Abstract:
Biphenyltetrayltetrakis(sulfonylimino)tetrabenzene dicarboxyic acid alkali metal salts, useful as complement inhibitors, and a biphenyltetrayltetrakis(sulfonylimino)tetrabenzene dicarboxylic acid octakis methoxyethyl ester that is a new intermediate for the preparation of the active salts.

Description:
BACKGROUND OF THE INVENTION 
     The term &#34;complement&#34; 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, allergic, immunochemical and/or immunopathological reactions. The reactions in which complement participates take place in blood serum or in other body fluids, and hence are considered to be humoral reactions. 
     With regard to human blood, there are at present more than 11 proteins in the complement system. These complement proteins are designated by the letter C and by number: C1, C2, C3 and so on up to C9. The complement protein C1 is actually an assembly of subunits designated C1q, C1r and C1. 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 C1 and before C2. The numerical assignments for the proteins in the complement system were made before the reaction sequence was fully understood. A more detailed discussion of the complement system and its role in body processes can be found in, for example, Bull. World Health Org., 39, 935-938 (1968); Ann. Rev. Medicine, 19, 1-24 (1968); The John Hopkins Med. J., 128, 57-74 (1971); Harvey Lectures, 66, 75-104 (1972); The New England Journal of Medicine,  287, 452-454; 489-495; 545-549; 592-596; 642-646 (1972); Scientific American, 229, (No. 5), 54-66 (1973); Federation Proceedings, 32, 134-137 (1973); Medical World News, Oct. 11, 1974, pp. 53-58; 64-66; J. Allergy Clin. Immunol., 53, 298-302 (1974); Cold Spring Harbor Conf. Cell Proliferation 2/Proteases Biol. Control/229-241 (1975); Annals of Internal Medicine, 84, 580-593 (1976); &#34;Complement: Mechanisms and Functions&#34;, Prentice-Hall, Englewood Cliffs, N.J. (1976); Pathologie Biologie, 25(1), January 1977, pp. 33-36. 
     The complement system can be considered to consist of three sub-systems: (1) a recognition unit (C1q) which enables it to combine with antibody molecules that have detected a foreign invader; (2) an activation unit (C1r, C1s, C2, C4, C3) which prepares a site on the neighboring membrane; and (3) and attack unit (C5, C6, C7, C8 and C9) which creates a &#34;hole&#34; in the membrane. The membrane attack unit is non-specific; it destroys invaders only because it is generated in their neighborhood. In order to minimize damage to the host&#39;s own cells, its activity must be limited in time. This limitation is accomplished partly by the spontaneous decay of activated complement and partly by interference by inhibitors and destructive enzymes. The control of complement, however, is not perfect, and there are times when damage is done to the host&#39;s cells. Immunity is therefore a double-edged sword. 
     Activation of the complement system also accelerates blood clotting. This action comes about by way of the complement-mediated release of a clotting factor from platelets. The biologically active complement fragments and complexes can become involved in reactions that damage the host&#39;s cells, and these pathogenic reactions can result in the development of immune-complex diseases. For example, in some forms of nephritis, complement damages the basal membrane of the kidney, resulting 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 of large amounts of antitoxin sometimes results in serum sickness, an immune-complex disease. Rheumatoid arthritis also involves immune complexes. Like disseminated lupus erythematosus, it is an autoimmune disease in which the disease symptoms are caused by pathological effects of the immune system in the host&#39;s tissues. In summary. the complement system has been shown to be involved with inflammation, coagulation, fibrinolysis, antibody-antigen reactions and other metabolic processes. 
     In the presence of antibody-antigen complexes the complement proteins are involved in a series of reactions 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&#39;s defense mechanism against infection it also results in inflammation and tissue damage in the immunopathological process. The nature of certain of the complement proteins, suggestions regarding the mode of complement binding to biological membranes and the manner in which complement effects membrane damage are discussed in Annual Review in Biochemistry, 38, 389 (1969). 
     A variety of substances have been disclosed as inhibiting the complement system, i.e., as complement inhibitors. For example, the compounds 3,3&#39;-ureylenebis-[6-(2-amino-8-hydroxy-6-sulfo-1-naphthylazo)]benzenesulfonic acid, tetrasodium salt (chlorazol fast pink), heparin and a sulphated dextran have been reported to have an anticomplementary effect, British Journal of Experimental Pathology, 33, 327-339 (1952). The compound 8-(3-benzamido-4-methylbenzamido)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 Pat. No. 2,254,893 or South African Pat. No. 727,923 discloses certain 1-(diphenylmethyl)-4-(3-phenylallyl)piperazines 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, 104, 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 inhibitors epsilon-aminocaproic acid, Suramin and tranexamic acid all have been used with success in the treatment of hereditary angioneurotic edema, a disease state resulting from an inherited deficiency or lack of function of the serum inhibitor of the activated first component of complement (C1 inhibitor), The New England Journal of Medicine, 286, 808-812 (1972). 
     SUMMARY OF THE INVENTION 
     This invention is concerned with biphenyltetrayltetrakis(sulfonylimino)tetrabenzene dicarboxylic acid alkali metal salts, having complement inhibiting activity, of formula I: ##STR1## wherein R is selected from the group consisting of alkali metal; and the pharmaceutically acceptable salts thereof. 
     This invention is also concerned with a compound of the formula II: ##STR2## (5,5&#39;,5&#34;,5&#39;&#34;-[2,2&#39;,4,4&#39;-biphenyltetrayltetrakis(sulfonylimino)]-tetraisophthalic acid octakis(2-methoxyethyl)ester), said compound being useful as an intermediate for the preparation of the complement inhibiting compounds described hereinabove. 
