US3886164A - Quinolyl oxamic acids - Google Patents

Abstract

A compound of the formula

WHEREIN M is selected from the group consisting of hydrogen and a pharmaceutically acceptable metal or amine cation, X 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, and trifluoromethyl with the proviso that when X is hydrogen, the

GROUPING IS LIMITED TO THE 6 POSITION; AND PHARMACEUTICAL COMPOSITIONS THEREOF, IN THE PROPHYLACTIC TREATMENT OF SENSITIZED HUMANS AND ANIMALS FOR ALLERGY AND ALL ANAPHYLACTIC REACTIONS OF A REAGIN OR NON-REAGIN MEDIATED NATURE.

Description

United States Patent 1191 Wright [451 May 27, 1975 1 QUINOLYL OXAMIC ACIDS [75] Inventor: John B. Wright, Kalamazoo, Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

22 Filed: Dec. 20, 1972 211 App]. No.: 316,977

OTHER PUBLICATIONS Teitz, Clinical Chemistry, 1971, pp. 383, 850.

Primary Examiner--Donald G. Daus Assistant Examiner-David E. Wheeler Attorney, Agent, or Firm-Martin B. Barancik; Roman Saliwanchik [57] ABSTRACT A compound of the formula wherein M is selected from the: group consisting of hydrogen and a pharmaceutically acceptable metal or amine cation,

X 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, and trifluoromethyl with the proviso that when X is hydrogen, the

grouping is limited to the 6 position; and pharmaceutical compositions thereof, in the prophylactic treatment of sensitized humans and animals for allergy and all anaphylactic reactions of a reagin or non-reagin mediated nature.

, 10 Claims, No Drawings QUINOLYL OXAMIC ACIDS BRIEF SUMMARY OF THE INVENTION It has been discovered that novel compounds of Formula la are useful in the prophylactic treatment of sensitized humans 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, rectal or inhalation means of administration.

DETAILED DESCRIPTION OF THE INVENTION In accordance with this invention are provided compounds represented by structure Ia:

wherein it is understood that Ia can exist in its tautomeric form Ib and that the compounds of this invention are likely to be mixtures of all tautomeric forms, the percentages of each tautomer to be at least partially dependent on the nature of M and X, and the physical environrnent of the compound.

grouping is limited to the 6 position.

The preferred compounds are those compounds where M is an amine cation, X is selected from the group consisting of alkyl of from one to three carbon atoms, inclusive; and halogen and the grouping is at the 7 position.

The most preferred M group is the cation of tris(hydroxymethyl)aminomethane. I

As employed in the above disclosure and throughout the specification, the term halogen includes fluoro, chloro, bromo, and iodo and the term alkyl includes methyl, ethyl, propyl, and isopropyl when limited to 3 carbon atoms. A pharmaceutically acceptable metal or amine cation includes alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, other acceptable metals such as aluminum and amine cations. The term amine cations includes all pharmaceutically acceptable amine cations of the invention, including for example, cations of the amine ammonia, tris(hydroxymethyl)aminomethane, D-threo-Z-aminol -p-nitrophenyll ,3- propanediol,N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyll -propanol, 2-amino-2-methyl-l ,3- propanediol and 2,2'-bis(liydroxymethyl)-2,2,2"- nitriloethanol and further amines including H NR, I'INR' and NR':, wherein R'is selected from the group consisting of alkyl from one to three carbon atoms, inclusive, and -CI-I CI-I OI-I.

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 nitroaniline (1) with an oxaloacetate sodium salt or acetylene dicarboxylate (111) in the presence of a solvent to form the adduct (111). The R group of reagent (11) is limited to alkyl offrorn one to three carbon atoms, inclusive; and phenyl. Ring closure to the 1,4- dihydronitro-8-substituted-4-oxoquinaldate (1V) is accomplished by heating the adduct at appropriate conditionsl (IV) is then reduced to the amino compound (V) under standard reducing conditions. Compound (V) is then reacted with ethyl oxalyl chloride in a solvent and base under suitable conditions to form ethyl (2- carboalkoxyl ,4-dihydro-8-substituted 4- oxoquinolyl)oxamate (VI), or its 2-carbophenoxy analog, which is then treated with sodium hydroxide to form the acid (VII).

