Note: Descriptions are shown in the official language in which they were submitted.
~L~658~3
This invention relates to an improved process for preparing
lower alkyl esters of fused pyrimidin-4(3H)-one-2-carboxylic acids and, in
particular, alkyl pyrimido~4,5-b]quinoline-4t3H)-one 2-carboxylates.
The preparation of a variety of fused pyrimidines, including
alkyl esters of pyrimido~4,5-b~quinoline-4(3H?-one-2-carboxylic acids, by
the cyclization of a 2-aminoquinoline-3-carboxamide with a dialkyl oxalate
is described in Belgian Patent 813,571, granted October 11, 1974. The pro-
cedures descrihed comprise conducting the condensation at temperatures of
from 150C. to 185C. with remov~ of by-product water and alcoholO A large
excess of the dialkyl oxalate is normally used as solvent and a base, such
as a sodium alkoxide or sodium hydride, is sometimes used as catalyst. The
reaction requires ~rom several hours to up to two days for completion depend-
ing upon the reactants. The yields of cyclized products are, in most
instances, rather poor. However, in the one instance wherein a satisfac-
tory yield was reportea; namely, the preparation of ethyl 7-fluoropyrim;do-
~4~5-b]quinoline-4(3H)-one-2-car~xylate, a molar ratio of diethyl oxalate
to 6-fluoro-2-aminoquinoline-3-carboxamide of 15 to 1 and a reaction period
of eighteen hours at 160C. was used.
--1-- '
.~ . ).1 ~ ,~;
, . ~ ,, .
S1363
The condensation of diethyloxalate and anthranilamide (2-1 molar
ratio) in the absence of a base at 170-180C. for six hours with product-
ion of a 5% yield o$ ethyl 4-quinazolone-2-carboxylate and formation of a
bis-substituted oxamide as by-product is reported by Baker et al., J. Org.
Chem. 27, 4672-4674 (1962).
The preparation of ethyl 4-quinazolone-2-carboxylate by the pro-
cess of this invention and using the same proportions of anthranilamide
(.OS mole), diethyloxalate (0.1 mole) and sodium ethoxide (0.15 mole) as
employed by ~aker et al. (loc. cit.) in e~hanol (100 ml.) as solvent at
70-75C. for one hour gave a 78% yield of product in contrast to the 57%
yield reported by Baker et al.
It has now been found, quite unexpectedly and surprisingly in
view of the harshness of the prior art conditions that alkyl pyrimido[4,5-
b]quin~lin-4(3H~-one-2-carboxylates can be prepared in highly satisfactory
and economic yield by reacting an appropriate 2-aminoquinolin-3-carboxamide
with an appropriate dialkyl oxalate under relatively mild conditions of
temperature and time. It is readily adaptable to large scale reaction, re-
quires no special apparatus, avoids formation of bis-substituted oxamides
as by-products and does not require removal of by-product alcohol and water.
According to the present invention there is provided a process
which comprises reacting a 2-aminoquinoline-3-carboxamide compound having
the formula
3 ~ ~H2~l2
R~ R5
wherein
R~ is selected from the group consisting of hydrogen, alkyl having
from one to four carbon atoms and phenyl;
--2--
.
. ~ . : -. . .
10~i58G3
two o$ R2, R3, Rl~ an~ R5 are selected from the g~oup consisting
of hydrogen, alkyl having from one to four carbon atoms, alkoxy having from
one to four carbon atoms, halo, benzyloxy, methylthio and benzylthio, and
the balance are selected from the group consisting of hydrogen, alkyl having
~rom one to four carbon a~oms, alkoxy having from one to four carbon atoms
and halo,
R~ and R3, R3 and R4 ~hen taken together are alkylenedioxy and
are selected from the group consisting of methylenedioxy and ethylenedioxy,
with from one to three molar equivalents of a dialkyl oxalate wherein çach
of the alkyl groups has from one to four carbon atoms at a temperature of
from about 20C. to about 100C. in a reaction-inert solvent and in the
presence of two to ~hree molar equivalents of base per mole of 2-amino-
quinoline-3-carboxamide, and said base being selected fro~ the group con-
sisting of sodium alkoxide having from one to four carbon atoms, triphenyl-
methylsodium, sodium hydride, sodium amide, sodium 3-aminopropylamide and
the corresponding potassium compounds.
