Note: Descriptions are shown in the official language in which they were submitted.
' 2909
~.()4~100
BRIEF SUMMARY OF THE INVENTION
It has now been discovered that novel compounds
of Figure I are useful in the prophylactic treatment of
sensitlzed humans and animals for allergy and all ana-
phylactic reacttons of a reagin or non-reagin mediated
nature, The compounds are formulated ~ith pharmaceuti- :
cal carriers for oral, parenteral, inhalat70n or rectal
means of admtnistration.
pETAILED DESCRIPTION OF THE I NVENT I ON
In accordance with this invention there are pro- , . ,
v7ded compounds represented by Figure 1, and hereafter
referred to as Group A:
,
RO-C~ C ~N ~ N C ~1l ~ OR
and
. 20 "
RO ~ ~C ~ ~ N ~ ~ C~
0 (I) '~ :
H 0`'0
whereln each -N-C-C-OR is located anywhere on the carbon :
ring with the proviso that one,group cannot be ortho to '
~0 the other group;
-2- :
' ~ ' ~ ' '
. .
, . .
.: ~
2909
~ Q ~ ~
R is selected fro~ the group consTsting of hydro-
gen, alkyl from one through six carbon atoms, phenyl, - :~
~nd a pharmaceutTcally acceptable metal or amine catTon; . --
X and Y can be the same or different and are selec-
ted from the group consisting of hydrogen, alkyl from onethrough four carbon atoms, phenyl, alkoxy from one through
three carbon atoms, nitro, amino, trifluoromethyl, halo-
gen, cyano and C-OD~ whereln D is selected from the group
conslsttng of hydrogen, alkyl from one through six car-
bon atoms and a pharmaceutTcally acceptable-metal or
amlne catlon ~Ith the provlso that when R Is hydrogen
or a pharmaceutlcally acceptable metal or amlne cation,
then D Is the same as R~ and ~hen R is alkyl from one
through slx carb~n atoms or phenyl, then D Ts alkyl from ~.
15 one through slx carbon atoms, phenyl or hydrogen; and
pharmaceutlcally acceptable acTd additlon salts thereof.
A preferred group of compounds, hereafter referred - :
to as Group B~ are where R is selected from the group
consistlng of hydrogen, alkyl of from one through four ..
. .
carbon atoms, and a pharmaceutlcally acceptable metal or
amlne catlon;
X and Y are the same or dlfferent and are selected
from the group conslstlng of hydrogen, alkyl of from one
through four c~rbon atoms, phenyl, alko~y of from one
through three carbon atoms, nitro, trifluoromethyl, halo~
gen, cyano, and ~-OD~ ~hereln D Is def7ned as in Group A~ .`~
wlth the provtso that when D is alkyl, the upper carbon : :
number llmltatlon t 5 four.
A more prefereed group of compounds, herelnafter ~;
referred to as Group C, are compounds wherein the ~ OR ~ ~
:
-3~
.
~ Q4 ~
groups are located at the 2 and 6 positions or the 3
and 5 poslt!ons;
R is selected from the group consistlng of hydro-
gen and a pharmaceutically acceptable metal or amTne
cation.
X and Y are as defTned Tn Group B.
A stlll more preferred group of compounds, hereln-
after referred to as Group D, are compounds whereln the
location of -~-C-~-OR and R are as deflned as In Group C,
X Is hydrogen and Y Is selected from the group consls-
ttng of hydrogen, alkyl of from one through four carbon
atoms, alkoxy of from one through three carbon atoms,
nltro, trlfluoromethyl, halogen, cyano, and ~c_OD,-~here-
In D Is deflned as In Group B. ' '
a further group of compounds, hereinafter referred
to as Group E, are compounds ~herein the location of
-x-~-8-oR ~ R, X and Y are deflned as In Group D wTth '
the provlso that Y !s limlted to the 4 posltlon.
A still further group of compounds, herelnafter
referred to as Group FJ are compounds whereln R, X and y
are deflned as In'Group E and the locatlon of the ~X ~-~-OR
groùps are at the 2 and 6 posltlons.
A further group of compounds herelnafter referred
to as Group G are compounds whereln the locatlon of'the
-X-R-l-OR group, R, X and Y are deflned as in GroupiF wlth ~'~
the p'rovlso that halogen Is fluoro, chloro, and bromo.