O H 11 H l I 0 0 H n n HO-C-C-N I .fter the above synthesis has been carried out, the aoxy acid is converted to the metal or amine salts by ldard methods.

-Substituted-nitroaniline starting materials are wn to the art. Included among starting materials 1e available in the art are the following twostituted nitroaniline compounds where nitro is deslted at either the 3,4, or 5 position.

TABLE I Ring Position In the formation of the adduct, subsequent ring closure and succeeding reactions in the synthetic pathway,

the following processing conditions and reagents can be employed.

When using the oxaloacetate reagent to form the adduct, there should be a sufficient amount of acid present to protonate the oxaloacetate carbanion and catalyze the removal of the keto grouping. 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. If a further reagent is needed to place the two reactants into solution (or a cosolvent desired), benzene, toluene, diethylether, dioxane, tetrahydrofuran, or alcohols from one to about four carbon atoms can be employed. The length of time for the formation of the adduct 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 C., although reaction temperatures can be above C., if desired.

With regard to the use of the acetylene dicarboxylate reactant in the formation of the adduct, 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 100C.

Ring closure of the adduct, prepared by the methods disclosed above, and formation of the quinoline ring can be accomplished by heating the adduct at a relatively high temperature. This heating can be done to the neat adduct. 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, diphenylether, or Dowtherm A, which appears to be primarily diphenylether, is suitable. The ring cyclization step is preferably carried out at temperatures of from about 220C. to about 280C, although lower or higher temperatures can be employed if desired. Particularly preferred solvents are Dowtherm A, or diphenylether, which boil at about 250C., thus enabling the ring I cyclization to occur during reflux.

An additional advantage of the elevated temperature during the ring cyclization 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.

The nitro grouping of the nitro l,4-dihydro-8- substituted-4-oxoquinaldate formed in the ring closure step is reduced to amino. This reduction can be conveniently effected by catalytic means such as Raney Nickel or palladium or charcoal or platinum in the presence of hydrogen. Additionally, chemical means quinolyloxamic acid by using dilute base such as sodium hydroxide, potassium hydroxide or potassium carbonate at temperatures ranging from about 25C. to about 100C. The acid can then be easily converted to the metal or amine salt by contacting the diacid with two equivalents of the desired metalhydroxide or amine and heating in a sufficient amount of water to effect solubilization. The crystalline salts can be precipitated by the addition of methanol.

Following is an illustrative list of compounds of the invention which can be prepared by the above disclosed procedures. Intended to be included are compounds made from the starting materials of Table l.

Where M is Hydrogen Ring Position of 0 -t 1'E-E0M 22 a iC3H7 5 oc 'n. r

[MC- H, 6

(Ll J l 7 cr TABLE III i the same manner as Table II, but the same illustrative scoping is intended.

The following examples are compounds in accordance with this invention. The compounds are intended not to limit but merely to exemplify the invention.

EXAMPLE 1 (2-Carboxy-l ,4-dihydro- 8-methyl-4-oxo- 7-quinolyl)oxamic acid a. Dimethyl (3-nitro-o-toluidino)butenedioate A suspension of 49.6 grams (0.325 mole) of 2-methyl-3-nitroaniline in 500 ml. of methanol is stirred at room temperature, and 46.15 grams (0.325 mole) of dimethyl acetylenedicarboxylate is added dropwise. The solution .stands at room temperature for 18 hours. As the reaction proceeds, a precipitate forms. The precipitate is removed by filtration and recrystallized from ethanol-water. The yellow needles melt at 99100C.

Anal. Calcd. for: G i-M09 0 C, 53.24; H, 4.47; N, 9.55; Found: C, 53.11; H, 4.77; N, 9.31.

The infrared spectra is in agreement. The NMR spectra indicates a 60/40 mixture of cis and trans isomers.

b. Methyl 7-aminol ,4-dihydro-8-methyl-4-oxoquinaldate A solution of 29.3 grams (0.1 mole) of dimethyl (3- nitro-o-toluidino)butenedioate in 200 ml. of refluxing Dowtherm. The reaction mixture is refluxed for 15 minutes and cooled to room temperature. The product is removed by filtration and recrystallized from dimethylformamide-ethanol to give yellow needles melting at 135.

