Note: Descriptions are shown in the official language in which they were submitted.
10~3~7~
This invention relates to fused pyridine-4-(3H)-
ones and preparation thereof.
This application is related to our copending appli-
cation, Serial No. 197461 (5468(A)), filed April 11, 1974.
This invention relates to fused heterocyclic ring
systems in which a quinoline, a naphthalene or a pyridine ring
system is fused to a 2-methyl, 2-ethyl~ or 2-acetyl pyrimi~ine-4
(3H)-one or to a pyrimidine-2-carboxylic acid 4(3H)-one or a
derivative thereof, and their use as anti-allergy agents.
More particularly, it relates to 2-alkyl-pyrimido[4,5-b]-
quinolin-4(3H)-ones, 2-alkylpyrido[4,5-b]-pyrimidon-4(3H)-ones
wherein alkyl is methyl or ethyl, and the corresponding 2-acetyl
derivatives, pyrimido[4,5-b]-quinolin-4(3H)-ones-2-carboxylic
acids, benzo[g]quinazolin-4(3H)-one-2-carboxylic acids, and
pyrido-[2,3-d]pyrimidin-4(3H)-one-2-carboxylic acids; esters,
amides, and pharmaceutically-acceptable salts thereof which are
useful as inhibitors of allergic reactions, and especially of
allergic bronchial asthma.
Similar compounds of this type are more fully
described in the above application which sets out the nature of
the art.
It has now been found in addition to ~he type of com-
pound illustrated and claimed in the above identified appli-
cation the following fused pyrimidines having the formulae:
-2- ~
~ OS3674
N-~
~ N ~ N ~ COR
and the pharmaceutically-acceptable cationic salts thereof
al~o exert potent allergy effect~ in mammals, including
man, by an Intal-like mechanism ("Intal" is a Trademark). In
contrast to Intal, many of these compounds are effective
via intraperitioneal and oral administration, as well as
by lnhalation and intravenous administration.
In the abovo Fromulaes
1~ R is selectod from the group consisting of
hydroxy, al~oxy of 1-4 carbon atoms, hydroxyalkoxy, amino,
hydroxyamino;
-3-
1053674
each of R3 and R4, is selected from the group
consisting of ~a~ hydrogen, alkyl of 1-4 carbon atoms,
alkoxy of 1-4 carbon atoms, halo benzyloxy methylthio,
methylsulfinyl and (b) hydroxy, thiol, alkanoyloxy of 1-4
carbon atoms, benzpyloxy, benzylthio and benzylsulfinyl;
providing that at least one of R3 and R4 is selected from
group ~b).
The terms "alkyl," "alkanoyloxy" and'alkoxy" as
used herein include alkyl, alkanoyloxy and alkoxy groups
of from 1 up to, and including, 4 carbon atoms; the term
"hydroxyalkoxy" includes hydroxyalkoxy groups having
from 2 up to, and including, 4 carbon; and
the term "carbalkoxy" including, 4 carbon atoms; and the
term "carbalkoxy" includes carbalkoxy groups having from 2
up to, and including, 5 carbon atoms. The term "halo"
includes chloro, bromo, fluoro, and iodo.
By the term "pharmaceutically-acceptable cationic
salts" is intended salts such as the alkali metal salts,
e.g., sodium and potassium; alkaline earth metal salts such
as calcium and magne~ium; aluminum salts; ammonium sal~s;
and salts with organic bases, e.g., amines such as triethyl-
amine, tri-n-butylamine, piperidine, triethanolamine, di-
ethylaminoethylamine, N,N'-dibenzylethylenediamine and
pyrrolidine.
The following compounds are of particular interest
to this invention:
Formula I: R is alkoxy or hydroxy; and R3 and R4
are hydrogen, hydroxy, or alkoxy; provided that when one of
R3 or R4 is hydroxy, the other is alkoxy.
Special interest exists in the following compounds
o~ Formula I:
-4-
-~;
1053674
R R3 4_
OH OH OCH3
alkoxy OC~3 OH
Compounds of Formula I, wherein R is alkoxy are
also valuable intermediates for production of compounds
wherein the 2-substituent is carboxy or carbamyl.
Compound~ wherein either of R3 and R4 is benzyloxy,
benzylthio or methylthio, serve as intermediates for compounds
whereln the R group is hydroxy, alkanoyloxy thiol, methyl-
sulfinyl, or benzylsulfinyl.
The antiallergy property of the compounds of thisinvention i8 evaluated by the passive cutaneous anaphylaxis
~CA~ test ~Ovary, J. Immun. 81, 355, 1958). In the PCA test,
normal animals are injected intradermally (i.d.) with anti-
bodies contained in ~erum obtained from actively sensitizedanimal~. The animals are then challenged intravenously with
antigen mixed with a dye such as Evans' Blue. The increased
capillary permeability caused by the an$igen-antibody reaction
cause~ the dye to leak from the site of the antibody injection.
Tho test animals aro then asphyxiated and the intensity of the
reaction determined by measuring the diameter and intensity
of the blue coloration on the inner surface of the animals
skin.
10536~4
Compounds of Formula I and the pharmaceutically
acceptable cationic salts thereof wherein;
each of R3 and R4 are as hereinbefore defined
may be obtained by reacting a compound of the Formula:
R3 _ =~ COR I
~'
1053674
with a reagent A-Z
A) wherein when R' i6 NH2 and R iB COR then
A-Z i~
(a) a dialkyl oxoalate;
(b~ a monoacid halide (chloride, bromide) of a
half-alkyl oxalic acid ester;
~c~ an alkyl cyanoformate;
~d) a dialkyl ester of monoiminooxalic acid
~a carbalkoxy formimidate);
~e~ an alkyl ester of oxamidic acid;
~f) l-cyanoformamide;
~g) cyanogen; and
~h~ l-carbalkoxyformamidine; or
B) wherein when Rl is an ester moiety then A-Z
is a l-carbalkoxyformamidine;
and when R in Formulae I or III is alkyl and at
Rl, R2, R3, R4 and R5 is other than hydrogen,
then A-Z i5 an alkanoic acid anhydride or triethyl ortho-
acet~te or triethyl orthopropionate;
and whon R i~ acetyl by oxidation of the compound
:l~S3~74
wherein R i8 ethyl;
and when A-Z contains a cyano group hydrolyzing
the thus produced cyano derivative;
and when R is alkoxy, reacting the ester with
hydroxylamine to convert R to hydroxyamino;
and when Y is other than hydrogen by reaction of
the compound where Y is hydrogen with an appropriate
reactant;
and when any of R2-R5 is benzyloxy or benzylthio
debenzylating the benzyl ether or benzylthio ether, if
desired;
and when any of R2-R5 is benzylthio, oxidizing it
to benzylsulfinyl, if desired.
The compounds of this invention can be prepared by
a variety of methods.
It will be appreciated that since the compounds of
this invention are similar to those of the earlier application
tochnlcal data appearing in that application is applicable
to the practicability in chemical terms for the preparation
of the fused compounds though otherwise the specific compounds
of the present invention and the properties thereof are not
nece~sarily practicable from data in that application.
Compounds of Formula I can be prepared by methods
in which u~e iB made of the intact carbocyclic ring and the
quinoline and pyrimidine systems built up in many ways.
These methods have, as a common gr~und, the construction
of the -2-aminoquinoline-3-carboxamide, or 3-
J
lOS367~carboxy acid or ester thereof, from the intact carbocyclic
ring and subsequent use of the quinoline system as a basis
for building up the pyrimidine ring. The general scope of
these methods is summarized in the se~uence below wherein
R' represents hydroxy, alkoxy and amino:
CN~ROUTE A)
R4 ~ C O CH3> R3 ~ \ ~ ~COR'
R3 ~ N-H 3 ~ ~ sOR'
R4 ~ ~ ~ COR~ R4 ~ ~ NH2
~ROUTE B~ ~
R3 ~ + 1~ V
R'
The preferred process on the basis of yield and
quality of the final product of Formula I is illustrated by
Route A. Alternate methods, e.g., Route B, can also be
used a~ i6 discu~sed below.
In each of Routes A and B, the condensation involves
the carbocyclic aldehyde or ketone with an active methylene
nucleoph$1e, The requisite carbocyclic aldehydes or ketone
1053~74
reactants are known materials or are prepared by methods
described in the art. By "active methylene" nucleophile
i~ meant a compound having a.relatively acidic methylene
group; that is, a methylene group linked to one, and
preferably two, electron-withdrawing groups such as -CN,
-COCl, -C(NH)NH2, COR' -C(NH~C-alkyl and CO-alkyl.
The condensation is conducted in the presence
of a reaction-inert solvent; that is, a solvent which is
not changed as a result of the reaction even though it
m~y partcipate in the reaction in the role of a cataly~t
or in salt formation with a reactant or product.
Suitable solvents are alkanols, such as methanol,
ethanol, isopropanol, n-butanol and n-hexanol; chlorinated
solvents such as methylene chloride, ethylene chloride,
chloroform and carbon tetrachloride; pyridine; aromatic
hydrocarbons such as benzene, toluene, xylene; hexane; and
N,N'-dimethylformamide. Other solvents are found by simple
experimentation. Methanol is a preferred solvent, especial-
ly when using piperidine as catalyst, because, of the
satisfactory yields, ease of separation and purity of
products. A solvent system of piperidine and pyridine is
frequently a useful system.
