CA1041100A - Pyridine-diyldioxamic acid and derivatives - Google Patents
Pyridine-diyldioxamic acid and derivativesInfo
- Publication number
- CA1041100A CA1041100A CA207,416A CA207416A CA1041100A CA 1041100 A CA1041100 A CA 1041100A CA 207416 A CA207416 A CA 207416A CA 1041100 A CA1041100 A CA 1041100A
- Authority
- CA
- Canada
- Prior art keywords
- group
- hydrogen
- pyridine
- carbon atoms
- accordance
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
Abstract
ABSTRACT OF THE DISCLOSURE
Novel compounds of Figure I
and
Novel compounds of Figure I
and
Description
' 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;
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- :
' ~ ' ~ ' ' . .
, . .
.: ~
~ 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 ~ ~
:
' ~ ' ~ ' ' . .
, . .
.: ~
~ 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 ~' . , ' ' ~
-' ' ' ' ,. ,, ' ' . :
..
~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 `
~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- ,.. . . .
~ .
~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- ' .
.
, 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, '~
- . `
~ 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-. ~ . .
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 ~; ~ ' ~ - : ' -- . . .. :
:' (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- ~
: , ~ ': .' .' . ~ .
~ .
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- :
: .:.
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 .. : . ~ . . ~ . . . .......... . . . . .
.. : - - . .. . . . , - ~.. - ... :.
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 .. -- . .. .;
~ -20-'.~
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 . . ~ '. .
, 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 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 ;;
-2~-,. ..
:`
- . . -29~y ,.. ...
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, , 290g 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~
.~ '~, ' -25- ~
~;, ' : `
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
.
~ 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 ~' . , ' ' ~
-' ' ' ' ,. ,, ' ' . :
..
~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 `
~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) ~
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~ ' : ' ~: .
':". :' ~ ~ .
, . . , , . -., . . ." ..
.. ~ . , . ;, ~ .. . .. . . - .
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la~ a$~ , -CO , CU
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~ ~ 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 .: ': ..
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O
C ~O " ' E
: :
_ 11~ ' ' l N N N I 011 :1~ O OO ~ ~-- ~ Z L~
. Z ZZQl~ CL~
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.
, ,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 : .
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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 , . ~ . ~ ,.
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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- ,.. . . .
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~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- ' .
.
, 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, '~
- . `
~ 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-. ~ . .
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 ~; ~ ' ~ - : ' -- . . .. :
:' (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- ~
: , ~ ': .' .' . ~ .
~ .
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- :
: .:.
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 .. : . ~ . . ~ . . . .......... . . . . .
.. : - - . .. . . . , - ~.. - ... :.
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 .. -- . .. .;
~ -20-'.~
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 . . ~ '. .
, 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 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 ;;
-2~-,. ..
:`
- . . -29~y ,.. ...
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, , 290g 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~
.~ '~, ' -25- ~
~;, ' : `
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 ~;
:
.
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, ... . . .
' .' :
TABLE Vll The compounds of Tables 11 and IV are converted tQ
pharmaceutically acceptable ac;d addition salts by con-ventional means.
' ~' ' '.
:~ ' .
, ~.
'' ... :. .
: ~ ' , - ?8- :
-.
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 ~;
:
.
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, ... . . .
' .' :
TABLE Vll The compounds of Tables 11 and IV are converted tQ
pharmaceutically acceptable ac;d addition salts by con-ventional means.
' ~' ' '.
:~ ' .
, ~.
'' ... :. .
: ~ ' , - ?8- :
-.
Claims (26)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing compounds of the formula and pharmaceutically acceptable metal, amine and acid addition salts thereof, wherein each group is located anywhere on the carbon ring with the proviso that one group cannot be ortho to the other group;
R is selected from the group consisting of hydrogen, alkyl from one through six carbon atoms, and a pharmaceutically acceptable metal or amine cation;
X and Y are the same or different and are selected from the group consisting of hydrogen, and alkoxy from one through three carbon atoms, which comprises reacting an X and Y substituted pyridyl diamine wherein X and Y are as previously defined and the NH2 groups are in the same positions as the previously defined oxamic groups with an alkyl oxalyl halide of the formula wherein alkyl is from one to three carbon atoms, and halo is fluoro, chloro, bromo or iodo, inclusive, in solvent and base or reacting the pyridyl diamine with a dialkyl oxalate of the formula wherein alkyl is from one to three carbon atoms, inclusive, in neat or with an additional solvent to form the corresponding dioxamate which is optionally transesterified to alkyl of one to six carbon atoms and optionally hydrolyzed to the dioxamic acids, and optionally converted to the metal or amine salt and each above ester or acid is optionally converted to a pharmaceutically acceptable acid addition salt.