- A still ~urther group of compounds are compou~ds of -
.
successive Groups D, E, F and G, wlth the proviso that ''
H O O I ~
the nucleus to which the -N-C-~-OR and the X and Y groups
are attached Is ~ and Its pharmaceutlcally acceptable
N ~'
. , ' ' ~
-
' ' ' ' ,. ,, ' ' . :
2909
..
~4~
acid addition salts.
As employed in the above disclosure and throughout ~-
the specification, the term "halogen" ;ncludes fluoro,
chloro, bromo and iodo. The term "alkyl" includes methyl,
ethyl, propyl and isopropyl when limited to three carbon
atoms, n-butyl and isomers thereof when limited to four
carbon atoms, n-pentyl and n-hexyl and isomers thereof ~ -
when limited to six carbon atoms. The term "pharmaceuti-
cally acceptable metal" includes alkali metals such as
sodium and potassium, alkaline earth metals such as cal-
cium and magnesium and other acceptable metals such as
alumTnum. The term "amine cation" includes all pharma- :
ceutically acceptable cations from amines such as ammonia,
tris-(hydroxymethyl)-aminomethane (THAM), D-threo-2-amino-
1-p-nitrophenyl-1J3-propanediol, N,N-bis(hydroxyethyl)-
piperazine, 2-amino-2-methyl-1-propanolg 2-amino-2-methyl-
1,3-propanedTol and 2,2-bis(hydroxymethyl)-2,2',2"-
nTtrolotriethanol and further am7nes Jnc~uding H2~R',
HNR'2, and NR'3, wherein RI is selected from the group
consisting of alkyl from one to three carbon atoms, in-
cluslve, and -CH2CH20H.
Pharmaceutlcally acceptable acid addi~tion salts
refer to the salts which can be prepared at the nitrogen
of the pyrldlne ~ing. Illustrative of these salts are
hydrochloric, hydrobromlc, hydriodic, nitrTc, sulfuric,
oxalic, cyclohexanesulfamlc, salicyllc, and the lIke.
- The compounds of this Invention can be prepared by
m`ethods known to the art. The appropriately substituted
~;~ diaminopyridines (II) are sultable startlng materials.
0 These compounds are reacted with an alkyl oxalyl halide,
. ~ .
. .
~ 5- ~ -
',,: . , , . ~ . ~ .
. .
~yuy
preferably ethyl oxalyl chloride (l11a), in a suitable
solvent and base to form the dioxamate (IV). An alter-
native method of preparing the dioxamate is to react (Il) ~.
with a dialkyl oxalate, preferably diethyl oxalate (Illb)
in neat solution or ~ith an additional solvent, if nec-
essary, at a temperature rangjng from about 25C to
about reflux temperature of the system:
û û .~ ~
X~ Y Cl-C-C-OC2H5 (Illa) :
HeN~ Hy t
( ) H5C20C-COC2H5 (Illb)
. ..
~' ;
:
X Y
8 ~ H l 0 ~ ;
HSC20C-C-N t --N- c- c- OC2H5
~3~ . ' .
. .
.
At this point of the synthetic pathway, the oxa-
mate can~b:e transesterlfied to other esters and/or con- . .
~0 verted to the dtacid by~hydro-lysis and thence to the
-6-
2909
`
~4~Q~
metal or amine salts by standard methods.
The N-oxide derivative of the pyridylyl dioxamic ~`
acid ester or salt can be readily prepared by oxidation
of the diester with an oxidizlng agent, such as m-chloro- -
~e~l~x~benJz o; c ~
r ~ 9
The appropriately X and r substituted d;aminopyri-
dine starting materials are prepared by conventional
substitution means well known in the art. These means
depend somewhat upon the substituent-itself, the place- `
ment of the substituent and the placement of the oxamic
group. O
The particular C-OD substituents can be prepar~d
by converting the corresponding d;amino or dinTtro pyri-
dinecarboxylic acid, for example, to the ester, amide,
etc., by standard methods. This can be done prior to
the preparatlon of the dioxamate from the substituted
diamino starting material.
Illustrative examples of starting materials of
Figure ll are below.
X Y
HeN ~ NHe
~3 ' ,,.",,, ~ ~' '
(Il) ~
'' . .:
~ ' : '
~: .
':". :'
~ ~ .
, . . , , . -., . . ." ..
.. ~ . , . ;, ~ .. . .. . . - .
