 6 3,3'J3"-[1,3, -Naphthalenetriyltris(sulfonylimino)]-tris[6-hydroxybenzoic acid~
A solution of 1.5 g of the product of Example 5 in 25~0 ml of lN sodium hydroxide is stirred at room temperature for 48 hours. The solution is acidified with dilute hydro-chloric acid. The resulting solid is separated, washed with _ ~9 _ water and dried to give 920 m~ of the product of the Example as a brown powder.
~ample 7
A third most preferred embodiment consists in the preparation o-f those compounds wherein the floating phenyl is at the carbon 6-position on the naphthalene.
The intermediates for preparing the compounds of formula (Il are the compounds of the for~ula:
~ I
~Zq~ i3 ~ 5 R6 S2 _ N
R5 \ ~ ~ ~ ~ R
wherein R5 is selected from the gxoup consisting of hy~rogen and methyl; R6 is selected from the group consisting of hydrcgen, methoxycarbonyl, 2-methoxyethoxycarbonyl and phenoxycarbonyl; and ~ is selected from the group consisting of hydrogen, hydro~y, methoxycarbonyl and phenoxycar~onyl.
A preferred embodiment of these intermediates consists of those ccmpounds wherein each ph nyl is only trisubsti-tuted.
A most pre~rred embodlment of the intermediates consists of those compGunds wherein said phenyl is only trisubstituted with ei-ther 2~
methoxyethoxycarbonyl or pheno~y carbonyl and the floating phenyl is at the carbon 6-position of the napthalene.
-2a-~' The novel intermediates of this invention may be prepared as set forth immediately below. A compound of the formula:
~Z l R7~ o2 wherein R6 is selected from the group consisting of hydrogen, methoxycarbonyl, 2-methoxyethoxycarbonyl and phenoxycarbonyl.;
and R7 is selected from the group consisting of hydrogen, hydroxy, methoxycarbonyl and phenoxycarbonyli is made by reacting a compound o~ the formula: ' ~O~
R8OOC ~ COORg Rg wherein R8 is selected from the group consisting of Cl-C6 alkyli and Rg is selected from the group consis-ting of hydrogen, hydroxy and COOR8, wherein R8 is as previously 5 , defined; with 1!3,6-naphthalenetrisulfonyl chloride in a suita~le diluent ~ith a suita~le acceptor for a~out 40 minutes to about 18 hours. The suitable diluent is selected from the group of polar solvents such as pyridine t acetonitrile t triethylamine and the like ~3L2~ ~3 The suitable acid acceptor is selected from the group of organic and inorganic bases such as pyridinel triethylamine, sodium carbonatel sodium acetate, quinoline r calcium oxide, calcium hydroxide and aluminum hydroxide. The methylated form of the novel intermediates is obtained by - 3a ~
LZ~i3 reacting them with methyl iodide in the presence of a strong base such as sodium hydroxide.
The novel complement inhlbitin~ compounds of thi~
invention clr~ as set forth immedi~tely below. A compound of the formula:
R
~ 1 ~ 2 R~ R~ 2 10 1~3?~N 2 SO_N~
~2 ~ R2 !
wherein Rl is selected from the group consisting of hydrogen and methyl; R2 is selected from the group consisting of hydrogen, carboxyl and COOR4, wherein R4 is selected from the group consisting of alkali metal and alkaline earth metal;
R2 is selected from the group consisting of hydrogen, hydroxy and C~OR4, wherein R4 is as previoùsly defined; with the proviso that each phenyl,must contain at least one COOR4i ZO is made by reacting the appropriate novel intermediates, as -shown and described above, in an alkali metal ~.ydroxide for about 45 minutes to about 16 hours and then neutralizing with a suitable weak acid capable of removing the N-alkali salt of the sulfamido moiety. The alkali metal hydroxide may be sodium hydroxide or the like~ and the weak acid may he a,mineral aci,d of Cl-C4 alkanoic acid.
The term "complement" refers to a complex group of proteins in body fluids that, working together with antibodies or other factors ! play an important role as mediators of immune, immunochemical and~or immunopathological ~ 4 reaction$. The react~ons ~n whi~ch complement pa~t~c~p~tes take place ln ~lood serum or ~n other body ~lu~ds ! and hence are considered to ~e ~umoral reactions, - 4a ;~' ~2~ i3 With regard to human blood, there are at present more than 11 proteins in the complement system. These com-plement proteins are designated by the letter C and by number;
Cl, C2, C3 and so on up to C9. ~he complement protein Cl is actually an assembly of subunits designa~ed Clq~ Clr and C15.
The numbers assigned to the complement proteins reflect the sequence in which they become active~ with the exception of complement protein C4, which reacts after Cl and before C2.
The numerical assignments ~or the proteins in the complement system were made before the reaction sequence was fully under-stood. A more detailed discussion of the comp]ement system and its role in body processes can be found in, for example, Bull. World Health Org., 39, 935-938 (1968); Ann. Rev. Medicin~
19, 1-24 (1968); The John Hopkins Med. J., 128, 57-74 (1971);
Harvey Lectures, 66, 75-~04 ~1972); The New England Journal of Medicine, 287, 452~454; 489-495; 545-549; 592-5~6; 642-646 (1972); Scientific American, 229, (No. 5), 54-66 (1973);
~ederation Proceedings, 32, 134-137 (1973); Medical World News, October 11, 1974, pp. 53-58; 64-66; J~ Allergy Clin. Immunol., 53, 298-302 (1974); Cold Spring Harbor Conf. Cell Proliferatior 2/Proteases Biol. Control/229-241 (1975); Annals of Internal Medicine, _ , 580-593 11976); "Complement: Mechanisms and Functions", Prentice-llall, Englewood Cliffs, N. J. (1976).
The complement system can be considered to consist of three sub-systems: (1) a recognition unit (Clq) which en-ables it to combine with antibody molecules that have detected a foreign invader; (2) an activation unit (Clr, Cls, C2, C4, C3) which prepares a site on the neighboring membrane; and (3) and attack unit (C5, C6, C7, C8 and C9) which cr~ates a "hole" in the membrane. The membrane attack unit is non--specific; it destroys in~aders only because it is ge}lerated in their neighborhood. In order to minimi2e damage to the host's own cells, its activity must be limited in time. This ~2~ii3 limitation is accomplished partly by the spontaneous decay of activated complement and partly by interference ~y inhibitors and destructive enzymes. The control of complement, however, is not perfect, and there are time~ when damage is done to the host's cells. Immunity is therefore a double-2dged sword.
Activation of the complement system also accelerates blood clotting. This action comes about by way of the comple-ment-mediated release of a clotting ~actor from platelets.
The biologically active complement fragments and complexes can become involved in reactions th~t damage the hostls cells, and these pathogenic reactions can result in the development of irnmune-complex diseases. For example, in some forms of nephri-tis, complement damages the basal membrane of the kiclney, re-sulting in the escape of protein from -the blood into the urine The disease disseminated lupus erythematosus belongs in this category; its symptoms include nephritis, visceral lesions and skin eruptions. The treatment of diphtheria or tetanus with the injection oE large amounts of antitoxin sometimes results i~ serum sickness, an immune-complex disease. Rheuma-toid arthritis also involves i~nune complexes. Like dissemin-ated lupu5 erythematosus, it is an autoimmune disease in which the disease symptoms are caused by pathological effects of the irnmune system in the host's tissues. In summary, the comple-rnent system has been shown to be involved with inflammation, coag~lation, fibrinolysis, antibody-antigen reactions and other metabolic processes.
In the presence of antibody-antigen complexes the complement proteins arei in~olved in a series of reactLons which may lead to irreversible membrane damage if they occur in the vicinity of biological membranes. Thus, while complement constitutes a part of the body's defense mechanism against infection it also results in inflammat~on and tlssue damage in the immunopathological process. The nature of the com-- 6a -~L~2~
plement proteins, suggestions regarding the mode of complement bindin~ to biological membranes and the manner ln which com-plement effects membrane damage are discussed in Annual Review in Biochemistry, 38, 389 (1969~.
