Abstract:
Ureylenebis substituted phenylenecarbonylimino symmetrical phenenylbiscarbonylimino dinaphthalenepoly-sulfonic acid salts, and nitro and amino substituted benzamido phenylenedicarbonyl dinaphthalenepoly-sulfonic acid salts that are new intermediates for the preparation of the active ureides, which have complement inhibiting activity.

Description:
This is division, of application Ser. No. 820,276, filed July 29, 1977, now U.S. Pat. No. 4,132,730. 
    
    
     DESCRIPTION OF THE INVENTION 
     This invention is concerned with dinaphthalene sulfonic acid urylene salts, having complement inhibiting activity, of general formula I: ##STR1## wherein A is selected from the group consisting of alkali metal; and the pharmaceutically acceptable salts thereof. 
     This invention is also concerned with compounds of the formula II: ##STR2## wherein R is selected from the group consisting of nitro and amino; and A is selected from the group consisting of alkali metal. These compounds are useful as intermediates for the preparation of the complement inhibiting compounds described hereinabove. The intermediate compounds also possess complement inhibiting activity. The compounds of the present invention may be prepared by the following method outlined in Flow Chart A. ##STR3## 
     The novel intermediate nitro (I) and amine (II) compounds of the invention are prepared by reacting 8-amino-1,3,6-naphthalenetrisulfonic acid trialkali metal salt with 5-nitroisophthaloyl chloride in basic aqueous medium for one hour. After acidification with hydrochloric acid, the solution is diluted with ethanol to provide the 8,8&#39;-[(5-nitro-1,3-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonic acid hexa alkali metal salt. Hydrogenation of the nitro-hexa alkali metal salt using 10% palladium-carbon catalyst, filtration, concentration and treatment with absolute ethanol provides the 8,8&#39;-[(5-amino-m-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonic acid hexa alkali metal salt. The amino hexa alkali metal salt is reacted with a 20% excess of 4-nitro-2-sulfobenzoic acid anhydride in aqueous medium with alkali metal acetate as a buffer at 0°-5° C. for 15-30 minutes. Filtration and acidification of the filtrate with hydrochloric acid followed by warming and dilution with ethanol provides 8,8&#39;-[5-(4-nitro-2-sulfobenzamido)-1,3-phenylenedicarbonylimino]di-1,3,6-naphthalenetrisulfonic acid hepta alkali metal salt (I). Hydrogenation of (I) using 10% palladium-carbon catalyst in water, filtration and concentration of the filtrate followed by dilution with ethanol and cooling yields the 8,8&#39;-[5-(4-amino-2-sulfobenzamido)-1,3-phenylenedicarbonylimino]di-1,3,6-naphthalenetrisulfonic acid hepta alkali metal salt (II). Phosgenation of (II) in aqueous medium with alkali metal carbonate until the solution is weakly basic followed by dilution with ethanol yields 8,8&#39;,8&#34;,8&#39;&#34;-({ureylenebis[(2-sulfo-4,1-phenylene)carbonylimino-s-phenenylbis(carbonylimino)]}tetra-1,3,6-naphthalenetrisulfonic acid tetradecyl alkali metal salt (III). 
     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 C1s. 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). 
     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). It has also been reported that the drug, pentosanpoly-sulfoester, has an anticomplementary activity on human serum both in vitro and in vivo, as judged by the reduction in total hemolytic complement activity; Pathologie Biologie, 25, 33-36 (1977). 
     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 aminals 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--Lethan 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 II shows the complement inhibiting activity of the intermediate compounds of the invention. 
     
                                           TABLE I__________________________________________________________________________Biological Activities                                  In Vivo Activity                                  (Guinea Pig)                                  % Inhibition               Cl  C-Late                       Shunt Inhi-                                  Intravenous               026*                   035*                       bition 036*                                  Time (mintues)Compound            Wells                   Wells                       Wells Cap 50*                                  2  30 20__________________________________________________________________________8,8&#39;,8&#34;,8&#39;&#34;-{(Ureylenebis[(2-sulfo-4,1-phenylene)carbonylimino-s-phenenylbis-               +8  +5  +5    87   -97                                     -96                                        -95(carbonylimino)]}tetra-1,3,6-naphthalene-trisulfonic acid tetradecyl sodium salt__________________________________________________________________________ *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 twofold. 
    
