US3865831A - 1,1{40 ,4,4{40 -tetrahydro-4,4{40 -dioxo(6,6{40 biquinoline)-2,2{40 -dicarboxylates - Google Patents

Abstract

Coupounds of formula

ARE USEFUL IN THE PROPHYLACTIC TREATMENT OF SENSITIZED HUMAN AND ANIMALS FOR ALLERGY AND ALL ANAPHYLACTIC REACTIONS OF A REAGIN OR NON-REAGIN MEDIATED NATURE. The compounds are formulated with pharmaceutical carriers for oral, parenteral, or insufflation means of administration.

Description

United States Patent 1 Hall et al.

1 1,1',4,4'-TETRAnYnRo-4,4'.

D10X0(6,6BlQUINOLINE)-2,2'. DICARBOXYLATES [75] Inventors: Charles M. Hall; Herbert G.

Johnson, both of Kalamazoo, Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: June 9, 1972 [21] Appl. No.: 261,524

[52] US. Cl..... 260/286 R, 260/268 R, 260/283 Bl, 260/283 SY, 260/283 CN, 260/286 R,

{51] int. Cl C07d 33/46 [58] Field of Search. 260/283 Bl, 345.2, 286 R,287

[56] References Cited FOREIGN PATENTS OR APPLICATIONS 2,145,423 3/1972 Germany 260/283 Bl 2,130,408 12/1971 Germany .1 260/287 [451 Feb. 11, 1975 Primary E.\'aminer-Donald G. Daus Attorney, Agent, or Firm-Martin B. Barancik; Roman Saliwanchik [57] ABSTRAQT Coupounds of formula 6 Claims, No Drawings 1 2 1,1 ',4,4-TETRAHYDRO-4,4'- lected from the above groups and can be located any- DIOXO(6,6'BIQUINOLINE)-2,2 where on the ring.

DICARBOXYLATES The preferred compounds are those compounds where R is selected from the group consisting of hydro- 5 gen, alkali metal and an amine salt; Z is hydrogen. X

BRIEF SUMMARY OF THE INVENTION and Y can be the same or different monosubstituents.

We have discovered that novel compounds of For- When X and Y are the same monosubstituentQthey are mula Ia are useful in the prophylactic treatment of senselected from the group consisting of hydrogen. alkyl sitized humans and animals for allergy and all anaphyfrom one to three carbon atoms, inclusive, alkoxy from lactic reactions ofa reagin or non-reagin mediated naone to three carbon atoms, inclusive. halogen. cyano, ture. The compounds are formulated with pharmaceuand tical carriers for oral, parenteral, or insufflation means 0 of administration. C 0.

. wherein Q is selected from the group consisting of hy- DETAILED DESCRIPTION OF THE INVENTION l5 drogen, alkali metal and an amine salt, with the proviso In accordance with this invention, we provide comthat Q is the same as R; and with the same aforemenpounds represented by structure la tioned restriction on the location of the monosubstitu- OR la wherein it is understood that la can exist in its tautoents. When X and Y are different, one monosubstituent meric form lb and that the compounds of this invention is hydrogen and the other monosubstituent is selected are likely to be mixtures of all tautomeric forms, the from the more preferred group and can be located anypercentages of each tautomer to be at least partially dewhere on the ring. pendent on the nature of R, X, Y, and Z, and the physi- The more preferred compounds are those comcal environment of the compound. pounds where R is an alkali metal or an amine salt and lb C OR For the purpose ofb revity throughout the application Z is hydrogen. X and Y can be the same or different and appended claims, the compounds will be referred monosubstituents. When X and Y are the monosubto hereinafter in their keto form, structure Ia; stituent, they are selected from the group consisting of The R substituent is selected from the group consisthydrogen, fluoro, chloro, methyl, ethyl, methoxy, ething of hydrogen, alkyl from one to three carbon atoms, oxy, cyano, and inclusive, phenyl, alkali metal or an amine salt.