A vari.ety of substances have been disclosed as in-hibiting the complement system, i.e., as complement inhibitors.
For example, the compounds 3,3'-ureylenebis-l6-(2-amino-8--hydroxy-6-sulfo-1-naphthylazo)]benzenesulfonic acid, -tetra-sodium salt (chlorazol fast pink), heparin and a sulphated dex~ran have been reported to have an anticomplementary effect, British Journal of Experimental Pathology, 33, 327-33g (1952)~
The compound 8-(3-benzamido-4-methylhenzamido)naphthalene-1,-3,5-trisulfonic acid (Suramin) is described as a competitive inhibitor of the complement system, Clin. Exp. Immunol., 10, 127-138 ~1972). German Patent No. 2,254,893 or South African Patent No. 727,923 discloses certain 1-(di~henylmethyl)-4--(3-phenylallyl)piperaæines useful as complement inhibitors.
Other chemical compounds having complement inhibiting activity are disclosed in, for example, 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, 1041 279-288 (1970); The Journal of Immunology, 106, 241-245 (1971~; and The Journal of Immunology, 111, 1061-1066 (1973).
It has been reported that the known complement in-hibitors epsilon-aminocaproic acid, Suramin and tranexamic acid all have been used with success in the treatment of her-editary angioneurotic edema, a disease state resulting from an inheri.ted defici.ency or lack of Eunction of the serum in-hibitor oE the activated first component of complement (Cl inhibitor), The New En~land Journal of Medicine, 286, 808-812 (1972).
~ 3 3 The compounds of the present invention may be admin-istered internallyr e.g., orally, intra-articularly or paren-terally~ e.g., intra-articular, to a warm blooded animal to inhibit complement in the body fluid of the animal, such in-hibition being useful in the amelioratioll or pr~vention of those reactions dependent upon the fullction of complement, such as inflammatory process and c~ll membrane dama~e induced by anti~en-antibody complexes. A range of doses may be em-ployed depending on the mo~e of administration 7 the condition being treated and the particular compound being used. For example, for intravenous or subcutaneous use from about 5 to about 50 mg/kg/day, or every six hours ~or more rapidly ex-creted salts, may be used. For intra-articular use for large joints such as the knee, rom about 2 to about 20 mg~joint pex week may be used, with proportionally smaller doses for smal-ler joints. The dosage ran~e is to be adjusted to provide optimum therapeutic response in the warm-bloodéd animal being treated. In general, the amount of compound administered can vary over a wide range to provide from about 5 mg/kg to about 100 mg/kg of body weigh~ of animal per day. The usual daily dosage for a 70 kg subject may vary from about 350 mq to about 3.5 g. Unit doses of the acid or salt can contain from about 0.5 mg to about 500 mg.
While in general the sodium salts of the acids of ~he invention are suitable for parenteral use, other salts may also ~e prepared, such as those of prirnary amines, e.g., ethylamine; secondary amines, e.g., diethylamine or diethanol amine; tertiary amines, e.g., pyridine or triethylamine or 2 dimethylaminomethyl-dibenzofuran; aliphatic diamines, e.~., decamethylenediamine; and aromatic diamines, can be prepared.
Some of these are soluble in water, others are soluble in saline solution, and still others are insoluble and can be used Eor purposes of preparing suspensions for injectionO
Furthermore as well as the sodium salt, those of the alkali metals, such as potassium and lithium; of ammonia; and of the alkaline earth metals, such as calci~n or magnesium, may be employed~ It will be apparent, therefore, that these salts embrace, in c3eneral derivatives of salt-forming cations.
In therapeutic use, the compounds of this invention may be administered in the form of conventional pharmaceutical compositions. Such compositions may be formulated so as to be suitable for oral or parenteral administration. The active ingredient may be combined in admixture with a pharmaceutic-ally acceptable carrier, whlch carrier may take a wide variety of forms depending on the fo~n of preparation desired for administration, i.e., oral or parenteral. The compounds can be used in compositions such as tablets. Here, -the principal active ingredient is mixed with conventional tabletting ingre-dients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesi~n stearate, dicalcium phosphate, gums, or similar materials as non-toxic pharmaceutically acceptable diluents or carriers. The tablets or pills of the novel com positions ca~ be laminated or otherwise compounded to provide 2~ a dosage form affording the advantage of prolonged or delayed action or predetermined successive action of the enclosed medi cation. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist dis-integration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or coatings, such materials including a number of polymcric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate and the like.
particularly advantageous enteric coating comprises a styrene maleic acid copolymer to~3ether with known materia:Ls contribu-~3 ting to the enteric properties of the coatinq. The tablet or pill may be colored through the use of an appropriate non--toxic dye, so as to provide a pleasing appearance.
The liquid forms in which the novel compositions of the present invention may be incorporated for administra-tion include suitable flavored emulsions with edible oils, such as, cottonseed oil, sesame oil, coconut oil, peanut oil, and the like, as well as elixirs and similar pharmaceutical vehicles. Sterile suspensions or solutions can be prepared for parenteral use~ Isotonic preparations containing suitable preservatives are also desirable for injeCtiQn use~
The term dosa~e form, as described herein, refers to physically discrete units suitable as unitary dosaqe for warm-blooded animal subjects, each unit containing a predeter-mined quantity of active component calculated to produce the desired therapeutic effect in as~ociation with the re~uired pharmaceutica~ diluent, carrier or vehicle. The specification for the novel dosage forms of this invention are indicated by characteristics of the active component and the particular therapeutic effect to be achieved or the limitations inherent in the art of compounding such an active component ior thera-peutic use in warm-blooded animals as disclosed in this speci-fication. Examples of suitable oral dosage forms in accord with this invention are tablets, capsules, pills, powder pack-ets, qranules, wafers, cachets, teaspoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foreqoing and other forms as herein described.
The complement inhibiting activity of the compounds of this invention has been demonstrated by one or more of the followinq identified tests: (i) Test, Code 026 tC1 inhibitor) This test measures the ability of activated human C1 to destro fluid phase human C2 in the presence of C4 and appropriate di-lutions of the test compound. An active inhibitor protects C2 from Cl and C4; (ii) Test, Code 035 (C3-C9 inhibitor) -This test determines the ability of the late components of human complement (C3-C9) to lyse EAC 142 in the presence of appropriate dilutions of the tes-t compound. An active inhibi-tor protects EAC 142 from lysis by human C3-C9; (iii) Test, S Code 036 ~C-Shunt inhibitor) - In this test human erythrocytes rendered fragile are lysed in autologous serum via the shunt pathway activated by cobra venom factor in the presence of appropriate dilutions of the test compound. Inhibition of the shunt pathway results in failure of lysis; (iv) Forssman Vas-culitis Test - Here~ the well known complement dependent les-ion, Forssman vasculitis, is produced in guinea pigs by intra-dermal injection of rabbit anti-Forssman antiserumO rrhe les-ion is measured in terms of diameter, edema and hemorrhage and the extent to which a combined index of these is inhibited by prior intraperitoneal injection of the tsst compound at 200 mg is then reported, unless otherwise stated; (v) Forssman Shock Test - Lethal shock is produced in guinea pigs by an i.v. in-jection of anti-Forssman antiserum and the harmonic mean death time of treated guinea pigs is compared with that of simul-taneous controls; (vi) Complement Level Reduction Test - In this test, the above dosed guinea pigs, or others, are bled for serum and the complement level is determined in undiluted serum by the capillary tube method of U.S. Patent No. 3,876,37 and compared to undosed control guinea pigs; and (vii) Cap 50 2S Test - Here, appropriate amounts of the test compound are addec to a pool of guinea pig serum in vitro, ~fter which the undi-luted serum capillary tube assay referred to above is run. Th~
concentration vf compound inhibiting 50% is reported.
