CA1058208A - Pharmaceutical n,n'(phenylphenylene) dioxamic acid derivatives - Google Patents
Pharmaceutical n,n'(phenylphenylene) dioxamic acid derivativesInfo
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- CA1058208A CA1058208A CA226,824A CA226824A CA1058208A CA 1058208 A CA1058208 A CA 1058208A CA 226824 A CA226824 A CA 226824A CA 1058208 A CA1058208 A CA 1058208A
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- chloro
- phenyl
- hydrogen
- phenylene
- carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/20—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings
- C07C205/21—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C205/22—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring having one nitro groups bound to the ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/07—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms
- C07C205/11—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings
- C07C205/12—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings the six-membered aromatic ring or a condensed ring system containing that ring being substituted by halogen atoms
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
It has now been discovered that novel compounds of formula ?
wherein the groups are meta or para to each other; R is hydrogen or a physiotogically acceptable metal or amine cation; and X, Y and Z are the same or different and are selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclu-sive, alkoxy of one to four carbon atoms, inclusive, hydroxy, fluoro, chloro, bromo and , wherein D
is selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclusive, and a physiologically acceptable metal or amine cation, with the proviso that when D is hydrogen or a physiologically acceptable metal or amine cation, D is the same as R;
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.
Additionally, the compounds are formulated with pharma-ceutical carriers for oral, parenteral, inhalation, or rectal means of administration.
It has now been discovered that novel compounds of formula ?
wherein the groups are meta or para to each other; R is hydrogen or a physiotogically acceptable metal or amine cation; and X, Y and Z are the same or different and are selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclu-sive, alkoxy of one to four carbon atoms, inclusive, hydroxy, fluoro, chloro, bromo and , wherein D
is selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclusive, and a physiologically acceptable metal or amine cation, with the proviso that when D is hydrogen or a physiologically acceptable metal or amine cation, D is the same as R;
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.
Additionally, the compounds are formulated with pharma-ceutical carriers for oral, parenteral, inhalation, or rectal means of administration.
Description
BRIEF SUMMARY OF THE INVENTION
It has now been discovered that novel compounds of Formula 1 are useful in -the prophylactic trea-tment o-E sensitized humans and animals Eor allergy and all anaphylactic reactions of a reagin or non-reagin med-iated nature. Additionally, the compounds are formu-lated with pharmece-utical ~arriers for oral, parenteral, inhalation, or rectal means of administration.
DETAILED DESCRIPTION OF THE INVENTION
.
In accordance with the invention, compounds of Formula 1, hereafter referred to as Group A, are provided ~Z
\ ~
~ H O O
O O H ~ ~ ~-C-C-OR
RO-C-C-N ~ (1) H O O
wherein the -N-C-C-OR groups are meta or para to each other; R is hydrogen or a physiologically acceptable metal or amine cation; X, Y, and Z are the same or different and are selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclu-sive, allcoxy of one to four carbon atoms, inclusive, hydroxy, fluoro, chloro, bromo, and C-- OD, wherein D
is selected from the group consisting of hydrogen ~235 l~S~8 alkyl of one to six carbon atoms, inclusive, and a physiologically acceptable metal or amine cation;
with the proviso that when D is hydrogen or a physio-logically acceptable me~al or amine cation, D is the same as R
Another yroup of compounds hereafter known as Group B are those compounds of Group A wherein Y is hydrogen.
A further group of compounds are those compounds of Group B wherein ~ is hydrogen, A still further group of compounds, hereafter known as Group D, are those compounds of tiroup A
wherein when one or all of X, Y, ~ and D is alkyl, alkyl has a maximum limitation of three carbon atom5 and when one or all of X, Y and ~ is alkoxy, then alkoxy has a maximum number of three carbon atoms, A further group of compounds, hereaf~:er known as Group E, are those compounds where X, Y and ~ are the same or differen~ and are selected from the group con~
sisting of hydrogen, alkyl of one to three carbon atoms, inclusive~ alkoxy of one to three carbon atoms, inclustve, fluoro, chloro, and C' OD wherein D is selected from the group consisting of hydr-ogen, alkyl of one to three carbon atoms, inclusive~ and a physio-logically acceptable metal or amine cation, with the proviso that when D is hydrogen or a physiologically acceptable metal or amine catlon, D is the same as R, The position of the ~ ~ ~ OR groups and P~ are defined as in Group A.
A still further group of compounds, hereafter known Z~
as Group F, are compounds of Group E ~herein the R groups are meta to each other.
A further group of compounds, hereafter referred to as Group Gg are compounds of Group F ~herein the phenyl H O O
ring is meta to both the ~ C-OR groups.
A still further group of compounds, hereafter re-ferred to as Group HJ are compounds of Group G wherein X is ortho to both ~ '-OR groups, Another group of compounds, hereafter referred to as Group 1, are compounds of Group H wherein Y is hydro-gen.
A still further group of compounds are compounds of Group I wherein ~ is hydrogen.
r The preferred ~ s N,N'(2-chloro-5-phenyl-m-phenylene)dioxamic acid.
As used in the above disclosure and throughout the specification the phrase "alkyl of one to six carbon atoms, inclusive" includes methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof. Illustrative examples of isomers include isopropyl, tert. butylJ neopentyl and
It has now been discovered that novel compounds of Formula 1 are useful in -the prophylactic trea-tment o-E sensitized humans and animals Eor allergy and all anaphylactic reactions of a reagin or non-reagin med-iated nature. Additionally, the compounds are formu-lated with pharmece-utical ~arriers for oral, parenteral, inhalation, or rectal means of administration.
DETAILED DESCRIPTION OF THE INVENTION
.
In accordance with the invention, compounds of Formula 1, hereafter referred to as Group A, are provided ~Z
\ ~
~ H O O
O O H ~ ~ ~-C-C-OR
RO-C-C-N ~ (1) H O O
wherein the -N-C-C-OR groups are meta or para to each other; R is hydrogen or a physiologically acceptable metal or amine cation; X, Y, and Z are the same or different and are selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclu-sive, allcoxy of one to four carbon atoms, inclusive, hydroxy, fluoro, chloro, bromo, and C-- OD, wherein D
is selected from the group consisting of hydrogen ~235 l~S~8 alkyl of one to six carbon atoms, inclusive, and a physiologically acceptable metal or amine cation;
with the proviso that when D is hydrogen or a physio-logically acceptable me~al or amine cation, D is the same as R
Another yroup of compounds hereafter known as Group B are those compounds of Group A wherein Y is hydrogen.
A further group of compounds are those compounds of Group B wherein ~ is hydrogen, A still further group of compounds, hereafter known as Group D, are those compounds of tiroup A
wherein when one or all of X, Y, ~ and D is alkyl, alkyl has a maximum limitation of three carbon atom5 and when one or all of X, Y and ~ is alkoxy, then alkoxy has a maximum number of three carbon atoms, A further group of compounds, hereaf~:er known as Group E, are those compounds where X, Y and ~ are the same or differen~ and are selected from the group con~
sisting of hydrogen, alkyl of one to three carbon atoms, inclusive~ alkoxy of one to three carbon atoms, inclustve, fluoro, chloro, and C' OD wherein D is selected from the group consisting of hydr-ogen, alkyl of one to three carbon atoms, inclusive~ and a physio-logically acceptable metal or amine cation, with the proviso that when D is hydrogen or a physiologically acceptable metal or amine catlon, D is the same as R, The position of the ~ ~ ~ OR groups and P~ are defined as in Group A.