Z is selected from the group consisting of hydrogen, -&

. alkyl from one to three carbon atoms, inclusive, and p y where Q is selected from the group consisting of alkali X and Y can he thg Same or d'ffereht mohosuhsmu metal and an amine salt with the proviso that Z is the chm when X and Y are the same mohosubsmuem 5 same as R, with the aforementioned restrictions on the h are Selected from the group consisting of hydra location of the monosubstituent; and when X and Y are g halogen alkyl from one to three carbon atoms different, one monosubstituent is hydrogen and the Cluslve, alkoxy having from one t0 three carbon atoms other monosubstituent is selected from the more preihclusive, Phehyh trifluommethyh cyaho and ferred group and can be located anywhere on the ring. 2 m As employed in the above disclosure and throughout the specification, the term halogen includes fluoro, where Q is selected from the group consisting of hydrochloro, bromo, and iodo and the term alkyl includes gen; alkyl from one to three carbon atoms, inclusive; methyl, ethyl, propyl, and isopropyl when limited to phenyl; an alkali metal and an amine salt, with the prothree carbon atoms. Alkali metal includes sodium viso that where R is hydrogen, alkali metal or an amine and potassium. The term amine salt" includes all salt, when Q must be the same as R; with the further pharmaceutically acceptable amine salts of the invenprovision that when tion, including, for example, the amines ammonia, trisa. X is at the 5 position, Y is at the 5' or 7' position, (hydroxymethyl)-aminomethane, D-threo-2-aminolb. X is at the 7 position, Y is at the 5 or 7' position, p-nitrophenyl-l ,3-propanediol, N,N- c. X is at the 8 position, Y is at the 8 position; his(hydroxycthyl)piperazine, 2-amino-2-methyl-land when X and Y are different, one monosubstituent propanol, 2-mnino-2-methyl-l ,3-propanediol and 2,2-

must be hydrogen and the other monosubstituent is sehis(hydroxymethyl)-2,2',2"-nitriolotriethanol and fur- 3 ther amines including H NR, NHR and NR wherein R is selected from the group consisting of alkyl from one to three carbon atoms, inclusive, and -CH CH OH.

The compounds of this invention can be prepared by methods known to the art. The basic synthetic pathway employed is the reaction of an appropriately substituted benzidine (II) with an oxaloacetate sodium salt (III) in the presence of a solvent to form the diadduct (IV). The R group is limited to the alkyl group of from one to three carbon atoms, inclusive; and phenyl. Ring closure to the desired compound (la) is accomplished by heating the diadduct at appropriate conditions.

4 vention. Included among starting materials made available in the art are the following substituted benzidine compounds:

TAB LE I NHg O Y O l Z C-OR R-C\ \I c-z C H I ll x N4: C C-0R After the above synthesis has been carried out, the X Y carboxylate can be transesterified to other esters or hy- H H drolyzed to the carboxy acid. The carboxy acid is con- 2 Br H verted to the alkali metal or amine salts by standard 59 3 methods. 3 I H It should be noted that because of the symmetry in S the benzidine starting material, a monosubstituent at 3 CH H the 2 position is equivalent to a monosubstituent at the gg 6 position, 2' position or 6' position. When the mono- 3 Cl H substituent is at the 3 position, equivalent positions are g at 5, 3' and 5. However, when the diadduct is heated, 3 OCi-L, H the ring is closed and a portion of the symmetry is lost. 3 Consequently, for every starting material substituted at 2 I H the 2 and 2 position, three different compounds of this invention are prepared. Referring to structure la, these 3 Cl 3'c1 compounds are the 5 5, 5 7, and 7 7' disubstituted ZP P 1,1, 4,4-tetrahydro-4,4'-dioxo[6,6'-biquinoline]-2,2'- 3 0iC H 3OiC,,H dicarboxylic acid. For example, when the starting ma- 2 terial 2,2-dimethyl benzidine is reacted with diethyl 2CH.'; ZICH, 1 sodium oxaloacetate, the compounds of the invention are diethyl 5,5'-dimethyl-l 4,4'-tetrahydro-4,4'- 3 Br 3'Br dioxo[6,6-biquinoline]-2,2'-dicarboxylate, diethyl gg gig 5,7-dimethyl-l,l 4,4'-tetrahydro-4,4-dioxo[6,6- 2 N0 2'NO biquinoline]-2,2'-dicarboxylate, and diethyl 7,7- 2 F dimethyl-l ,l 4,4-tetrahydro-4,4-dioxo[6,6- biquinoline]-2,2'-dicarboxylate.