With reference to Table I, guinea pigs weighing about 300 g were dosed intravenously (i.v.) or intraperito-neally (i.p.) with 200 mg/kg of the test compound dissolved in saline and adjusted to pl~ 7-8. One hour after dosing, the -- l 1 --guinea pigs were decapitated, blood was collected and the serum separated. The serum was tested for whole complement using the capilla~y tube assay~ Percent inhibition was cal-culated by comparison with simultaneous controls. The results appear in Table I together with results of tests, code 026, 035, 036, Cap 50, % inhibition and Forssman shock. Table I
shows that the compounds of the invention possess highly sig-nificant in _tro and ln vivo, complement inhibiting activity in warm-blooded animals.
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~Z~)9~3 5,5~,5"-l1,3,6-Naphthalenetriyltris(sulfonylimino)]-ester To a mixture of 40 ml of concentrated sulfuric acid and 33 ml of concentrated nitric acid stirrecl for 10 minutes is slowly added 10 ml of glacial acetic acid and a suspension of 10 g of 2-hydroxyisophthalic acid (prepared as described in Organic Synthesis Coll., Vol. V, 617) in 20 ml of glacial acetic acid. The reaction mixture is cooled and an additional 10 ml of acetic acid is added. The solid formed is dissolved in water, and is extracted with diethyl ether. The ether extract is washed with saturated sodium chloride, dried over anhydrous sodium sulEate ancl evaporated to an orange oil identifiecd as 2-hydroxy-5-nitroisophthalic acid.
The product is treated with 250 ml of methyl alcohol and 10 ml of concentrated sulfuric acid, and is reflux~
for 5 days. The reaction mixture is cooled and concentrated in vacuo to afford a solid. The solid is collected by fil-tration, washed with water, followed by ether, then is air dried. The material is recrystallized from ethyl acetate~
-hexane to afford 2.84 g of 2-hydroxy-5-nitroisophthalic acid dimethyl ester.
A 2.0 g portion of the preceding compound and 200 mg of 10% palladium on carbon catalyst in 200 ml of ethyl acetate is hydrogenated on a Parr shaker until no additional hydrogen is absorbed. The reaction mixture is then filtered through diatomaceous earth. The Eiltrate is evaporated to afford a ycllow soli~1. 'I`he ~olicl is rccryst~]li~c(l ~rom cthyl acetate--hexane to yield 1.04 g of 2-hydroxy-S-aminoisophthalic acid dimethyl ester.
A mixture of 60.0 g of 1,3,6-naphthalenetrisulfonic acid trisodium salt, 250 ml of thionyl chloride and 5 drops Q~5i3 of dimethyl~ormamide is refluxed for 16 hours. The solid is removed by filtration and the filtrate is evaporated.
The residue is triturated with chloroform, and filtered, washed with chloroform, and dried to yield 25.4 g of l,3,6-naphthalenetrisulfonyl chloride as a whi-te solid.
To a stirred solution of 695 mg of 2 hydroxy--5-aminoisophthalic acid dimethyl ester~ l~ ml of acetonitrile and 270 mg of pyridine is added 428-mg of 1,3,6-naphthalenetrisulfonyl chloride. The reaction mixture is stirred for 16 hours under an atmosphere of argon, then is acidified with dilute hydrochloric acid~
and the acetonitrile is removed by distillation ln vacuo.
The aqueous mixture is extracted twlce with ether. The ether extract is evaporated to yield a brown oil which affords brown crystals on being worked with ether. The crystals are collected, washed with ether, and dried in vacuo to give 780 mg of 5,5',5'-[1,3,6-naph*halenetriyl~
tris(sulfonylimino]tris[2-hydroxyisophthalic acid~hexa-methyl ester as a tan powder.
Example 2 5,5l,5"-[1,3,6-Naphthalenetriyltris(sulfonylimino)]-tris[2-hydroxyisophthalic acid]
A solution of 680 mg of the product of Example l in lO ml of l_ sodium hydroxide is stirred for 5 hours, then is acidified with dilute hydrochloric acid to afford a~ hxo~n ~um. The gum is separated and washed twice with bokh water and ethanol, then once with ether affording a light brown powder. The filtrate above is evaporated and the resulting residue is washed several times with water, then ether, affording a brown crystalline powder. The ~ ;.,~, fractions are combinedf recrystaill~i`zed from ethanol~
and dired ~ va~uo to yield 428 mg of the product of :~
the Example as orange-~ro~n crystals.
- 16a --~2~9~ii3 Example 3 5,5',5"-il,3,6-Naphthalenetr yltris(sulfonylimino)]-triisophthalic acid hexakis(2-n!ethoxyethyl~ester A mixture of 500 g of 5-nitroisophthalic acid, 3500 g of thionyl chloride and 6.0 ml of dimethylformamide is heated gradually until the evolution of gases subsides. Heat-ing is continued for approximately 2 hours with stirring until solution is achieved, then reflux is continued for an addi-tional 30 minutes. The resulting clear solution is allowed to stand, then is evaporated in acuG to afford an oil. The oil solidifies and is recrystallized twice from carbon tetra-chloride to give 501 g of 5-nitroisophthaloyl chloride.
A mixture of 100 g of the product above and 100 g of 2-methoxyethanol ~dried over molecular sieves) in 400 ml of acetonitrile (dried over molecular sieves) is heatecl to lS reflux on a steam bath~ ~leating is continued for 15 minutes, then the mixture is cooled to room temperature and poured into 2 liters of cold water with vigorous stirring. The pro-duct is collected by filtration and air dried to give 129 g of material. Additional product (5.7 g) is recovered from the filtrate by extraction with benzenev The combined frac-tions are dissolved in 530 ml of hot ethyl alcohol. The solu-tion is neutralized with 5.0 ml of 5N sodium hydroxide, then diluted with 450 ml of water. The solution is kept at room temperature, crystals separate, and then the mixture is placed overnight in a chill room (5C). The colorless needles are recrystallized from a solution of 450 ml of ethanol and 350 ml of water to give 92.1 g of 5-nitroisophthalic acid bis(2--methoxyethyl)ester.
A total of 86.0 g of the preceding product is hydrogenated on a Parr shaker in 300 ml of ethyl acetate using 2.0 g of 10% palladium on carbon catalyst. The mixture is filtered and the filtrate evaporated to give off-white crys-~ 17 -3L~Z~3 tals. The crystals are dissolved in 350 ml of hot benzene and diluted with 140 ml of hexane~ The solution is allowed to crystallize overnigh-t at room temperature to yield 72.0 g of 5-aminoisophthalic acid bis(2-methoxyethyl)ester.
To a solution of 15.16 g of the product above and 6.18 g of dimethylaniline in 75 ml of acetonitrile is added 7 . 2 g of 1, 3 1 6 -naphthalenetrisulfonyl chloride. The solution is refluxed on a steam bath for 2 hours, then is poured into 250 ml of cold water and stirred until a product is solidi-fied. The product is collected and washed with water, then is dissolved in 150 ml of methylene chloride:methanol ~2:1) and the solution is dried over anhydrous sodium sulfate.
Evaporation in vacuo provides a solid which is dissolved in 100 ml of methylene chloride. The solution is dried over sodium sulfate for 16 hours -filtered and is concentrated on a steam bath with the addition of methanol until 2/3 of the methylene chloride has been removed, at which point a thick colorless paste is formed. The mixture is diluted to 250 ml with me~hanol and filtered~ The product is washed on the filter with methanol and eth~r and air dried for 16 hours.
The material is dissolved in 500 ml of reEluxing acetonitrile, filtered and allowed to crystallize 16 hours. The product is filtered and dxied to give 16.35 g of 5,5'l5"-[1,3,6-naphthalenetriyltris(sulfonylimino)]triisophthalic acid hexakis(2-methoxyethyl)ester as a colorless powder.