A catalyst is often used to facilitate the con-
densation even when the nucleophiles possess two activating
groups as do derivatives of cyanoacetic acid. Suitable
catalysts are ammonia, primary, secondary, and tertiary
amines, such as n-butylamine, diethylamine, triethylamine,
pyridine, piperidine, pyrrolidine, alkali metal alkoxides
and fluorides, stannous fluoride, and basic ion-exchange
resins of the amine type, e.g., Amberlite IR-45 (a weakly
--10--
1~53~i7~
basic polystyrene with polyamine groups, available from Rohm
& Haas Co. ~Amberlite" is a trademark)and De-Acidite G ~poly-
styrene resin with diethylamino groups; available from the
Permutit Co., Ltd., London "De-Acidite" is a trademark).
The amount of catalyst used is not critical but can
vary over a wide range, i.e., from about 0.1~ to about 100% b~
weight based upon the carbocyclic aldehyde reactant. The
favored range of catalyst i8 from about 10~ to about 30% by
weight of the carbocyclic aldehyde reactant.
The reaction is conducted at a temperature of from
about 0C. to about 50C. and generally at about ambient tem-
perature for periods of from about one-fourth to five hours.
The products generally separate from the reaction mixture as
solids and are recovered by filtration. Those which do not
separate as solids are recovered by evaporation of the solvent
or by pouring into a large volume of a non-solvent for
the product.
The use of an o-nitrobenzaldehyde or an Rl-(2-nitro-
phenyl) ketone as the reactant (Route A) produces an ~-cyano-
~-(2-nitrophenyl)-acrylamide derivative, e.g., an amide when R'
of the active methylene reactant is NH2, which must subsequently
be reduced and cyclized to provide the desired 2-aminoquinoline-
3-carboxylic acid derivative. Reduction tof the nitro group to
an amino group) i~ accomplished by a variety of reagents. In
brief, any reagent which will selectively or preferentially
reduce the nitro group to an amino group can be used. Rep-
resentative of such reagents are metal-acid combinations such
as iron-acetic acid, iron-hydrochloric acid, tin or stannous
chloride-hydrochloric acid, zinc-hydrochloric acid, zinc dust-
alkali; and catalytic hydrogenation using catalysts such as
--11--
lOS;~674
platnum, palladium and Raney nickel.
The reduced product appears to cyclize immediately,
or almost immediately, to provide the 2-aminoquinoline-3-
carboxylic acid derivative.
When using an o-aminobenzaldehyde as reactant
(Route B) the condensation product with the cyanoacetic acid
derivative cyclizes at a very rapid rate to the 2-aminoquino-
line-3-carboxylic acid derivative as noted above for the reac-
tion product of Route A.
Formation of the fused pyrimidine ring with its
2-carboxylic acid derivative (ester or amide) substituent can
be accomplished by a number of methods. For convenience,
these methods are considered on the basis of the structure
of reactant W-Z which contributes the one-carbon fragment
to complete the pyrimidine ring system upon the appropriate
2-aminoquinoline-3-carboxylic acid derivative:
(1) Reaction of a 2-amino~uinoline-3-carboxamide
~Formula V, R'=NH2) with:
(a) a dialkyl oxalate;
(b) a monoacid halide (chloride, bromide) of a
half-alkyl oxalic acid ester;
(c) an alkyl cyanoformate;
(d) a dialkyl ester of moniminooxalic acid (a
carbalkoxy formimidate);
(e) an alkyl ester of oxamidic acid;
(f) l-cyanoformamide;
(g) cyanogen; and
(h) l-carbalkoxyformamidine; or
(2) Reaction of an alkyl 2-aminoquinoline-3-
carboxylate with:
-12-
1053674
(a) a l-carbalkoxyformamidine.
Reactant W-Z (an oxalic acid derivative) of the
step common to Routes A and B provides the one-carbon frag-
ment needed to complete the fused pyrimidine ring. It may,
depending upon choice of reactants, also provide the -NH group.
It represents cyanogen and W-COR whrein W is -COCl, -CN,
-COR , -CO-alkyl, -C(NH)NH2 and -C(NH)O-alkyl. When W-Z
is an alkyl ester of oxamidic acid, e.g., HsC2OOC-CONH2, the
cycl~zation reaction occurs 80 as to produce the amide
(R=COL~H2) of Formula I.
It is evident that one of the two reactants in
the final step of Routes A and B above must provide the
-NH moiety. When the reactant upon which the fused pyrimidine
ring i8 to be formed containq a carboxamide group (e.g.
formula V wherein -COR' is -CONH2), reactant W-Z can be any
of the substances enumerated above; i.e., cyanogen or ~-COR.
However, when the reactant upon which the fused pyrimidine
ring is to be formed does not contain a carboxamide group;
that i9, when -COR' is carboxy or carbalkoxy, or haloformyl,
reactant W-Z must provide the -NH group.
The favored process comprises using the appropriate
2-amino-3-carboxamide (Formula V wherein R'~,~H2) as reaatant
which is condensed with the W-Z reactant to provide only the
one-carbon fragment to complete the pyrimidine ring.
Reaction of the 2-aminoquinoline-3-carboxylic acid
derivative with reactant W-Z is carried out in a reaction-
inert sclvent and desirably, when W is -COR or C(NH)-O-alkyl,
one which will permit removal of by-product alcohol and water
by distillation. Representative solvents for this cyclization
are aromatic hydrocarbons such as xylene, toluene, benzene;
-13
1053674
an excess of the chosen dialkyloxalate reactant; tetralin
and decalin.
Suitable solvents are readily determined by ex-
perimentation. A favored solvent when W-Z i8 a dialkyl
oxalate i9 an excess of the dialkyl oxalate because of its
ability to ~olubili2e the reactants and to permit slmplo
removal of by-product alcohol and water. Although the reac-
tion temperature is not critical, the reaction i8 generally
run at an elevated temperature to facilitate removal of
alcohol and water. Temperatures of from about 150C. to
about 185C. are useful when a dialkyl oxalate i8 used as
solvent. Lower temperatures can be employed with the more
reactive oxalic acid derivatives (W-Z) 6uch as ethyl oxalyl-
chloride. A final fusion or heating period is sometimes
beneficial to achieving maximum cyclization and yield of the
desired pyrimido~,5-b7quinolin-4(3H)-one-2-carboxylic acid
derivative. The addition of a ~mall amount of a base, ~uch
as sodium hydride and alkali metal alkoxides, i8 frequently
useful in promoting cyclization, expecially in making com-
pounds of Formula II.
When reactant W-Z reqults in production of the
2-cyano derivative rather than a 2-COR derivative, the ~yano
group is converted to the corre~ponding 2-carboxamide by acid
hydrolysis. When W-Z is a monoacid halide of a half-alkyl
oxalic acid ester, an acid acceptor; i.e., an organic or
inorganic base, such as triethylamine, pyridine, sodium
methoxide, sodium hydroxide, is used to neutralize the by-
product acid formed.
When reactant W-Z represents an alkyl ester of0 glycolic acid, the fused pyrimidine~ of Formulae I-III pro-
-14-
1053674
duced bear the hydroxymethyl group at the 2-position. Such
compounds serve as precursors for corresponding aldehydes.
The conversion is accomplished by oxidation using chromic
anhydride in pyridine (Sarett reagent) or chromic anhydride-
pyridine-water (Cornforth reagent). The latter reagent is
preferred because of its ease of preparation and handling
relative to the Sarett reagent. Further oxidation of the
2-carboxaldehyde leads by, for example, chromic anhydride-
sulfuric acid at about 30C-50C. produces the 2-carboxylic
acid.
Alternatively, the appropriate alkyl benzyloxy
acetate; e.g., ethyl benzyloxyacetate, is used as reagent
W-Z to produce compounds of Formulaes I-III wherein the
substituent is a 2-benzyloxymethyl group. The benzyl groups
of the 2-benzyloxymethyl derivatives thus-produced are
removed by reaction with strong acids such as trifluoroacetic
acid in the manner described below.
The 5-substituted compounds of Formula I are also
prepared from the appropriate 4-substituted 2-aminoquinoline-
3-carboxamide which, in turn, is prepared by the reaction of
malononitrile with the appropriate Rl-(2-aminophenyl) ketone,
e.g., 2-aminobenzophenone (Rl-phenyl) and aminoacetophenone
(Rl=CH3). The 2-amino-3-cyano-4-substituted quinoline thus
produced is hydrolyzed to the corresponding 4-substituted-
2-aminoquinoline-3-carboxamide by heating with 95% sulfuric
acid, followed by aqueous work-up. The process is that
described by Campaigne et al., J. Hetero. Chem. 8, 111-120 (1971).
A further method comprises condensation of an
appropriate o-nitrobenzaldehyde with a dialkylmalonate to
0 produce an alkyl -carbalkoxy-~-(2-nitrophenyl)acrylate which
-15-
~053674
is subsequently reduced to the corresponding alkyl a-
carbalkoxy-~-(2-aminophenyl)acrylate according to procedures
described above. The reduced product spontaneously cyclizes
to an alkyl 2-oxo-quinoline-3-carboxylate. The 2-oxo deriva-
tive is heated directly with l-carbalkoxy formamidine in
ethanol using sodium ethoxide to give compound~ of Formula I.
Or, the 2-oxo derivative is chlorinated with a suitable
chlorinating agent such as phosphorous trichloride, phospho-
rous pentachloride, phosphorous oxychloride in a reaction-
inert solvent such as an aromatic hydrocarbon or a halogenatedaliphatic or aromatic hydrocarbon (benzene, toluene, xylene,
methylene chloride, ethylene chloride, chloroform, chloro-
benzene) at a temperature of from about 50C. to 100C.
The alkyl 2-chloroquinoline-3-carboxylate thus
produced is reacted with an alkyl l-guanylformate to provide
the corre~ponding alkyl pyrimido-~,5-b7quinolin-4(3H)-one-
2-carboxylate. This cyclization is carried out according to
known methods.