When the starting material is substituted at the 3 position, only one compound of the invention is prepared, the monosubstitution at the 8 position.

X and Y substituted benzidines where X and Y are the same monosubstituent or where either X orY is hydrogen, have been prepared in the art prior to this inexample, trifluoromethyl benzidine is prepared by reacting sulfur tetrafluoride with carboxy-paradinitrobiphenyl followed by reduction to the benzine starting compound. The carboxyamide is prepared by reacting the carboxy-para-dinitrobiphenyl with thionyl chloride followed by ammonia treatment to give the carboxyamide-para-dinitrobiphenyl This compound is then readily reduced by either of the methods described above to the corresponding benzidine compound. Furthermore, cyanobenzidine is prepared by reacting carboxyamide-para-dinitrobiphenyl with titanium tetrachloride in tetrahydrofuran and base at 0 C. to give the cyano-para-dinitrobiphenyl compound which is readily reduced by either of the methods disclosed above to the cyanobenzidine.

The second reactant, the oxaloacetate derivative is also readily available. Compounds where R is ethyl and Z is hydrogen, methyl, ethyl or phenyl are known in the art.

Where Z is hydrogen, an alternative reagent to the oxaloacetate derivative is available to form the diadduct. Acetylene dicarboxylate (V), where R is limited to alkyl of from one to three carbon atoms, inclusive, or phenyl, can be added to the substituted benzidine to form the diadduct (IV) as illustrated below:

ll g ROC-CC- 0R MHz In the formation of the diadduct and subsequent ring closure, the following processing conditions can be observed.

When using the oxaloacetate reagent to form the diadduct, there should be a sufficient amount of acid present to protonate the oxaloacetate carbanion and catalyze the removal of the keto grouping as water. The acid can also serve as a solvent for the two reagents as well. For example, glacial acetic acid, propionic acid, p-toluene sulfonic acid, and butyric acid are acids which can be used. lf a further reagent is needed to place the two reactants into solution, (or a cosolvent desired), benzene, toluene, diethyl ether, dioxane, tetrahydrofuran, or alcohols from one to about four carbon atoms can be employed. The length of time for the formation of the diadduct is temperature dependent.

At room temperature the reaction proceeds rather slowly but as the temperature is raised, reaction time is decreased. Acceptable reaction times are achieved at temperatures ranging from about 40 to about (7.. although reaction temperatures can be above C. if desired.

With regard to the use ofthe acetylene dicarboxylate reactant, in the formulation of the diadduct, appropriate solvents are alcohols having from one to about six carbon atoms. preferably one to about three carbon atoms, benzene, diethylether, dioxane, tetrahydrofuran, or any other solvent which places both of the reactants in solution and allows the desired compound to form. Generally the reaction proceeds readily at room temperature and can be promoted by an increase in temperature to about 100 C.

Ring closure of the diadduct, prepared by the methods disclosed above, and formation of the desired compound can be accomplished by heating the diadduct at a relatively high temperature. This heating can be done to the neat diadduct. However, it is preferred to use a solvent which can function as a heat transfer medium. Any high boiling inert solvent such as a mineral oil, hexamethylphosphoric triamide, diphenyl ether, or Dowtherm A, which appears to be primarily a diphenyl ether side product of the Dow Chemical Company preparation of phenol, is suitable. The ring cyclization step is preferably carried outlat temperatures of from about 220 C. to about 280 (3., although lower or higher temperatures can be employed ifdesired. Particularly preferred solvents are Dowtherm A, or diphenyl ether, which boil at about 250 C., thus enabling the ring cyclization to occur during reflux.

An additional advantage of the elevated temperature during the ring cyclization step is that any adduct formed in the preceding step which is not in a position to cyclize since it is trans to the benzene ring is isomerized to the cis configuration during the heating, thereby allowing substantial yields of the desired compound to be produced. This trans adduct preparation occurs more frequently when an aprotic solvent and acetylene dicarboxylate are used in the adduct formation step. As stated previously, at this point various esters, the acid, or salts can be prepared at the R position of the carboxy group. Different esters can be prepared by a standard transesterification reaction. Ester groups are converted to the acid by treatment with base and acid. The acid can then be easily converted to an amine salt or alkali metal by contacting the diacid with two equivalents of the desired amine or alkali metal and heating in-a sufficient amount of water to effect solubilization. The crystalline salts can be precipitated by the addition of methanol. When R is hydrogen, alkali metal or amine. and X or Y is then Q is the same as R.