A suspension of 10.44 grams (0.04 mole) of the above compound in 180 ml. of dimethylformamide and 1 gram of 10% palladium on. charcoal is hydrogenated on a Parr apparatus. The theoretical amount of hydrogen is taken up in 15 minutes. The catalyst is removed by filtration and the solvent removed by distillation in vacuo. The residue is recrystallized from ethanol-water to yield yellow crystals melting at 238 (dec.).

c. Product To a solution of 6.97 grams (0.03 mole) of methyl 7- amino-8-methyll ,4-dihydro-4-oxoquinaldate, in l ml. of dry dimethylformamide is added 3.06 grams of triethylamine. The resulting solution is cooled to 0C and there is added, dropwise., 4.10 grams of ethyl oxalyl chloride, keeping the temperature below 5. The mixture is then stirred at 0for 2 hours and allowed to stand overnight. The dimethylformamide is removed by distillation under reduced pressure. Water is added, the mixture stirred, and the solid removed by filtration. The resulting solid is dissolved in methylene chloride and the resulting solution extracted with a 5% sodium hydroxide solution. The mixture is shaken for 15 minutes. The agueous layer is separated, acidified by the addition of dilute hydrochloric acid, and'the precipitate removed by filtration and washed with water. The material is purified by dissolving it in dilute Nal-lCO solution, filtering the solution, reacidifying the filtrate by the addition of a filtered solution of dilute hydrochloric acid, removing the precipitate by filtration and washing the precipitate with hot water and then hot ethanol. There is obtained 1.66 gram of a tan solid melting at 275 (dec.).

Anal. Calcd. for: C I-1 N 0 N, 9.65. Found: N, 9.21

Example 2 (2-Carboxy-1,4-dihydro-4-oxo-6quinolyl)oxamic acid a. Methyl 6-amino-l ,4-dihydro-4-oxoquinaldate A suspension of 9.92 grams (0.04 mole) of methyl 6-nitro-1,4-dihydro-4-oxoquinaldate and 180 ml. of dimethylformamide with 1 gram of 10% palladium on charcoal is hydrogenated on a Parr apparatus at 50 pounds of pressure. After 15 minutes the theoretical amount of hydrogen has been absorbed. The catalyst is removed by filtration. The filtrate is evaporated to onethird the original volume and poured into 1500 ml. of water. The resulting green needles are filtered off to yield 8.70 grams (100%) of material melting at 230 (dec.). The needles are boiled in ethanol and filtered, increasing the melting point to 235 (dec.).

Anal. Calcd. for: C H N O C, 60.54; H, 4.62; N, 12.84. Found: C, 60.38; H, 4.69; N, l2.65.

The infrared and NMR spectra are in agreement.

b. Ethyl (2-carbomethoxy-1,4-dihydro- 4-oxo-6-quinolyl)oxamate A solution of 3.26 grams (0.02 mole) of methyl 6- amino-l ,4,dihydro-4-oxoquinaldate in 100 ml. of dimethylformamide is stirred and cooled to in an ice bath. To the cold solution is added 2.05 grams of triethylamine and, dropwise, 2.73 grams of ethyl oxalyl chloride while the temperature of the solution is maintained at 0C. The reaction mixture is stirred for 2 hours in the ice bath, then warmed to room temperature and stands for 48 hours. The resulting yellow precipitate is filtered off and washed with ethyl acetate. The yellow solid is boiled in hot ethanol and filtered to give 4.74 grams (74%) of material melting at 295 (dec.).

Anal. Calcd. for: C H N O C, 56.60; H, 4.43; N, 8.80. Found: C, 56.13; H, 4.50; N, 8.84.

The infrared and NMR spectra are in agreement.

0. Product A solution of 3.64 grams (0.0114 mole) of ethyl (2 carbomethoxy-l ,4-dihydro-4 oxo-6-quinolyl)-oxamate in 100 ml. of methylene chloride is shaken well with 74 ml. of a sodium hydroxide solution for minutes. The aqueous phase is separated and acidified with dilute hydrochloric acid. The precipitate is removed by filtration, washed with water and then with ethanol. The product is purified by dissolving it in a 1% sodium hydroxide solution, filtering, and reacidifying the filtrate with a filtered solution of dilute hydrochloric acid. There is obtained 1.57 gram of a tan solid melting at 305 (dec.).