The cyclization reaction is summarized by the equation:
2 ROOC BDse ~ ~
H2 ROO~ 2~o_l00C. / ~ COOR
The cyclization products obtained from the above reactants are
valuable antiallergy agents as is described in Belgian Patent 813,571.
The cyclization is conducted by reacting the appropriate 2-amino-
quinoline-3-carboxamides and appropriate dialkyl oxalate in a molar ratio of
from about 1:1 to a~out 1:3 in a reaction-inert solvent medium at a tempera-
ture below about 100C., and in the presence of a suitable base. Suitable
solvents are alcohols correspond~ng to the alkyl groups of the dialkyl
oxalate reactant, an& combinations of such alcohols and xylene, toluene,
benzene, dioxane, tetrahydrofuran and other alcohol miscible solvents and
. --3--
f~ -
.. ~ . . _ ... . ..
5~363
dimethylsulfoxide The usa of a solvent does not appear to be necessary for
the reaction to occur but is h;ghly advantageous from the standpoin~ of rate
and yield of reaction.
The nature of the dialkyl oxalate is not critical to the success
of the process of this invention. However, the favored dialkyl oxalates
are those wherein the alkyl groups are identical and have from one to four
carbon atoms. They are favored as reactants because oE their availability,
the valuable antiallergy activity~'of the cyclized products which they pro-
duce, their overall ease of reaction in this process and the fact that they
permlt use of readily availablè alcohols as solvents and sodium tor potas-
sium) alXoxide cyclizing agents in which the alkyl portions of the alcohol
and alkoxide correspond to that of the dialkyl oxalate and afford satisfac-
tory yields of cyclized product. The use of dialkyl oxalates in which the
alkyl groups are different produces a mixture of esters. For this reason,
it is preferred to use dialkyl oxalates in which the alkyl groups are the
same in order ~o obtain a single product rather than a mixture of esters.
The preferred solvents are alcohols. In order to avoid ester
exchange it is, of course, necessary to use as solvent an alcohol corres-
ponding to the ester group of the dialkyl oxalate reactant. However, as
those skilled in the art will recognize, ester exchange can be avoided or
minimized by using as solvent a branched alcohol such as t-butyl alcohol-~
h h~s~ *~1è:ten~ncy:*~enter into`~ster exchange.
The molar ratio of dialkyl oxalate to 2-aminoquinoline-3-carbox-
amide reactant is not critical but should be at least 1:1. For reasons of
yield of cyclized product and of economy, in general, a ratio of about
three molar equivalents of dialkyl oxalate to one of the 2-aminoquinoline-
3-carboxamide reac~ant is preferred. Highe~ ratios appear ~o be of no
advantage.
A variety of bases can be used for this cyclization reaction.
Suitable bases are sodium and potassium alkoxides, particularly those wherein
--4--
- -= : , :
8~;3
the alkoxide moiety corresponds to the alcohol moiety of the dialkyl oxal-
ate, sodium and potassium hydridas, amides and 3-aminopropylamides, tri-
phenylmethyl sodium and triphenylmethylpotassium.
The base is desirably used in the ratio of two to three molar
equivalents per mole of the 2-aminoquinoline-3-carboxamide reactant. It
is preferred to use a three to one molar ratio for optimum yield. Higher
ratios appear to be of no advantage. Lower ratios tend to reduce the yield
of cyclized product. The preferred base is the sod;um alkoxide wherein the
alkoxide moiety corresponds to the alkyl moiety of the dialkyl oxala~e.
The reaction is conducted at a temperature below about 100C.
The favored temperature range is from about 20C. to about 100C. It ;s
advantageous for reasons of economy, to conduct the reaction at the lowest
temperature which is consistent with good reaction rate and yield and
which requires a minimum of cooling or heating. This, of course, is readily
determined by experimentation. The preferred temperature is thus found to
be within the range of about 25C. to about 50Co The lower range is highly
satisfactory when using dimethyl and diethyl oxalates as reactants. The
upper range is sometimes advantageous when using a dibutyl oxalate as re-
actant.
The products of this invention and the pharmaceutically-acceptable
cationic salts thereof, are useful for t~e control (prophylactic and thera-
peutic treatment)~of allergic symptoms and reactions in mammals, and can be
administered either as ndividual therapeutic agents or as mixtures of thera-
peutic agents, ~or example, with theophylline or sympathomimetic"~amines.