~yu~
la~ a$~ , -
CO , CU
E -
.~ . ..
~ ~ U) '
~ ~ a~ Q I ~ ID ~ N
In t~ J S I ID Z LL I ~ ~ ~ O Z
O ~-) O O O ~ ~ ~ C IL~ Q Z ~)
~! N N CU C\J C~
CO . ,.
._
E
.I - 11
l N I 0~0~ ~ N liq N
U' O --ID Z IL I C~ , ~ )- O Z ~ O Z
t.~ )t~ C ILJ Q Z ~ ) Z ~
N I I II . I I I II I I I , I .
<~ 1~1~\ 1~ 1~1~ 1<~ ~ ~ ~~O
..
~t
.: ': ..
., ~ .' .
~_ ZZ Z Z
O
C ~O " '
E
: :
_ 11~ ' '
l N N N I 011
:1~ O OO ~ ~-- ~ Z L~
. Z ZZQl~ CL~
Xl~ ~
.
,
,j~ ', , ,'.' :,., :
E
._ ~ :~ I :.
N O ~ T I
~ :3 ~O) O O-- ~ ~ O O I .:
N a~ ILI ~ ZZ O -- LLI-- O O--
: ~',, . : ,.
~ : ' ', :' ' ~" ''
8~
- : . .
.
. : .: -..... ~ . . .. ~ ''
... ... . . .
~yuy
~ :
~ o~ N a~ ~ o : -
S ~I~ ~ o ~ L~ O .-
LLI a~ o ~ ~ ~ z o o ~ ~.) ~ ~_) .
E : .
_ . ,`
U` ~ ~ ~ O --~ ~ ~ S _ LL Z
L~ ~ ~ z ~ o o ~ o
X¦ ~ ~ ~ J CU CU N
O
z ~ Z -- ~ 8
O ~ O~O ~0 ~ ~ ~ :1~ ~ , ,
._ . :' `
_ T
U' LL ~ Z _IL _~ 00 ~, Z- . . .
~ Z ~ ~ ~~ O~ '-- ~ ~ ~ O :` '
- X! ' ' ~ ' ~ ~ ~ ~ ~ ~ ~ ~ ~ :' '
J : . '
w ~ -- LL Z -- 8 -- ~ oN
I L O Z 1~ ~ oN I w -- Z -- O
C~ Z` ~ ~ CL. Z ) O ~,) ~ ~ ~) O :
X! ~ o ~o u~
~ ` : .
o Z
jil :1: I I I I lr~ LC~ I I = I I I I .
C~ o v
`~ -. ;, . ,. ~. . . . ...
I
O '
.C
E
I I ::
l ' O
It` O
~ ;.
~ xl cu
O I .
r ~: :
E .
a
I Xl ,
. ~ . ~ ,.
~C . . ~
L .. ~ ~
~ O . ' , ~', '
c , :. . :.. ; ! '::
E . . " .
~
L~
Xl ~
'~:
':
.
/~ ~1) 0 I~J N tl~
~ L S _ LL Z-- 0 ~ 0 0
v ~ ~ o s~ ~~) ~ ~ ~ ~ z -
c ''II , , , , , , I , , , ~ ~ ~ . . . :
._ . ' '
N 0 N Q~ ~. O
O Z IL L O T I IJ _ Z -- O
z ~ ~ ~ z ~ o ~ t~ t.~ ~ o 1
~ xl ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
- 10- ,.. . . .
~ .
2909
~0~
An additional route of preparing the starting materi-
als, (Il~, for example, is by reacting a substituted
dihalopyridine, for example, dichloropyridine (V) with
ammonia under pressure and elevated temperature to pro-
duce the substituted diamtnopyridine starting material
( l l )
Cl ~ Cl N~ ~ H,N ~ NH~
N pressure N
(V) ` ( ~'' '"
Once starting material II is prepared, it is reacted
with an alkyl oxalyl halide or dialkyl oxalate. When
using an alkyl oxalyl halide, reaction is carried out in
base and solvent at standard condit-ions. Examples of
suitable solvents are dimethylformamide (DMF), dioxane,
and tetrahydrofuran. Appropriate bases include triethyl-
amine, N-methylmorpholine, dimethylpiperazine, and N-
methylpiperldlne. When the dlalkyl oxalate Is employed,
the startlng materlal II or Its substltuted analogue is
heated together with the dlalkyl oxalate or an addltlonal
solvent such as a xylene or diphenyl ether if desired,
thereby forming the dioxamate. The temperature is from
about 25C. to the reflux temperature of the system,
preferably temperature between about 100C. and reflux
temperature of the system.