R is selected from the group consisting of hydrogen, alkyl from one through six carbon atoms, and a pharmaceutically acceptable metal or amine cation;
X and Y are the same or different and are selected from the group consisting of hydrogen, and alkoxy from one through three carbon atoms, which comprises reacting an X and Y substituted pyridyl diamine wherein X and Y are as previously defined and the NH2 groups are in the same positions as the previously defined oxamic groups with an alkyl oxalyl halide of the formula wherein alkyl is from one to three carbon atoms, and halo is fluoro, chloro, bromo or iodo, inclusive, in solvent and base or reacting the pyridyl diamine with a dialkyl oxalate of the formula wherein alkyl is from one to three carbon atoms, inclusive, in neat or with an additional solvent to form the corresponding dioxamate which is optionally transesterified to alkyl of one to six carbon atoms and optionally hydrolyzed to the dioxamic acids, and optionally converted to the metal or amine salt and each above ester or acid is optionally converted to a pharmaceutically acceptable acid addition salt.
2. Process in accordance with claim 1 wherein in the reactants R is selected from the group consisting of hydrogen, alkyl of from one through four carbon atoms, and a pharmaceutically acceptable metal or amine cation;
X and Y are the same or different and are selected from the group consisting of hydrogen, and alkoxy from one through three carbon atoms.
X and Y are the same or different and are selected from the group consisting of hydrogen, and alkoxy from one through three carbon atoms.
3. Process in accordance with claim 2 wherein in the reactants the -NH2 groups are located at the 2 and 6 positions or the 3 and 5 positions;
R is selected from the group consisting of hydrogen and a pharmaceutically acceptable metal or amine cation.
R is selected from the group consisting of hydrogen and a pharmaceutically acceptable metal or amine cation.
4. Process in accordance with claim 3 wherein in the reactants X is hydrogen and Y is selected from the group consisting of hydrogen, and alkoxy from one through theee carbon atoms.
5. Process in accordance with claim 4 with the proviso that Y is located at the 4-position.
6. Process in accordance with claim 5 wherein the -NH2 groups are located at the 2 and 6 positions.
7. Process in accordance with claim 6 wherein halogen is selected from the group consisting of fluoro, chloro, and bromo.
8. Process in accordance with claim 1 wherein in the reactants the -NH2 groups are at the 2 and 6 positions of , R is selected from the group consisting of hydrogen, alkyl of one to three carbon atoms, inclusive, and a pharmaceutically acceptable metal or amine cation and X and Y are hydrogen.
9. Process in accordance with claim 1 wherein in the reactants the -NH2 groups are at the 2 and 5 positions of , R is selected from the group consisting of hydrogen, alkyl from one to three carbon atoms, inclusive, and a pharmaceutically acceptable metal or amine cation and X and Y are hydrogen.
10. Process in accordance with claim 1 wherein in the reactants the -NH2 groups are at the 3 and 5 positions of , R is selected from the group consisting of hydrogen, alkyl from one to three carbon atoms, inclusive, and a pharmaceutically acceptable metal or amine cation;
X is 2-methoxy, Y is 6-methoxy.
X is 2-methoxy, Y is 6-methoxy.
11. Process in accordance with claim 8 where R is selected from the group consisting of hydrogen and tris-(hydroxymethyl)methylammonium.
12. Process in accordance with claim 9 where R is selected from the group consisting of hydrogen and tris-(hydroxymethyl)methylammonium.
13. Process in accordance with claim 10 where R is selected from the group consisting of hydrogen and tris-(hydroxymethyl)methylammonium.
14. A process for preparing diethyl N,N-2,6-pyridine diyldioxamate which comprises reacting 2,6-diaminopyridine with ethyl oxalylchloride in solvent and base.
15. The process defined in claim 14 including the step of hydrolyzing the diethyl ester to produce pyridine-2,6-diyldioxamic acid.
16. A process for preparing diethyl N,N'-2,5-pyridine-diyldioxamate which comprises reacting 2,5-diaminopyridine with ethyl oxalylchloride in solvent and base.
17. The process defined in claim 16 including the step of hydrolyzing the diethyl ester to produce pyridine-2,5-diyldioxamic acid.
18. A process for preparing diethyl N,N'-(2,6-dimethoxy-3,5-pyridine diyl)dioxamate which comprises reacting 3,5-diamino-2,6-dimethoxy pyridine dihydrochloride with ethyl oxalychloride in solvent and base.