     DESCRIPTION OF THE INVENTION 
     To prepare the compounds of this invention an amine ester of an organic acid of the formula: ##STR3## is prepared by reduction of the corresponding nitro derivative, followed by reaction with 2,2&#39;,4,4&#39;-tetrachlorosulfonyl biphenyl in a mixture of organic solvents such as acetonitril and pyridine for about 18 to about 20 hours. The reaction mixture is filtered. The filtrate is concentrated, treated with 0.2N hydrochloric acid and extracted with benzene. The benzene soluble material is dried, dissolved in acetone and treated by conventional chromatographic means to isolate the intermediate octakis methoxyethyl ester compound of the formula: ##STR4## 
     The intermediate (II) is reacted with an alkali metal hydroxide to provide the active complement inhibiting octaalkali metal salt. 
     The compounds of the present invention may be administered internally, e.g., orally, intra-articularly or parenterally, e.g., intra-articular, to a warm-blooded animal to inhibit complement in the body fluid of the animal, such inhibition being useful in the amelioration or prevention of those reactions dependent upon the function of complement, such as inflammatory process and cell membrane damage induced by antigen-antibody complexes. A range of doses may be employed depending on the mode of administration, 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 for more rapidly excreted salts, may be used. For intra-articular use for large joints such as the knee, from about 2 to about 20 mg/joint per week may be used, with proportionally smaller doses for smaller joints. The dosage range is to be adjusted to provide optimum therapeutic response in the warm-blooded 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 weight of animal per day. The usual daily dosage for a 70 kg subject may vary from about 350 mg 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 the invention are suitable for parenteral use, other salts may also be prepared, such as those of primary 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.g., 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 for purposes of preparing suspensions for injection. 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 calcium or magnesium, may be employed. It will be apparent, therefore, that these salts embrace, in general 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 pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form 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 ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums, or similar materials as non-toxic pharmaceutically acceptable diluents or carriers. The tablets or pills of the novel compositions can be laminated or otherwise compounded to provide a dosage form affording the advantage of prolonged or delayed action or predetermined successive action of the enclosed medication. 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 disintegration 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 polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate and the like. A particularly advantageous enteric coating comprises a styrene maleic acid copolymer together with known materials contributing to the enteric properties of the coating. 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 administration 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 injection use. 
     The term dosage form, as described herein, refers to physically discrete units suitable as unitary dosage for warm-blooded animal subjects, each unit containing a predetermined quantity of active component calculated to produce the desired therapeutic effect in association with the required pharmaceutical 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 for therapeutic use in warm-blooded animals as disclosed in this specification. Examples of suitable oral dosage forms in accord with this invention are tablets, capsules, pills, powder packets, granules, wafers, cachets, teaspoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing 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 following identified tests: (i) Test, Code 026 (C1 inhibitor)--This test measures the ability of activated human C1 to destroy fluid phase human C2 in the presence of C4 and appropriate dilutions of the test compound. An active inhibitor protects C2 from C1 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 test compound. An active inhibitor protects EAC 142 from lysis by human C3-C9; (iii) Test, 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 Vasculitis Test--Here, the well known complement dependent lesion, Forssman vasculitis, is produced in guinea pigs by intradermal injection of rabbit anti-Forssman antiserum. The lesion 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 test compound at 200 mg/kg is then reported, unless otherwise stated; (v) Forssman Shock Test--Lethal shock is produced in guinea pigs by an i.v. injection of anti-Forssman antiserum and the harmonic mean death time of treated guinea pigs is compared with that of simultaneous 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. Pat. No. 3,876,376 and compared to undosed control guinea pigs; and (vii) Cap 50 Test--Here, appropriate amounts of the test compound are added to a pool of guinea pig serum in vitro, after which the undiluted serum capillary tube assay referred to above is run. The concentration of compound inhibiting 50% is reported. 
     With reference to Table I, guinea pigs weighing about 300 g were dosed intravenously (i.v.) or intraperitoneally (i.p.) with 200 mg/kg of the test compound dissolved in saline and adjusted to pH 7-8. One hour after dosing, the guinea pigs were decapitated, blood was collected and the serum separated. The serum was tested for whole complement using the capillary tube assay. Percent inhibition was calculated 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 significant in vitro and in vivo, complement inhibiting activity in warm-blooded animals. 
     