Following is an illustrative list of starting materials and desired compounds which can be prepared by the above disclosed procedures. It is to be understood that the Table I] X and Y monosubstituents are at the designated position of the starting material and that the final compounds have isomeric structures as previously explained.

TABLE n .SLlLLLLlQ Mei ll ll I ll RO-CC-C-C-OR whe re Z=H The above illustrative examples of Table ll are prepared where Z in the oxaloacetate sodium salt is methyl, ethyl, pro'pyl, isopropyl, or phenyl.

TABLE IV Example 1 1,1, 4,4'-tetrahydro-4,4-diox0[6,6'-biquinoline]-2,2'- dicarboxylic acid Thirty grams of dimethyl acetylenedicarboxylate is added dropwise to a solution of I84 grams of benzidine in 500 ml. of methanolat 0 C. The reaction mix- 'ture is stirred at 0 C. for 30 minutes and at room temperature for l6 hours. The crystalline product is collected by filtration. Recrystallization gives yellow needles melting at l36-l38 C. 3.0 Gram of the above solid was dissolved in IQ ml. of Dowtherm A and heated at 250 C. for 5 minutes, during which time a yellow solid precipitates. 2.2 Grams of the yellow solid is refluxed in aqueous 5% NaOH solution for 1 hour. The reaction mixture is cooled and acidified with concentrated HCl to pH 4. The resulting light yellow acid is collected by filtration.

Example 2 Disodium-l l ',-4,4'-tetrahydro-4,4'-dioxo-[6,6- biquinoline]-2,2-dicarboxylate The acid'prepared in Example 1 is converted to its sodium salt by treatment with an approximately halfsaturated, hot solution of NaHCO The disodium salt precipitates upon cooling. Recrystallization from water gives the disodium compound as its trihydrate.

Anal. Calcd: for: C H O N JH O:

C, 50.64; H, 3.40; N, 5.91. Found: C, 50.24; H, 2.99; N, 5.94.

The compositions of the present invention are presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-in-water and water-inoil emulsions containing suitable quantities of the compound of Formula la. The preferred method of administration is by inhalation into the lung by means of an aerosol, liquid or powder for insufflation.

For oral administration either solid or fluid unit dosage forms can be prepared. For preparing solid compositions such as tablets, the compound of Formula la is mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers. Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.

Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared. The water-soluble forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup. An elixir is prepared by using a hydro-alcoholic (ethanol) vehicle with suitable sweetners such as sugar and saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with an aqueous vehicle with the aid ofa suspensing agent such as acacia, tragacanth, methylcellulose and the like.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The preferred compositions are those adapted for in-- halation into the lung and containing a compound of the invention which is water-soluble.

Compositions for inhalation are of three basic types; (1 a powder mixture preferably micro-pulverized; (2) an aqueous solution to be sprayed with a nebulizer; and (3) an aerosol with volatile propellant in a pressurized container.

The powders are quite simply prepared by mixing a compound of the formula with a solid base which is compatible with lung tissue, preferably lactose. The powders are packaged in a device adapted to emit a measured amount of powder when inhaled through the mouth.

Aqueous solutions are prepared by dissolving the compound of the formula la in water and adding salt to provide an isotonic solution and buffering to a pH compatible with inhalation. The solutions are dispersed in a spray device or nebulizer and sprayed into the mouth while inhaling.

Aerosols are prepared by dissolving a compound of the Formula la in water or ethanol and mixing with a volatile propellant and placing in a pressurized container having a metering valve to release a predetermined amount of material.

The liquefied propellant employed is one which has a boiling point below 65F. at atmospheric pressure. For use in compositions intended to produce aerosols for medicinal use, the liquefied propellant should be nontoxic. Among the suitable liquefied propellants which may be employed are the lower alkanes containing up to five carbon atoms, such as butane and pentane, or a lower alkyl chloride, such as methyl, ethyl, or propyl chlorides. Further suitable liquefied propellants are the fluorinated and fluorochlorinated lower alkanes such as are sold under the trademarks Freon and Genetron. Mixtures of the above-mentioned propellants may suitably be employed. Example of these propellants are dichlorodifluoromethane (Freon l2), dichlorotetrafluorethane (Freon 114), trichloromonofluoromethane (Freon ll"), dichloromonofluoromethane (Freon 2i monochlorodifluoromethane (Freon 22), trichlorotrifluoroethane (Freon ll3), difluoroethane (Genetron 142-A) and monochlorotrifluoromethane (Freon 13).