19. The process defined in claim 18 including the step of converting the diethyl ester to the corresponding diacid disodium salt.
20. A compound of the formula wherein X, Y and R are as defined in claim 1, whenever prepared or produced by the process defined in claim 1 or by the obvious chemical equivalent.
21. Diethyl N,N'-2,6-pyridine diyldioxamate, whenever prepared or produced by the process defined in claim 14 or by the obvious chemical equivalent.
22. Pyridine-2,6-diyldioxamic acid, whenever prepared or produced by the process defined in claim 15 or by the obvious chemical equivalent.
23. Diethyl N,N'-2,5-pyridine diyldioxamate, whenever prepared or produced by the process defined in claim 16 or by the obvious chemical equivalent.
24. Pyridine-2,5-diyldioxamic acid, whenever prepared or produced by the process defined in claim 17 or by the obvious chemical equivalent.
25. Diethyl N,N'-(2,6-dimethoxy-3,5-pyridine diyl) dioxamate whenever prepared or produced by the process defined in claim 18 or by the obvious chemical equivalent.
26. Disodio 2,6-dimethoxy-3,5-pyridine diyldioxamate, whenever prepared or produced by the process defined in claim 19 or by the obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US40367773A | 1973-10-04 | 1973-10-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1041100A true CA1041100A (en) | 1978-10-24 |
Family
ID=23596609
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA207,416A Expired CA1041100A (en) | 1973-10-04 | 1974-08-20 | Pyridine-diyldioxamic acid and derivatives |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS603060B2 (en) |
| BE (1) | BE820723A (en) |
| CA (1) | CA1041100A (en) |
| CH (1) | CH605767A5 (en) |
| DE (1) | DE2445002C2 (en) |
| FR (1) | FR2247237B1 (en) |
| GB (1) | GB1436304A (en) |
| NL (1) | NL179110C (en) |
| ZA (1) | ZA745754B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3132885A1 (en) * | 1981-08-20 | 1983-03-03 | Wella Ag | AGENT AND METHOD FOR COLORING HAIR |
| DE3229539A1 (en) * | 1982-08-07 | 1984-02-09 | Basf Ag, 6700 Ludwigshafen | NEW OXAMID ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THERAPEUTIC AGENTS CONTAINING THEM |
| US5082467A (en) * | 1990-02-08 | 1992-01-21 | Kao Corporation | Dye composition for keratinous fibers |
| WO1996019454A1 (en) * | 1994-12-20 | 1996-06-27 | Terumo Kabushiki Kaisha | Pyridylalkyl phenyl sulfone derivatives and medicinal preparation containing the same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH531000A (en) * | 1970-03-11 | 1972-11-30 | Sandoz Ag | Process for the preparation of new benzocycloheptathiophenes |
| BE789822A (en) * | 1971-10-08 | 1973-04-06 | Allen & Hanburys Ltd | NEW HETEROCYCLIC COMPOUNDS |
-
1974
- 1974-08-20 CA CA207,416A patent/CA1041100A/en not_active Expired
- 1974-08-28 GB GB3753374A patent/GB1436304A/en not_active Expired
- 1974-09-10 ZA ZA00745754A patent/ZA745754B/en unknown
- 1974-09-20 DE DE2445002A patent/DE2445002C2/en not_active Expired
- 1974-09-23 CH CH1282474A patent/CH605767A5/xx not_active IP Right Cessation
- 1974-10-03 FR FR7433394A patent/FR2247237B1/fr not_active Expired
- 1974-10-03 NL NLAANVRAGE7413053,A patent/NL179110C/en not_active IP Right Cessation
- 1974-10-04 BE BE149229A patent/BE820723A/en not_active IP Right Cessation
- 1974-10-04 JP JP49114632A patent/JPS603060B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CH605767A5 (en) | 1978-10-13 |
| DE2445002C2 (en) | 1984-11-22 |
| NL179110C (en) | 1986-07-16 |
| NL179110B (en) | 1986-02-17 |
| FR2247237B1 (en) | 1978-07-21 |
| NL7413053A (en) | 1975-04-08 |
| GB1436304A (en) | 1976-05-19 |
| JPS603060B2 (en) | 1985-01-25 |
| JPS5062979A (en) | 1975-05-29 |
| FR2247237A1 (en) | 1975-05-09 |
| DE2445002A1 (en) | 1975-04-10 |
| ZA745754B (en) | 1975-10-29 |
| BE820723A (en) | 1975-04-04 |
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