Example 4 5,S',5"-[1,3,6-~aphthalenetriyltris(sulfonylimino)]-triisophthalic acid hexasodium salt __ .__ ~ mixture of 9.05 g of the product of Example 3 and 45 ml of 2N sodium hydroxide is stirred at room temperature for 45 minutes. The sol~tion is filtered, the filtrate is neutralized with 2.5 ml of glacial acetic acid, ancl diluted wi-th 250 ml of ethanol. The product formed is collected by filtration, washed with ethanol followed by ether and dried to give 7.85 g of the product of the Example as a yellow powder.
~xample 5 3,3',3"-[1 3 6-Na hthalenetri ltris(sulfonylimino)]-S trisl6-hydroxybenzoic acid]trimethyl ester A solution of 20.0 g of 5-aminosalicylic a~id, 250 ml of methanol and 10 ml of concentrated sulfuric acid is refluxed overnight. The reaction mixture is cooled~ made alkali~e with dilute aqueous sodium carbonate solution and concentrated. The resulting solid is separated and washed with water. The solid is then washed with ether, and the ether is evaporated to dryness yielding a brown solidO The aqueous filtrate above is extracted with ether, the extract is dried over anhydrous sodium sulfate, and evaporated yield-ing a brown solid. The solids arè combined and recrystallized from ether to afford 10.7 g of 5-aminosalicylic acid methyl ester.
To a stirred solution of 2.1 g of the above com-pound~ 994 mg of pyridine and 10 ml of acetonitrile is added 1.7 g of 1,3,6 naphthalenetrisulfonyl chloride~ The mixture is stirred for 16 hours, then acid~fied wi-th dilute hydro-chloric acid, concentrated and extracted with ether. The extract is washed with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to give 2.91 g of the product of the Example as a pink solid.
Example 6 3,3'J3"-[1,3, -Naphthalenetriyltris(sulfonylimino)]-tris[6-hydroxybenzoic acid~
A solution of 1.5 g of the product of Example 5 in 25~0 ml of lN sodium hydroxide is stirred at room temperature for 48 hours. The solution is acidified with dilute hydro-chloric acid. The resulting solid is separated, washed with _ ~9 _ water and dried to give 920 m~ of the product of the Example as a brown powder.
~ample 7
4,4',4"-fl/3,6-Naphthalenetriyltris(sulfonylimino)]-tribenzoic acid t ~ ster To a warmed and stirred mixture of 10.7 g of ~--aminobenzoate, 200 ml of acetonitrile and 5~59 g of pyridine is added 10.0 g of 1,3,5-naphthalenetrisulfonyl chloride.
The mixture is stirred and refluxed ~or 16 hours, then is coole~ and filtered. The filtrate is poured into cold water with the separation of a solid after stirring and standing at room temperature. The solid is separated, washed with water, dissolved in 60 ml of 30~ acetone in benæene and filtered through hydrous magnesium silicate. The latter containing the product is washed with 30~ acetone in benzene, then is treated with acetone to dissolve ~he product. The acetone eluates are combined and evaporated to yield a residue which is dissolved in 200 ml of acetonitrile and allowed to stancl 16 hours in a chill room (5C). The white solid formed is separated, washec3 with acetonitrile and petroleum ether, and dried at 70C to give 12.0 g of 4,4',4"-~1,3,6-naphthalene-triyltris(sulfonylimino)3tribenzoic acid trimethyl ester.
F ~
4, 4 ', 411 [1,3,6-Naphthalenetriyltris(sulfonylimino)]-tribenzoic acid trisodium salt A 9.0 g portion of the product of Example 7 is dis-solved in 46.5 ml of 2N sodium hydroxide and stirred for 45 minutes. I'he solution is neutralized with 2.7 ml of glacial acetic at~id and ~3ilutet3 witll 2~0 ml of eth~nol. ~ yellow solid separates which is collected by filtration, washed with ethanol and ether, and dried to give 8.7 g of the product of the ~xample.
~LZ~
Example 9
The mixture is stirred and refluxed ~or 16 hours, then is coole~ and filtered. The filtrate is poured into cold water with the separation of a solid after stirring and standing at room temperature. The solid is separated, washed with water, dissolved in 60 ml of 30~ acetone in benæene and filtered through hydrous magnesium silicate. The latter containing the product is washed with 30~ acetone in benzene, then is treated with acetone to dissolve ~he product. The acetone eluates are combined and evaporated to yield a residue which is dissolved in 200 ml of acetonitrile and allowed to stancl 16 hours in a chill room (5C). The white solid formed is separated, washec3 with acetonitrile and petroleum ether, and dried at 70C to give 12.0 g of 4,4',4"-~1,3,6-naphthalene-triyltris(sulfonylimino)3tribenzoic acid trimethyl ester.
F ~
4, 4 ', 411 [1,3,6-Naphthalenetriyltris(sulfonylimino)]-tribenzoic acid trisodium salt A 9.0 g portion of the product of Example 7 is dis-solved in 46.5 ml of 2N sodium hydroxide and stirred for 45 minutes. I'he solution is neutralized with 2.7 ml of glacial acetic at~id and ~3ilutet3 witll 2~0 ml of eth~nol. ~ yellow solid separates which is collected by filtration, washed with ethanol and ether, and dried to give 8.7 g of the product of the ~xample.
~LZ~
Example 9
5,5',5"-[1,3,6-Naphthalenetriyltrislsulfonylimino)~-tri 1,2,3-benzenetricarboxylic acid nonaphenyl ester .
To a stirred mixture of 125 g of 1,2,3-~enzenetri-carboxylic acid and 900 ml of concentrated sulfuric acid at 60-70C is added, gradually over a 2 hour period, 312 g of potassium nitrate. The mixture is heated at 135-140C for 16 hours, cooled and treated with ice and water. Some solid is separated out ~nd is dissolved in water. The entire aque-ous mixture is extracted with ether, the extract is washed with water and dried over magnesium sulfate. The ethex is concentrated to a small volume, and petroleum ether is adcled to precipitate a white solid. The solid is collected and dried to give 76.5 g of 5-nitro-1,2,3-benzenetricarboxylic acid.
A mixture of 50.0 g of the preceding product, 300 ml of thionyl chIoride and 2.0 ml of dimethylformamide is heated under reflux for 16 hours. The solvent is evaporated in vacuo and the residue is dissolved in chloroform~ The chloro-form is concentrated to a small volume, and the residue is dissolved in carbon tetrachloride. On standing, a yellow solid is separated, 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 refluxed for 16 hours. The solvent is evaporated and the resulting yellow solid is crystallized from chloroform:carbontetrachloride to give 23.0 g of 5 nitro-1,2,3-benzenetricarbonyl chloride.
To a stirred solution of 30.6 g of phenol in 100 ml of pyridine (dried over molecular sieves3 is added 22.7 g of thP product above. The solution is heated on a steam bath for one hour, cooled and poured into 500 ml of cold water with vigorous stirring resulting in the s~aration of a solid.
The mixture is filtered, and the solid is washed with water - 2~ -to give a brown powder. The product is dissolved in 100 ml of methylene chloride and filtered. The filtrate is boiled on a steam bath and 250 ml of ethanol is added portionwise to the boiling solution until all of the methylene chloride has been remo~ed. The mixture is cooled to room temperature, S and the product formed is separated, washed with ethanol and ether, then is dissolved in 75.0 ml o~ methylene chloride.
It is then recrystallized from 200 ml of ethanol as above, separated and dried to yield 30.8 g of 5-nitro-1,2,3-benzene-tricarboxylic acid triphenyl ester.
A solution of 29.0 g of the above nitrocompound in dimethylformamide is hydrogenated on a Parr shaker in the presence of 10% palladium-on-carbon catalyst. The mixture is filtered through diatomaceous earth and the filtrate is diluted with water and extracted with methylene chloride.
The extract is dried over anhydrous sodium sulfate and evap-orated to give an oil. The oil is crystallized ~rom ether, and the product i5 rPcrystallized from benzene and twice from ethanol to provide 15.0 g of 5-amino-1l2,3-benzenetricarbox-ylic acid triphenyl ester as tan crystals.