A still further group of compounds, hereafter known Z~
as Group F, are compounds of Group E ~herein the R groups are meta to each other.
A further group of compounds, hereafter referred to as Group Gg are compounds of Group F ~herein the phenyl H O O
ring is meta to both the ~ C-OR groups.
A still further group of compounds, hereafter re-ferred to as Group HJ are compounds of Group G wherein X is ortho to both ~ '-OR groups, Another group of compounds, hereafter referred to as Group 1, are compounds of Group H wherein Y is hydro-gen.
A still further group of compounds are compounds of Group I wherein ~ is hydrogen.
r The preferred ~ s N,N'(2-chloro-5-phenyl-m-phenylene)dioxamic acid.
As used in the above disclosure and throughout the specification the phrase "alkyl of one to six carbon atoms, inclusive" includes methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof. Illustrative examples of isomers include isopropyl, tert. butylJ neopentyl and
2,2-dimethylbutyl. Limitations of a different carbon number are interpreted in the same manner.
The phrase "a physiologically acceptable metal or amine cation" is that metal or amine which is accepted in an essentially non-toxic manner by a mammal, Illustrative examples of such metals are the alkali metals, e.g., lithium, sodium and potassium, and the alkaline earth metals, e.g , magnesium and calcium Other metals, e,g., aluminum, zinc, and iron are also ~ithin the scope of this inventlon. Illustrative of the amines are those ~5 ~Z ~ ~
derived from primary, secondary or tertiary amines, Examples of suitable amines are methylamine, dime$hyl-amine, triethylamine, ethylamine, dibutylamine3 triiso-propylamine, N-methylhexylamine, decylamineg dodecyl-amine, allylamine, crotylamine, cyclopentylamine, di-cyclohexylamine, benzylamine, dibenzylamine, a-phenyl ethylamine~ ~-phenylethylamine, ethylenediamine, diethyl-enetriamine, and like aliphatic/ cycloaliphatic, and araliphatic amines containing up to and including about eighteen carbon atoms, as well as heterocyclic amines, e g,, piperidineJ morpholineJ pyrrolidine, piperazine, and lower-alkyl derivatives thereofJ e.g., 1-methyl piperidine, 4-ethylmorpholine, 1-isopropylpyrrolidineJ
2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methyl-piperidineg 1,5-dimethylpiperazine, 2-methylpiperidine, and the like, as well as amines containing water-solu-bilizing or hydrophilic groups, e.g., mono-, di-, and tri-ethanolamine, ethyldiethanolamine, N-butylethanolarnine, 2-amino-1-butanol, 2-amTno~2-ethyl-1,3-propanediol, 2-amino-2-metjyl-1-propanol, tris(hydroxymethyl)amino-methane (THAM), N-phenylethanolamine, N-(p-tert amylphenyl)di-ethanolamine, glactamine, N-methylglucamine, N-methyl glucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like, Also included within the amine scope are quaternary amines such as ammonium, tetra-methylammonium, tetraethylammonium, benzyltrimethylammoni-ium~ phenyltriethylammonium and the like.
The compounds of the invention can be prepared by methods known in the art. For example~ me-thods outlined in U. S. 3,639~249, Column 3, line 38J to Column 5, ~1~5~32~
line 18, can be used with facility to form the ester.
From thereon, the ester is readily converted to metal salts, the free acid, or amine salts by conventional methods. The Upjohn Company's Canadian ~atent 1,030,156 (issued April 25, 1978) also discloses methods of preparing the compounds of this invention.
Following is an illustrative list of compounds of the invention which can be prepared by the above disclosed procedures:
_ABLE 1 y ~1/ o O
\ ~" 11 11 5~;~ N-C-c-oR
O O /~
R is hydrogen, H O O is at position 3 or a -N-C-C-OR
~Z
X Y Z
2-Cl H H 5 6-Cl H H 5 2-i-C3H7 . H H 5 ~7 ~ Z ~ 8 3235 2-C5Hll H H 5 2-i-C~Hlg H H 5 2-OC~H7 H H 5 2-OC6H,9 H H 5 2-Br H H 5 2-COOC~Hg H H 5 6-i-C9H7 H H 5 6-nH H H 5 6-CooC2H5 H H 5 2-Cl 2l-C1 61-Cl 5 2-C2H5 3'-OCH95'-COC5H 1 1 5 2-OC4Hg 47-C2Hs 5-Cl 5 2-F 4'-COOH H 5 5-Br H H 2 5-CH9 2l-CH3 5'-CH~ 2 5-OC3H7 3'-COOH 5'-C2H5 2 5-COOC2H5 4'-Cl H 2 6-Cl 37-OCH~ H 2 5-C4H~ 2'-Cl 4'-COOCH3 2 6-OCH3 21~OCHg6'-oCH9 2 5-Cl H H 6 5-l-C~Hl9 H 4'~Cl 6 5-OCH3 2'-COOCH~ 4'-Br . 6 5-COOC2Hs 3'-CH3 5~-OC2Hs 6 3o 5 ~
TABLE li The compounds of Table I are converted to their physiologically acceptable metal or amine cations by standard means.
The following examples are compounds in accordance with the invention, They are not intended to limit but merely to exemplify the invention, Ex.am~e 1 N,N'-(2-Chloro-~-phenyl-m-phenvlene~-dioxamic acid ; 10 a. 2-Chloro-5-p~henyl-m-Phenylenediamine A solution of 2.79 g. (0.01 mole) of 4-chloro-3,5-dinitrobiphenyl [R. C. Hall and C. S. Giam, J0 Agr, Food Chem 20 (3~ 546-52 (1972)] in 200 ml. of dioxane is hydrogenated at 3 atmospheres using Raney Nickel Catalyst, The catalyst is removed by -filtra-tion and the residue concentrated under reduced pres-sure. The residue is recrystallized from ethanol-water. There is obtained 1.12 g. (51~) of material melting at 142-144.5 , Additional recrystallization raises the melting point to 146.7.
2HllClN2 C, 65.91; H, 5.07; Cl, 16,21; N, 12,81 Found: C~ 65.75; H, 5.26; Cl, 15,52; N, 12.76 b. Diethyl N,N'- (?- Chloro-5-phenyl-m_ To a stirred solution of 7.45 9. (0.034 mole) of 2-chloro-5-phenyl-m-phenylene diamine in 16 ml.
of dry ethyl acetate and 8.~o g. (0.082 mole) of tri-ethylamine, cooled below 5 is added~ dropwise, 11.20 g.
(0.082 mole) oF ethyl oxalyl chloride, An additional 1~58~
20 ml, oF ethyl acetate ;s added, the mixture is stirred in the ice-bath for an additlonal hour and -then overnight at room temperature.
The mixture is diluted to a volume of 200 ml. by the addition of ethyl acetate and the solid removed by fil-tration and washed with water. The ethyl acetate Filtrate is concentrated to dryness to give additional material.