                       TABLE I______________________________________Biological Activities         Cl      C-Late  Shunt Inhi-         026*    035*    bition 036*Compound      Wells   Wells   Wells   Cap 50*______________________________________5,5&#39;,5&#34;,5&#39;&#34;-[2,2&#39;,4,4&#39;-Biphenyltetrayl-tetrakis (sulfonyl-imino)]tetraisophthalic         +7**    N       +3**     89acid octasodium salt                  139______________________________________ *Code designation for tests employed as referred herein. **Activity in wells a serial dilution assay. Higher well number indicates higher activity. The serial dilutions are two-fold. N = Negative 
    
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Example 1 
     5,5&#39;,5&#34;,5&#39;&#34;-[2,2&#39;,4,4&#39;-Biphenyltetrayltetrakis(sulfonylimino)]tetraisophthalic acid octakis(2-methoxyethyl)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 gas subsides. Heating is continued for approximately 2 hours, with stirring, until solution is achieved, and then reflux is continued for an additional 30 minutes. The resulting clear solution is allowed to stand, and then is evaporated in vacuo to afford an oil. The oil solidifies and is recrystallized twice from carbon tetrachloride 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 heated to reflux on a steam bath. Heating 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 product 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 benzene. The combined fractions are dissolved in 580 ml of hot ethanol. The solution is neutralized with 5.0 ml of 5N sodium hydroxide, then diluted with 450 ml of water. The solution is kept at room temperature until crystals separate, and then the mixture is placed in a chill room (5° C.) overnight. 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 crystals. The crystals are dissolved in 350 ml of hot benzene and diluted with 140 ml of hexane. The solution is allowed to crystallize overnight at room temperature to yield 72.0 g of 5-aminoisophthalic acid bis(2-methoxyethyl)ester. 
     A solution of 31.4 g of 4,4&#39;-diamino-2,2&#39;-biphenyldisulfonic acid in 150 ml of water and 7.7 g of sodium hydroxide is filtered, then diluted with 300 ml of absolute ethanol. The product formed is collected, washed with ethanol and ether, and dried to give 31.9 g of 4,4&#39;-diamino-2,2&#39;-biphenyldisulfonic acid disodium salt. 
     To a mixture of 25.6 g of the above product in 10.0 ml of water is added 9.8 g of sodium nitrite, forming a paste. The paste is added to a cooled solution (0°-5° C.) of 45.0 ml of concentrated hydrochloric acid and 16.3 ml of water, in a manner suitable to maintain the temperature at 0°-5° C., and a milky mixture results. 
     A solution of 3.0 g of cuprous chloride in 3.0 ml of water is added to 130 ml of glacial acetic acid, and saturated with sulfur dioxide gas. The resulting mixture is added to the above milky mixture in such a manner as to maintain the temperature at 5°-7° C. When the addition is complete, the mixture is stirred at room temperature for 2 hours. The solvent is evaporated at 24° C. in a water bath and the residue is dissolved in water. The solution is adjusted to pH 8.0 with anhydrous sodium carbonate, and the solid removed by filtration. The filtrate is diluted with absolute ethanol and stirred, separating as an oil. The oil is separated and allowed to solidify on standing to yield a white solid. The solid is collected, washed with 85% aqueous ethanol, ethanol and ether, and dried to give 36.0 g of 2,2&#39;,4,4&#39;-biphenyltetrasulfonic acid tetrasodium salt. 