To a stirred solution of 13.6 g of the preceding product in 50 ml of pyridin~ (dried over 4A molecular sieves) is added 4.24 g of 1,3,6-naphthalenetrisulfonyl chloride.
The mixture is stirred for 10 minutes, then is heated on the steam bath for 30 minutes, cooled and poured into 300 ml of ice-cold 2,05N hydrochloric acid. The mixture is stirred until the product solidifies. The material is collected by filtration and washed with water until neutral, and dried to give 19.3 g of crude product. The crude product is treated by conventional chromatographic techniques to obtain a frac-tion of 14.9 ~ of material. This material is recrystallized twice from methylene chloride:ether (2:3), and dried by con~
ventional means to give 9.8 g of the product of the Example as colorless crystals.
) 7 ~L~Z~i3 Example 10 -5,5',5"-~1,3,6-Naphthalenetriyltris(sulfonylimino)]-tri-1,2,3-benzenetricarboxylic acid nonasodium salt A 6.7 g portion of the product of Rxample 9 is added to S0 ml of 2N sodium hydroxide and stirred for 30 min-S utes, then 3.68 ml of glacial acetic acid is added. The solution is poured with vigorous stirring into 500 ml o abso-lut~e ethanol. The fine granular precipitate produced is separate~ by filtration and is washed with ethanol and ether, tben is dissolved in 35.0 ml of water containing 1.0 g of ~10 sodium acetate trihydrate. The solution is filtered through diatomaceous earth and poured into 350 ml of absolute ethanol.
The produc-t of the Example is separated and dried to give 5.3 y of yellow powder.
Example 11 3,3',3"-[1,3,6-Naphthalenetriyltris(sulfonylimino)]-tribenzoic acid trimethyl ester ~ To a stirred mixture of 10.7 g of methyl-m~amino-benzoate, 80 mI of acetonitrile and 6.1 ml of pyridine is added 10.8 g of 1,3,6-naphthaIenetrisulfonyl chloride. The mixture is stirred and refluxed for 2 hours, then is cooled.
The solution is poured into water resulting in the separation of an oil which solidifies on standing and on being stirred.
The separated solid is dried, dissolved in acetonitrile and filtered. The solvent is evaporated ln vacuo, and the residue is dried to give 16.0 g of the product of the Example as a beige solid.
Example 12 3,3',3"-[1,3,6-Naphthalenetriy~tris(sulfonylimino?]-tribenzoic acid trisodium salt A mixture of 12.0 g of the produc-t of Example 11 and 62.0 ml of 2N sodium hydroxide is stirred for 45 minutes ;;3 The solution is neutralized with 3.6 ml of glacial acetic acid and diluted with 400 ml of ethanol. The solvent is concentrated in vacuo to a small volume. Then it is diluted again with ethanol with the separation of an oil. The sol-vent is decanted off, and the oil is triturated with fresh ethanol to produce a yellow solid. The solid is separated, washed with ethanol and ether, and dried at 70C to yield 7.3 g of the product of the Example.
Example 13 5,5',5" El, 3~6-Naphthalenetriyltris(sulfo-ylim:Lno)]
triisophthalic acid ~ mixture of 12.06 g of the product of Example 3 and 60 ml of 2N sodium hydroxide is stirred for one hour.
The resulting yellow solution is acidified with 65 ml of 2N hydrochloric acid to give a colorless gum which solidi-fies on standing. The mixture is filtered and the separated product is washed with water until the washings are neutral.
The material is dried _ vacuo, then is pulverized, and dried again to give 8.36 g of the product of the Example as a colorless powder.
Example 14 5,5',5"-[1,3,6-Naphthalenetriyltris(sulfonylmethylimino]-triisophthalic acid hexakis(2-methoxyethyl)ester To a stirred solution of 6.03 g of the product of Example 3 in 25 ml of dimethylformamide, which is cooled in a water-bath, is added dropwise, 3.25 ml of 5N sodium hydroxide followed by 3.75 ml of methyl iodide. The mixture is stirred in a stoppered flask for a total of 3 hours at room temperature. The mixture is filtered, and the separated product is washed on the filter with a 91$3 small amount of dimeth~l~ormamide.. Then it i~ stirred in 100 ml water, separated and dried. The product is dissolved in 30 ml o~ methylene chloride and iltered throught diatomaceous earth. Th.e ~iltrate i.s boile.d with ~ 24~ -~ 3 the addition of methanol until all the methylene chloride is removed. The mixture is allowed to cool and crystallize.
Th~ product is collected and dried to give 5.7 g of colorless crystals as the product of the Example.
Example lS
5,5',5"-[1,3,6-Naphthalenetriyltris~sulfonylmethyl-imino)~triisophthalic acid hexasodium salt To a stirred, warm solution of 5.0 g of the product of Example 14 in 40 ml of dioxane is added 20 ml of 2N sodium hydroxide. The mixture is stirred vigorously for 10 minutes, then 10 ml of water is added, and stirring is continued for a total of one hour. The resulting solution is poured into 300 ml of absolute ethanol. The mixture is filtered and the separated product is washed with ethanol and ether. The pro-duct with 1.0 g of sodium acetate trihydrate is dissolved in 20 ml of water and poured into 250 ml of absolute ethanol.
The resulting mixture is stirred for one hour, and then is filtered. The separated product is washed with ethanol and ether, and dried to give 4.22 g of the product of the Example as a beige powder.
Example 16 Preparation of Compressed Tablet Ingredient mg/Tablet Active Compound.. ~.... ~..... ~............. 0.5-500 Dibasic Calcium Phosphate N.F. ...~... qs Starch USP....... ~0.... ~... ~......... ~.... ..40 Modified Starch........ .... .......... ..... ..10 Magnesium Stearate ~SP............... 0......... O.... ..1-5 ~lZ~i3 Example 17 _eparation of Compressed Tablet - Sustained Action In~redient mg/Tablet Active Compound........ ,.... ~.~.... 0~5-500(as acid as Aluminum Eake*, Micronized equivalent) Dibasic Calcium Phosphate N.F. ... ~ qs Alginic A~id~ 20 Starch USP~ O~ 3S
Magnesium Stearate USP~ O~oo~ 10 *Complement inhibitor plus aluminum sulfate yields aluminum complement inhibitor. Complement inhibitor content in aluminum lake ranges from 5~30%.
Example la ; Preparation of Hard Shell Capsule Ingredient m~/Capsule Active Compound..~.,............. 0.5-500 Lactose, Spray Dried.~.O.v.v. qs Magnesium Stearate.~.............. l-10 Example 19 Ingredient % W~V
Active Compound.~.v..~. 0v05-5 Liquid Suyar...... ~.. O........... 75~0 Methyl Paraben USP..~.... 0.18 ~*
Propyl Paraben USP...O... 0.02 Flavoring AgentO...... v............ qs Purified Water qs ad............ 100.0 Example 20 Preparation of Oral Liquid ~Elixir) In~redient ~ W/V
Active Compound............... ~ 0.05-5 ~lcohol USP.......~.............. ~ 12.5 GlycPrin USP...... v.v..... ~.... 45.0 ** ITrademark - ?f ~L~Z~3 Syrup USP..................... 20.0 ~lavoring Agent............... qs Purified Water qs ad.~ . 100.0 Example 21 Pxeparation of Oral Suspens on ~Syrup) .
In~redient % W/V
Active Compound..O.............................. 0.05-5 as Aluminum Lake, Micronized (acid equivalent) Polysorbate 80 USP~Oo~ 0.1 Magnesium Aluminum Silicate, ~ Colloidal........ ~............... ~................. 0.3 .0 Flavoring Agent..... ~;....O..................... ~ . q5 Methyl Paraben USP..~....................... ~.~.~ 0.18 Propyl Paraben USP.............. .................. 0.02 . Liquid Sugar........ O..... ~......... ~.... .75.0 Purified Water qs ad...................... 100.0 L5 Example 22 ration of In~ectable Solution In~redient - % W~V
Active Compound.O......... 0.05-5 . . Benzyl Alcohol N.F. .~..... .Ø9 Water for Injection... O.~. 100.0 Example 23 Preparation of Iniectable Oil _ _ Ingredient ~ W/V
. .