The solids are comb7ned and recrystallized from ethanol. There is obtained 11.66 g, (78~) of long thin rose-colored needles melting at 204 - 205, Anal, Calcd. for: C20H1gClN2D~
C, 57,36, H, 4.57; Cl, 8.46; N, 6.69 Found: C, 57.38; H, 4.52; Cl, 8.51; N, 6.73 c. N,N'-~-Chloro-5-phenyl-m-phenylene¦dioxamic acid A solution of 5.00 g. (0.12 mole) of diethyl-N,N'-(2-chloro-5-phenyl-m-phenylene~dToxamate in 125 mlv of chloroform is mixed in a separation funnel with 29 ml.
of 1 M NaOH, Water (approximately 900 ml.) is added to dissolve all the solids. The aqueous phase is drawn off through a filter into a flask. After stirring for fif-teen minutes, 30 ml. of 1 M HCl is added, The precipi-tate wh7ch forms is collected by filtration. The solid obtained is recrystallized from H20 to give 2.41 g, (55~) f product, M.P. 190 (dec.). A second recrystal-li~ation raises the melting point to 195 (dec~).
Example 2 N,N'-(4-Chloro 5-phenyl-rn-phenylene-dioxamic acid a ~ 5-Dini-tro 2-biphenylol The procedure of Borche and Scholtin 32~5 2 ~ 8 ~Chem. Ber. 50, 602] is foll~wed.
To a stirred solution of 25 g. (0.15 mole) of 2-phenylphenol in 250 ml. of glacial acetic acid at 30 is added a solution of 25 ml.of nitric acid in 75 ml, of glacial acetic acid. The temperature is kept below 40. The mixture is heated on a steam bath for thirty minutes. The mixture is cooled to room temperature and poured into 300 gO of ice. The precipitate is removed by filtra~ion and washed with water and ethanol. There is obtained 3104 9~ (81%) of yellow crystalline ma~erial melting at 204-205 .
b, 2-Chloro-~l~-dinitrobiphenyl A mixture of 30,00 g. of 3,5-dinitro-2-bi-phenylol7 15 ml~ of dimethylformamide, and 113 ml, of -15 phosphorous oxychloride is heated on a steam bath for 2.25 hours. The mixture is then cooled -to room tempera-ture and poured slowly into approximately 600 g, of crushed ice. The precipitate that forms is isolated by filtration and washed with water. The solid is dis-solved in chloroform and the chloroform solution is washed several times with 10~ Na2C03 and once with water.
The chloroform solution is dried over MgS04 and concen-trated, The product is recrystallized from benzene-hexane to give 19,07 g, o-f material (melting at 119-20 ), c. 4-Chloro-5-phenYl-m-phenYlene diamine -A solution of 10.00 g, (0.0359 mole) of 2 chloro-3~5-dinitrobiphenyl in 200 ml. of dioxane is hy-drogenated at 3 atmospheres of hydrogen using Raney nickel Catalyst. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure, ~ 0 S 8 ~ ~ ~
110 ml. oF benzene is added to the residue and this is removed by distillation. The resulting oil is used di-rectly in the following reaction.
d. DiethYl N,N'-(4-Chloro-4-phenYl-m-phenylene)dioxamate To a solution 7.89 g, (o~036 mole) of 4-chloro-5-phenyl-m-phenylene diamine in 8.80 9. (0~087 mole) of triethylamine and 20 ml. of ethyl acetate cooled in an ice bath to 5 is added 11.90 9. (o.087 mole) of ethyl oxalyl chloride, keeping the temperature belo~ 15 .
The reaction mixture is allowed to stand overnight at room temperature. To the reaction mixture is added 200 ml. of chloroform and the mixture is filtered. The pre-cipitate is added ~o ~ater and this is filtered. The water insoluble material is dissolved in chloroform and the solution is added to the original filtrate. The re-sulting solution is concen-trated and the residue is re-crystallized from ethanol with charcoal treatment. There is obtained 12~25 g, (83~) of material melting at 184.2-85.2 .
Anal ~ Calcd. for: C20H1~ClN
C~ 57.~6; H, 4.57; Cl, 8.46; N, 6.99 Found: C, 57.~6; H, 4.58; Cl, 8.39; N, 6~62 e, N,N'-(4-Chloro-5-phenyl-m-~henylene)-dioxamic acid _-- ;
To a solution of 5,0 9. (0.014 mole) oF di-ethyl N,N'(4-Chloro-5-phenyl-m-phenylene)dioxamate in 125 ml 7 of chloroform in a separatory funnel is added 29 ml. of 1 M sodium hydroxide solution. Water is added to the mixture until the solid that forms on shaking ~235 ~ ~5 ~
redissolves The mixture is allowed to stand with oc-casional shaking for fifteen minutes. The aqueous layer is dra~n off, filtered and the filtrate acidified by the addition of lN hydrochloric acid~ The precipitate that forms is removed by filtration. There is obtained 3.89 9.
of material melting above 310 .
The compositions of the present invention are presented for administration to humans and animals 7n unit dosage forms, such as tablets, capsules, pill SJ
powders, granules~ sterile parenteral solutions or sus-pensions, eye drops~ oral solutions or suspensions, and ~ILlIS8~0~3 oil-in-water and water-in-oil emulsions containing suitable quantities of the compound of Formula 1. The ~referred 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 1 is mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl-cellulose, 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 admin-istration 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 hydroalcoholic (ethanol) vehicle with suitable sweeteners such as suger and saccharin, together with an aromatic flavoring agent.
Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
cm/p~ - 13 ~
~5~3~0~
~ 'or 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 can be 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 mammal cannot be treated conveniently by means of other dosage forms, such as orally or by 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 cm/~
~ ~ 8Z~ ~ ~235 methods kno~n in the art. Examples of such bases include cacoa butterg polyethylene glycols (Carbowaxes)~ poly-etlny1ene sorbitan monostearate, and mixtures of these with other co~pat7ble materials to modify the melting point or d1ssolution rateO These rectal suppositories caln weigh from about 1 to 2.5 GmD
The preferred comp~sitions are those adapted for inhalation ;nto the lun3. For treatment of allergic colnditions of the nose, such as rhinitis, compositions adapted for con~act ~ith nasal linings are pr~ferred.
Compositions for inhalation are of three basic types: 1) a powder mixture preferably micropulverized with partTcle size~ pref~rably from about 1 to about 5 microns; 2) an aqueous solution or suspension to be sprayed with a nebulizer; and ~) an aerosol with vola-tile propellant in a pressurized container.
The powders are quite simply prepared by mixing a compound of the formula ~ith 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 po~der when inhaled through the mouth.
Aqueous solutions are prepared by dissolving the compound of the Formula I in water and adding salt to provide an isotonic solution and buffering to a pH com-patib1e ~ith inhalation. The solutions are dispersed ina spray device or nebulizer and sprayed into the mouth while inhaling.
Aerosols are prepared by dispersing a cornpound of the ~ I in water or ethanol and mixing ~ith a 30 volatile propellant and placing in a pressurized 5~
container having a metering valve to release a predete~-~ined amount of material, The liquefied propellant employed is one ~hich has a boiling point below 65Fo at atmospheric pressure.
For use in compositions intended to produce aerosols for medicinal use, the liquefied propel lant should be non-toxic. Among the suitable liquefled propellan~s ~hich 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 l7guefied 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 propella~ts are dichlorodifluoromethane ("Freon 12"), dichlorotetra-fluoroethane ("Freon 114"), trichloromonofluoromethane ("Freon 11"), dichloromonofluoromethane ("Freon 21"), monochlorodifluoromethane ("Freon 22")9 trichlorotri-fluoroethane ("Freon 113"), difluoroethane ("Genetron142-A") and monochlorotrifluoromethane ("Freon 1~").