They can be administered alone, but are generally administered with a pharma-
ceutical carrier selected on the basis of the chosen route of administration
and standard pharmaceutical practice. For example, they can be combined with
various pharmaceutically-acceptable inert carriers in the form of tablets,
capsules, lozenges, troches, hard candies, powders, aerosol sprays, aqueous
suspensions or solutions, injectable solutions, elix;rs, syrups and the like.
.,,
.
5863
Sudh carriers include solid diluen-ts or ~illers, sterile aqueous media and
various non-toxic organic solvents. Moreover, the oral ~harmaceutical com-
positions of th;s invention can be suitably sweetened and flavored by means
of various agents of the type commonly used for this purpose.
The particular carrier selected and the proportion of active
ingredient-to carrier are influenced by the solubility and chemical nature
of the therapeutic compounds, the chosen route of administration and the
needs of standard pharmaceutical practice. For example, when the compounds
of this invention are administered orally in tablet form, excipients such
as lactose, sodium citrate, calcium carbonate and dicalcium phosphate can
be used. Various disintegrants such as starch, alginic acids and certain
complex silicates, toge~har with lubricating agents such as magnesium
stearate, sodium lauryl sulphate and talc, can also be used in producing
tablets for the oral administration of these compounds. For oral adminis-
tration in capsule form, lactose and high molecular weight polyethylene
glycols are among the preferred materials for use as pharmaceutically-
acceptable car~iers. Where aqueous suspensions are to be used for oral
administration, the compounds of this invention can be combined with emu}si-
fying or suspending agents.~ Dilubnts such as ethanol~ propylene glycol,
glycerine and chloroform ~nd their combinations can be employed as well as
other materials.
For the purpose of parenteral administration and inhalation7 solu-
tions or suspensions of these compounds in sesame or peanut oil or in aque-
ous propylene glycol solutions can be employed, as well as sterile aqueous
solutions of the soluble pharmaceutically-acceptable salts described herein.
These particular solutions are espscially suited for intramuscular and sub-
cutaneous injection ~urposes should such method of administration be desired.
The aqueous solutions, including those of the salts dissolved in pure dis-
tilled water, are also useful ~or in~ravenous injection purposes provided
that their pH is properly adjusted beforehand. Such solutions should also be
--6--
~:36~i8~3
suitably buffered, if necessary, and ~he liquid diluent first rendered iso-
tonic with sufficient saline or glucose.
The compounds can be administered to asthmatic subjects suffering
from bronchoconstriction by means of inhalators or other devices which
permit the active compounds to come into direct contact with the constricted
areas of the tissues of the subject.
Wh~n administered by inhalation, the compositions can comprise
(1) a solution ~rrsuspension of the active ingred;ent in a liquid medium o
the type mentioned above for administration via a nebulizer; (2) a suspen-
sion or solution of the active ;ngredient in a liquid propellant such as
dichlorodifluoromethane or chlorotrifluoroethane for administration from a
pressurize~ container;~or (3) a mix~ure of the active ingredient and a solid
dilubnt ~e.g., lactose) for administration from a powder inhalation device.
Compositions suitable for inhalation by means of a conventional nebulizer
will comprise about 0.1 to about 1% of active ingredient, and those for use
in pressurized containers will comprise from about 0.5 to about 2~ of active
ingredient. Compositions for use as powder inhalants can comprise ratios of
active ingredient to diluent of from about 1:0.5 to about 1:1.5.
It is necessary that the active ingredient form a proportion of
the composition such that a suitable dosage form will be obtained. Obvious-
ly, several dosage unit forms can be administered at about the same time.
Although compositions with less than 0.005% by weight of active ingredient
might be used in certain in~tances, it ig preferred to use compositions con-
taining not less than 0.005~ of the active ingredient, otherwise, the amount
of carrier becomes excessively iarge. Activity increases with the concentra-
tion of the active ingredient. The composition may contain 10, 50, 75, 95
or an even higher percentage by weight of the active ingredient.