Example 3 (2-Carboxy-l ,4-dihydro-8-methyl-4-oxo-5- quinolyl)oxamic acid a. Methyl l,4,dihydro-8-methyl-4-oxo-5-nitroquinaldate To a stirred solution of 30.43 grams (0.2 mole) of 2-methyl-5-nitroaniline in 500 ml. of methanol is added 28.5 grams (0.02 mole) of dimethyl acetylenedicarboxylate. A yellow precipitate forms within minutes. The reaction mixture is allowed to stand at room temperature for 18 hours. There is obtained 48.5 grams (33%) of yellow needles melting at 129-13l.

Anal. Calcd. for: C,,,H,,N,o,,.

C, 53.24; H, 4.47; N, 9.55. C, 53.65; 'H. 4.83; N, 9.56. The infrared spectra is in agreement. 5 the NMR spectra indicated a mixture of cis and trans isomers.

Found:

To 150 ml. of refluxing Dowtherm A is added 22.3 grams (0.75 mole) of the above sample. Refluxing is continued for 30 minutes. The solution is cooled to room temperature. The resulting tan needles are filtered off and washed with Skellysolve B. There is obtained 14.00 grams (72%) of tan needles melting at 215-216.

Anal. Calcd. for: C H N O C, 54.96; H, 3.84; N, 10.68.

Found: C, 55.09; H, 4.l2; N, 10.46.

The infrared and NMR spectra are in agreement.

g b. Methyl S-amino- 1 ,4-dihydro-8-methyl-4-oxoquinaldate Anal. Calcd. for: C, H, N O

C, 62.06; H, 5.21; N, 12.06. Found: C, 61.85; H, 5.21; N, 12.02.

The infrared and NMR spectra are in 40 agreement.

c. Ethyl (2-carbomethoxy-1,4-dihydro-8-methyl-4-oxo-5- 5 quinolyl )oxamate To a stirred solution of 17.5 grams (0.075 mole) of methyl S-amino- 1 ,4-dihydr0-8-methyl-4-oxoquinaldate in 350 ml. of dimethylformamide at 0C. is added 7.7 grams of triethylamine and dropwise, at 5C. 10.4 5 grams of ethyl oxalyl chloride. The mixture is stirred at 5C. for 2 hours and then allowed to stand overnight. The precipitate is removed by filtration and recrystallized from dimethylformamide to give yellow needles melting at 250-252".

Anal. Calcd. for: C ,H, =,N O,;.

C, 57.83; H, 4.85; N, 8.94. Found: C, 58.17. H. 4. 9; N, .51.

d. Product A mixture of 4.39 grams (0.0132 mole) of ethyl (2- carbomethoxy-l ,4-dihydro-8-methyl-4-oxo-5- quinolyl)oxamate, 100 ml. of methylene chloride, and

65 ml. of 5% sodium hydroxide solution is shaken for 10 minutes in a separatory funnel. The aqueous layer is separated and acidified by the addition of a dilute hydrochloric acid solution. The yellow precipitate is removed by filtration. There is obtained 3.70 grams of material melting at 275 (dec.).

Anal. Calcd. for: C H N O N, 9.65. Found: N, 9.64.

EXAMPLE 4 2-Carboxy1,4-dihydro-8-methyl-4-oxo-6- quinolyl )oxamic acid Anal. Calcd. for: C H N O C, 53.06; H, 4.80; N, 9.52. Found: C, 53.00; H, 4.79; N, 9.54.

To 500 ml. of refluxing Dowtherm is added 56 grams (0.19 mole) of the material obtained above. The mixture is heated under reflux for 10 minutes and allowed to cool. The r sulting precipitate is removed by filtration. There is obtained 39.7 grams (80%) of yellow-tan needles melting at 222 (dec.). Recrystallization from dimethylformamide gives material melting at 270 (dec.).

Anal. Calcd. for: C H N O C, 54.96; H, 3.84; N, 10.68. Found: C, 54.61; H, 3.93; N, 11.00.