Still a further method comprises construction of
the central pyridine ring. It involves condensation of the
appropriate o-nitrobenzaldehyde with an ester, e.g., an alkyl
ester of 4,6-dioxo(3H,SH)-tetrahydropyrimidine-2-carboxylic
acid, in the presence of a base to produce the corresponding
4,6-dioxo(3H,5H)-5-(2-nitrobenzylidene)tetrahydropyrimidine-
2-carboxylic acid ester which, upon subsequent reduction in
the manner described above, spontaneously cyclizes to a com-
pound of Formula I. A variation on this method involves çon-
densation of the o-nitrobenzaldehyde malondiamide, followed
by reaction of the product with a dialkyl oxalate to form
the above nitrobenzylidene compound.
-16-
1053674
Compounds of Formula II (R = COR) are prepared
by methods similar to those described above for compounds of
Formula I but using, of course, in place of a 2-aminoquinoline-
3-carboxamide, a 2-aminonaphthalene-3-carboxamide. The reac-
tion conditions for achieving construction of the pyrimidinering are substantially the same as those described for com-
pounds of Formula I.
The compounds of Formula III (R = COR) are similar-
ly prepared from appropriate 2-aminonicotinamide or precursors
thereto, e.g., 2-aminonicotinic acid, 2-nitropyridine-3-
carboxamides or 3-carboxylic acids, 2-nitro or 2-aminopyridine-
3-carboxaldehydes. In preparing compounds of Formulae II and
III, the favored routes comprise reacting W-Z with the
appropriate 2-amino-3-carboxamide reactant.
lS The amide and hydroxamic acid derivatives of
Formulae I,II, and III (R =NH2,NHOH) are prepared by methods
described above from W-CONH2, W-CONHOH or by reaction of the
precursor alkyl ester of Formulae I, II, and III with ammonia
or hydroxylamine. The usual procedure which o~prises reacting the
appropriate ester with ammonia or with hydroxylamine hydro-
chloride, usually in excess, in the presence of an acid
acceptor such as triethylamine. The reaction is facilitated
by heating under pressure, i.e., the reaction is carried out
in a bomb, in a solvent such as ethanol for from about ~ to
about 20 hours and the product then recovered by suitable
means.
The 2-methyl and 2-ethyl analogs of Formulae I and
III are prepared by cyclization of the appropriate 2-amino-
quinoline-3-carboxamide or 2-aminonicotinamide with the appro-
0 priate alkanoic acid anhydride e.g., acetic or propionic-17-
1053674
anhydride; or with triethyl orthoacetate or triethyl orthopro-
pionate in the presence of sulfuric acid. Treatment of the
product with dilute alkali followed by reacidification
provides the 2-methyl or ethyl analogs. The preparation of
2-methylpyrimido/4,5-b7quinolin-4(3H)-one by this procedure
i8 reported by Taylor et al., J. Am. Chem. Soc. 78, 5108-15
(1956) as previously noted. The 2-ethyl analogs, new compounds
are primarily of value as intermediates for preparation of
the corresponding 2-acetyl derivatives of Formulae I and III.
The 2-acetyl derivatives of Formulae I and III
are prepared by oxidation of the corresponding 2-,ethyl
derivatives with selenium dioxide and water in a suitable
solvent medium, for example, dioxane. In the usual procedure
the 2-ethyl derivative and selenium dioxide are used in about
a 2:1 molar ratio at an elevated temperature, e.g. from about
50 to about 100C. Additional selenium dioxide beyond the
2:1 molar ratio can be used to expedite the oxidation.
The 2-methyl analogs of Formulae I and III are
useful intermediates for preparation of corresponding 2-
carboxaldehydes and 2-carboxylic acids, and from them, of
corresponding esters of the acids.
A useful procedure for preparing 2-carboxylic
acids comprises refluxing the appropriate 2-methyl derivatives
in a solvent such as ethanol with a slight excess of benzal-
dehyde in the presence of sodium ethoxide or piperidine, or
other base, to form the benzylidine adduct. The amount of
base used is not critical but can vary from a catalytic amount
(<1%) up to an equivalent amount. The benzylidene adduct is
isolated by removal of the solvent and is then oxidized to
the acid by excess cold potassium permanganate in aqueous
-18-
1053674
acetone, or by ozonolysis. Alternatively, the methyl group
is converted to the corresponding 2-bromomethyl compound by
reaction with N-bromosuccinimide in chloroform. The succinimide
by product is removed by concentration of the reaction mix-
ture and filtration. The filtrate is taken to dryness andthe residue dissolved in aqueous sulfuric acid and treated
with chromium trioxide to provide the acid.
Conversion of the 2-methyl groups to 2-carboxal-
dehyde groups is achieved by oxidation with selenium dioxide
and water in the manner described above for conversion of
2-ethyl to 2-acetyl groups. Alternatively, the 2-methyl
group is transformed to the 2-bromomethyl group according to
the procedure mentioned above which is then hydrolyzed to the
corresponding 2-hydroxymethyl group.
lS The alkylene glycol esters of Formu]ae I-III
(R=COR wherein R is hydroxyalkoxy) are conveniently
prepared by a base catalyzed transesterification process.
The process comprises treating a compound of Formulae I-III
wherein R is alkoxy with an alkylene glycol, preferably in
the presence of a catalytic amount of a base (i.e., from
about 5% to about 20% by weight based upon the alkylene glycol
used), such as triethylamine or calcium hydroxide, in air at
a temperature of from about 20C. to about 50C. Higher
temperatures can be used but appear to offer na advantage.
Compounds of Fromula I wherein Y is other than
hydrogen are prepared by alkylation of Formula I compounds
wherein Y is hydrogen. The procedure comprises formation of
the sodium salt by reaction of the appropriate Formula I
compound with sodium hydride in a suitable solvent e.g., N,
N-dimethylformamide. Reaction of the sodium salt with I-Y,
--19--
~OS3674
Br-Y (or Cl-Y) affords the alkylated derivatlve. When using
Cl-Y as alkylating agent, the presence of a small amount of
sodium or potassium iodide ~from about 10% to 20% by weight
of C1-Y) serves to accelerate the reaction.
Compounds of Formulae I-III wherein any of R2, R3,
R4, or R5 is benzyl or methylsulfinyl are readily prepared
from the corresponding thioether compounds by oxidation with
an appropriate oxidizing agent such as hydrogen peroxide or
a per acid such as m-chlorperbenzoic acid accord to methods
known to those skilled in the art.
The methylthio compounds are, in turn, readily
prepared by the reaction of the corresponding chloro com-
pound of Formula IV; i.e., an ~-cyano-~-(2-nitro-chlorophenyl)
acrylamide, with sodium methyl mercaptide. Modifications of
this method are obvious to those skilled in the art. For
example, the methylthio ether of Formula IV can be made by
in situ formation of the methyl mercaptide salt. Similarly,
benzyloxy, benzylthio, and alkoxy compounds are prepared by
reacting the corresponding chloro compound of Formula IV with
sodium benzyloxide, sodium benzylmercaptide, or a sodium
alkoxide.
Compounds of Formulae I-III wherein any of R2-R5
is benzyloxy or benzylthio serve as intermediates for the
corresponding hydroxy and thiol compounds and acyl derivatives
thereof. Debenzylation is conveniently accomplished by treat-
ing the benzyl ether or benzylthio ether with trifluoroacetic
acid. The debenzylated products are obtained as their tri-
fluoroacetate salts. The hydroxy and thiol compounds, in
turn, are intermediates for preparation of corresponding
alkanoyloxy, and benzoyloxy derivatives by acylation using
-20-
-
lOS3674
the appropriate acid anhydride e.g. acetic anhydride. A
catalytic amount of p-toluenesulfonic acid is generally used
to expedite the reaction.
The products of this invention and the pharmaceuti-
S cally-acceptable cationic salts thereof, are useful for the
control (prophylactic and therapeutic treatment) of allergic
symptoms and reactions in mammals and can be administered
either as individual therapeutic agents or as mixtures of
therapeutic agents, for example, with theophylline or
sympathomimetic amines, by the oral, parenteral or inhalation
routes. They can be administered alone, but are generally
administered with a pharmaceutical carrier selected on the
basis of the chosen route of administration and standard
pharmaceutical practice.
Typical methods of administration and butylene com-
positions are described in greater detail in the aforesaid
patent application.
It is necessary that the active ingredient form a
proportion of the composition such that a suitable dosage
form will be obtained. Obviously, several dosage unit forms
can be administered at about the same time. Although com-
positions with less than 0.005~ by weight of active ingredient
might be used in certain instances, it is preferred to use
compositions containing not less than 0.005% of the active
~ngredient; otherwise, the amount of carrier becomes exces-
sively large. Activity increases with the concentration of
the active ingredient. The composition may contain 10, 50,
75, 95 or an even higher peLcentage by weight of the active
ingredient.
The PCA reaction test procedure employed to evalu-
-21-
1053674
ate the compounds of the present invention demonstrates an
excellent correlation between activity for compounds in this
test and their utility in the treatment of allergic asthma.