The dioxamate is then readily converted to the di- -
oxamic acid by using dilute base such as sodium hydroxide~
.~ . .
- 1 1- ' .
.
2909
,
potassium hydroxide or potassium carbonate at temperatures
ranging from about 25 to about 100C., follo~ed by addi-
tion of acid. The alkal'ine metal salts of the oxamate may
be soluble in aqueous medium or relatively insoluble. If
soluble in aqueous medium, the pH is adjusted with acid and
the resulting precipitate is collected. If the alkaline
metal salt is insoluble in aqueous medium, the precipitate
per se can be collected and then heated in aqueous acid to
an appropriate temperature, collecting the mixture, and
isolating the desired diacid. The acTd can then be easily
converted to the metal or amine salt by contacting the di~
acid with two equivalents of the desired amine or metal hy- '
droxide and heating in a sufficient amount of water to ef- ''`
fect solubilization. The crystalline salts can be precipi-
tated by the addition of,an organic solvent, for example,
methanol. '~
TABLE ll
:
An illustratlve listof compounds of this invention are
the dToxamic acids prepared from the starting materials of
Table I by methods ~ this application, and can be consider-
ed as being made'and stated under the tltle "Table ll".
TABLE lll
The dioxamlc aclds of Table ll are converted to '
pharmaceutically acceptable salts, e.g., metal and amine
cations, and partTcularly the trTs(hydroxymethyl)methyl~
ammonTum salt by standard methods. ; '
TABLE IV ' '
The dioxamlc acids of Table ll are converted into ~
compounds where R is alkyl of from one through six carbon
atoms and phenyl by standard methods, '~
- . `
-12-
2909
~ Q ~
TABLE V
The compounds of Table IV are converted to pyridyl
N-oxide oxamates by standard means.
TABLE Vl
The compounds of Table V are converted to pyridyl -;
N-oxide dioxamic acids by standard means. ~ -
TABLE ~
The dioxamic acids of Table Vl are converted to
pharmaceutically acceptable salts, e.g., metal and amine
.~ . ...
cations, and particularly the tris(hydroxymethyl)methyl-
ammonium salt by standard methods.
Tables li through ~lll are not rendered in the same
manner as Table I for the purpose of brevity, However,
the same scoping is intended.
The following examples are compounds in accordance
with this inventTon. The compounds are intended not to ~ -
limit but merely to exemplify the invention,
Example 1 PYridineq2,6-diyldioxam7c acid
a, Diethyl N.N'-2 6-pyridinediyldioxamate
2,6-Diaminopyridine (13.6 9.) is dissolved
in 100 ml, of anhydrous DMF containing trlethylamlne
(~1 9,), The sttrred reac~,lon mixture is cooled to tce
bath temperature and treated dropwise with ethyl oxalyl-
ahloride (30 9,), Sttrring is conttnued for eightee~
hours at room temperature, then the reactton mTx~re is ~ured
into 1 l. of water, The product is collected by ftltra~ '~
tion, washed with water and dried under reduced pressure
àt 60. Recrystallization from acetone gives a material
,
;~ ~ melting at 179-180 (15.0 9.),
q13-
. ~ . .
2909
10~
b. Product
The diethyl ester (13.0 9.) is stirred at
room temperature in 1 M sodium hydroxide (250 ml.) for
one hour. The solution is acidified with 3M HCl to give
the desired acid as a white solid. The product is col-
lected by filtration, washed with water and dried at
reduced pressure at 60 . (7.~ g.), m. p. >310.
IR (Nujol): 3190, 1720, 1650, 1625, 1575, 735. ;
Example 2 Pyridine-2,5-diyldioxamic acid
,
a. 2,5-Diaminopyrid_ne ~-
A mixture of 2-amino-5-nitropyridine (10 g., -~
0.071 mole), 5~ palladium on charcoal (1,0 9.), and
methanol (200 ml.) is treated with hydrogen (40 psi)
on a Parr hydrogenator until hydrogen uptake stops. The ~ -
catalyst is removed by filtration and the solvent re-
moved to leave a dark red oil which crystallizes upon
standing.