The term "unit dosage form"~ as used in the specification and claims, refers to physically discrete units suttable as unitary dosages for human subjects and animals, each unit containing a predetermined quan-tity of active material calculated to produce the desired therapeutic effect in association ~ith the required pharmaceutical diluen~, carrier or vehicle.
The specifications for ~he novel unit dosage forms of this invention are dictated by and directly dependent -~6-32~5 ~ S82~lS
on (a) the unique characteristics of the active mat-erial 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 ;n this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord ~ith this invention are ~ablets, capsules, pillsg suppositories, po~der packets, wafers, granules~ cachets, teaspoonfuls~ tablespoonfuls, dropperfuls, arnpuls, vials, aerosols with metered dis-charges, segrega~ed multiples of any of the foregoingJ
and other forms as herein described~
An effective but non-toxic quantity of the com-pound is employed in treatment. The dosage of the com-pound for treatment depends on the route of administra-tion and the potency of the particular compound. A
dosage schedule for humans of from about 0.01 to about 20 mg. of compound in a single dose, admin;stered par-enterally or by inhalation in the compositions of this invention, are effective for preventing allergy attacks.
More specificall YJ the single dose is from about 0.5 to about 10 mg. of compound. The oral and rectal dose is from about 5.0 to about 250 mg. in a single dose. More specifically, the single dose is from about 10 to about ~5 125 mg. of compound. The dosage to be administered can be repeated up to four ~imes daily.
The administration of the compositions of the present invention to humans and animals provides a method for the prophylactic trea~ment of allergy or all anaphylactic reactions of a reagin or non-reagin mediated 32~5 1 ~5~
nature. That is to say9 these compositions, when adminis-tered to a sensitized individual prior to the time that the individual comes into contac~ with substances (anti-gens) to whTch he is allergic, ~ill prevent the allergic reaction which ~ould other~ise occur.
For example, the process can be used for pro--phylactic treatment of such chronic conditions as bron-chial asthmaJ allergic rhin;tis, food allergy, hay fever, urticaria, auto-immune diseases, exercise induced asthma, stress induced asthma, systemic anaphylaxis~ and bird fancier's disease.
~e~_ A lot oF 10,000 tablets, each containing 50 mg.
of N,N'-(2-Chloro-5-phenyl-m-phenylene~dioxamic acid 15 is prepared from the following types and amounts of ingredients N,N'-~2~Chloro-5-phenyl-m-phenylene)-dioxamic acid 5 Gm.
Dicalcium phosphate 1,000 Gm.
Methylcellulose, U.S.P. (15 cps)60 Gm.
Talc 150 Gm.
Corn starch 200 Gm.
Magnesium stearate 10 Gm.
The compound and dicalcium phosphate are mixed well~ granulated with 7.5 percent solution of methyl-cellulose 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 32~5 1~58 ~ ~
or asthma attacks at a dose of one tablet every six hours.
Example 4 One thousand tablets, each containing 100 mg. of NJN'-(2-Chloro-5-phenyl-m-phenylene)dioxamic acid are prepared from the following types and amounts of ingredients:
N,N'-(2-Chloro-5 phenyl-m-phenylene)-dioxamic acid 100 Gm.
Microcrystalline cellulose N~410 Cm.
Starch 100 Gm.
Magnesium stearate powder 3 Gm.
The ingredients are screened and blended together and pressed into tablets.
The tablets are useful to protect agains~ food allergy at a dose of one tablet before meals.
.~
A sterile preparation suitable for intramuscular injection and containing 4.0 mg. of N,N'-(2-Chloro-5-20 phenylene)dioxamic acid in each mill71iter is prepared from the follo~ing ingredients:
N,N'-(2-Chloro-5-phenyl-m-phenylene)-dioxamic acid 4.0 Gm.
Benzyl benzoate 200 ml.
Methylparaben 1.5 Gm.
Propylparaben o.5 Gm.
Cottonseed oil q.s. 1,000 ml.
One milli1iter of this sterile preparation is injected for prophylactic treatment of allergic rhinitis.
I
I 32~5 ~SI~
_6 Six hundred ml. of an aqueou~ suspension contain-ing 20 mg~ of the N,NI-(2~Chloro-5-phenyl-m-phenylene)~
dioxamic acid per ml. is prepared as Follows:
N,N'-(2-Chloro-5-phenyl-m-phenylene)-dioxamic acid 12 Gm.
Sodium chloride 5 Gm.
Water for injection q.s.600 ml.
The and sod;um chloride are dispersed in sufficienl: water to make 600 ml. and sterilized.
The liquid is placed in nebulizers designed to deliver 0,25 ml. per spray.
The liquid is inhaled into the lungs every fouL
to six hours for prevention of asthmatic attacks.
Example 7 A powder mixture consisting of 1.0 gram of N,Ns-(2-Chloro-5-phenyl-m-phenylene)dioxamic acid and sufficient lactose to make five grams of mixture is micropulverized and placed in an insufflator designed to deliver 50 mg. of powder per dose.
The powder is inhaled into the lungs evel-y four to six hours for prevention of asthmatic attacks.
The powder is inhaled intranasally every four hours for prevention of rhinitis.
Exam~!e 8 A powder mixture consisting of 2.0 gram of N,N'-(2-chloro-5-phenyl-m-phenylene~dioxamic acid ~235 ~ Q ~
and sufficient lactose to make five grams of mixture is micropulveri zed and placed in an insufFlator designed to del îver 50 mg. of powder per dose.
The powder is inhaled into the lungs every four to six hours for prevention of asthmatic attacks.
The powder is inhaled intranasally every four hours for prevention of rhinitis.
E mE~Q_2 Twelve grams of an aerosol composition are pre-pared from the following ingredients:
NJN'-(2-Chloro-5-phenyl-m-ph~nyl~ne)-dioxamic ~cid 0.500 6m.
Freon 12 1.440 Gm.
~reon 114 2,160 Gm~
Water 7.788 Gm~
Sorbitan monoleate 0.600 Gm.
The compound is dispersed in the water and chi11ed to -30 C. and added to the chilled Freons. The t~elve grams of compositions are added to a 13 ml, plastic 2G coated bott1e and capped with a metering valve. The metering valve releases 80 mg, of composition in an aero-sol. The aerosol is inhaled every four to six hours for prevent7On of asthmatic attacks, Example lQ
ci~4~r~ n q After allowing for the ~ solubilities of the compounds and the activity of the particular com-pound as measured, for example, by the ~ y~rat pas-sive cutaneous anaphylaxis assay, a suitable quantity of each of the compounds of Table I through Tabie ll and Examples 1-2, is substituted for the active ~ .~ ~
~9S8ZO~ -compound in th~ compositions ancl uses of Examples 3 through 9. Results showing anti-allergy activity are obtained.
It should be noted that in all the com-positions and treatment examples of this patent application, the quantity ofdru~ ernployed refers to the acid equivalent.
When repeated administration is desired, the compounds of this application which have a relatively short duration of activity can be administered in a priming dose-maintenance dose regimen as described in Canadian Patent No.
1,030,156.
Following the rat passive cutaneous anaphylaxis assay procedure of Example 3 of Canadian Patent No. 1,030,156, the inhibitory dose50 of N,N'-(2-chloro-5-phenyl-m-phenylene) dioxamic acid is 0.01 mg./kg. by the intravenous route.