The ability of agents to interfere with PCA reactions is
measured in male Charles River Wistar rats, 170-210 g. Re-
aginic antisera is prepared according to Mota, Immunology,
7. 681 (1964) using hen egg albumin and B. pertussis. Hyper-
immune antisera to hen egg albumin is prepared according to
Orange, et al., J. Exptl. Med., 127, 767 (1968). Forty-eight
hours prior to antigen challenge the reaginic antisera is
injected intradermally (i.d.) into the shaved skin of a normal
rat's back; five hours before challenge the hyperimmune
antisera is similarly injected; five hours later, at a third
site, 60 meg. histamine dihydrochloride is injected (i.d.) as
a check for antihistaminic and unspecific types of blockage;
the compounds of the instant invention or saline are then ad-
ministered i.v. and immediately followed by 2.5 mg. Evan's
blue dye and 5 mg. egg albumin in saline. In the case of
oral administration Evan's blue dye and egg albumin are
given five minutes after administration of the drug. Thirty
minutes later the animals are asphyxiated using chloroform
and the skin of the back removed and reversed for observa-
tion. A score is assigned each injection site equal to the
product of the diameter of the site in mm. and a grade of
0.1, 0.5, 1, 2, 3 or 4 proportional to intensity of dye
coloration. The scores for a given injection site are summed
for each group of 8 animals and compared to the saline treat-
ed controls. The difference is expressed as per cent blockage
due to the compound employed.
Compounds representative of those in the present
-22-
~053674
invention are tested by the aforementioned procedure and the
resulting activities are reported as the degree (%) of pro-
tection.
R~ i~ J
TABLE I
Antiallergy Activity of Pyrimido[4,5-b]Quinolin-4(3H)-
One-2-Carboxylic Acid Derivatives (Formula I).
I.V.* Oral*
R Rl R2 R3 R4 R5 mg/kg. ~ mg/kg. %
.
C00C2H5 H H CH3COO OCH3 H 3 100 10 40
0C2H5 H H OH OCH3 H 0. 03 97 30 6
0.01 98
0.003 94
0.0003 38
a)OH H H OH CCH3 H 3 100
0.01 86
.003 90
C00-(n-C4Hg~ H H OH OCH3 H 3 100 10 672
.003 52
OX~(n-C4Hg~ H H CH3COOOCH3 H 3 100 10 36
COCC2H H H OH H H0.3 92 10 13
0.Q3 21 3 4
COOH H H OH H H 3 100
0.03 91
.003 4
Cooc2H H H CCH3 OH H0.003 0
0.3 100
3.0 100
*The superscripts indicate a particular value is an
average of two or more determinations.
It is considered that an effective daily oral dosage of
the compounds of the present invention in humans of from about
-23-
1(~53~74
10 to about 1,500 mg. per day, with a pre erred 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 ef-
fectively alleviate broncho-constriction in human subjects.
These values are illustrative and there may, of course, be
individual cases where higher or lower dose ranges are merited.
When administered 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 body weight in single or
divided doses.
EXAMPLE I
Ethvl-9-benzyloxy pyrimido[4,5-b]quinolin-4(3H)-one-2-carb-
oxylate.
A) 2-Amino-8-benzyloxy quinoline-3-carboxamide.
Cyanoacetamide (19.4 g., 0.23 mole) is added to a
solution of sodium ethoxide (6.65 g., 0.29 mole) in absolute
ethanol (460 ml.) maintained at 50C. The mixture is stirred
and 2-amino-3-benzyloxybenzaldehyde (52.3 g., 0.23 mole) in
absolute ethanol (100 ml.) added. After fifteen minutes
stirring at 50C., the reaction mixture is cooled in an ice
bath, filtered and dried to give the product.
B) Ethyl-9-benzyloxy Pyrimido[4,5-b]quinoline-4(3H)-
one-2-carbox~late.
A mixture of 2-amino-8-benzyloxyquinoline-3-carbox-
amide (41.7 g., 0.134 mole) and dibutyl oxalate (500 ml.) is
heated to reflux for 4 hours while distilling off the butanol-
water formed. The reacticn mixture is then cooled to room
temperature, the solid product filtered off, washed with di-
ethyl oxalate and air dried. It is purified by recrystal-
-24~
1053674
lization, with decolorization, from hot chloroform.
EXAMPLE II
Ethyl-7-benzyloxy-8-methoxy pyrimido[4,5-b]quinolin-4~3H)-
one-2-carboxylate.
A~ ~-cyano-B-(2-Nitro-4-methoxv-5-benzyloxvphen
acrylamide.
Piperidine (2.1 g., 0.0237 mole) and 2-~yano-
acetamide (22.0 g., 0.263 mole) are added to a slurry of 3-
benzyloxy-4-methoxy-6-nitroben2aldehyde (0.237 mole) in
methanol (500 ml.). The mixture is heated to r~flux for t~o
hour~ and then cooled in an ice bath and filtored. The
bright yellow filter cake is washed with cold isopropanol
~300 ml.) and then air dried. Yield - 45 g.~; m.p. 157-158-C.
Following the procedure of preparations above, but
using the appropriate alkoxy substituted nitrobenzaldehyde
reactant, the compounds listed below are prepared:
R2
R3~CONH2
R4 ~ 2 CN
R2 R3 R4 R5 m.p.(C) Yield
H OC2H5 OC7H7 H 167-167.5 (dec.) 73
H OCH3 OC7H7 H 182-3 52
H OC7H7 H H 125-6 47
B) 6-Benzyloxy-7-methoxy-2-aminoquinoline-3-carbox-
amide.
Iron powder (65.2 g., 1.22 mole~) is added over a
period of one-half hour to a slurry of the product of proce-
dure A ~0.271 molç) in a 50% solution of acetic acid-N,N-di-
-25-
1~53674dimethylformamide (750 ml.) at 75C. When addition of the
iron powder is complete, the mixture is hea~ed to 90C., for
four hours and then filtered while hot. The filter cake is
washed with hot acetic acid (150 ml.). The dark red filtrate
is gradually added to lN hydrochloric acid (1,500 ml.) and
the pink precipitate recovered by filtration and rQcrystal-
lized from an excess (10%) of aqueous sodium hydroxide. The
solid is filtered, washed with cold isopropanol and dried to
give the title product as yellow crystals. Yield ~ 80%;
m.p. 264-266C.
Upon repetition of procedure B above but using the
appropriate a-cyano-~-(2-nitrophenyl)acrylamide from proce-
dure A, the following compounds are prepared:
R2
~, ~ ~ ~2
R2 R3 R4 R5 m-p. (C.) % Yield
H OC2H5 OC7H7 H 279-80 (dec.) 73
H OCH3 OC7H7 H 282-3 (dec.) 95
H OC7H7 H H 238-9 94
C) Ethyl-7-benzyloxy-8-methoxy pyrimido[4,5-b]guinolin-
4(3H)-one-2-carboxylate.
To a round-bottomed flask equipped with stirrer,
reflux condenser and Dean-Stark apparatus and containing a
mixture of diethyl oxalate (50 ml.) and xylene (80 ml.) at
reflux is added the product of procedure B (0.012 mole). The
xylene, water and ethanol are distilled off and collected
over a four hour period. When all the xylene is removed, the
-26-
1053674reaction mixture is brought to 185C., cooled to about 100C.
and then slowly poured into chloroform (300 ml.). The chloro--
form solution is cooled and the brown precipitate which forms
removed by filtration. The filtrate is decolorized with
charcoal, concentrated and chilled to give a crystalline mass.
The crystals are taken up in hot chloroform, the ~olution
charcoaled, filtered and concentrated to give pale yellow
crystals 25%; m.p. 274-275C.
Still further, a mixture of 6,7-dimethoxy-2-amino-
quinoline-3-carboxamide (0.5 g., 2 millimoles), ethyl cyano-
formate (0.43 g., 44 millimoles) and benzene (30 ml.) is
refluxed for three days. The mixture is then cooled, filter-
ed and the solid extracted with chloroform. Concentration of
the chloroform extract affords the product which is recrystal-
lized from chloroform.
Following the procedure of C above, but using theappropriate alkoxy substituted 2-aminoquinoline-3-carboxamide
reactant from B above and the appropriate ester of oxalic
acid, the compounds listed below are prepared:
R2 Q
11
R 1 ~ ~ ~ ~ ~H
R ~2 R3 R4 R5 m-p- (C.) ~ Yield
OC2H5 H OC2H5 OC7H7 H 241-2 (dec.) 41
OC2H5 H OCH3 OC7H7 H 254-5 (dec.) 8
O-n-C4Hg H OC7H7 OCH3 H 261-2 ~dec.) 13
C2H5 H OC7H7 H H 255-7 (dec.) 32
-27-
1~)53674
D) 7-Benzvloxy-8-methoxy pyrimido[4,5-b]quinolin-
4(3H)-one-2-carboxylic acid.
Ethyl 7-benzyloxy-8-methoxy pyrimido[4,5-b]quinolin-
4(3H)- one-2-carboxylate (7.4 mM) in 5~ aqueou~ sodiumhydroxlde
(37.5 ml.) i~ stirred at room temperature for twenty hours.
The e~ter dissolves within ten minutes and is followed by the
gradual appearance of a light colored precipitate. The reaction
mixture is acidified by the 8Iow addition of 10% aqueous hydro-
chloric acid (13 ml.). The light colored precipitate di~solves
and a yellow precipitate forms. The acid mixture is stirred
for 45 minutes and then filtered. The filter cake is washed-
with water and then dried in vacuo.
The remaining products of Example II-C are hydrolyzed
according to procedure D to afford the corresponding acids.
EXAMPLE III
EthYl-7-benzYloxv-8-ethoxy pyrimido[4,5-b]quinolin-4(3H)-
one-2-carboxylate.
A) ~-Cyano-~-(2-nitro-4-benzyloxy-5-ethoxyphenyl)-
acrylamide.
A mixture of 3-ethoxy-4-benzyloxy-6-nitni~ eoldehyde
(0,0592 mole), 2-cyanoacetamide (5.24 g. , 0.0622 mole),
piperidine (0.37 g., 4.36 millimole) and ethanol (92 ml.) i8
heated to reflux on a steam bath for two hours. It is then
cooled in an ice-bath whereupon the product precipitates and
is recovered by filtration, washed with cold ethanol and dried.