As regards the dosage regimen of these compounds, the physician
will ultimately determine the dosage which will be most suitable for a parti-
cular individual, and it will vary with age, weight, and response of the
--7--
}r~ `
~c;58~3
particular patient as wall as with the nature and extent of the symptoms,
the pharmacodynamic charac~eristics of the particular agent to be adminis- -
tered, and the route of administration chosen. Generally, small doses will
be administered initially, with a gradual increase in the dosage until the
optimum level is determined. It will often be found that when the composi-
tion is administered orally, larger quantities of the active ingredient will
be required to produce the same level as produced by a small quanti~y
administered~parentërally.
Having full regard for the foregoing factors, it is considered
that an effective daily oral dosage of the compounds of the present inven-
tion in humans of from about 10 to about 1500 mg. per day, with a preferred
range of about 10 to about 600 mg. per day in single or divided doses, or
at about 0.2 to about 12 mg./kg. of body weight will effectively control
bronchoconstriction in human subjects. These values are illustra~ive and
there may, of course, be individual cases where higher or lower dose ranges
are merited.
When administ~red intravenously or by inhalation, the effective
daily dose is from about 0.5 to about 400 mg. per day, and preferably from
about 0.25 to 200 mg. per day, or at about 0.005 to 4 mg./kg. of ~ody
weight in single or divided doses.
EXAMPLE I
Ethyl 7,8-Dimethoxyp~rimido~4,5=b]quinolin-4(3H)-One-2-Carboxylate
To a solution of diethyl oxalate (8.8 g., 0.06 mol) and sodium
ethoxide (4.0 g., 0.06 mol) in ethanol (160 ml ) at room temperature is added
with stirring 2-amino-6,7-dimethoxyquinoline-3-carboxamide (5.0 g., 0.02 mol).
A yellow suspension forms. Within approximately one hour the reaction mixture
becomes turbid. After two hours of stirring, diatomaceous earth (3.0 g.)
and charcoal (1.3 g.) is added and the mixture stirred an additional fifteen
minutes. It is then filtered through diatomaceous earth and the filter cake
washed with ethanol (S0 ml.). Th~ filtrate is heated to reflux and glacial
--8--
;3
acetic acid (2.4 ml~, 0.04 mol) added. A yellow solid precipitates. After
a half-hour oE refluxing, the reaction mixture is cooled to room tempera-
ture and then stirred for an additional hour. The product is filtered and
dried at 70C. in vacuo. Yield = 6.8 g., 98.8%.
Analysis: Calcd. for C16H15N305, C, 58.35, H,4.59, N, 12.76%
Found: Cg 57~81; H~4.589 N, 12.46%
Repetition of this procedure bu~ usîng ten times the above
quantities afforded a 91.7~ yield of product.
:;
,, ,,:
, . ~- - - : ~ - . .: ,
C~6~863
.
.i Xh~PLE II
The following compounds are prepared accordi.ng to the procedure
of Example I but substituting for the reactants used therein equimolar
quantities of the appropriate 2-aminoquinoline-3-carboxamide, the appropriate
5 i,dialkyl oxalate and the sodium alcoholates and alcohols in which the alkyl
`groups correspond to those of the dialkyl oxalate used.
4 ~ COOR
j¦ 5
ji R Rl ~ R~ R4 R5 TC
ll C2H5 H H H H ~ 11 22-
¦! 2 5 F H H 22
ll C2H5 li H H F H 22
5 j! C2H5 H H Cl H H 22
I! C2H5 H H -O-CH2-0- H 22
il CH3 H H OCH3 OCH3 H 22
ll n-C4Hg H H OCH3 OCH3 H 45-50
il C2H5 H H OCH3 H OCH3 30
lO !i CH3 H OCH3 H H OCH3 20
~¦ n C3H7 H H H OCH3 H 20
,~ 3 H H OCH3 OCH3 OCH3 25
!I CH3 H H C2H5 O-n-C4Hg H 22 :
i C2H5 H H OC2H5 OC7H7 H 22
15 j i C3H7 H OC2H5 OCH3 H 25
C2H5 H H -O-CH2-CH2-0- H 30
n C4~19 H H H H H 70-75
n C4Hg H Cl H H 11 70-75
~1 n C4 9 H OCH3 H H 2,
20 1- 4 9 H H OCH3 OCH3 40-45
C2H5 H H Br H Br 25
i; C2H5 H Cl H H Cl 25
C2H5 H OCH -O-CH -O- H 25
jj 2 5 HSC7H7 SC7H7 H 30
'-¦ C2~15 11 H OCH3 OC7~17 Br 35
¦! C2H5 H 717 OC7H7 H 25
ll -10- ~
- . :: . .. . : - .:
58~3
R Rl R~ R R~ R r~ '1' C .