     
                                           TABLE II__________________________________________________________________________Biological Activities (Intermediates)                                 In Vivo Activity (Guinea Pig)                                 % Inhibition              Cl  C-Late                      Shunt Inhi-                                 Intraperitoneal                                          Intravenous              026*                  035*                      bition 036*                                 Time (min.)                                          Time (min.)Compound           Wells                  Wells                      Wells Cap 50*                                 30 60 120                                          2  30 120__________________________________________________________________________8,8&#39;-[5-(4-Nitro-2-sulfobenzamido)-1,3-phenylenedicarbonylimino[di-1,3,6-              +4  +2  +1    201  -40                                    -55                                       -74                                          -91                                             -59                                                -51naphthalenetrisulfonic acid hepta-sodium salt8,8&#39;-[5-(4-Amino-2-sulfobenzamido)-1,3-phenylenedicarbonylimino[di-1,3,6-              +6  +3  +2    142  -45                                    -61                                       -73                                          -98                                             -79                                                -45naphthalenetrisulfonic acid hepta-sodium salt__________________________________________________________________________ *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 twofold. 
    
    
    
     EXAMPLE 1 
     8,8&#39;-[5-(4-Nitro-2-sulfobenzamido)-1,3-phenylenedicarbonylimino]di-1,3,6-naphthalenetrisulfonic acid heptasodium salt 
     A mixture of 10.0 g of 5-nitroisophthalic acid, 50 ml of thionyl chloride and 0.2 ml of dimethylformamide is refluxed with stirring for 21/2 hours. The solution is allowed to stand 48 hours at room temperature then is evaporated to an oil in vacuo. The evaporation step is repeated several times with cyclohexane and then toluene. Finally hexane is added and partial evaporation produces crystals. The mixture is cooled, then filtered. The crystals are washed with cold hexane to give 5-nitroisophthaloyl chloride. 
     To a solution of 25.5 g of 8-amino-1,3,6-naphthalenetrisulfonic acid, trisodium salt in 100 ml of water and 60 ml of N sodium hydroxide at room temperature is added 8.13 g of 5-nitroisophthaloyl chloride with about 25 ml of ether. The mixture is shaken briefly and a second 60 ml portion of N sodium hydroxide is added. The mixture is shaken for 5 minutes and a third 60 ml portion of N sodium hydroxide is added. The mixture is shaken for 15 minutes and a 1.0 g portion of the acid chloride is added with a few ml of ether, shaking is resumed for an additional 45 minutes then the mixture is acidified with 5 ml of concentrated hydrochloric acid and extracted with four 150 ml portions of ether. The aqueous solution is neutralized and is concentrated to about 50 ml in vacuo at 55° C. The remaining liquid is allowed to stand at room temperatures for 48 hours and forms a solid which is diluted with 125 ml of 80% ethyl alcohol and triturated. The material is filtered and washed with 80% ethyl alcohol, absolute ethanol and ether, then dried at 120° C. for a few hours. The product is then dissolved in 60 ml of water, heated on the steam bath and diluted with 300 ml of absolute ethanol. The material is filtered and washed and the final product is then dried at 120° C. overnight to give 8,8&#39;-[(5-nitro-1,3-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonic acid, hexasodium salt. 
     A mixture of 23.0 g of the preceding product, 150 ml of water and 2.3 g of 10% palladium catalyst on carbon is hydrogenated at room temperature for 5 hours at an average pressure of 43 lbs., then is filtered through diatomaceous earth and washed with water. The filtrate is then concentrated to a small volume in vacuo, absolute ethanol is added and the resulting oil is triturated until a solid is formed. This material is filtered and washed with absolute ethanol followed by ether. The product is then oven dried at 120° C. to give 8,8&#39;-[(5-amino-m-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonic acid, hexasodium salt. 