I~ is of sufficient purity for use in the succeeding
step.
B) 6-Ethoxy-7-benzyloxy-2-aminoquinoline-3-carboxamide.
Iron powdes (8.52 g., 0.152 mole) is gradually added
over a forty-minute period to a slurry of the product of
-28-
~OS3679t
Procedure A (0.034 mole) in acetic acid (100 ml.) at 85C.
When addition of the iron powder is complete, the mixture is
heated to 95-100~., for 1.5 hours and then filtered hot
through diatomaceous earth. The filtra~e is cooled in an ice
bath and then filtered to give a tan crystalline solid. The
solid is partitioned between ethyl acetate and water, the
organic phase separated, dried over anhydrous sodium sulfate
and concentrated to yield the title amide as yellow crystals.
C) Ethyl-7-benzyloxy-8-methoxy pyrimido[4,5-b]quinolin-
4(3H)-one-2-carboxylate.
A mixture of diethyl oxalate (57.2 g., 0.392 mole)
and the product of procedure B (0.0261 mole) is heated for
eighteen hours at 160C., under a nitrogen atmosphere and
then allowed to cool to room temperature. Hexane (300 ml.)
is added, the mixture stirred and filtered to provide the
desired product. It is washed with hexane and dried.
EXAMPLE IV
7-Benzyloxy-8-methoxy pyrimidol4~s-~lquinolin-4(3H)-one-2
carboxamide.
Anhydrous ammonia is bubbled into a mixture of ethyl
7-benzyloxy-8-methoxy pyrimido[4,s_b]quinolin-4(3H)-one-2-
carboxylate (9.00 millimoles) in absolute ethanol (75 ml.)
for fifteen minutes. A clear solution formed followed after
a few minutes by ormation of a precipitate. The reaction
mixture is transferred to a pressure bomb (Monel, "Monel" is a
trademark)and heated in a 95C., oil bath overnight. The
bomb is then cooled to room temperature and the contents
removed. The bomb is washed with ethanol and the combin~
reaction mixture plus wash filtered to recover the product.
The filter cake is washed with ethanol and then dried in air.
-29-
.
1053674
EXAMPLE V
7-Methoxy-8-benzyloxy pyrimido[4,5-b]quinolin-4(3H)-one-2-
carboxamide.
A mixture of 2-amino~6-methoxy-7-benzyloxyquinoline-
3-carboxamide (1.15 millimoles), ethyl oxamate (2.71 g.,
23.1 millimoles), ethylene glycol (10 ml.) and Qodium methox-
ide (10 mg.) is heated at 170C., for one hour. The product
is precipitated by 510w addition of ice cold methanol (50 ml.)
to the hot reaction mixture followed by chilling in an ice
bath. It is filtered off, washed with cold methanol and
dried ln vacuo.
EXA~PLE VI
7-Methoxv-8-benzYloxv PYrimido~4,5-b]quinolin-4(3H)-one-2-
hYdroxamic acid.
Ethyl 7-methoxy-8-benzyloxy pyrimido[4,5-b]quinolin-
4~3H)-one-2-carboxylate (6.08 millimoles) is added to a solu-
tion of hydroxylamine hydrochloride (69 mg., 100 millimoles)
and triethylamine (100 mg., 100 millimoles) in absolute
ethanol ~50 ml.). The mixture is heated at 95C., overnight
in a bomb and then cooled. The insoluble yellow solid is
filtered off, washed with hot ethanol and dried to provide
the product.
EXAMPLE VII
Ethyl 7-hydroxy-8-methoxy pyrimido[4,5-b]quinolin-4(3H)-
one-2-carboxylate trifluoroacetate.
A 301ution of ethyl 7-benzyloxy-8-methoxy pyrimido-
14,5-b]quinolin-4(3H)-one-2-carboxylate (~50 mg., 0.618
mmole) in trifluoroacetic acid (5 ml.) is refluxed for 2.5
hours. (Alternatively the mixture is sti~red at room tem-
perature for three days). The reaction mixture is then poured
-30-
~053674
into ether (25 ml.) and the resulting bright yellow precipi-
tate of the trifluoroacetate salt recovered by filtration,
washed with ether and dried.
Yield - 194 mg., 72~; m.p. 279C.
Analysis:
C~lcd- for C15H13N35CF3CH 1/2 H2O: C, 46-58; H 5
N, 9.58%
Found: C, 46.81; H, 3.41;
N, 9.21%.
Repetition of the above procedure but using the
corresponding n-butyl ester (862 mg., 0.199 mmole) in place
of the ethyl ester, 8 ml. trifluoroacetic acid and a reflux
period of 3.5 hours affords n-butyl 7-hydroxy-8-methoxy-
pyrimido[4,5-b]quinolin-4~3H)-one-2-carboxylate trifluoro-
acetate (0.67 g., 74%); m.p. 240C. (dec.)
Analysis:
Calcd- for C17H17Os~3CF3COOH: C, 49.89; H, 3.96; N, 9.18;
F, 12.46%
Found: C, 49.93; H, 3.97; N, 8.79;
F, 11.17%.
Similarly, ethyl 7-benzyloxypyrimido[4,5-b]-
quinolin-4(3H)-one-2-carboxylate is debenzylated to give a
74~ yield of ethyl 7-hydroxypyrimido[4,5-b]quinolin-4(3H)-
one-2-carboxylate hemitrifluoroacetate; m.p. 274-275C.
(dec.)
Analysis:
Calcd- for C14H114N3 1/2 CF3COOH: C, 57.43; H, 3.6
N, 13.39%
Found: C, 57.75; H, 4.05;
N, 13.65~.
-31-
1053674
EXAMPLE VIII
7-Hydroxy-8-methoxypyrimido[4,5-b]quinolin-4 (3E-I) -one-2-
carboxylic acid.
The trifluoroacetate-hemihydrate salt of ethyl 7-
hydroxy-8-methoxypyrimido[4,5-b]quinolin-4(3X)-one-2-carboxyl-
ate (200 mg., 0.456 mmole) is slurried in O.lN sodium hydrox-
ide (5 ml.~ and 15% sodium hydroxide added dropwise with
stirring until solution is complete. The mixture is stirred
at room temperature for 18 hours and is then made strongly
acid by addition of trifluoroacetic acid. The precipitate
which forms is separated by filtration, washed with water
and then with isopropyl alcohol and air-dried. Yield -
114 mg.; m.p. 281C. (dec.).
Analysis-
Calcd. for C13HgOsN32H2O: C, 48.29; H, 4.02; N, 13.00%
Found: C, 47.3; H, 3.32; N, 12.73%.
In like manner, ethyl 7-hydroxypyrimido[4,5-b]-
quinolin-4(3H)-one-2-carboxylate hemitrifluoroacetate (210
mg.) is converted to 7-hydroxypyrimido[4,5-b]quinolin-4(3H)-
one-2-carboxylic acid. Yield = 191 mg., 91% m.p. 340C.
(dec.).
EXAMPLE IX
Ethyl-7-methoxy-8-hydr-oxy pyrimido[4,5-b]quinolin-4(3H)-one-
2-carboxylate.
A solution of ethyl 7-methoxy-8-benzyloxypyrimido-
~4,5-b~quinolin-4(3H)-one-2-carboxylate (198 mg., 0.488 mmole)
in trifluoroacetic acid (4 ml.) is stirred at room temperature
for 8 days. Ether (15 ml.) is added and the yellow precipi-
tate which forms separated by filtration. It is taken up in
chloroform and the solution filtered through diatomaceous
-32-
1053674
earth to remove a small amount of insoluble material. The
filtrate is decolorized with charcoal and concentrated under
reduced pressure to small volume. The solid which forms is
filtered and dried; 9 mg., 6% yield; m.p. 265-266C. (dec.).
EXAMPLE X
The compounds below are prepared from appropriate
reactants by the procedures of the preceding examples.
12 R
R3 ~ -H
~ N ~ N ~ COR
Method
R R2 - R4 R5 f Ex
OC2H5 H H OC7H7 OCH3 II
O-n-C3H7 H H OC7H7 H II
OCH3 OC7H7 OCH3 H H II
C2H5 H OC7H7 OC7H7 H II
C2H5 OC7H7 H H H II
C2H5 OC7H7 Br H Br II
OCH3 H OCH3 OC7H7 Br II
OCH3 H OC7H7 OC7H7 H II
C2H5 OC7H7 OCH3 OCH3 H II
OC2H5 H Br H OC7H7
O-n-C3H7 C2H5 H OC7H7 H III
O-n-C3H7 C2H5 OC7H7 H H III
C2H5 H OC7H7 C2H5 H II
C2H5 H OC2H5 OC7H7 H II
C2H5 H F OC7H7 H II
OC2H5 H Br OC7H7 H II
OCH3 H Cl OC7H7 H IV
-33-
1053674
Method
R R2 R3 R4 R5 f Exp
_
NH2 H OC7H7 H OCH3 IV
NHOH H OC7H7 OCH3 H VI
NHOH OC7H7 OCH3 OCH3 H VI
NHOH H OC2H5 OC7H7 H VI
NH2 H OC7H7 0C2H5 H IV
NH2 H F OC7H7 H IV
NHOH H Cl OC7H7 H VI
C2H5 H SC7H7 H H II
NH2 H H H SC7H7 IV
C2H5 H SC7H7 C2H5 H II
OC2H5 H H SC7H7 H II
NHOH H H SC7H7 H VI
C2H5 SC7H7 H H SC7H7 II
NH2 SC7H7 H H SC7H7 VI
The benzyl ethers and benzylthio ethers tabulated
above are converted ts the corresponding hydroxy and thiol
compounds by the procedure of Example VII.