., ~~,,j, , .
The phrase "a physiologically acceptable metal or amine cation" is that metal or amine which is accepted in an essentially non-toxic manner by a mammal, Illustrative examples of such metals are the alkali metals, e.g., lithium, sodium and potassium, and the alkaline earth metals, e.g , magnesium and calcium Other metals, e,g., aluminum, zinc, and iron are also ~ithin the scope of this inventlon. Illustrative of the amines are those ~5 ~Z ~ ~
derived from primary, secondary or tertiary amines, Examples of suitable amines are methylamine, dime$hyl-amine, triethylamine, ethylamine, dibutylamine3 triiso-propylamine, N-methylhexylamine, decylamineg dodecyl-amine, allylamine, crotylamine, cyclopentylamine, di-cyclohexylamine, benzylamine, dibenzylamine, a-phenyl ethylamine~ ~-phenylethylamine, ethylenediamine, diethyl-enetriamine, and like aliphatic/ cycloaliphatic, and araliphatic amines containing up to and including about eighteen carbon atoms, as well as heterocyclic amines, e g,, piperidineJ morpholineJ pyrrolidine, piperazine, and lower-alkyl derivatives thereofJ e.g., 1-methyl piperidine, 4-ethylmorpholine, 1-isopropylpyrrolidineJ
2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methyl-piperidineg 1,5-dimethylpiperazine, 2-methylpiperidine, and the like, as well as amines containing water-solu-bilizing or hydrophilic groups, e.g., mono-, di-, and tri-ethanolamine, ethyldiethanolamine, N-butylethanolarnine, 2-amino-1-butanol, 2-amTno~2-ethyl-1,3-propanediol, 2-amino-2-metjyl-1-propanol, tris(hydroxymethyl)amino-methane (THAM), N-phenylethanolamine, N-(p-tert amylphenyl)di-ethanolamine, glactamine, N-methylglucamine, N-methyl glucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like, Also included within the amine scope are quaternary amines such as ammonium, tetra-methylammonium, tetraethylammonium, benzyltrimethylammoni-ium~ phenyltriethylammonium and the like.
The compounds of the invention can be prepared by methods known in the art. For example~ me-thods outlined in U. S. 3,639~249, Column 3, line 38J to Column 5, ~1~5~32~
line 18, can be used with facility to form the ester.
From thereon, the ester is readily converted to metal salts, the free acid, or amine salts by conventional methods. The Upjohn Company's Canadian ~atent 1,030,156 (issued April 25, 1978) also discloses methods of preparing the compounds of this invention.
Following is an illustrative list of compounds of the invention which can be prepared by the above disclosed procedures:
_ABLE 1 y ~1/ o O
\ ~" 11 11 5~;~ N-C-c-oR
O O /~
R is hydrogen, H O O is at position 3 or a -N-C-C-OR
~Z
X Y Z
2-Cl H H 5 6-Cl H H 5 2-i-C3H7 . H H 5 ~7 ~ Z ~ 8 3235 2-C5Hll H H 5 2-i-C~Hlg H H 5 2-OC~H7 H H 5 2-OC6H,9 H H 5 2-Br H H 5 2-COOC~Hg H H 5 6-i-C9H7 H H 5 6-nH H H 5 6-CooC2H5 H H 5 2-Cl 2l-C1 61-Cl 5 2-C2H5 3'-OCH95'-COC5H 1 1 5 2-OC4Hg 47-C2Hs 5-Cl 5 2-F 4'-COOH H 5 5-Br H H 2 5-CH9 2l-CH3 5'-CH~ 2 5-OC3H7 3'-COOH 5'-C2H5 2 5-COOC2H5 4'-Cl H 2 6-Cl 37-OCH~ H 2 5-C4H~ 2'-Cl 4'-COOCH3 2 6-OCH3 21~OCHg6'-oCH9 2 5-Cl H H 6 5-l-C~Hl9 H 4'~Cl 6 5-OCH3 2'-COOCH~ 4'-Br . 6 5-COOC2Hs 3'-CH3 5~-OC2Hs 6 3o 5 ~
TABLE li The compounds of Table I are converted to their physiologically acceptable metal or amine cations by standard means.
The following examples are compounds in accordance with the invention, They are not intended to limit but merely to exemplify the invention, Ex.am~e 1 N,N'-(2-Chloro-~-phenyl-m-phenvlene~-dioxamic acid ; 10 a. 2-Chloro-5-p~henyl-m-Phenylenediamine A solution of 2.79 g. (0.01 mole) of 4-chloro-3,5-dinitrobiphenyl [R. C. Hall and C. S. Giam, J0 Agr, Food Chem 20 (3~ 546-52 (1972)] in 200 ml. of dioxane is hydrogenated at 3 atmospheres using Raney Nickel Catalyst, The catalyst is removed by -filtra-tion and the residue concentrated under reduced pres-sure. The residue is recrystallized from ethanol-water. There is obtained 1.12 g. (51~) of material melting at 142-144.5 , Additional recrystallization raises the melting point to 146.7.
2HllClN2 C, 65.91; H, 5.07; Cl, 16,21; N, 12,81 Found: C~ 65.75; H, 5.26; Cl, 15,52; N, 12.76 b. Diethyl N,N'- (?- Chloro-5-phenyl-m_ To a stirred solution of 7.45 9. (0.034 mole) of 2-chloro-5-phenyl-m-phenylene diamine in 16 ml.
of dry ethyl acetate and 8.~o g. (0.082 mole) of tri-ethylamine, cooled below 5 is added~ dropwise, 11.20 g.
(0.082 mole) oF ethyl oxalyl chloride, An additional 1~58~
20 ml, oF ethyl acetate ;s added, the mixture is stirred in the ice-bath for an additlonal hour and -then overnight at room temperature.
The mixture is diluted to a volume of 200 ml. by the addition of ethyl acetate and the solid removed by fil-tration and washed with water. The ethyl acetate Filtrate is concentrated to dryness to give additional material.
The solids are comb7ned and recrystallized from ethanol. There is obtained 11.66 g, (78~) of long thin rose-colored needles melting at 204 - 205, Anal, Calcd. for: C20H1gClN2D~
C, 57,36, H, 4.57; Cl, 8.46; N, 6.69 Found: C, 57.38; H, 4.52; Cl, 8.51; N, 6.73 c. N,N'-~-Chloro-5-phenyl-m-phenylene¦dioxamic acid A solution of 5.00 g. (0.12 mole) of diethyl-N,N'-(2-chloro-5-phenyl-m-phenylene~dToxamate in 125 mlv of chloroform is mixed in a separation funnel with 29 ml.
of 1 M NaOH, Water (approximately 900 ml.) is added to dissolve all the solids. The aqueous phase is drawn off through a filter into a flask. After stirring for fif-teen minutes, 30 ml. of 1 M HCl is added, The precipi-tate wh7ch forms is collected by filtration. The solid obtained is recrystallized from H20 to give 2.41 g, (55~) f product, M.P. 190 (dec.). A second recrystal-li~ation raises the melting point to 195 (dec~).
Example 2 N,N'-(4-Chloro 5-phenyl-rn-phenylene-dioxamic acid a ~ 5-Dini-tro 2-biphenylol The procedure of Borche and Scholtin 32~5 2 ~ 8 ~Chem. Ber. 50, 602] is foll~wed.