b. Diethyl N.N'-2,5-pyridinediyldioxamate
~ To a mixture of the diamine prepared above,
triethylamine (14 9,, 0.14 mole), and anhydrous dlmethyl-
formamide (125 ml,), ethyl oxalyl chloride (18,4 g.~
0.14 mole) ts added slo~ly. The reactton mtxture is
sttrred overnight at room temperature and then poured
into water, The resulting solid is collected, treated
wtth Darco~ and recrystallized from methanol to gTve a
light red solid (5.68 g., 26%, m,p, 178-180). A small
, . .
sample is recrystallized.
c. Product
Diethyl NJN'-2j5-pyrTdTnedTyldToxamate
(1.0 g., 0.0032 mole) is stTrred Tn 1,0N sodTum hydroxTde
~; ~ ' ~ - : ' -
-14-
- . . .. :
- 2909
00
:'
(25 ml.) at 70-85 until solution is complete. The re-
action mixture is diluted with water (25 ml.) and acidi-
fied (pH=3) with concentrated hydrochloric acid. The ;~
desired product is collected by filtration (0.35 g.,
43~J m.p. 290-295 dec.).
Analysis:
nmr (D20 with THAM): 5.95~ (dJ IH, 3-proton, J9 4-8cps);
6.95~ (m, IH, 4-proton, ~4 9=8cps, ~ -
J4,~-2cps); 7.35~ (d, IH, 6-proton,
J6,4-2cps). ~ -
IR(Nujol)3500, 3130, 2650 (broad), 1700, --
1610, 1580, 1200 and others.
Example 3 Disodio 2 6-dimethoxy-305-pyridine-
diyldioxamate
a. Diethyl N,N'-(2.6-dimethoxY-3.5- -
pyr~dinediyl)dioxamate
Ethyl oxalyl chloride (5.71 g.J 0.0418 moles)
T~s added slowly with stirring at 0 to a solution of 3,5-
diamino-2,6-dimethoxypyridine dihydrochloride (S. 9.J
0.027 moles) in DMF (50 ml.) and triethylamine (8.3 9.,
o.o828 moles), The reactton mixture Is stlrred for one
hour at 0, then eighteen hours at room temperature,
DTlution with ~ater (500 ml.) gives a dark product that
is collected by filtration, washed wTth water and dried.
(3.8 9" m.p. 170-173). Recrystallization from ethanol
.
and treatment with Darco gives a light green product.
t1.9 9., m.p. 173-174.5OJ 25~ yield).
Analysis: Calcd. for Cl5H1908N3
CJ 48.78; HJ 5.19; NJ 11.38
Found:CJ 49.06; H, 5.18; NJ 11.36
-15- ~
: , ~ ': .' .'
. ~ .
2909
~ .
uv (EtOH) A max (e): 222 (10,300), 316 (14,600)
IR (NuJol): NH 3390, = CH 312OJ C=O 1730, 1710
C=C/C=N/amide Il 1610, 1535, 1515, -~
CH/C-O/C-N/ether 1475, 1405, 1365,
C=O/C-N/ether 1290, 1230, 1175, 1115,
1020, 1000.
Mass. Spec.: Mol ion 338
b. Product
1.75 9., (o.oo48 moles) is stirred at room
temperature in 1 0N NaOH (25 ml.). The sodium salt pre-
¢ipitates out as an off-white mass and is filtered and
dissolved in water (400 ml.). The solution is acidified
~ith 3N HCl (pH=4) and filtered. The filtrate is con-
. .
centrated to 200 ml. under reduced pressure and the di-
acid dlsodium salt precipitates out as a white solid
(.75 g., m,p >310)
.. .: .
Analysis Calcd. for C1lH~N30~Na2:
C, 36.99; H, 2.54; N, 11.76; Na, 12.88 r~
Found: C, 37.53; H, 2.54; N, 12.05, Na, 11.95 ~ -
uv (H20) ~ max (e): 210 sh (11,600), 304 (9,400)
IR (Nujol): NH/OH 3480, 3400, 3350, C=O/COæ/-
C=N/C=C 1685, 1610, 1530
CH/C-O/C-N 1395, 1345, 1220, 1015
The compositions of the present invention are pre-
sented for administration to humans and animals in unit
dosage forms, such as tablets, capsules, pills, powders,
~ranules, sterile parenteral solutions or suspensions,
eye drops, oral solutions or suspensions, and oil~in-
water and ~ater in oil emulsions containing suitable
quantities of the compound of Figure I. The preferred
,',,' ;-
,
:~ .~ ' ... ' "' ~
1 04 ~
method of administration is by inhalation into the lungby means of an aerosol liquid or powder for insufflation.