20The thus-produced hydroxy and thiol substituted 2-
carboxylic acid e~ters are hydrolyzed to the corresponding
2-carboxylic acid derivatives by the procedure of Example
VIII.
EXAMPLE XI
25Ethyl 7-acetoxy-8-methoxy pyrimido[4,5-b]quinolin-4(3H)-one-
2-carboxylate p-toluenesulfonate.
A mixture of acetic anhydride (4 ml.), ethyl 7-
hydroxy-8-methoxypyrimido[4,5-b]quinolin-4(3H)-one-2-
carboxylate trifluoroacetate hemihydrate (250 mg., 0.572
mmole) and p-toluenesulfonic acid monohydrate (100 mg.,
-34-
1053674
0.572 mmole) is heated at 100C., for 24 hours. The acetic
anhydride is then stripped from the reaction mixture ln
vacuo. The solid residue is dissolved in hot chloroform and
the solution decolorized with activated charcoal. Benzene
(4 volumes) is added to the decolorized solution which is
then ahilled in ice. The crystals which separate are recover-
ed by filtration and air dried. Yield = 174 mg., 58%;
m.p. 215-217C.
AnalysiS: Calcd- for Cl7Hl5o6N3c7H8o3
N, 7.98%
Found: C, 53.74; H, 4.28;
N, 7.24%.
The above procedure is repeated but using the
corresponding n-butyl ester trifluoroacetate salt (200 mg.,
0.437 mmole) in place of the ethyl ester trifluoroacetate
salt. The product is recovered by concentration of the
chloroform solution to 1/3 volume and filtration of the solid
which precipitates rather than by precipitation with benzene.
Yield = 30 mg., 18%; m.p. 260-261C. (dec.).
The above procedure is repeated but using the ap-
propriate acid anhydride and in place of acetic anhydride and
the appropriate hydroxy or thiol Formula I compound as reac-
tant to give the following compounds:
R J ~ l ¦ N H
R4~J~N NlR
R5
1053674
Rl R2 R3 R4 ~5 R
H H C2H5C OCH3 H COOC2H5
H H C3H7cOO OCH3 H COOC2H5
H H HCOO OCH3 H COOC2H5
H H OCH3 CH3COO H COOC~H5
H H OCH3 C2H5C H COOC2H5
H H OCH3 HCOO H COOC2Hs
H H HCOO OCH3 H ~X~n-C4Hg
H H CH3COO OCH3 H COO-n-C~Hg
C6H5 H HCOO H H CH~
C6H5 H C3H7COO OCH3 H CH3
H H H HCOO H COO-n-C3H7
H H H CH3COO H COO-n-C3H7
C6H5 H H CH3COO OCH3 CH3
H H CH3COO CH3COO H COOC2H5
H H HCOO HCOO H COOC2H5
H H OCH3 CH3COO Br COOCH3
H CH3COO OCH3 H H C2H5
CH3 H C6H5C OCH3 H C2H5
n-C4Hg H C6H5C OCH3 H C2H5
C6H5 H CH3COO H H C2H5
H C3H7cOO OCH3 H H COOCH3
H CH3COO OCH3 OCH3 H COOC2H5
H H Br H CH3COO COOC2H5
H H H H HCOO OX~n-C4Hg
H H H H C3H7COO ~X~n-C4Hg
H C2H5 H CH3COO H COOC2H5
CH3 H CH3COO C2H5 H CH3
C2H5 H F CH3COO H C2H5
n-C4Hg C2H5 CH3COO H H C~H5
-36-
1053674
Rl R2 R3 R4 R5 R
-
H H Cl CH3COO H COOCH3
c2H5 H F 3 7 H COOC2H5
C2 5 HCOO H H COO-n-C3H7
H CH3COO H H COO~n-C3H
H H C3H7COO H H COO-n-C3H7
H H CH3COO H H COOCH3
H H C3H7COO H H COOCH3
H H CH3COO CH3COO H COOCH3
H H H C2H5C H COOC2H5
CH3 ~ C6H5C OCH3 H COOC2H5
H H OCH3 6 5COO H COOC2H5
H H Cl C6H5C H COOC2H5
EXAMPLE XII
2-HydroxYethyl-7-benzyloxy-8-methoxy pyrimidin[4,5-b]-
quinolin-4-(3H)-one-2-carboxylate.
Triethylamine (1 ml.) is added to a slurry of ethyl
7-benzyloxy-8-methoxy pyrimidin[4,5-b]quinoline-4(3H)-one-
2-carboxylate (500 mg.) in ethylene glycol (5 ml.). The mix-
ture i8 stirred for 6 hours and is then diluted with water
(30 ml.). The resulting clear yellow solution i~ acidified
with acetic acid and the precipitate which forms filtered off.
It is recrystallized while still damp from N,N-dimethylform-
amide (20 ml.).
In like manner, the alkyl esters of Example II, XI,
XIII-XV and XIX-XXII are transesterified to the corresponding
2-hydroxyethyl esters. Replacement of ethylene glycol by
propylene glycol, butylene glycol or 1,4-dihydroxybutane
affords the corresponding hydroxyalkoxy e~ters.
1053674
EXAMPLE XIII
Ethyl 7-benzylthio pyrimido[4,5-b]quinolin-4(3H)-one-2-
carboxylate.
A) -CYano-~-(2-nitro-5-benzylthiophenyl)acrylamide
A solution of the sodium salt of benzylmercaptan
(2.78 g., 0.0398 mole) in N,N-dimethylformamide (50 ml.) is
prepared by adding benzylmercaptan to a mixture of sodium
hydride (1.67 g. of 57% NaH) in N,N-dimethylformamide (50 ml.).
The reaction mixture is cooled by means of an ice-bath until
the reaction is complete.
The sodium benzylmercaptide solution is then added
dropwlse to a mixture of a-cyano-~-(2-nitro-5-chlorophenyl)-
acrylamide (10 g., 0.0398 mole) in N,N-dimethylformamide
(35 ml.) cooled in an ice-bath. The mixture is stirred for
one hour and then removed from the ice-bath and stirred for
an additional two hours. The reaction mixture is poured into
water (600 ml.) and the resulting mixture thoroughly stirred.
Ether (30 ml.) is added and the precipitate filtered off,
washed with ether and dried.
B) 6-BenzYlthio-2-aminoquinoline-3-carboxamide
A mixture of a-cyano-~-(2-nitro-5-benzylthiophenyl)-
acrylamide (0.032 mole) in acetic acid - N,N-dimethylformamide
(110 ml. of 1:1) is heated in a 75C., bath. Iron powder
(2.0 g.) is added and the mixture stirred until the internal
temperature rose to 95C. Additional iron powder (6.16 g.
total iron added = 0.146 mole) is added in small portions over
a fifteen-minute period. The reaction mixture is stirred for
one hour following completion of addition and then filtered
hot. The iron residue is washed with hot acetic acid
and the combined filtrate and wash solution pou`red into
-38-
.
1053674
LN hydrochloric acid (200 ml.). The hydrochloride salt which
separates is filtered off and dissolved in hot dilute aqueous
oodium hydroxide. The yellow solid which separates on cooling
is filtered off, washed with isopropyl alcohol and air dried.
It is used in Step C without further purification.
C) EthYl-7-benzylthio Pyrimido[4,5-b]quinoline-4(3H)-
one-2-carboxylate.
A round-bottom flask equipped with stirrer, con-
denser, thermometer and Dean-Stark trap and containing a
mixture of 6-benzylthio-2-aminoquinoline-3-carboxamide (4.3
millimoles), diethyl oxalate (20 ml.) and xylene (15 ml.) is
immersed in an oil-bath heated to 200C. Xylene, water and
ethanol are distilled from the reaction mixture until the
internal temperature of the mixture reaches 165C. The mixture
is stirred at 165C., for three hours and is then poured into
chloroform (40 ml.). After cooling to room temperature the
mixture is filtered. The brown filter cake is air-dried and
then slurried in hot chloroform (100 ml.) to which activated
charcoal is added. The slurry is filtered hot and the
filtrate evaporated to half-volume and chilled in ice. The
yellow solid which precipitates is filtered and dried in air.
EXAMPLE XIV
EthYl-7-benzylsulfinyl pyrimido[4,5-b]quinoline-4(3H)-one-
2-carboxylate
.
A solution of ethyl 7-benzylthio pyrimido[4,5-b]-
quinoline-4(3H)-one-2-carboxylate (1 millimole) in trifluoro-
acetic acid (2 ml.) is heated in an oil bath tc 55C. Hydro-
gen peroxide (113 mg. of 30% H2O2, 1 millimole~ is added and
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the solution stirred for ten minutes. After cooling to room
temperature, absolute ethanol (6 ml.) is added. The resulting
yellow precipitate is filtered off, washed with ether and air-
dried. Recrystallization from absolute ethanol gives
S the product.
The thiobenzyl compounds of Example X are oxidized
to the corresponding sulfinyl~enzyl compounds by this procedure.
EXA~PLE XV
Repetition of the procedures of Examples XIII A-C
and XIV, but using the appropriate chloro substituted 2-nitro-
benzaldehyde as reactants, affords the following compounds:
ll
R ~ ~ N-H
R~N~J--COOC2H5
R2 R3 R4 R5
H SOC7H7 C2H5 H
H H SOC7H7 H
SOC7H7 H H SOC7H7
EXAMPLE XVI
2-MethYl-7-hydroxv-8-methoxy pyrimido[4,5-b]quinolin-4( 3H)-one.