The term unit dosage form, as used in the specification and claims, refers to physically discrete units suitable as unitary dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired thera peutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specifications for the novel unit dosage forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular effect to be achieved and (b) the: limitations inherent in the art of compounding such an active material for use in humans and animals, as disclosed in detail in this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, pills, suppositories, powder packets, wafers, granules, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampuls, vials, aerosols with metered discharges, segregated multiples of any of the foregoing, and other forms as herein described. An effective but non-toxic quantity of the compound is employed in treatment.

The dosage of the compound for treatment depends on the route of administration. A dosage schedule of from about 0.01 to 50 mg. in a single dose administered parenterally or by inhalation embraces the effective range for preventing allergic attack for which the compositions are effective. More specifically, the single dose is from about 0.5 to about l'O mg. of compound. The oral dose is from about 0.1 to about 500 mg. in a single dose. More specifically, the single oral dose is from about l to about 50 mg. of compound. The dosage to be administered is repeated up to four times daily.

The administration of the compositions of the present invention to humans and animals provides a method for the prophylactic treatment of allergy or all anaphylactic reactions of a reagin or a non-reagin mediated nature. That is to say, these compositions when administered to a sensitized individual prior to the time that the individual comes into contact with substances (antigens) to which he is allergic, will prevent the allergic reaction which would otherwise occur.

For example, the process can be used for prophylactic treatment of such chronic conditions as bronchial asthma, allergic rhinitis, food allergy, hay fever, urticaria, auto-immune diseases, exercise induced asthma, stress induced asthma, and bird fanciers disease.

Example 3 A lot of l0,000 tablets, each containing 50 mg. of dimethyl 1,1 ',4,4 '-tetrahy|dro-4,4'-dioxo[6,6- biquinoline]-2,2'-dicarboxylate is prepared from the following types and amount of ingredients:

Dimethyl l,l ',4,4'-tetrahydro-4,4'-

dioxo[ 6,6 '-biquinoline 2,2-dicarboxylate 500 Gm. Dicalcium phosphate 1,000 Gm. Methylcellulose, U.S.P. (l5 cps) 6O Gm. Talc I50 Gm. Corn Starch 200 Gm. Calcium stearate l2 Gm.

1 1 Example 4 One thousand two-piece hard gelatin capsules, each containing 50 mg. of dimethyl 1,1, 4,4'-tetrahydro- 4,4-dioxo[6,6'-biquinoline]-2,2'-dicarboxylate are prepared from the following types and amounts of ingredients:

Dimethyl 1,1 4,4'-tetrahydro-4.4'-

dioxo[6,6'-biquinoline]-2,2-

dicarboxylate 50 Gm. Talc 150 Gm. Magnesium stearate l Gm.

The ingredients are mixed well and filled into capsules of the proper size.

Capsules so prepared are useful in preventing attacks of bronchial asthma at a dose of one capsule every 4 to 6 hours.

Example 5 One thousand tablets, each containing 50 mg. of dimethyl 1,1, 4,4'-tetrahydro-4,4-dioxo[6,6- biquinoline]-2,2'-bicarboxylate are made from the following types and amounts of ingredients:

Dimethyl l, l 4,4'-tetrahydro- 4,4-dioxo[6,6'-biquinoline]- 2,2-dicarboxylate 50 Gm. Microcrystalline cellulose NF 420 Gm. Starch 100 Gm. Magnesium stearate powder 5 Gm.

The ingredients are screened and blended together and pressed into 575 mg. tablets.

The tablets are useful to protect against food allergy at a dose of 1 tablet before meals.

Example 6 A sterile prepartion suitable for intramuscular injection and containing 1 mg. of dimethyl 1,1, 4,4- tetrahydro-4,4-diox0[6,6'-biquinoline]-2,2'- dicarboxylate in each milliliter is prepared from the following ingredients:

2.2'-dicarboxylate l Gm. Benzyl benzoate 200 ml. Methylparaben 1.5 Gm. Propylparaben 0.5 Gm. Cottonseed oil q.s. 1,000. ml.