For oral admin;stration, either solid or fl~id unit
dosage forms can be prepared. For preparing solid compo-
sitions such as tablets, the compound of Figure l is
mixed with conventional ingredients such as talc, magne- -
sium stearate, dicalcium phosphate, magnesium aluminum
silicate, calcium sulfate, starch, lactose, acacia,
methylcellulose, and functionally similar materials as
pharmaceutical diluents or carriers. Capsules are pre-
pared 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 admjnistration,
such as syrups, elixirs, and suspensions, can be pre-
pared. The water-soluble forms can be dissolved in an
aqueous vehicle together with sugar, aromatic flavoring
agents and preservatives to form a syrup, An ellxlr Is
prepared by ustng a hydroalcoholic (ethanol) vehicle
with suitable sweeteners such as sugar and saccharln?
together with an aromatic flavoring agent.
Suspensions can be prepared with an aqueous vehlcle
~ith the aid of a suspending agent such as acacia, traga-
~ ~anth, methylcellulose and the like.
; For parenteral administration, fluid untt dosage
~: ~ forms are prepared utilizing the compound and a sterile
vehicle, water being preferred. The compound, depending
17 - ~
' - "
lO~ V
on the vehicle and concentration used, can be either sus-
pended or dissolved in the vehicle. In preparing solu-
~ions the compound can be dissolved in ~ater for injec-
tion 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
7nto the vial and the water removed under vacuum. The
dry lyophilized powder is then sealed in the vial and
an accompanying vial of ~ater 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 vehi~le ;
instead of being dissolved and sterilization cannot be `
accomplished by filtration. The compound can be steri-
lIzed by exposure to ethylene oxide before suspending in
the sterile vehicle. Advantageously, a surfactant or
wetting agent is included in the composition to facili-
tate uniform distribution of the compound.
Addlttonally, a rectal suppository can be employed
to deliver the active compound. This dosage form is of ;
particular interest where the mammal cannot be treated
conventently by means of other dosage forms, such as
drally or Insufflation, as in the case of young children
or debilttated persons. The actTve compound can be. :
tncorporated ~nto any of the known suppository bases by
methods known in the art. Examples of such bases include
cocoa butter, polyethylene glycols (Carbo~axe~, poly- ~ -
ethylene sorbttan monostearate, and mixtures of these
. .. . .
- 18- :
: .:.
2909
with other compatible materials to modify the melting
point or dissolution rate. These rectal suppositories
can weigh from about 1 to 2.5 Gm.
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
with particle size, preferably from about 1 to about 5
microns; 2) an aqueous solution to be sprayed with a
nebulizer; and 3) an aerosol with volatile propellant
i-n a pressurized container.
The powders are quite simply prepared by mixing a
compound of the formula with a solid base which is com-
patible with lung tissueJ preferably lactose. The pow-
ders 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 ~igure I ;n water and adding salt to
provide an isotonic solution and buffering to a pH com-
patible with inhalatlon. 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 Figure I in water or ethanol and mi~ing with a
volatile propellant and placing in a pressurized contaTn-
er having a metering valve to release a predetermined
-19-
.. : . ~ . . ~ . . . .......... . . . . .
.. : - - . .. . . . , - ~.. - ... :.
2g~y
amount of material,
The liquefied propellant employed is one which has
a boiling point below 65F. at atmospheric pressure.
For use in compositions intended to produce aerosols for
medicinal use, the liquefied propellant should be non-
toxic. Among the suitable liquefied propellants which
may be employed are the lower alkanes containing up to
five carbon atoms, such as butane and pentane, or a - -
lower alkyl chloride, such as methyl, ethyl, or propyl
chlorides. Further suitable liquefied propellants are
the fluorinated and fluorochlorinated lower alkanes such
as are sold under the trademarks "Freon" and "Genetron".