     An 8.65 g portion of the product above, 1.63 g of sodium acetate trihydrate and 2.2 g of 4-nitro-2-sulfobenzoic acid anhydride in 25 ml of water is stirred for 15 minutes at 0°-5° C. The solution is filtered, the filtrate is acidified with one ml of concentrated hydrochloric acid, warmed on a steam bath and diluted with 120 ml of ethanol. The mixture is cooled, filtered and the product is washed with 80% aqueous ethanol, ethanol and ether, then is dried by conventional means to give 9.8 g of the product of the example as a pale yellow powder. 
     EXAMPLE 2 
     8,8&#39;-[5-(4-Amino-2-sulfobenzamido)-1,3-phenylenedicarbonylimino]di-1,3,6-naphthalenetrisulfonic acid heptasodium salt 
     A mixture of 8.38 g of the product of Example 1, 75 ml of water and 0.5 g of 10% palladium on carbon catalyst is hydrogenated at room temperature for one hour in a Parr shaker. The resulting mixture is filtered through diatomacous earth. The filtrate is concentrated to 20-25 ml, warmed and diluted with 200 ml of ethanol. The mixture is cooled and the granular precipitate is collected, washed with ethanol and ether then is dried to give 7.8 g of the product of the example as a tan powder. 
     EXAMPLE 3 
     8,8&#39;,8&#34;,8&#39;&#34;Ureylenebis[(2-sulfo-4,1-phenylene)carbonylimino-s-phenenylbis(carbonylimino)]tetra-1,3,6-naphthalenetrisulfonic acid tetradecyl sodium salt 
     A 5.1 g portion of the product of Example 2 in 25 ml of water plus 850 mg of sodium carbonate is phosgenated until acidic. An additional 500 mg of sodium carbonate is added plus 5 ml of water, then phosgene is bubbled in, keeping the solution weakly basic. The solution is warmed and diluted with 100 ml of ethanol to give a gum which solidifies on cooling. The mixture is filtered and precipitate is washed with 77% aqueous ethanol, ethanol and ether to give a tan-yellow powder. The product is dissolved in 30 ml of water and diluted with 60 ml of ethanol. The resulting oil is collected by filtering through diatomaceous earth then is dissolved on the filter with 30 ml of water. The resulting aqueous solution is again diluted with 60 ml of ethanol and is triturated with ethanol until a solid is formed. The solid is collected and dried by conventional means to give 2.2 g of the product of the example as a tan powder. 
     EXAMPLE  4 
     Preparation of Compressed Tablet 
     
         ______________________________________Ingredient           mg/Tablet______________________________________Active Compound      0.5-500Dibasic Calcium Phosphate N.F.                qsStarch USP           40Modified Starch      10Magnesium Stearate USP                1-5______________________________________ 
    
     EXAMPLE 5 
     Preparation of Compressed Tablet--Sustained Action 
     
         ______________________________________Ingredient           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 6 
     Preparation of Hard Shell Capsule 
     
         ______________________________________Ingredient          mg/Capsule______________________________________Active Compound     0.5-500Lactose, Spray Dried               qsMagnesium Stearate  1-10______________________________________ 
    
     EXAMPLE 7 
     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 8 
     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 9 
     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 10 
     Preparation of Injectable Solution 
     
         ______________________________________Ingredient          % W/V______________________________________Active Compound     0.05-5Benzyl Alcohol N.F. 0.9Water for Injection 100.0______________________________________ 
    
     EXAMPLE 11 
     Preparation of Injectable Oil 
     
         ______________________________________Ingredient          % W/V______________________________________Active Compound     0.05-5Benzyl Alcohol      1.5Sesame Oil qs ad    100.0______________________________________ 
    
     EXAMPLE 12 
     Preparation of Intra-Articular Product 
     
         ______________________________________Ingredient            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 13 
     Preparation of Injectable Depo Suspension 
     
         ______________________________________Ingredient          % 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______________________________________