One milliliter of this sterile preparation is injected for prophylactic treatment of allergic rhinitis.

Example 8 A powder mixture consisting of 1.0 Gm. of tris(hydroxymethyl)aminomethane salt of l,l,4,4-tetrahydro- 4,4' dioxo[6,6-biquinoline]-2,2-dicarboxylic acid and sufficient lactose to make 5 grams of mixture is micropulverized and placed in an insufflator designed to deliver mg. of powder per dose.

The powder is inhaled into the lungs for prevention of asthmatic attacks.

Example 9 Twelve grams of an aerosol composition is prepared from the following ingredients:

Tris( hydroxymethyl )aminomethane salt of l,l'.4,4'-tetrahydro- 4.4'-dioxo[6,6'-biquinolinel- 2.2'-dicarboxylate acid 0.25 Gm. Absolute ethanol 4.620 Gm. Freon 12 1.43 Gm. Freon 114 5.70 Gm.

The THAM salt is dissolved in the ethanol and chilled to 30C. and added to the chilled Freons. The 12 grams of composition is added to a 13 cc. plastic coated bottle and capped with a metering valve. The metering valve releases mg. of composition in an aerosol.

The aerosol is inhaled every 4 to 6 hours for prevention of asthmatic attacks.

Example 10 After allowing for the differing solubilities of the compounds and the activity of the particular compound as measured by the in vivo rat passive cutaneous anaphylaxis reaction, a suitable quantity of each of the compounds of Table ll, 111 and IV are substituted for the active compound in the compositions and uses of Examples 3 to 9. Results showing anti-allergy activity are obtained.

We claim: 1. A compound of the formula Example 7 Six hundred ml. of an aqueous solution containing 1.0 mg. of the tris(hydroxymethyl)aminomethane (THAM) salt of 1,1,4,4'-tetrahydro-4,4'-dioxo[6,6-

wherein R is selected from the group consisting of hydrogen, alkyl from one to three carbon atoms, inclusive, phenyl, alkali metal or a pharmaceutically acceptable amine salt;

Z is selected from the group consisting of hydrogen, alkyl from one to three carbon atoms, inclusive, and phenyl;

X and Y are the same or different monosubstituents, and when X and Y are the same monosubstituent, it is selected from the group consisting of hydrogen, halogen, alkyl from one to three carbon atoms, inclusive, alkoxy from one to three carbons inclulsive, phenyl, nitro, trifluoromethyl, cyano and o I c -o where Q is selected from the group consisting of hydrogen alkyl from one to three carbon atoms, inclusive; phenyl, an alkali metal and a pharmaceutically acceptable amine salt, with the proviso that where R is hydrogen, alkali metal or an amine salt, then Q must be the same as R; with the further provision that when a. X is at the position, Y is at the 5 or 7 position, b. X is at the 7 position, Y is at the 5 or 7 position c. X is at the 8 position, Y is at the 8' position and when X and Y are different, one monosubstituent must be hydrogen and the other monosubstituent is selected from the above group and can be located anywhere on the ring.

2. A compound in accordance with claim 1 wherein R is selected from the group consisting of hydrogen, alkali metal and a pharmaceutically acceptable amine salt;

Z is hydrogen;

X and Y are the same or different monosubstituents, and when X and Y are the same monosubstituent, it is selected from the group consisting of hydrogen, alkyl from one to three carbon atoms, inclusive; alkoxy from one to three carbon atoms, inclusive; halogen, cyano, and

wherein Q is selected from the group consisting of hydrogen, alkali metal and a pharmaceutically acceptable amine salt, with the proviso that Q is the same as R; and when X and Y are different, one monosubstituent is hydrogen and the other monosubstituent is selected from the above group.

3. A compound in accordance with claim I wherein R is an alkali metal or a pharmaceutically acceptable amine salt;

Z is hydrogen;

X and Y are the same or different monosubstituents and when X and Y are the same monosubstituent, it is selected from the group consisting of hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, cyano and where Q is selected from the group consisting of alkali metal and a pharmaceutically acceptable amine salt with the proviso that Q is the same as R, and when X and Y are different, one monosubstituent is hydrogen and the other monosubstituent is selected from the above group.