Mixtures af the above-mentioned propellants may suitably
be employed. Fxamples of these propellants are dichloro-
dlfluoromethane ("Freon 12"), dichlorotetrafluoroethane
("Freon 114"), trichloromonofluoromethane ("Freon ~
dichloromonofluoromethane ("Freon 21") J monochlorodi-
f~luoromethane ("Freon 221l)g trichlorotrifluoroethane
("Freon 113"), difluoroethane ("Genetron 142-~") and
monochlorotrifluoromethane ("Freon 13"), ;
The term "unit dosage form", as used in the speci-
fication and claims, refers to physically discrete unTts
suitable as unitary dosages for human sub~ects 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 ;
r~ovel unit dosage forms of this invention are dictated
by and directly dependent on (a) the unique characteris-
3 tics of the active material and the particular effect to
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V
be achieved and (b) the limitations inherent in the art
of compounding such an active material for use in human~
and animals, as disclosed in detall ;n this specification,
these being features of the present invention. Examples
of suitable unit dosage forms in accord with this inven-
tion are tabletsJ capsules, pills, suppositories, powder
packets, wafers, granules, cachets3 teaspoonfuls, table-
spoonfuls, dropperfuls, ampuls, vials, aerosols with
metered discharges, segregated multiples of any of the
foregoing, and other forms as herein described
It should be understood that the compositions
disclosed herein refer to the groups of compounds A
through G and those groups wherein the structure is
pyridine and its pharmaceutically acceptable acid addi-
tion salts~ as well as species illustratively exemplified
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
for humans cf from about 0.05 to about 20 mg, of compound
in a single dose, admlnlstered parenterally or by inhala-
tion in the compositions of this invention, are effec-
tive for preventing allergy attacks Preferably, the
single dose is from about 0.2 to about 20 mg. of compound.
The oral and rectal dose is from about 1 to about 60 mg.
in a single dose. Preferably, the single dose is from
about 3 to about ~0 mg, of compound. The dosage to be
admlnistered can be repeated up to four times daily. How-
ever, when it is necessary to repeat treatment, a pre-
ferred dosage schedule reduces the secondary treatment
. . ~ '. .
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Q~) :
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
S is taken until that dosage no longer provides effective pro~
tection. At that time, the larger dosage is repeated,
followed by the reduced dosage. An example of such a dosage
schedule is the following: An asthmatic individual insuf-
flates 0.5 mg. of the tris(hydroxymethyl)aminomethane salt
of pyridine-2,6-diyl-dioxamic acid. Four hours later the
.. . .
individual insufflates 0.005 mg. of the same compound and
every four to six hours continues this reduced dosage until
effective allergy prophylaxis is not provided. At that point
0,5 mg. of the compound is then taken followed by the re- :
duced dosage every four ~ six hours The dosage schedule
conti~ues in this manner,
The administration of the compositions of the present ~,
invention to humans and animals provides a method for the
prophylactic treatment of allergy or all anaphylactic re-
actions of a reagin or non-reagTn mediated nature, That is
to say, these composTtions, when administered to a sensiti~d
ihdividual prior to the time that the individual comes into
contact with substances (antigens) to which he is aller~ic, `~
will preventthe allergic reaction which would otherwiæ occur.
For example, the process can be used for prophylactic
treatment of such chronic cond;tions as bronchial asthma,
allergic rhinitis, food allergy, hay fever, urticaria, a~o-
immune diseases, exercise induced asthmag stress induced
asthma, systemic anaphylaxis, and bird fanc7er's disease.
~0 It should be noted that in the examples below
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wherein the salt form is used, the weight of compounds
refers only to the compound in its acid form.
Example 4
A lot of 10,000 tablets, each containing 1 mg of
pyridine-2,6~diyldioxamic acid, is prepared from the
following types and amounts of ingredients:
Pyridine-2,6-diyldioxamic acid10 Gm.
Dicalcium phosphate 1,000 Gm.
Methylcellulose, U.S.P. (15 cps)60 Gm.
Talc 150 Gm.
Corn starch 200 Gm.
Magnesium stearate 5 Gm.
The compound and dicalcium phosphate are mixed well,
granulated with 7.5 percent solution of methylcellulose
in water, passed through a No, 8 screen and dried care- `
fully. 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 four to s1x hours,
ExamPle 5
One thousand two-piece hard gelatin capsules, each
containing 20 mg. of pyridine-2,5-diyldioxamic acid, are
prepared from the following types and amounts of ingredi-
ents:
Pyridine-2,5-diyldioxamic acid20 Gm.
Lactose 400 Gm.
Talc 15 Gm.
Magensium stearate 1 Gm.
The ingredients are mixed well and filled into ;;
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0
capsules of the proper size.