CH3 H H C113 H H 30
C H H CH3 H CH3 11 25
2 5 H 11 4 9 H H ~5
j CH3 11 H 3 7 20
CH3 H OCH3 OC7H7 H 11 20
C113 H OCH3 3 OC113 H 20
,j C113 H H C~13 CH3 11 25
'~ C2115 11 11 11 t-C4119 11 30
10 1I CH3 H H Cl 13r Cl 22
li 3 7 OCH3 -O-CH2-O- OC113 35
C H5 H 11 o i c3H7 3 22
~, CH3 H U O-n-C4H9 0-n-C4~19 il 90-100
ii C2H5 H H SCH3 H H 25
15 il~ C2H5 H H SCH3 SCH3 H 25
i C3 7 H H H SCH3 25
i! C2H5 H 1I SC7117 H H 30
'¦ 3 7 7 2 5 11 25
C2H5 H H OCH3 OC71-17 H 30
20 !, C2H5 H H OC7H7 OCH3 H 20
i; C2H5 H 7 7 3 OCH3 ~ H 25
¦~ CH3 H H C1 OC7H7 H 25
~¦ C2 s 6 5 H H H 22
~j C2H5 C6H5 H CH3 H H 22 -
25 !i CH3 C6H5 H SCH3 H H 22
CH3 C H H OCH3 OCH3 H 35
CH3 CH3 H C1 Br C1 35
n-C4Hg CH3 H F H H 40
,I n-C3H7 CH3 H 2 2 H 25
'j n-C3H7 C6H5 H -O-CH2-O- H 25
il C2H5 C6H5 H SCH3 H H 25
~I CH3 n C4Hg H H H i C3 7
1~ i-C3H7 C2H5 Br H H H 22
ll CH3 n C3H7 C1 H H 22
35'1 CH3 n~C4H9 H H H H 22
~; C2H5 C6H5 H OC7H7 O~CH3 H 25
¦ CH3 C2H5H HC7 7 3 H H 25
CH3 4 9 SCH3 H H 25
~I CH3 H sc7H7 H 11 SC7H7 30
!' CH3 H OC7H7 Br H Br 35
40j~ C2H5 iH H SC7H7 C2U5 U 30
CH3 H 3 3 CH3 OCH3 35
.Ij i
~ 5~363
,
~ EX~MPI.~
ij ,
.~ The procedure of Example I is repeated but-using equimolar quantities~. of the following bases in place of sodium ethoxide:
1: potassium ethoxide
5 jl triphenylmethyl sod:;~m
Ij sodium amide
, potassium 3-aminopropylamide
sodium hydride
Il I
~¦ In each instance yields approximating those of Example I
¦lare obtained.
,!
1,
~
i~ t
'3 - 12 -
1. i
. . .
, . .
.
.~, i .
,.1 i
- ~ ' ' : , ..
5863
EXAMPLE IV
!
; Ethyl 7,8-Dimethoxypyrimido[4,5-b]~uinolin-4`(3H)-One-2-Carboxylate
Diethyloxalate (DEO) and 6,7-dimethoxy-2-aminoquinoline-3-carboxamide
(0.02 mole) are reacted in ethanol in the presence of an ~ppropriate ba~e
5 ,'using the conditions of time, temperature and molar ratios o~ reactants ~et
¦orth below. In each instance, substantial cycli~ation occurs to produce
the title product, which is recovered by the procedure of Example I.
~I Moles Moles ~1. Time
i! DEO Base _ Base Solvent TC. (hr~q.)
!l 0.06 KOC2ll5 0.06 160 20 2
LO~¦ 0.06 NaOC2HS 0 04 160 25 2
o.O4 NaOC2H5 0.06 150 25 2
0.06 NaNH2 0.06 200 35 3
~¦ 0.06 (C6H5)3CNa0.06 200 30 2
¦~ 0.06 (C6 5)3 0.06 200 30 2
15l 0.02 NaOC2H5 0.04 150 22 2
! 0.06 ~aNH(cH2)3NH2 0-06 250 50 2
. i
!
Il - 13 -
Il i
,~