4. l,l 4,4-tetrahydro-4,4'-dioxo[6,6'-biquinoline]- 2,2-dicarboxylate acid according to claim 1.

5. Disodium l,l 4,4-tetrahy'dro-4,4-dioxo[6,6- biquinoline]-2,2-dicarboxylate according to claim 1.

6. Di(tris-hydroxymethyl)ammonium l,l ,4,4- tetrahydro-4,4-dioxo[6,6-biquinoline]-2,2-

dicarboxylate according to claim 1.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,865,831 Page 1 of 2 DATED February 11, 1975 vE T0R(5) Char1es M. Ha11 and Herbert G. I Johnson It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Front Page; change references to inc1ude "U.S. Patents Cited" and "Other References" I U.S. Patents 2,499,661 3/1950 Marc1'1hacy 260-286R 2,760,964 8/1956 Carrington 260-286R 3,519,652 7/1970 P1 112 Maurice 260-3452 3,660,084 5/1972 VanHeerton et a1 260-28381 3,673,218 6/1972 Cairns et a1 260-345R Other References Mentzer et a1. Chem. Abstr. V01. 38 C01. 6337 (1944) Sardesai et a1. Chem. Abstr. V01. 55 C01. 22313h (1961) Siveramakrishnan et a1. Chem. Abstr. V01. 56 C01; 2419-20 Throughout the patent, change 1'ta11'c1'zed "Ia" to --Ia--. Co1umn 2, 11'nes 41-2; change "the monosubstituents" to --the same m0nosubst1'tuents--.

Co1umn 3, 11'ne 1; change "NHR' to --HNR' Co1umn 5, 11' ne 7; change "d1n1'tr0b1'pheny1" t0 --d1'n1'tr0b1'pheny1 Co1umn 6, 11'ne 8; change "formu1at1'on to --formation--.

Co1umn 6, 11ne 25; change "A" to '--A Co1umn 8, 11'ne 2; change "m1. of methano1" t0 --m1 methano1-- Co1umn 8, 11'ne 25; change "C H 0 N .3H 0" to --C H O N -3H O--.

Co1umn 8, 11ne 58; change "sweetners" to --sweeteners--.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,865,831 I Page 2 of 2 DATED February 11, 1975 INVENTOR(S) Charles M. Hall and Herbert G. Johnson It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Column 8, line 62; change "suspensing to -suspending--. Column 9, line 34; change "formula" to --Formula--.

Column 9, line 57; change "Example" to --Examples--. Column 10, line 57; change "(15 cps) 60 Gm." to

-- D 60 Gm.-.

Column 14, lines 1-3, change 0 to O Column 14 line 4; change "wherein" to --where-. Column 14, line 31; change "dicarboxylate to --d1carboxyl1'c--.

Signed and Scaled this Twenty-sixth Day of August I980 smu Attest:

SIDNEY A. DIAMOND Attesting Officer Commissioner of Patents and Trademarks

Claims (6)

1. A COMPOUND OF THE FORMULA

2. A compound in accordance with claim 1 wherein R is selected from the group consisting of hydrogen, alkali metal and a pharmaceutically acceptable amine salt; Z is hydrogen; X and Y are the same or different monosubstituents, and when X and Y are the same monosubstituent, it is selected from the group consisting of hydrogen, alkyl from one to three carbon atoms, inclusive; alkoxy from one to three carbon atoms, inclusive; halogen, cyano, and

3. A compound in accordance with claim 1 wherein R is an alkali metal or a pharmaceutically acceptable amine salt; Z is hydrogen; X and Y are the same or different monosubstituents and when X and Y are the same monosubstituent, it is selected from the group consisting of hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, cyano and

4. 1,1'', 4,4''-tetrahydro-4,4''-dioxo(6,6''-biquinoline)-2,2''-dicarboxylate acid according to claim 1.

5. Disodium 1,1'', 4,4''-tetrahydro-4,4''-dioxo(6,6''-biquinoline)-2,2''-dicarboxylate according to claim 1.

6. Di(tris-hydroxymethyl)ammonium 1,1'',4,4''-tetrahydro-4,4''-dioxo(6,6''-biquinoline)-2,2''-dicarboxylate according to claim 1.