Capsules so prepared are useful in preventing
attacks of bronchial asthma at a dose of one capsule
every four to six hours.
Example 6
One thousand tablets, each containing 4 mg. of
2,6-dimethoxypyridine-3,5-diyldioxamic acid, are pre-
pared from the following types and amounts of ingredi-
ents: -
2,6-Dimethoxypyridine-~,5-diyl-
. . .
dioxamic acid 4 Gm, -` `
.
Microcrystalline cellulose NF410 Gm.
Starch 100 Gm.
Magnesium stearate powder 2 Gm.
The ingredients are screened and blended together
and pressed into 516 mg. tablets.
The tablets are useful to protect against food
allergy at a dose of 1 tablet before meals.
ExamPle 7
A sterile preparation suitable for intramuscular
7njection and containing 0.1 mg. of pyridlne-2,6-diyl-
dio~amic acid in each milliliter is prepared from the
following ingredients:
Pyridine-2,6-diyldioxamic acid0.1 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 in-
jected for prophylactic treatment of allergic rhinitis,
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Example 8
Six hundred ml. of an aqueous solution containing
3 mg. of the tris(hydroxymethyl)aminomethane (THAM) sa1t
of pyridine-2,6-diyldioxam;c acid per ml. is prepared as
follows:
Tris(hydroxymethyl)aminomethane
(THAM) salt of pyridine-2J6-
diyldioxamic acid 1.8 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 four
to six h~urs for prevention of asthmatic attacks,
Example 9
A powder mixture consis~ing of 0.2 gram of tris-
(hydroxymethyl)aminomethane salt of pyridine-2J6-diyl-
dioxamic acid and sufficient lactose to make 5 grams of
mlxture is mlcropulvertzed and placed in an insufflator
designed to deliver 50 mg. of powder per dase,
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,
Example 10
Twelve grams of an aerosol composition are prepared
from the following ingredients:
3~
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: `
lOO
Tris(hydroxymethyl)aminomethane
salt of pyridine-2,6-diyl-
dioxamic acid 0.10 Gm. -
Freon 12 1.440 Gm.
Freon 114 2.160 Gm. -
Water 7.7 Gm,
Sorbitan monoleate o.600 Gm.
The THAM salt is dissolved in the water and chilled
to -30C. and added to the chilled Freons. The twelve
grams of compositions are added to a 1~ 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 four to six hours
for prevention of asthmatic attacks.
ExamPle 11 ,
In individuals who requtre continual treatment in
the Examples 4 through 10, the dosage of the Example is
given 7nitially and each succeeding administration of
the drug Ts at 1/50 of the initial dosage. This main-
tenance dos7ng is continued until effectIve allergy pro-
phylaxis is not obtained. The 1nitlal dosage of Examples
4 through 10 is then started once moreJ follo~ed by
the maintenance dosages.
Examp,le 12
` after allowing for the different solubilities of
the compounds and the actiuity of the particular com-
pound as measured, for example, by the in vivo rat pas-
sive cutaneous anaphylaxis assay, a suitable quantity of
each of the compounds of Table II through Table Vi~II and
Examples 1-3, is substituted for the active compound in ~;
:
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.
the compositions and uses of the Examples 4 through 10. -
Results sho~ing anti-allergy activity are obtained. -~
Example 13
The rat passive cutaneous anaphylaxis assay is run
in the follo~ing manner:
Female Sprague-Dawley 250 gm. rats are skin- ~
sensitized with rat anti-ovalbumin homocytotropic anti- ;
body that is heat labile and has a passive cutaneous
anaphylaxis titer of 1:128. A$ter a 72-hour latency
period, the animals are challenged i.v. with 4 mg, oval-
bumin (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
site 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 divided by the number of animals.
The tris(hydroxymethyl)aminomethane salt of
pyridine-2,6-diyldioxamic acid is prepared by dissolving
the dicarboxylic acid in an equivalent weight of aqueous
tris(hydroxymethyl)aminomethane and is tested in the rat `
.
passive cutaneous anaphylaxis assay in the above manner
The inhibitory dose50 for the tris(hydroxymethyl)-
aminomethane salt of pyridine-2,6-diyldioxamic acid is
0.01 mg./kg,
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TABLE Vll
The compounds of Tables 11 and IV are converted tQ
pharmaceutically acceptable ac;d addition salts by con-
ventional means.
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