A) 7-Benzyl ether of title compound:
A mixture of 6-benzyloxy-7-methoxy-2-amino-quinoline-
3-carboxamide (1. 50 g.), concentrated sulfuric acid (0.05 ml.)
and acetic anhydride (20 ml.) is heated at 85C., for 15
minutes. The mixture is then cooled and ice chips
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1053674
added to the reaction mixture. The yellow solid which pre-
cipitates is filtered, washed with water and then with iso-
propyl alcohol-ether (1:1) and air-dried. Yield = 1.60 g.
(99~); m.p. 202-203C. (dec.).
B) Debenzylation of 7-benzyl ether:
The 7-benzyl ether from preparation A above is
treated with trifluoroacetic acid according to the procedure
of Example VII to give the title compound in 95~ yield;
m.p. 135C. (dec.).
EXAMPLE XVII
2-Methyl-7-methox~-8-benzyloxy pyrimido[4,5-b]quinolin-
4(3H)-one.
Concentrated sulfuric acid (1.5 ml.) is added to a
slurry of 2-amino-6-methoxy-7-benzyloxyquinoline-3-carboxamide
(0.02 mole) and acetic anhydride (40 ml.). The slurry dis-
solves to give a dark orange solution from which a heavy
yellow precipitate separates. Acetic anhydride (10 ml.) is
added to facilitate stirring and heating continued for an
additional 75 minutes. The mixture is cooled, water (50 ml.)
added and the resulting solution made alkaline with 5N ~odium
hydroxide (225 ml.). It i8 chilled, the precipitate collected
by filtration and air-dried. The yellow solid is recryqtallized
from ethanol.
In like manner, the following compounds are prepared
from appropriate reactants:
3 ~ ~-H
R4 ~-- CH3
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Rl R2 R3 R4 R5
C6H5 H OCH3 OC7H7
H H OCH3 OC7H7 H
H H OC7H7 OCH3 H
H H SC7H7 H H
H H H OC7H7 OCH3
H H H OC7H7 H
H OC7H7 OCH3 H H
H OC7H7 H H H
H OC7H7 Br H Br
H H OCH3 OC7H7 Br
H C2H5 H OC7H7 H
H C2H5 OC7H7 H H
H H SC7H7 C2H5 H
~5 H H OC2H5 SC7H7 H
H H Br SC7H7 H
H H Cl OC7H7 H
H H F OC7H7 H
C6H5 OC7H7 OCH3 OCH3 H
C6H5 H OCH3 OC7H7 H
C6H5 H OC7H7 OCH3 H
C6H5 H SC7H7 H H
C6H5 H H OC7H7 OCH3
C6H5 H Cl OC7H7 H
CH3 H OC7H7 OCH3 H
CH3 H SC7H7 C2H5
CH3 H F OC7H7 H
C2H5 H OC7H7 H H
n~C3H7 H OC7H7 OCH3 H
30 n-C4Hg H OC7H7 OCH3 H
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Rl R2 R3 R4 R5
_
n C4H7 C2H5 SC7H7 H H
n-C4Hg OC7H7 OCH3 OCH3 H
The benzyl ethers and benzylthio ethers enumerated
above are debenzylated by treatment with trifluoroacetic
acid as is described in Example VII.
EXAMPLE XVIII
2-Ethyl-7-ethoxy-8-benzyloxy pyrimidin[4,5-b]quinolin-
4(3H)-one.
To a stirred mixture of 6-ethoxy-7-benzyloxy-2-
aminoquinoline-3-carboxamide (0.002 mole) in propionic
anhydride (10 ml.) at 60C., is added concentrated sulfuric
acid (0.5 ml.). The reaction mixture is stirred for one hour
and is then cooled to room temperature and added to water
(25 ml.). The aqueous mixture is stirred and made basic with
6N sodium hydroxide. It is stirred overnight and then
acidified to pH 5.0 with 10% hydrochloric acid. The yellow
precipitate which forms is filtered off and recrystallized
from ethanol.
The following compounds are prepared in li~e manner
from appropriate reactants:
4 ~rJ ~i C H
Rl R2 R3 R4 R5
H H OCH3 OC7~i7
H H OC7H7 OCH3 H
H H OC7H7 H
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Rl R2 R3 R4 R5
H H F OC7H7 H
H H Cl OC7H7 H
H C2H5 H OC7H7 H
H OC7H7 OCH3 OCH3 H
C6H5 H OC7H7 OCH3 H
C6H5 H OC7H7 H H
C6H5 OC7H7 Br H Br
CH3 H OC7H7 OCH3 H
CH3 H OCH3 OC7H7 H
CH3 H OC7H7 C2H5 H
CH3 H OCH3 OC7H7 Br
C2H5 H F OC7H7 H
C2H5 H OC7H7 OCH3 H
C2H5 OC7H7 OCH3 H H
n C3H7 H C2H7 C2H5 H
i C3H7 H OC7H7 C2H5 H
n-C4Hg H OC7H7 H H
n-C4Hg C2H5 OC7H7 H H
n~C4Hg H OC7H7 OCH3 H
H H OC2H5 OC7H7 H
Debenzylation of the benzyl ethers cited above by
reaction with trifluoroacetic acid according to the procedure
of Example VII affords the corresponding hydroxy compounds.
EXAMPLE XIX
2-Acetyl-7-ethoxy-8-benzyloxy pyrimido[4,5-
~.
To a solution of selenium dioxide (24.5 mg.,
2.2 millimoles) in dioxane water ~11 ml. of 10:1) is added
2-ethyl-7-ethoxy-7-benzyloxy pyrimido[4,5-b]quinolin-4(3H)-
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one (125 mg., 4.4 millimoles~. The mixture is heated to
reflux for 48 hours after which more selenium dioxide (24.5
mg.) is added and refluxing continued for an additional 24
hours. The mixture is cooled, the selenium filtered off and
the filtrate concentrated to dryness. The residue is taken
up in ethanol/chloroform (1:99) and chromatographed on a
column of silica using the same solvent as eluant (250 ml.)
followed by ethanol/chloroform (2:98). Concentration of the
second eluate (625 ml.) gives a yellow solid.
Similarly, the remaining 2-ethyl derivatives of
Example XVIII are oxidized to their corresponding 2-acetyl
derivatives.
EX~LE XX
Ethyl 3-methyl-7-benzyloxy-8-methoxy Pyrimido[4,5-b]quinolin-
4(3H)-one-2-carboxylate.
Sodium hydride (470 mg. of 50~ in oil, 0.011 mole)
i~ added to a slurry of ethyl 7-benzyloxy-8-methoxy pyrimido-
[4,5-b]quinolin-4(3H)-one-2-carboxylate (3.3 g., ~.01 mole)
in N,N-dimethylformamide (75 ml.). The mixture is stirred
and heated on a steambath for ten minutes and then at room
temperature for a half hour. It is cooled in an ice-bath
and iodometane (2.1 g., 0.015 mole) added dropwise over a 30
minute period. Following completion of addition, the mixture
is stirred for an additional 15 minutes in an ice-bath and
then for a half-hour at room temperature. The reaction mix-
ture is poured into ice-water (200 ml.) and the resulting
solid filtered off, air-dried and recrystallized from ethanol
to give yellow crystals.
In like manner, but using the appropriate compound
of Formula I (Y=H) and the appropriate alkyl iodide, the pro-
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ducts of the preceding examples are converted ~o their
corresponding 3-methyl, 3-ethyl, 3-n-propyl, 3-isopropyl and
3-n-butyl derivatives.
Compounds wherein one of R2, R3, R4 or R5 i~ thiol
or hydroxy are obtained by debenzylation of the corresponding
benzylthio ethers or benzylethers by reaction with tri-
fluoroacetic acid according to the procedure of Example VII.
EXAMPLE XXI
Ethyl 3-carbethoxYmethyl-7-ethoxy-8-benzYloxy pvrimido[4,5-b~-
quinolin-4(3H)-one-2-carboxylate.
To a slurry of ethyl 7-ethoxy-8-benzyloxy pyrimido-
t4~5-b]quinolin-4(3H)-one-2-carboxylate (1.6 g., 5.0 milli-
moles) in N,N-dimethylformamide (30 ml.) is added sod~um
hydride (235 mg., 5.5 millimoles of 56% in oil). The 31urry
i8 heated on a steambath for ten minutes and then cooled to
room temperature. Ethyl bromoacetate (968 mg., 5.8 milli-
mOle8) i9 added and the reaction mixture heated on a steam-
bath for one hour. After standing o~ernight at room tempera-
ture the mixture is diluted with water (75 ml.) and the re-
sulting yellow solid filtered off ~1.4 g.). It i3 purifi~d
by chromatography on a column of silica gel using chloroform
as solvent and eluant. The eluant is evaporated to give a
yellow ~olid. It is recrystallized from hot ethanol ~S0 ml.)
containing sufficient chloroform to achieve solution.
EXAMP~E XXII
Pyrimido[4,5-b]quinolin-4(3H)-one compounds of
Examples I-XIX are alkylated substantially according to the
procedure of Example XXI but using the appropriate alkyl
bromoalkanoate or alkylating agent. The products are re-
crystallized from suitable solvents such as ethanol or
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~053674
benzene: hexane (1:1).