The infrared and NMR spectra are in agreement.

b. Methyl 6-amino-1,4-dihydro-8-methyl-4-oxoquinaldate A suspension of 5.24 grams (0.02 mole) of methyl 1,4-dihydro-8-methyl-6-nitro-4-oxoquinaldate and 1 gram of 10% palladium-on-charcoal catalyst, and 40 ml. of dimethylformamide is hydrogenated at an initial pressure of 3 atmospheres. The catalyst is removed by filtration and the filtrate is poured into 500 ml. of water. The precipitate is removed by filtration and recrystallized from methanol. There is obtained 2.72 grams of yellow prisms melting at 236 (dec.).

Anal. Calcd. for: C, H, N O;,.

C, 62.06; H, 5.21; N. 12.06. Found: C, 61.54; H, 5.38; N, 12.04.

The infrared and NMR spectra are in agreement.

c. Ethyl (2-carbomethoxyl ,4-dihydro-8-methyl-4-oxo-6- quinolyl )oxamate Utilizing the procedure described above for ethyl 2- carboxymethoxy-l ,4 dihydro--8-methyl-4-oxo-5- quinolyl)oxamate with an equivalent amount of methyl 6-aminol ,4-dihydro-8-methyl-4-oxoquinaldate, there is obtained ethyl (Z-carbomethoxy-l ,4-dihydro-8- l0 methyl4-oxo-6-quinolyl)oxamate.

d. Product Hydrolysis of the diester above with sodium hydroxide solution according to the procedure described above for (2-carboxyl1,4-dihydro-8-methyl-4-oxo-5- quinolyl)oxamic acid gives (2-carboxy-1,4-dihydro-8- methyl-4-oxo-6-quinolyl)oxamic acid.

EXAMPLE 5 (2-Carboxy-8-chloro l ,4-dihydro-4-oxo-5 quinolyl)oxamic acid a. Methyl 8-chloro-1,4-dihydro-5-nitro-4-oxo-quinaldate A mixture of 29.0 grams (0.164 mole) of 2-chloro-5- nitroaniline, 150 ml. of methanol and 25.4 grams (0.164 mole) of dimethyl acetylenedicarboxylate is heated under reflux for 6 hours and allowed to stand overnight. The precipitate is removed by filtration.

There is obtained 41.0 grams (89%) of yellow needles melting at l57-158. Recrystallization from methanol does not raise the melting point.

Anal. Calcd. for: C H ClN O,

C, 45.80; H, 3.52; Cl, 11.27; N, 8.90 Found: C, 45.75; H, 3.51; Cl, 11.44; N, 8.98

To 300 ml. of refluxing Dowtherm is added 29.4

grams (0.094 mole) of the product obtained above. The mixture is heated under reflux for 1 hour, allowed to cool, the precipitate is removed by filtration. There is obtained 21.6 grams of yellow needles melting at 196-200. A sample is purified by boiling with methanol and filtering. The product obtained melts at 197-198.

Anal. Calcd. for: C H-,ClN O C, 46.74; H, 2.49; Cl, 12.5 N, 9.9 5

5 1 Found: C, 46.47; H, 2.50; Cl. 12.64; 9. 9

b. Methyl 5-amino-8-chlorol ,4-dihydro-4-oxoquinaldate A mixture of 6.06 grams (0.0214 mole) of methyl 8- chloro-1,4-dihydro-5-nitro-4-oxoquinaldate in ml. of methanol and 6 grams of Raney Nickel is hydrogenated on a Parr apparatus under 3 atmospheres of pressure for 1 hour. The catalyst is removed by filtration 65 and the solvent removed by distillation in vacuo, to

yield 290 grams melting at l65-173. Recrystallization from methanol yields 2.45 grams of red needles melting at -176.

Anal. Calcd. for: C H CIN Q,

C. 52.29; H, 3.59; Cl, 14.02; N, 11.09 Found: C, 51.96; H. 3.53; Cl, 13.51; N. 11.11 The infrared and NMR spectra are in agreement.

0. Product Treatment of methyl 5-amino-8-chloro-l,4-dihydro- 4-oxoquinaldate with ethyl oxalyl chloride in the presence of triethylamine followed by saponification of the resulting diester according to the procedure described above for (2-carboxy-l,4-dihydro-8-methyl-4-oxo-7- quinolyl)oxamic acid gives (2-carboxy-8-chloro-1,4- dihydro-4-oxo-5-quinolyl)oxamic acid.