To a stirred solution of 25 g. (0.15 mole) of 2-phenylphenol in 250 ml. of glacial acetic acid at 30 is added a solution of 25 ml.of nitric acid in 75 ml, of glacial acetic acid. The temperature is kept below 40. The mixture is heated on a steam bath for thirty minutes. The mixture is cooled to room temperature and poured into 300 gO of ice. The precipitate is removed by filtra~ion and washed with water and ethanol. There is obtained 3104 9~ (81%) of yellow crystalline ma~erial melting at 204-205 .
b, 2-Chloro-~l~-dinitrobiphenyl A mixture of 30,00 g. of 3,5-dinitro-2-bi-phenylol7 15 ml~ of dimethylformamide, and 113 ml, of -15 phosphorous oxychloride is heated on a steam bath for 2.25 hours. The mixture is then cooled -to room tempera-ture and poured slowly into approximately 600 g, of crushed ice. The precipitate that forms is isolated by filtration and washed with water. The solid is dis-solved in chloroform and the chloroform solution is washed several times with 10~ Na2C03 and once with water.
The chloroform solution is dried over MgS04 and concen-trated, The product is recrystallized from benzene-hexane to give 19,07 g, o-f material (melting at 119-20 ), c. 4-Chloro-5-phenYl-m-phenYlene diamine -A solution of 10.00 g, (0.0359 mole) of 2 chloro-3~5-dinitrobiphenyl in 200 ml. of dioxane is hy-drogenated at 3 atmospheres of hydrogen using Raney nickel Catalyst. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure, ~ 0 S 8 ~ ~ ~
110 ml. oF benzene is added to the residue and this is removed by distillation. The resulting oil is used di-rectly in the following reaction.
d. DiethYl N,N'-(4-Chloro-4-phenYl-m-phenylene)dioxamate To a solution 7.89 g, (o~036 mole) of 4-chloro-5-phenyl-m-phenylene diamine in 8.80 9. (0~087 mole) of triethylamine and 20 ml. of ethyl acetate cooled in an ice bath to 5 is added 11.90 9. (o.087 mole) of ethyl oxalyl chloride, keeping the temperature belo~ 15 .
The reaction mixture is allowed to stand overnight at room temperature. To the reaction mixture is added 200 ml. of chloroform and the mixture is filtered. The pre-cipitate is added ~o ~ater and this is filtered. The water insoluble material is dissolved in chloroform and the solution is added to the original filtrate. The re-sulting solution is concen-trated and the residue is re-crystallized from ethanol with charcoal treatment. There is obtained 12~25 g, (83~) of material melting at 184.2-85.2 .
Anal ~ Calcd. for: C20H1~ClN
C~ 57.~6; H, 4.57; Cl, 8.46; N, 6.99 Found: C, 57.~6; H, 4.58; Cl, 8.39; N, 6~62 e, N,N'-(4-Chloro-5-phenyl-m-~henylene)-dioxamic acid _-- ;
To a solution of 5,0 9. (0.014 mole) oF di-ethyl N,N'(4-Chloro-5-phenyl-m-phenylene)dioxamate in 125 ml 7 of chloroform in a separatory funnel is added 29 ml. of 1 M sodium hydroxide solution. Water is added to the mixture until the solid that forms on shaking ~235 ~ ~5 ~
redissolves The mixture is allowed to stand with oc-casional shaking for fifteen minutes. The aqueous layer is dra~n off, filtered and the filtrate acidified by the addition of lN hydrochloric acid~ The precipitate that forms is removed by filtration. There is obtained 3.89 9.
of material melting above 310 .
The compositions of the present invention are presented for administration to humans and animals 7n unit dosage forms, such as tablets, capsules, pill SJ
powders, granules~ sterile parenteral solutions or sus-pensions, eye drops~ oral solutions or suspensions, and ~ILlIS8~0~3 oil-in-water and water-in-oil emulsions containing suitable quantities of the compound of Formula 1. The ~referred 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 1 is mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl-cellulose, 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 admin-istration 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 hydroalcoholic (ethanol) vehicle with suitable sweeteners such as suger and saccharin, together with an aromatic flavoring agent.
Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
cm/p~ - 13 ~
~5~3~0~
~ 'or 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 can be 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 mammal cannot be treated conveniently by means of other dosage forms, such as orally or by 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 cm/~
~ ~ 8Z~ ~ ~235 methods kno~n in the art. Examples of such bases include cacoa butterg polyethylene glycols (Carbowaxes)~ poly-etlny1ene sorbitan monostearate, and mixtures of these with other co~pat7ble materials to modify the melting point or d1ssolution rateO These rectal suppositories caln weigh from about 1 to 2.5 GmD
The preferred comp~sitions are those adapted for inhalation ;nto the lun3. For treatment of allergic colnditions of the nose, such as rhinitis, compositions adapted for con~act ~ith nasal linings are pr~ferred.
Compositions for inhalation are of three basic types: 1) a powder mixture preferably micropulverized with partTcle size~ pref~rably from about 1 to about 5 microns; 2) an aqueous solution or suspension to be sprayed with a nebulizer; and ~) an aerosol with vola-tile propellant in a pressurized container.
The powders are quite simply prepared by mixing a compound of the formula ~ith 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 po~der when inhaled through the mouth.
Aqueous solutions are prepared by dissolving the compound of the Formula I in water and adding salt to provide an isotonic solution and buffering to a pH com-patib1e ~ith inhalation. The solutions are dispersed ina spray device or nebulizer and sprayed into the mouth while inhaling.
Aerosols are prepared by dispersing a cornpound of the ~ I in water or ethanol and mixing ~ith a 30 volatile propellant and placing in a pressurized 5~
container having a metering valve to release a predete~-~ined amount of material, The liquefied propellant employed is one ~hich has a boiling point below 65Fo at atmospheric pressure.
For use in compositions intended to produce aerosols for medicinal use, the liquefied propel lant should be non-toxic. Among the suitable liquefled propellan~s ~hich 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 l7guefied 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 propella~ts are dichlorodifluoromethane ("Freon 12"), dichlorotetra-fluoroethane ("Freon 114"), trichloromonofluoromethane ("Freon 11"), dichloromonofluoromethane ("Freon 21"), monochlorodifluoromethane ("Freon 22")9 trichlorotri-fluoroethane ("Freon 113"), difluoroethane ("Genetron142-A") and monochlorotrifluoromethane ("Freon 1~").
The term "unit dosage form"~ as used in the specification and claims, refers to physically discrete units suttable as unitary dosages for human subjects and animals, each unit containing a predetermined quan-tity of active material calculated to produce the desired therapeutic effect in association ~ith the required pharmaceutical diluen~, carrier or vehicle.
The specifications for ~he novel unit dosage forms of this invention are dictated by and directly dependent -~6-32~5 ~ S82~lS
on (a) the unique characteristics of the active mat-erial 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 ;n this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord ~ith this invention are ~ablets, capsules, pillsg suppositories, po~der packets, wafers, granules~ cachets, teaspoonfuls~ tablespoonfuls, dropperfuls, arnpuls, vials, aerosols with metered dis-charges, segrega~ed multiples of any of the foregoingJ
and other forms as herein described~
An effective but non-toxic quantity of the com-pound is employed in treatment. The dosage of the com-pound for treatment depends on the route of administra-tion and the potency of the particular compound. A
dosage schedule for humans of from about 0.01 to about 20 mg. of compound in a single dose, admin;stered par-enterally or by inhalation in the compositions of this invention, are effective for preventing allergy attacks.