     A mixture of 39.0 g of the preceding product (prepared as described above), 500 g of thionyl chloride and 3.0 ml of dimethylformamide is heated at reflux for 18 hours. The mixture is cooled and filtered. The filtrate is evaporated, and the residue is triturated with hot chloroform. The mixture is cooled, the solid is collected, washed with chloroform and dried. The solid is triturated with methylene chloride and acetonitrile, collected and dried to yield 13.0 g of 2,2&#39;,4,4&#39;-tetrachlorosulfonyl biphenyl. 
     To a stirred solution of 23.8 g of 5-aminoisophthalic acid bis(2-methoxyethyl)ester and 7.0 ml of pyridine in 200 ml of acetonitrile at room temperature is added 12.0 g of the product above. Stirring is continued for 3 hours, then the mixture is allowed to stand overnight at room temperature. The solution is filtered, the filtrate is concentrated to 100 ml and poured into 500 ml of 0.2N hydrochloric acid to give an oily precipitate. The mixture is extracted three times with a total of 500 ml of benzene. The extract is washed twice with 250 ml of dilute sodium chloride solution and dried over sodium sulfate. The mixture is filtered and the filtrate evaporated to an orange glass. The solid is dissolved in 250 ml of warm benzene and allowed to crystallize overnight. The solid is collected by filtration, and the filtrate (A) is saved. The solid is washed with benzene and ether and air dried. The pink powder is dissolved in 75.0 ml of methylene chloride. The solution is treated with activated charcoal and filtered through diatomaceous earth. The filtrate is combined with 350 ml of benzene and boiled until all of the methylene chloride is removed. The mixture is cooled to room temperature, the product formed is collected by filtration and the filtrate (B) is saved. The product is washed with benzene and ether and is recrystallized again from methylene chloride:benzene (1:7). The solid is removed by filtration and the filtrate (C) is combined with filtrates (A) and (B) and evaporated to give 8.5 g of an orange-red glass. A 5.0 g portion of this material is dissolved in 250 ml of acetone, added to 60.0 g of silica gel (dry column chromatography grade), evaporated and placed on top of a dry column containing 1500 g of silica gel, previously equilibrated with 150 ml of acetone:hexane (1:1). The column is eluted with acetone:hexane (1:1) and the desired fractions of the column packing are selectively removed and extracted with acetone to provide a glass. The glass is triturated with diethyl ether to give a solid. The solid is dissolved in methylene chloride and ethanol, treated with activated charcoal, filtered, and then recrystallized from ethanol and dried to yield 900 mg of the product of the Example as cream colored crystals. 
     Example 2 
     5,5&#39;,5&#34;,5&#39;&#34;-[2,2&#39;,4,4&#39;-Biphenyltetrayltetrakis(sulfonylimino)[tetraisophthalic acid octasodium salt 
     A 640 mg portion of the product of Example 1 is stirred at room temperature in 6.0 ml of 1N sodium hydroxide for 45 minutes, then 2.8 ml of 1N acetic acid is added followed by 50.0 ml of absolute ethanol. The mixture is heated to reflux on a steam bath, and then cooled to room temperature. The solvent is decanted and the gummy residue is solidified by stirring with fresh ethanol. The solid is collected and dissolved in 1.0 ml of water, neutralized with two drops of glacial acetic acid and diluted with 50 ml of ethanol to provide a gum. The solvent is decanted and the gum is solidified by stirring with fresh ethanol, then is dried to give 564 mg of the product of the Example as a cream colored powder. 
     Example 3 
     