EXAMPLE 6 (2-Carboxy-8-chloro-1,4-dihydro-4-oxo-6- quinolyl)oxamic acid a. Methyl 8-chloro-l ,4-dihydro-6-nitro-4-oxoquinaldate To a solution of 70.8 grams (0.4 mole) of 2-chloro-4- nitroaniline in 300 ml. of methanol is added with stirring 56.8 grams of dimethyl acetylenedicarboxylate. The solution is heated under reflux for 6 hours and allowed to cool. The yellow needles removed by filtration melt at l42-l48.

Twelve and one-half grams of the above product are placed in 150 ml. of refluxing Dowtherm and the mixture heated under reflux for 1 hour. After the mixture has cooled to room temperature the resulting yellow precipitate is removed by filtration. There is obtained 9.10 grams of material melting at 244-245. Recrystallizing from dimethylformamide melthanol gives material possessing the same melting point.

Anal. Calcd. for: C l-l ClN O C, 46.74; H, 2.49; Cl, 12.55; N, 9.91 Found: C, 46.29; H, 2.55; C1, 12.39; N, 10.10

b. Methyl 6-amino-8-chloro-1,4-dihydro-4-oxoquinaldate Catalytic reduction of methyl 8-chloro-l,4-dihydro- 6-nitro-4-oxoquinaldate by the procedure described above for methyl 5-amino-8-chloro-1,4-dihydro-4- oxoquinaldate gives 6-amino-8-chloro-l,4-dihydro-4- oxoquinaldate.

c. Product Treatment of methyl 6-amino-8-chloro-1,4-dihydro- 4-oxoquinaldate with ethyl oxalyl chloride in the presence of triethylamine followed by saponification of the resulting diester according to the general procedure described above for (2-carboxy-l,4-dihydro-8-methyl-4- oxo-7-quinolyl)oxamic acid gives (2-carboxy-8-chlorol,4-dihydro-4-oxo-6-quinolyl)oxamic acid.

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, eye drops and oral solutions or suspensions, and oil-inwater and water-in-oil 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 witu suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent sush 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 preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampul and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use. Parenteral 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.

Additionally, a rectal suppository can be employed to deliver the active compound. This dosage form is of particular interest where the manual cannot be treated conveniently by means of other dosage forms, such as orally or insufflation, as in the case of young children or debilitated persons The active compound can be incorporated into any of the known suppository bases by methods known in the art. Examples of such bases include cocoa butter, polyethylene glycols (Carbowaxes), polyethylene sorbitan monostearate, and mixtures of these with other compatible materials to modify the melting point or dissolution rate. These rectal suppositories can weigh from about 1 to 2.5 grams.

The preferred compositions are those adapted for inhalation into the lung and containing a compound of the invention which is water-soluble. For treatment of allergic conditions of the nose, such as rhinitis, compositions adapted for contact with nasal linings are preferred.

Compositions for inhalation are of three basic types: (1) a powder mixture preferably micropulverized; (2) an aqueous solution to be sprayed with a nebulizer; and (3) an aerosol with volatile propellant in a presurized 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 liquified propellant should be nontoxic. Among the suitable liquefied propellants which may be employed are the lower alkanes containing up to 5 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. Examples of these propellants are dichlorodifluoromethane (Freon 12), dichlorotetrafluoroethane (Freon 115), trichloromonofluoromethane (Freon ll), dichloromonofluoromethane (Freon 21), monochlorofidluoromethane (Freon 22), trichlorotrifluoroethane (Freon l 13), 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 therapeutic 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 and the potency of the particular compound. A dosage schedule of from about 0.2 to about 200 mg. of compound in a single dose administered parenterally or by inhalation in the composition of this invention are effective for preventing allergy attacks. More specifically, the single dose is from about 1.0 to about 20 mg. of compound. The oral and rectal dose is from about 2 to about 400 mg. in a single dose. More specifically, the single dose is from about 2 to about mg. of compound. The dosage to be administered can be repeated up to four times daily. However, when it is necessary to repeat treatment, a preferred dosage schedule reduces the secondary treatment dosage to from about 0.5 percent to about 20 percent of the above dosages, more specifically, from about 1 to about 10 percent of the above dosages. In this manner, a state of allergy prophylaxis can be maintained. The reduced dosage is taken until that dosage no longer provides effective protection. At that time, the larger dosage is repeated, followed by the reduced dosage. An example of such dosage schedule is the following: An asthmatic individual insufflates 1.0 mg. of the tris-(hydroxymethyl- )aminomethane salt of 2-carboxy-8-chloro-l,4- dihydro-4-oxo-5-quinolyloxamic acid. Four hours later the individual insufflates 0.01 mg. of the same compound and every 4 to 6 hours thereafter insufflates 0.01 mg. of the same compound until effective asthma prophylaxis is provided. The individual then insufflates 1.0 mg. of the same compound, then reduces the insufflation dosage to 0.01 mg. 4 to 6 hours later. The dosage schedule continues in this manner.