More specificall YJ the single dose is from about 0.5 to about 10 mg. of compound. The oral and rectal dose is from about 5.0 to about 250 mg. in a single dose. More specifically, the single dose is from about 10 to about ~5 125 mg. of compound. The dosage to be administered can be repeated up to four ~imes daily.
The administration of the compositions of the present invention to humans and animals provides a method for the prophylactic trea~ment of allergy or all anaphylactic reactions of a reagin or non-reagin mediated 32~5 1 ~5~
nature. That is to say9 these compositions, when adminis-tered to a sensitized individual prior to the time that the individual comes into contac~ with substances (anti-gens) to whTch he is allergic, ~ill prevent the allergic reaction which ~ould other~ise occur.
For example, the process can be used for pro--phylactic treatment of such chronic conditions as bron-chial asthmaJ allergic rhin;tis, food allergy, hay fever, urticaria, auto-immune diseases, exercise induced asthma, stress induced asthma, systemic anaphylaxis~ and bird fancier's disease.
~e~_ A lot oF 10,000 tablets, each containing 50 mg.
of N,N'-(2-Chloro-5-phenyl-m-phenylene~dioxamic acid 15 is prepared from the following types and amounts of ingredients N,N'-~2~Chloro-5-phenyl-m-phenylene)-dioxamic acid 5 Gm.
Dicalcium phosphate 1,000 Gm.
Methylcellulose, U.S.P. (15 cps)60 Gm.
Talc 150 Gm.
Corn starch 200 Gm.
Magnesium stearate 10 Gm.
The compound and dicalcium phosphate are mixed well~ granulated with 7.5 percent solution of methyl-cellulose 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 32~5 1~58 ~ ~
or asthma attacks at a dose of one tablet every six hours.
Example 4 One thousand tablets, each containing 100 mg. of NJN'-(2-Chloro-5-phenyl-m-phenylene)dioxamic acid are prepared from the following types and amounts of ingredients:
N,N'-(2-Chloro-5 phenyl-m-phenylene)-dioxamic acid 100 Gm.
Microcrystalline cellulose N~410 Cm.
Starch 100 Gm.
Magnesium stearate powder 3 Gm.
The ingredients are screened and blended together and pressed into tablets.
The tablets are useful to protect agains~ food allergy at a dose of one tablet before meals.
.~
A sterile preparation suitable for intramuscular injection and containing 4.0 mg. of N,N'-(2-Chloro-5-20 phenylene)dioxamic acid in each mill71iter is prepared from the follo~ing ingredients:
N,N'-(2-Chloro-5-phenyl-m-phenylene)-dioxamic acid 4.0 Gm.
Benzyl benzoate 200 ml.
Methylparaben 1.5 Gm.
Propylparaben o.5 Gm.
Cottonseed oil q.s. 1,000 ml.
One milli1iter of this sterile preparation is injected for prophylactic treatment of allergic rhinitis.
I
I 32~5 ~SI~
_6 Six hundred ml. of an aqueou~ suspension contain-ing 20 mg~ of the N,NI-(2~Chloro-5-phenyl-m-phenylene)~
dioxamic acid per ml. is prepared as Follows:
N,N'-(2-Chloro-5-phenyl-m-phenylene)-dioxamic acid 12 Gm.
Sodium chloride 5 Gm.
Water for injection q.s.600 ml.
The and sod;um chloride are dispersed in sufficienl: water to make 600 ml. and sterilized.
The liquid is placed in nebulizers designed to deliver 0,25 ml. per spray.
The liquid is inhaled into the lungs every fouL
to six hours for prevention of asthmatic attacks.
Example 7 A powder mixture consisting of 1.0 gram of N,Ns-(2-Chloro-5-phenyl-m-phenylene)dioxamic acid and sufficient lactose to make five grams of mixture is micropulverized and placed in an insufflator designed to deliver 50 mg. of powder per dose.
The powder is inhaled into the lungs evel-y four to six hours for prevention of asthmatic attacks.
The powder is inhaled intranasally every four hours for prevention of rhinitis.
Exam~!e 8 A powder mixture consisting of 2.0 gram of N,N'-(2-chloro-5-phenyl-m-phenylene~dioxamic acid ~235 ~ Q ~
and sufficient lactose to make five grams of mixture is micropulveri zed and placed in an insufFlator designed to del îver 50 mg. of powder per dose.
The powder is inhaled into the lungs every four to six hours for prevention of asthmatic attacks.
The powder is inhaled intranasally every four hours for prevention of rhinitis.
E mE~Q_2 Twelve grams of an aerosol composition are pre-pared from the following ingredients:
NJN'-(2-Chloro-5-phenyl-m-ph~nyl~ne)-dioxamic ~cid 0.500 6m.
Freon 12 1.440 Gm.
~reon 114 2,160 Gm~
Water 7.788 Gm~
Sorbitan monoleate 0.600 Gm.
The compound is dispersed in the water and chi11ed to -30 C. and added to the chilled Freons. The t~elve grams of compositions are added to a 13 ml, plastic 2G coated bott1e and capped with a metering valve. The metering valve releases 80 mg, of composition in an aero-sol. The aerosol is inhaled every four to six hours for prevent7On of asthmatic attacks, Example lQ
ci~4~r~ n q After allowing for the ~ solubilities of the compounds and the activity of the particular com-pound as measured, for example, by the ~ y~rat pas-sive cutaneous anaphylaxis assay, a suitable quantity of each of the compounds of Table I through Tabie ll and Examples 1-2, is substituted for the active ~ .~ ~
~9S8ZO~ -compound in th~ compositions ancl uses of Examples 3 through 9. Results showing anti-allergy activity are obtained.
It should be noted that in all the com-positions and treatment examples of this patent application, the quantity ofdru~ ernployed refers to the acid equivalent.
When repeated administration is desired, the compounds of this application which have a relatively short duration of activity can be administered in a priming dose-maintenance dose regimen as described in Canadian Patent No.
1,030,156.
Following the rat passive cutaneous anaphylaxis assay procedure of Example 3 of Canadian Patent No. 1,030,156, the inhibitory dose50 of N,N'-(2-chloro-5-phenyl-m-phenylene) dioxamic acid is 0.01 mg./kg. by the intravenous route.
., ~~,,j, , .
Claims (19)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula wherein the groups are meta or para to each other;
R is hydrogen or a physiologically acceptable metal or amine cation; and X, Y and Z are the same or different and are selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclusive, alkoxy of one to four carbon atoms, inclusive, hydroxy, fluoro, chloro, bromo and , wherein D is selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclusive, and a physiologically acceptable metal or amine cation, with the proviso that when D
is hydrogen or a physiologically acceptable metal or amine cation, D is the same as R, which comprises reacting an X, Y and Z sub-stituted biphenyl diamine of the formula wherein the amino groups are meta or para to each other and X, Y and Z are as previously defined, with an alkyl oxalyl halide wherein alkyl is one to three carbon atoms and halo is fluoro, chloro, bromo or iodo of the formula in solvent and base or reacting the above diamine with a dialkyloxalate wherein alkyl is from one to three carbon atoms in neat or with an additional solvent to form the corres-ponding dioxamate which is hydrolyzed to the dioxamic acids and optionally converted to the metal or amine salt.