         ______________________________________Preparation of Compressed TabletIngredient           mg/Tablet______________________________________Active Compound       0.5-500Dibasic Calcium Phosphate N.F.                qsStarch USP           40Modified Starch      10Magnesium Stearate USP                1-5______________________________________ 
    
     Example 4 
     
         ______________________________________Preparation of Compressed Tablet - Sustained ActionIngredient          mg/Tablet______________________________________Active Compound     0.5-500 (as acidas Aluminum Lake*, Micronized               equivalent)Dibasic Calcium Phosphate N.F.               qsAlginic Acid        20Starch USP          35Magnesium Stearate USP                1-10______________________________________ *Complement inhibitor plus aluminum sulfate yields aluminum complement inhibitor. Complement inhibitor content in aluminum lake ranges from 5-30%. 
    
     Example 5 
     
         ______________________________________Preparation of Hard Shell CapsuleIngredient          mg/Capsule______________________________________Active Compound      0.5-500Lactose, Spray Dried               qsMagnesium Stearate   1-10______________________________________ 
    
     Example 6 
     
         ______________________________________Preparation of Oral Liquid (Syrup)Ingredient          % W/V______________________________________Active Compound    0.05-5Liquid Sugar       75.0Methyl Paraben USP 0.18Propyl Paraben USP 0.02Flavoring Agent    qsPurified Water qs ad              100.0______________________________________ 
    
     Example 7 
     
         ______________________________________Preparation of Oral Liquid (Elixir)Ingredient          % W/V______________________________________Active Compound     0.05-5Alcohol USP         12.5Glycerin USP        45.0Syrup USP           20.0Flavoring Agent     qsPurified Water qs ad               100.0______________________________________ 
    
     Example 8 
     
         ______________________________________Preparation of Oral Suspension (Syrup)Ingredient          % W/V______________________________________Active Compound     0.05-5as Aluminum Lake, Micronized               (acid equivalent)Polysorbate 80 USP  0.1Magnesium Aluminum Silicate,Colloidal           0.3Flavoring Agent     qsMethyl Paraben USP  0.18Propyl Paraben USP  0.02Liquid Sugar        75.0Purified Water qs ad               100.0______________________________________ 
    
     Example 9 
     
         ______________________________________Preparation of Injectable SolutionIngredient          % W/V______________________________________Active Compound     0.05-5Benzyl Alcohol N.F.  0.9Water for Injection 100.0______________________________________ 
    
     Example 10 
     
         ______________________________________Preparation of Injectable OilIngredient          % W/V______________________________________Active Compound     0.05-5Benzyl Alcohol       1.5Sesame Oil qs ad    100.0______________________________________ 
    
     Example 11 
     
         ______________________________________Preparation of Intra-Articular ProductIngredient            Amount______________________________________Active Compound        2-20 mgNaCl (physiological saline)                 0.9%Benzyl Alcohol        0.9%Sodium Carboxymethylcellulose                 1-5%pH adjusted to 5.0-7.5Water for Injection qs ad                 100%______________________________________ 
    
     Example 12 
     
         ______________________________________Preparation of Injectable Depo SuspensionIngredient          % W/V______________________________________Active Compound     0.05-5               (acid equivalent)Polysorbate 80 USP  0.2Polyethylene Glycol 4000 USP               3.0Sodium Chloride USP 0.8Benzyl Alcohol N.F. 0.9HCl to pH 6-8       qsWater for Injection qs ad               100.0______________________________________