The administration of the composition 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.

(2Carboxy-l ,4-dihydro-8-methyl- 4-oxo-4-quinolyl)oxamic acid 200 Gm. Dicalcium phosphate 1,000 Gm. Methylcellulose, U.S.P. (l5 cps) 60 Gm. Talc Gm. Corn starch 200 Gm. Calcium stearate l2 Grn.

The compound and dicalcium phosphate are mixed well, granulates with 7.5 percent solution of methylcellulose in water, passed through a No. 8 screen and dried carefully. The dried granules are passed through a No. 12 screen, mixed thoroughly with the talc, starch and magnesium stearate, and compressed into tablets.

These tablets are useful in preventing hay fever attacks at a dose of 1 tablet every 4 to 6 hours.

EXAMPLE 8 One thousand two-piece hard gelatin capsules, each containing 20 mg. of(2-carboxy-l,4-dihydro-8-methyl- 4-oxo-5-quinolyl)oxamic acid are prepared from the following types and amounts of ingredients:

4-oxo-5-quinolyl)oxamic acid 20 Gm. Talc 150 Grn. Magnesium stearate 1 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 9 One thousand tablets, each containing 20 mg. of (2- carboxy-l ,4-dihydro-8-methyl-4-oxo-5- quinolyl)oxamic acid are prepared from the following types and amounts of ingredients:

(2-Carboxyl ,4-dihydro-8-methyl- 4-oxo-5-quinolyl)oxamic acid 20 Gm. Microcrystalline cellulose NF 420 Gm. Starch 100 Gm. Magnesium stearate powder Gm.

The ingredients are screened and blended together and pressed into 545 mg. tablets.

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

EXAMPLE 10 A sterile preparation suitable for intramuscular injection and containing 2 mg. of (2-carboxy-l ,4dihydro-8- methyl-4-oxo-7-quinolyl)oxamic acid in each milliliter is prepared from the following ingredients:

(Z-Carboxyl ,4 dihydro-8-methyl- 4-oxo-7-quinolyl)oxamic acid 2 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 1 1 Six hundred ml. of an aqueous solution containing 2.0 mg. of the tris(hydroxymethyl)aminomethane (THAM) salt of (2-carboxy-8-chloro-1,4-dihydro-4- oxo-5-quinolyl)oxamic acid per ml. is prepared as follows:

I Tris(hydroxymethyl)aminomethane salt of (2-carboxy-8- chlorol ,4-dihydro-4-oxo-5- quinolyl)oxamic acid 1.2 Gm. Sodium chloride 5 Gm. Water for injection q.s. 600 ml.

The THAM salt and sodium chloride are dissolved in sufficient water to make 600 ml. and sterile filtered.

The solution is placed in nebulizers designed to deliver 0.25 ml. of solution per spray.

The solution is inhaled into the lungs every 4 to 6 hours for prevention of asthmatic attacks.

EXAMPLE 12 EXAMPLE l3 Twelve grams of an aerosol composition are prepared from the following ingredients:

Tris(hydroxymethyl )aminomethanesalt of (Z-carboxy-8-chlorol ,4- dihydro-4-oxo-5-quinolyl )oxamic acid .50 Gm. Freon 12 L440 Gm. Freon 114 2.160 Gm. Water 7.300 Gm. Sorbitan monoleate 0.600 Gm.

The THAM salt is dissolved in the water and combined with the other constituents under pressure. The 12 grams of composition are added to a 13 cc. plastic coated bottle and capped with a metering valve. The metering valve releases 80 mg. of composition in an aerosol. The aerosol is inhaled every 4 to 6 hours for prevention of asthmatic attacks.