R is hydrogen or a physiologically acceptable metal or amine cation; and X, Y and Z are the same or different and are selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclusive, alkoxy of one to four carbon atoms, inclusive, hydroxy, fluoro, chloro, bromo and , wherein D is selected from the group consisting of hydrogen, alkyl of one to six carbon atoms, inclusive, and a physiologically acceptable metal or amine cation, with the proviso that when D
is hydrogen or a physiologically acceptable metal or amine cation, D is the same as R, which comprises reacting an X, Y and Z sub-stituted biphenyl diamine of the formula wherein the amino groups are meta or para to each other and X, Y and Z are as previously defined, with an alkyl oxalyl halide wherein alkyl is one to three carbon atoms and halo is fluoro, chloro, bromo or iodo of the formula in solvent and base or reacting the above diamine with a dialkyloxalate wherein alkyl is from one to three carbon atoms in neat or with an additional solvent to form the corres-ponding dioxamate which is hydrolyzed to the dioxamic acids and optionally converted to the metal or amine salt.
2. Process in accordance with claim 1 wherein X, y and Z are the same or different and are selected from the group consisting of hydrogen, alkyl of one to three carbon atoms, inclusive, alkoxy of one to three carbon atoms, inclusive, fluoro, chloro and , wherein D is selected from the group consisting of hydrogen, alkyl of one to three carbon atoms, inclusive, and a physiologically acceptable metal or amine cation with the proviso that when D is hydrogen or a physiologically acceptable metal or amine cation, D is the same as R.
3. Process in accordance with claim 2 wherein the groups are meta to each other.
4. Process in accordance with claim 3 wherein the phenyl substituent is meta to both the groups.
5. Process in accordance with claim 4 wherein X
is ortho to both groups.
is ortho to both groups.
6. Process in accordance with claim 5 wherein Y
is hydrogen.
is hydrogen.
7. Process in accordance with claim 6 wherein Z is hydrogen.
8. A process for the preparation of N,N'-(2-chloro-5-phenyl-m-phenylene)dioxamic acid which comprises reacting 2-chloro-5-phenyl-m-phenylenediamine with ethyl oxalyl chloride in solvent and base to form diethyl N,N'-(2-chloro-5-phenyl-m-phenylene)dioxamate which is then hydrolyzed to the corresponding dioxamic acid.
9. The process of claim 8, including the step of converting said acid to the corresponding disodium salt.
10. A process for the preparation of N,N'-(4-chloro-5-phenyl-m-phenylene)dioxamic acid which comprises reacting 4-chloro-5-phenyl-m-phenylene diamine with ethyl oxalyl chloride in solvent and base to form diethyl N,N'-(4-chloro-5-phenyl-m-phenylene)dioxamate which is then hydrolyzed to the corresponding dioxamic acid.
11. The process defined in claim 10, including the step of converting said acid to the corresponding disodium salt.
12. The process defined in claim 8, including the step of converting said acid to the corresponding ditri (hydroxymethyl)methyl-ammonium salt.
13. A compound of the structure wherein , R, X, Y and Z are as defined in claim 1, whenever prepared or produced by the process defined in claim 1 or by the obvious chemical equivalent.
14. A compound of the structure in accordance with claim 13, wherein X, Y and Z are as defined in claim 2, whenever prepared or produced by the process defined in claim 2 or by the obvious chemical equivalent.
15. N,N'-(2-chloro)-5-phenyl-m-phenylene) dioxamic acid, whenever prepared or produced by the process defined in claim 8 or by the obvious chemical equivalent.
16. Disodio N,N'-(2-chloro-5-phenyl-m-phenylene) dioxamate, whenever prepared or produced by the process defined in claim 9 or by the obvious chemical equivalent.
17. N,N'-(4-chloro-5-phenyl-m-phenylene) dioxamic acid, whenever prepared or produced by the process defined in claim 10 or by the obvious chemical equivalent.
18. Disodio N,N'-(4-chloro-5-phenyl-m-phenylene) dioxamate, whenever prepared or produced by the process defined in claim 11 or by the obvious chemical equivalent.
19. Ditris(hydroxymethyl)methyl-ammonium N,N'-(2-chloro-5-phenyl-m-phenylene)dioxamate, whenever prepared or produced by the process defined in claim 12 or by the obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US47781874A | 1974-06-10 | 1974-06-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1058208A true CA1058208A (en) | 1979-07-10 |
Family
ID=23897489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA226,824A Expired CA1058208A (en) | 1974-06-10 | 1975-05-13 | Pharmaceutical n,n'(phenylphenylene) dioxamic acid derivatives |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS5829779B2 (en) |
| BE (1) | BE830069A (en) |
| CA (1) | CA1058208A (en) |
| CH (1) | CH614191A5 (en) |
| DE (1) | DE2525249C2 (en) |
| FR (1) | FR2273526A1 (en) |
| GB (1) | GB1497735A (en) |
| NL (1) | NL7506865A (en) |
| ZA (1) | ZA753107B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1075092A (en) * | 1976-01-19 | 1980-04-08 | Seatek (A California Partnership) | Method and apparatus for stabilization of a floating semi-submersible structure |
| JPS604037B2 (en) * | 1978-02-10 | 1985-02-01 | 九州大学長 | floating marine station |
| JPS5587690A (en) * | 1978-12-26 | 1980-07-02 | Mitsui Eng & Shipbuild Co Ltd | Wave trap at barge integrator |
| JPS628894A (en) * | 1985-07-08 | 1987-01-16 | Toshio Kato | Wave affection removing device |
| JPS62292587A (en) * | 1986-06-10 | 1987-12-19 | Sumitomo Heavy Ind Ltd | Underwater floating body for semi-submerged marine structure |
| DE4208019A1 (en) * | 1991-06-10 | 1992-12-24 | Banning Gmbh J | Blanks prodn. for rotationally symmetrical components - using ring to prevent diametral expansion of blank |
-
1975
- 1975-05-13 CA CA226,824A patent/CA1058208A/en not_active Expired
- 1975-05-14 ZA ZA00753107A patent/ZA753107B/en unknown
- 1975-05-28 CH CH687175A patent/CH614191A5/en not_active IP Right Cessation
- 1975-06-02 GB GB23816/75A patent/GB1497735A/en not_active Expired
- 1975-06-06 DE DE2525249A patent/DE2525249C2/en not_active Expired
- 1975-06-09 FR FR7517979A patent/FR2273526A1/en active Granted
- 1975-06-10 BE BE157191A patent/BE830069A/en not_active IP Right Cessation
- 1975-06-10 JP JP50070086A patent/JPS5829779B2/en not_active Expired
- 1975-06-10 NL NL7506865A patent/NL7506865A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5829779B2 (en) | 1983-06-24 |
| DE2525249A1 (en) | 1976-01-02 |
| BE830069A (en) | 1975-12-10 |
| AU8128975A (en) | 1976-11-25 |
| CH614191A5 (en) | 1979-11-15 |
| NL7506865A (en) | 1975-12-12 |
| JPS516952A (en) | 1976-01-20 |
| FR2273526A1 (en) | 1976-01-02 |
| DE2525249C2 (en) | 1984-04-26 |
| ZA753107B (en) | 1976-04-28 |
| FR2273526B1 (en) | 1978-11-10 |
| GB1497735A (en) | 1978-01-12 |
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