Active Compound....~.~. 0.05-5 Benzyl Alcohol...... ~ . 1.5 Sesame Oil qs ad.~........ 100.0 * Trademark :~!
i3 _ample 24 Preparation of Intra Articular Product In~redient Amount Active Compound... ~... ~..... ~........................... ~. 2-20 mg ~aCl (physiological saline)........... .....Ø9%
Ben2yl Alcohol........................ .....Ø9%
Sodium Caxboxymethylcellulose......... ......1-5%
p~l adjusted to 5.0-7.5 Water for Injection qs ad............. ......100%
Example 25 Preparation of Injectable Depo Suspension Inqredient ~ W/V
Active Compound...... 0........ ~......................... ..~. 0.05-5 ~acid equivalent) Polysorbate 80 VSP.~ O~ ............ u... .0~2 Polyethylene Glycol 4000 USP.O.......... .3.0 Sodium Chloride USP.. ~..... ~.~.......................... ~. a ~ O o 8 Benzyl Alcohol N.F. ~ 0.9 HCl to p~3 6-8 ............ ..... ........................ .....qs Water for Injection qs ad.. ~....... O.... 100.0 - 2~ -
To a stirred mixture of 125 g of 1,2,3-~enzenetri-carboxylic acid and 900 ml of concentrated sulfuric acid at 60-70C is added, gradually over a 2 hour period, 312 g of potassium nitrate. The mixture is heated at 135-140C for 16 hours, cooled and treated with ice and water. Some solid is separated out ~nd is dissolved in water. The entire aque-ous mixture is extracted with ether, the extract is washed with water and dried over magnesium sulfate. The ethex is concentrated to a small volume, and petroleum ether is adcled to precipitate a white solid. The solid is collected and dried to give 76.5 g of 5-nitro-1,2,3-benzenetricarboxylic acid.
A mixture of 50.0 g of the preceding product, 300 ml of thionyl chIoride and 2.0 ml of dimethylformamide is heated under reflux for 16 hours. The solvent is evaporated in vacuo and the residue is dissolved in chloroform~ The chloro-form is concentrated to a small volume, and the residue is dissolved in carbon tetrachloride. On standing, a yellow solid is separated, 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 refluxed for 16 hours. The solvent is evaporated and the resulting yellow solid is crystallized from chloroform:carbontetrachloride to give 23.0 g of 5 nitro-1,2,3-benzenetricarbonyl chloride.
To a stirred solution of 30.6 g of phenol in 100 ml of pyridine (dried over molecular sieves3 is added 22.7 g of thP product above. The solution is heated on a steam bath for one hour, cooled and poured into 500 ml of cold water with vigorous stirring resulting in the s~aration of a solid.
The mixture is filtered, and the solid is washed with water - 2~ -to give a brown powder. The product is dissolved in 100 ml of methylene chloride and filtered. The filtrate is boiled on a steam bath and 250 ml of ethanol is added portionwise to the boiling solution until all of the methylene chloride has been remo~ed. The mixture is cooled to room temperature, S and the product formed is separated, washed with ethanol and ether, then is dissolved in 75.0 ml o~ methylene chloride.
It is then recrystallized from 200 ml of ethanol as above, separated and dried to yield 30.8 g of 5-nitro-1,2,3-benzene-tricarboxylic acid triphenyl ester.
A solution of 29.0 g of the above nitrocompound in dimethylformamide is hydrogenated on a Parr shaker in the presence of 10% palladium-on-carbon catalyst. The mixture is filtered through diatomaceous earth and the filtrate is diluted with water and extracted with methylene chloride.
The extract is dried over anhydrous sodium sulfate and evap-orated to give an oil. The oil is crystallized ~rom ether, and the product i5 rPcrystallized from benzene and twice from ethanol to provide 15.0 g of 5-amino-1l2,3-benzenetricarbox-ylic acid triphenyl ester as tan crystals.
To a stirred solution of 13.6 g of the preceding product in 50 ml of pyridin~ (dried over 4A molecular sieves) is added 4.24 g of 1,3,6-naphthalenetrisulfonyl chloride.
The mixture is stirred for 10 minutes, then is heated on the steam bath for 30 minutes, cooled and poured into 300 ml of ice-cold 2,05N hydrochloric acid. The mixture is stirred until the product solidifies. The material is collected by filtration and washed with water until neutral, and dried to give 19.3 g of crude product. The crude product is treated by conventional chromatographic techniques to obtain a frac-tion of 14.9 ~ of material. This material is recrystallized twice from methylene chloride:ether (2:3), and dried by con~
ventional means to give 9.8 g of the product of the Example as colorless crystals.
) 7 ~L~Z~i3 Example 10 -5,5',5"-~1,3,6-Naphthalenetriyltris(sulfonylimino)]-tri-1,2,3-benzenetricarboxylic acid nonasodium salt A 6.7 g portion of the product of Rxample 9 is added to S0 ml of 2N sodium hydroxide and stirred for 30 min-S utes, then 3.68 ml of glacial acetic acid is added. The solution is poured with vigorous stirring into 500 ml o abso-lut~e ethanol. The fine granular precipitate produced is separate~ by filtration and is washed with ethanol and ether, tben is dissolved in 35.0 ml of water containing 1.0 g of ~10 sodium acetate trihydrate. The solution is filtered through diatomaceous earth and poured into 350 ml of absolute ethanol.
The produc-t of the Example is separated and dried to give 5.3 y of yellow powder.
Example 11 3,3',3"-[1,3,6-Naphthalenetriyltris(sulfonylimino)]-tribenzoic acid trimethyl ester ~ To a stirred mixture of 10.7 g of methyl-m~amino-benzoate, 80 mI of acetonitrile and 6.1 ml of pyridine is added 10.8 g of 1,3,6-naphthaIenetrisulfonyl chloride. The mixture is stirred and refluxed for 2 hours, then is cooled.
The solution is poured into water resulting in the separation of an oil which solidifies on standing and on being stirred.
The separated solid is dried, dissolved in acetonitrile and filtered. The solvent is evaporated ln vacuo, and the residue is dried to give 16.0 g of the product of the Example as a beige solid.
Example 12 3,3',3"-[1,3,6-Naphthalenetriy~tris(sulfonylimino?]-tribenzoic acid trisodium salt A mixture of 12.0 g of the produc-t of Example 11 and 62.0 ml of 2N sodium hydroxide is stirred for 45 minutes ;;3 The solution is neutralized with 3.6 ml of glacial acetic acid and diluted with 400 ml of ethanol. The solvent is concentrated in vacuo to a small volume. Then it is diluted again with ethanol with the separation of an oil. The sol-vent is decanted off, and the oil is triturated with fresh ethanol to produce a yellow solid. The solid is separated, washed with ethanol and ether, and dried at 70C to yield 7.3 g of the product of the Example.
Example 13 5,5',5" El, 3~6-Naphthalenetriyltris(sulfo-ylim:Lno)]
triisophthalic acid ~ mixture of 12.06 g of the product of Example 3 and 60 ml of 2N sodium hydroxide is stirred for one hour.
The resulting yellow solution is acidified with 65 ml of 2N hydrochloric acid to give a colorless gum which solidi-fies on standing. The mixture is filtered and the separated product is washed with water until the washings are neutral.
The material is dried _ vacuo, then is pulverized, and dried again to give 8.36 g of the product of the Example as a colorless powder.