EXAMPLE 14 In individuals who require continual treatment in the Examples 7 through 13, the dosage of the Example is given initially and each succeeding administration of the drug is at 1/50 of the initial dosage. This maintenance dosing is continued until effective allergy prophylaxis is not obtained. The initial dosage of Examples 7 through 13 is then started once more, followed by the maintenance dosages.

EXAMPLE 15 After allowing for the differing solubilities of the compounds and the activity of the particular compound as measured, for example, by the in vivo rat passive cutaneous anaphylaxis assay, a suitable quantity of each of the compounds of Table II and Table III are substituted for the active compound in the compositions and uses of Examples 7 through 14. Results showing anti-allergy activity are obtained.

EXAMPLE 16 The rat passive cutaneous anaphylaxis assay is run in the following manner:

Female Sprague-Dawley 250 gm. rats are skinsen'sitized with rat ani-ovalbumin homocycotropic antibody that is heat labile and has a passive cutaneous anaphylaxis titer of 1:128. After a 72-hour latency period, the animals are challenged i.v. with 4 mg. ovalbumin (OA) 5 mg. Evans blue dye and the test compound. Thirty minutes later the extravascular bluing that results from antigen antibody combination at the skin side is read. Antibody dilutions are used such that in control animals a 4 mm spot is the lowest detectable spot, and 4 or 5 lower dilutions are used to give a range of antibody in each animal. Four to five animals are used for each variable in the experiment. Percent inhibition of the PCA assay is calculated by comparing the spot scores of treated rats with the spot scores of control rats. The spot score is the total number of detectable spots over the number of animals.

The tris (hydroxymethyl)aminomethane salt of (2- carboxy-8-chlorol ,4-dihydro-4-oxo-5- quinolyl)oxamic acid is prepared by dissolving the carboxylic acid in an equivalent weight of aqueous tris(hydroxymethyl)-aminomethane and is treated in the rat passive cutaneous anaphylaxis assay in the above manner.

The inhibitory dose for the tris(hydroxymethyl)- aminomethane salt of (2-carboxy-8-chloro-1,4- dihydro-4-oxo-5-quinolyl)oxamic acid, when given i.v., is 0.10 mg./kg.

I claim:

1. A compound of the formula wherein M is selected from the group consisting of hydrogen and a non-toxic pharmaceutically acceptable cation;

X 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, and trifluoromethyl with the proviso that when X is hydrogen, the

grouping is limited to the 6 position.

2. A compound in accordance with claim 1 wherein M is an amine cation, X is selected from the group consisting of alkyl from one to three carbon atoms. inclusive, and halogen; and

is at the 7 position.

3. A compound in accordance with claim 2 wherein M is tris(hydroxymethyl)methylammonium.

4. (Z-Carboxy-l ,4-dihydro-8-methyl-4-oxo-7- quinolyl)oxamic acid according to claim 1.

5. (2-Carboxy-l,4-dihydro-4-oxo-6-quinolyl)oxamic acid according to claim 1.

quinolyl)oxamic acid according to claim 1.

10. A compound in accordance with claim 3 wherein X is methyl.

Claims (10)

1. A COMPOUND OF THE FORMULA

2. A compound in accordance with claim 1 wherein M is an amine cation, X is selected from the group consisting of alkyl from one to three carbon atoms, inclusive, and halogen; and

3. A compound in accordance with claim 2 wherein M is tris(hydroxymethyl)methylammonium.

4. (2-Carboxy-1,4-dihydro-8-methyl-4-oxo-7-quinolyl)oxamic acid according to claim 1.

5. (2-Carboxy-1,4-dihydro-4-oxo-6-quinolyl)oxamic acid according to claim 1.

6. (2-Carboxy-1,4-dihydro-8-methyl-4-oxo-5-quinolyl)oxamic acid according to claim 1.

7. (2-Carboxy-1,4-dihydro-8-methyl-4-oxo-6-quinolyl)oxamic acid according to claim 1.

8. (2-Carboxy-8-chloro-1,4-dihydro-4-oxo-5-quinoly)oxamic acid according to claim 1.

9. (2-Carboxy-8-chloro-1,4-dihydro-4-oxo-6-quinolyl)oxamic acid according to claim 1.

10. A compound in accordance with claim 3 wherein X is methyl.