Example 14 5,5',5"-[1,3,6-Naphthalenetriyltris(sulfonylmethylimino]-triisophthalic acid hexakis(2-methoxyethyl)ester To a stirred solution of 6.03 g of the product of Example 3 in 25 ml of dimethylformamide, which is cooled in a water-bath, is added dropwise, 3.25 ml of 5N sodium hydroxide followed by 3.75 ml of methyl iodide. The mixture is stirred in a stoppered flask for a total of 3 hours at room temperature. The mixture is filtered, and the separated product is washed on the filter with a 91$3 small amount of dimeth~l~ormamide.. Then it i~ stirred in 100 ml water, separated and dried. The product is dissolved in 30 ml o~ methylene chloride and iltered throught diatomaceous earth. Th.e ~iltrate i.s boile.d with ~ 24~ -~ 3 the addition of methanol until all the methylene chloride is removed. The mixture is allowed to cool and crystallize.
Th~ product is collected and dried to give 5.7 g of colorless crystals as the product of the Example.
Example lS
5,5',5"-[1,3,6-Naphthalenetriyltris~sulfonylmethyl-imino)~triisophthalic acid hexasodium salt To a stirred, warm solution of 5.0 g of the product of Example 14 in 40 ml of dioxane is added 20 ml of 2N sodium hydroxide. The mixture is stirred vigorously for 10 minutes, then 10 ml of water is added, and stirring is continued for a total of one hour. The resulting solution is poured into 300 ml of absolute ethanol. The mixture is filtered and the separated product is washed with ethanol and ether. The pro-duct with 1.0 g of sodium acetate trihydrate is dissolved in 20 ml of water and poured into 250 ml of absolute ethanol.
The resulting mixture is stirred for one hour, and then is filtered. The separated product is washed with ethanol and ether, and dried to give 4.22 g of the product of the Example as a beige powder.
Example 16 Preparation of Compressed Tablet Ingredient mg/Tablet Active Compound.. ~.... ~..... ~............. 0.5-500 Dibasic Calcium Phosphate N.F. ...~... qs Starch USP....... ~0.... ~... ~......... ~.... ..40 Modified Starch........ .... .......... ..... ..10 Magnesium Stearate ~SP............... 0......... O.... ..1-5 ~lZ~i3 Example 17 _eparation of Compressed Tablet - Sustained Action In~redient mg/Tablet Active Compound........ ,.... ~.~.... 0~5-500(as acid as Aluminum Eake*, Micronized equivalent) Dibasic Calcium Phosphate N.F. ... ~ qs Alginic A~id~ 20 Starch USP~ O~ 3S
Magnesium Stearate USP~ O~oo~ 10 *Complement inhibitor plus aluminum sulfate yields aluminum complement inhibitor. Complement inhibitor content in aluminum lake ranges from 5~30%.
Example la ; Preparation of Hard Shell Capsule Ingredient m~/Capsule Active Compound..~.,............. 0.5-500 Lactose, Spray Dried.~.O.v.v. qs Magnesium Stearate.~.............. l-10 Example 19 Ingredient % W~V
Active Compound.~.v..~. 0v05-5 Liquid Suyar...... ~.. O........... 75~0 Methyl Paraben USP..~.... 0.18 ~*
Propyl Paraben USP...O... 0.02 Flavoring AgentO...... v............ qs Purified Water qs ad............ 100.0 Example 20 Preparation of Oral Liquid ~Elixir) In~redient ~ W/V
Active Compound............... ~ 0.05-5 ~lcohol USP.......~.............. ~ 12.5 GlycPrin USP...... v.v..... ~.... 45.0 ** ITrademark - ?f ~L~Z~3 Syrup USP..................... 20.0 ~lavoring Agent............... qs Purified Water qs ad.~ . 100.0 Example 21 Pxeparation of Oral Suspens on ~Syrup) .
In~redient % W/V
Active Compound..O.............................. 0.05-5 as Aluminum Lake, Micronized (acid equivalent) Polysorbate 80 USP~Oo~ 0.1 Magnesium Aluminum Silicate, ~ Colloidal........ ~............... ~................. 0.3 .0 Flavoring Agent..... ~;....O..................... ~ . q5 Methyl Paraben USP..~....................... ~.~.~ 0.18 Propyl Paraben USP.............. .................. 0.02 . Liquid Sugar........ O..... ~......... ~.... .75.0 Purified Water qs ad...................... 100.0 L5 Example 22 ration of In~ectable Solution In~redient - % W~V
Active Compound.O......... 0.05-5 . . Benzyl Alcohol N.F. .~..... .Ø9 Water for Injection... O.~. 100.0 Example 23 Preparation of Iniectable Oil _ _ Ingredient ~ W/V
. .
Active Compound....~.~. 0.05-5 Benzyl Alcohol...... ~ . 1.5 Sesame Oil qs ad.~........ 100.0 * Trademark :~!
i3 _ample 24 Preparation of Intra Articular Product In~redient Amount Active Compound... ~... ~..... ~........................... ~. 2-20 mg ~aCl (physiological saline)........... .....Ø9%
Ben2yl Alcohol........................ .....Ø9%
Sodium Caxboxymethylcellulose......... ......1-5%
p~l adjusted to 5.0-7.5 Water for Injection qs ad............. ......100%
Example 25 Preparation of Injectable Depo Suspension Inqredient ~ W/V
Active Compound...... 0........ ~......................... ..~. 0.05-5 ~acid equivalent) Polysorbate 80 VSP.~ O~ ............ u... .0~2 Polyethylene Glycol 4000 USP.O.......... .3.0 Sodium Chloride USP.. ~..... ~.~.......................... ~. a ~ O o 8 Benzyl Alcohol N.F. ~ 0.9 HCl to p~3 6-8 ............ ..... ........................ .....qs Water for Injection qs ad.. ~....... O.... 100.0 - 2~ -
Claims (23)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula:
(I) wherein R1 is hydrogen or methyl; R2 is hydrogen, carboxyl or COOR4, wherein R4 is an alkali metal or alkaline earth metal; R3 is hydrogen, hydroxy or COOR4, wherein R4 is as previously defined; with the proviso that each phenyl must contain at least one COOR4; which comprises;
a) hydrolyzing a compound of the formula:
(II) wherein R5 is hydrogen or methyl; R6 is hydrogen, methoxycarbonyl, 2-methoxyethaxycarbonyl or phenoxycarbonyl; and R7 is hydrogen, hydroxy, methoxycarbonyl or phenoxycarbonyl; in an alkali metal hydroxide and then neutralizing with a suitable weak acid capable of removing the N-alkali salt of the sulfamido moiety, b) when required reacting a compound of general formula (I) wherein R1 is hydrogen with methyl iodide in the presence of a strong base to give a compound of the general formula (I) wherein R1 is a methyl group, and c) when required converting the free acid into an alkali metal or alkaline earth metal salt thereof.
(I) wherein R1 is hydrogen or methyl; R2 is hydrogen, carboxyl or COOR4, wherein R4 is an alkali metal or alkaline earth metal; R3 is hydrogen, hydroxy or COOR4, wherein R4 is as previously defined; with the proviso that each phenyl must contain at least one COOR4; which comprises;
a) hydrolyzing a compound of the formula:
(II) wherein R5 is hydrogen or methyl; R6 is hydrogen, methoxycarbonyl, 2-methoxyethaxycarbonyl or phenoxycarbonyl; and R7 is hydrogen, hydroxy, methoxycarbonyl or phenoxycarbonyl; in an alkali metal hydroxide and then neutralizing with a suitable weak acid capable of removing the N-alkali salt of the sulfamido moiety, b) when required reacting a compound of general formula (I) wherein R1 is hydrogen with methyl iodide in the presence of a strong base to give a compound of the general formula (I) wherein R1 is a methyl group, and c) when required converting the free acid into an alkali metal or alkaline earth metal salt thereof.
2. A process according to Claim 1, wherein the alkali metal hydroxide in step (a) is sodium hydroxide and the suitable weak acid is a mineral acid.
3. A process according to Claim 1, wherein the alkali metal hydroxide in step (a) is sodium hydroxide and the suitable weak acid is a C1-C4 alkanoic acid.
4. A process according to Claim 3, wherein the suitable weak acid is glacial acetic acid.
5. A compound of the formula (I) defined in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
6. A process for the preparation of 5,5',5"-[1,3,6-naphthalene-triyltris(sulfonylimino)] tris-[2-hydroxyisophthalic acid], characterized by hydrolyzing 5,5',5"-[1,3,6-naphthalenetris(sulfonylimino)]tris[2-hydroxyisophthalic acid]hexamethyl ester in aqueous sodium hydroxide and then acidifying with dilute hydrochloric acid.
7. The compound of 5,5',5"-[1,3,6-naphthalenetriyltris-(sulfonyl-imino)]-tris[2-hydroxyisophthalic acid] whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.
8. The process for the preparation of 3,3',3"-[1,3,6-naphthalene-triyltris(sulfonylimino)]tris[6-hydroxybenzoic acid], characterized by hydrolyzing 3,3',3"-[1,3,6-naphthalenetriyltris(sulfonylimino)tris[6-hydroxybenzoic acid]trimethylester in aqueous sodium hydroxide and then acidifying with dilute hydrochloric acid.
9. The compound 3,3',3"-[1,3,6 naphthalenetriyltris(sulfonylimino)]-tris[6-hydroxybenzoic acid] whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.
10. The process for the preparation of 5,5',5"-[1,3,6-naphthalenetriyltris(sulfonylimino)] triisophthalic acid character-ized by hydrolyzing 5,5',5"-[1,3,6-naphthalenetriyltris(sulfonyl-imino)]triisophthalic acid hexakis(2-methoxyethyl)ester in aqueous sodium hydroxide and then acidifying with dilute hydrochloric acid.
11. The compound 5,5',5"- [1,3,6-naphthalenetrlyltris(sul-fonylimino)] triisophthalic acid whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.
12. A process for the preparation of 4,4',4"-[1,3,6-naphth-alenetriyltris(sulfonylimino)] tribenzoic acid trisodium salt, characterized by hydrolyzing the following compound:
4,4',4"-[1,3,6-naphthalenetriyltris(sulfonylimino)]-tribenzoic acid trimethyl ester, with aqueous sodium hydroxide and then neutralizing the compound thus formed with glacial acetic acid.
4,4',4"-[1,3,6-naphthalenetriyltris(sulfonylimino)]-tribenzoic acid trimethyl ester, with aqueous sodium hydroxide and then neutralizing the compound thus formed with glacial acetic acid.
13. The compound 4,4',4"- [1,3,6-naphthalenetriyltris(sul-fonylimino)] tribenzoic acid trisodium salt, whenever prepared according to the process of claim 12 or by an obvious chemical equivalent thereof.
14. A process for the preparation of 5,5',5"-[1,3,6-naphthalenetriyltris(sulfonylimino)] tri-1,2,3-benzenetricarboxylic acid nonasodium salt, characterized by hydrolyzing the following compound:
5,5',5"-[1,3,6-naphthalenetriyltris(sulfonylimino)] tri-1,2,3-benzenetricarboxylic acid nonaphenyl ester with aqueous sodium hydroxide and then neutralizing the compound thus formed with glacial acetic aeid.
5,5',5"-[1,3,6-naphthalenetriyltris(sulfonylimino)] tri-1,2,3-benzenetricarboxylic acid nonaphenyl ester with aqueous sodium hydroxide and then neutralizing the compound thus formed with glacial acetic aeid.
15. The compound 5,5'-5"[1,3,6-naphthalenetriyltris(sul-fonylimino)] tri-1,2,3-benzenetricarboxylic acid nonasodium salt, whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.
16. A process for the preparation of 3,3',3"-[1,3,6-naph-thalenetriyltris(sulfonylimino)] tribenzoic acid trisodium salt, characterized by hydrolyzing the following compound:
3,3',3"- [1,3,6-naphthalenetriyltris(sulfonylimino)]-tribenzoic acid trimethyl ester, with aqueous sodium hydroxide and then neutralizing the compound thus formed with glacial acetic acid.
3,3',3"- [1,3,6-naphthalenetriyltris(sulfonylimino)]-tribenzoic acid trimethyl ester, with aqueous sodium hydroxide and then neutralizing the compound thus formed with glacial acetic acid.
17. The compound 3,3',3"-[1,3,6-naphthalenetriyltris(sul-fonylimino)l tribenzoic acid trisodium salt, whenever prepared according to the process of claim 16 or by an obvious chemical equivalent thereof.
18. A process for the preparation of 5,5',5" [1,3,6-naph-thalenetriyltris(sulfonylmethylimino)] triisophthalic acid hexa-sodium salt, characterized by hydrolyzing the compound:
5,5'5"-[1,3,6-naphthalenetriyltris(sulfonylmethyl-imino)] triisophthalic acid hexakis(2-methoxyethyl) ester with aqueous sodium hydroxide, and then neutralizing the compound thus formed with sodium acetate trihydrate.
5,5'5"-[1,3,6-naphthalenetriyltris(sulfonylmethyl-imino)] triisophthalic acid hexakis(2-methoxyethyl) ester with aqueous sodium hydroxide, and then neutralizing the compound thus formed with sodium acetate trihydrate.
19. The compound 5,5',5"-[1,3,6-naphthalenetriyltris(sul-fonylmethylimino)] triisophthalic acid hexasodium salt, whenever prepared according to the process of claim 18 or by an obvious chemical equivalent thereof.
20. A process for the preparation of 5,5',5"-[1,3,6-naph-thalenetriyltris(sulfonylimino)] triisophthalic acid hexasodium salt, characterized by hydrolyzing 5,5',5"-[1,3,6-naphthalene-triyltris(sulfonylimino)] triisophthalic acid hexakis(2-methoxy-ethyl)ester with aqueous sodium hydroxide and then neutralizing the compound thus formed with glacial acetic acid.
21. The compound 5,5',5"-[1,3,6-naphthalenetriyltris(sulfonylimino)]-triisophthalic acid hexasodium salt, whenever prepared according to the process of claim 20 or by an obvious chemical equivalent thereof.
22. A process according to Claim 1, wherein the starting material of formula II is prepared by reacting a compound of the formula:
wherein R8 is C1-C6 alkyl and R9 is hydrogen, hydroxy or COOR8, wherein R8 is as previously defined; with 1,3,6-naphthalenetrisulfonyl chloride in a suitable diluent with a suitable acid acceptor to give a compound of general formula (II) wherein R5 is hydrogen and when required reacting a compound of general formula (II) wherein R5 is hydrogen with methyl iodide in the presence of a strong base to give a compound of the general formula (II) wherein R5 is a methyl group.
wherein R8 is C1-C6 alkyl and R9 is hydrogen, hydroxy or COOR8, wherein R8 is as previously defined; with 1,3,6-naphthalenetrisulfonyl chloride in a suitable diluent with a suitable acid acceptor to give a compound of general formula (II) wherein R5 is hydrogen and when required reacting a compound of general formula (II) wherein R5 is hydrogen with methyl iodide in the presence of a strong base to give a compound of the general formula (II) wherein R5 is a methyl group.
23. A process according to Claim 22, wherein the diluent is a polar solvent, and the suitable acid acceptor is an organic or inorganic base.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000301048A CA1120953A (en) | 1978-04-13 | 1978-04-13 | Trisubstituted naphthalene compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000301048A CA1120953A (en) | 1978-04-13 | 1978-04-13 | Trisubstituted naphthalene compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1120953A true CA1120953A (en) | 1982-03-30 |
Family
ID=4111223
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000301048A Expired CA1120953A (en) | 1978-04-13 | 1978-04-13 | Trisubstituted naphthalene compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1120953A (en) |
-
1978
- 1978-04-13 CA CA000301048A patent/CA1120953A/en not_active Expired
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