R ~ ~ ~ ~ Y
Y R R R2 R3 R4
CH2COOC2H5 COOC2H5 H H OC2H5 C7H7
S CH2COOCH3 COOC2H5 H H OC7H7 OCH3 H
(CH2~2COOc2H5 COO-n-C4Hg H H OC7H7 OCH3 H
CH2COo-n-c4H9 COOC2H5 H H OC7H7 H H
(CH2~3COOC2H5 COOC2H5 H H OCH3 OC7H7 H
CH2COOC2H5 COOCH3 H H OC7H7 OC7H~ H
(CH2~4COOCH3 COOC2H5 H OC7H7 OCH3 OCH3 H
(CH2)2COO-n-C4Hg COO-n-C4Hg H H H H OC7H
CH2COO-n-C3H7 COO-n-C3H7 H C2H5 OC7H7 H H
CH2COOC2H5 COOC2H5 H H Br OC7H7 H
CH2COOC2H5 COOCH3 H H Cl CC7H7 H
lS CH2COOCH3 COOCH2CH20H H H OC7H7 OCH3 H
CH2COOCH3 COOCH2CH20H H H OCH3 OC7H7 H
(CH2)2COOC2H5 COO(CH2)40H H H OC7H7 H H
CH2COO-n-C4Hg COO~CH2)30H H H F OC7H7 H
CH2COOC2H5 CH3 H H OC7H7 O~H3 H
CH2COOC2H5 CH3 H H OC2H5 OC7H7 H
CH2COOC2H5 CH3 H OC7H7 CCH3 E H
CH2COOC2H5 C2H5 H H OC7H7 H H
CH2COOC2H5 C2H5 H H OCH3 OC7H7 Br
CH2COOC2H5 C2H5 H H Br 0~7H7 H
CH2COOC2H5 ~OCH3 H H OC7~7 ~CH3
CH2COOC2H5 COCH3 H C2H5 H OC7H7 H
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Y R Rl R2 R3 R4 R5
CH2oXX~3 CH3 C6H5 H Oc7H7 OCH3 H
(CH2)3COCC2H5 C2H5 C2H5 OC7H7 OCH3 H
(CH2)2~x~n-c4H9 CH3 n-C4Hg C2H5 OC7H7 H H
CH2CCOC2H5 CH3 CH3 H OC7H7 OCH3 H
CH2000CH3 COOC2H5 H H SC7H7 H H
(CH2)4ccOc2H5 COOC2H5 H H H H SC7H7
CH2COOC2H5 COOC2H5 H H SC7H7 C2H5 H
(CH2)2oX~n-C4H9 COOC2H5 H H H SC7H7 H
CH2OXX~3 COOC2H5 H SC7H7 H H SC7H7
CH2COOCH3 COOC2H5 H SOC7H7 H H H
(CH2)3COO-i-C3H7 COOC2H5 H SOC7H7 C2H5 H
CH2CH2COOC2H5 COOC2H5 H H SOC7H7 H H
CH20XXH3 COOC2H5 H H CH3COO OCH3 H
(CH2)4COOC2H5 COOC2H5 H H OCH3 C6H5COO H
The benzyl ethers and benzylthio ethers tabulated
above are converted to the corresponding hydroxy and thiol
compounds by reaction with trifluoroacetic acid according to
the procedure of Example VII.
EXAMPLE XXIII
Eth~l 3-acetoxyethyl-7-ethoxy-8-benzyloxy pyrimidin[4,5-b]-
quinolin-4(3H)-one-2-carboxylate.
The procedure of Example XXI is repeated but using
bromoethyl acetate (969 mg., 5.8 millimoles) as alkylating
agent. The solid product which separates upon dilution of
the reaction mixture with water is filtered off, dried and
recrystalli~ed from ethanol (20 ml.) containing sufficient
acetonitrile to achieve solution.
In like manner, the following compounds are prepared
from the appropriate pyrimidin[4,5~b]quinolin~4(3H)-one com-
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1053674
pounds of the preceding example and the appropriate bromo-
alkanoate or bromoalkyl benzoate:
R3 ~ ~ ~ ~
Y R Rl R2 R3 R4 R5
(CH2)30COCH3 COOC2H5 H H C2H5 C7H7 H
CH2CH2000c6H5 H H OC2H5 OC7H7 H
CH2CH2oX~6H5 CC2H5 H H OC7H7 OCH3 H
CH2cH2ococ6H5 COO n C4Hg H H C7H7 CH3 H
CH2cH2ococH3 COOC2H5 H H OCH3 OC7H7 H
~CH2)40COC3H7 CC2H5 H H OC7H7 H H
(CH2)30COC2Hs COOC2H5 H OC7H7 0CH3 H H
CH2CH20COC2H5 COOC2H5 H H F OC7H7 H
CH2CH20COCH3 CH3 H H OC7H7 OCH3 H
(CH2)30oOC6H5 CH3 C6H5 H OCH3 OCH3 H
CH2CH20occH3 CH3 n-C4Hg C2H5 C7H7 H
CH2cH2ococ3H7 C2II5 H H OC7H7 0C7H7 H
CH2CH20COCH3 C2H5 CH3 H OCH3 OC7H7 Br
CH2CH20COCH3 COCH3 H H OC7H7 OCH3 H
CH2CH20COC6H5 COOCH2CH20H H OC7H7 OCH3 H
CH2CH200CCH3 COOC2H5 H H SC7H7 H H
(CH2)40XC2H5 COOC2H5 H H SC7H7 C2H5 H
CH2cH2oooc6H5 CC2H5 H H H SC7H7 H
CH2CH20coc3H7 COOC2H5 H H SC7H7 H H
CH2CH20xc6Hs COOC2H5 H H H SOC7H7 H
CH2CH2oX~H3 COO-n-C4Hg H H CH3COO OCH3 H
(CH2)40QCC2Hs CC2H5 H H C3H7CC0 OCH3 H
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Y R Rl R2 R3 _ 5 _
CH2CH2o~6H5 COOCH3 H HCOO OCH3 H H
(CH2)3Oox~3 COOC2H5 H H H C2H5COS H
CH2CH2~X~3H7 COOC2H5 H C6H5C OCH3 H
CH2CH20COCH3 CC2H5 H CH3COO H H
(CH2)4QCcc2H5 COOC2H5 H C6H5C H H
EXAMPLE XXIV
Ethyl-7-benzyloxy benzo[q]quinazolin-4(3H)-one-2-carboxylate.
A) 5-Benzyloxybenzo-isatoic anhydride
2-amino-5-benzyloxybenzoic acid (0.133 mole) is dissolved,
warming if necessary, in a mixture of water (50 ml.), concen-
trated hydrochloric acid (50 ml.) and dioxane (100 ml.).
Phosgene is passed into the solution with good stirring at
such a rate that bubbles of the gas escape slowly into an
ammonia scrubber attached to the reaction flask. The tempera-
ture is held below 50C., by regulating the rate of introduc-
tion of the phosgene. After passing phosgene into the mix-
ture for four hours, the residual phosgene is blown out by
passing air through the mixture. The mixture is cooled and
the product filtered off, washed with cold water and dried.
B) 2-Amino-6-benzyloxynaphthalene-3-carboxamide.
Ammonia is intermittently bubbled into a suspension
of the product of procedure A (2.25 millimoles) and ethanol
(80 ml.) for a period of two days. The bright green solid
which formed is filtered from the reaction mixture, dried and
then recrystallized from ethanol.
C) Ethyl-7-benzyloxybenzo[g]quinazolin-4(3H)-one-2-
carboxylate.
Diethyl oxalate (2.35 g., 16.1 millimoles), sodium
0 methoxide (10 mg.) and 2-aminonaphthalene-3-carboxamide
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(1.50 g., 8.05 millimoles) are mixed together and heated atreflux for two days. The mixture is then cooled in an ice
bath and the brown precipitate recovered by filtration.
D) The ester is hydrolyzed to the disodium salt as
follows:
The ester (3.92 millimoles) is added to 15% aqueous
sodium hydroxide (20 ml.) and the mixture stirred for two
days. It is then acidified at room temperature with 10%
hydrochloric acid to pH 2 and evaporated to dryness under re-
duced pressure. The residue is treated with methanol-water
~1:1, 50 ml.) and the suspension filtered to give 0.70 g. of
yellow crystals. The crystals are added to a saturated solu-
tion of aqueous sodium bicarbonate (35 ml.) and water (20
ml.). The mixture is stirred for a half-hour and the yellow
solid filtered off and dried.
E) Repetition of this hydrolysis procedure but using
potassium bicarbonate or ammonium bicarbonate in place of
sodium bicarbonate affords the dipotassium salt and the di-
ammonium salt.
EXAMPLE XXV
Alkyl Benzo[g]quinazolin-4(3H)-one-2-carboxylate.
The following alkyl benzo[g]quinazolin-4(3H)-one-
2-carboxylates are prepared from the appropriate reactants
by the procedure of Example XXIV.
~ NlCOR
R R2 ~`3 R4
-
OC~3 H SC7H7 H
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R R2 R3 R4
O-n-C3H7 SC7H7 H H
C2H5 H H SC7H7
C2H5 H OC7H7 H
OC2H5 OC7H7 H H
The thioethers are converted to the corre~ponding
sulfinyl derivatives by oxidation with hydrogen peroxide ac-
cording to the procedure of Example XIV.
Benzyl ether~ and benzylthio ethers are debenzyl-
ated by reaction with trifluoroacetic acid as described inExample VII to the corresponding hydroxy and thiol compounds.
EXAMPLE XXVI
enzotg]quinazolin-4(3H~-one-2-carboxamides.
Following the procedure of Example V but using the
appropriate 2-aminonaphthalene-3-carboxamide in place of 2-
aminoquinolin-3-carboxamide, the amides corresponding to ~he
ester products of Examples XXIV and XXV are prepared. The
compounds have the formula:
R3 ~ ~2
EXAMPLE XXVII
Benzo~g]quinazolin-4(3H)-one-2-hydroxamic acids.
The ester products of Example XXIV-XXV are convert-
ed to the corresponding hydroxamic acids by the procedure
of Example VI. The compounds have the formula:
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R4 ~ ~ CONHOH
EXAMPLE XXVIII
Repetition of the procedure of Example XVII but
using the appropriate 2-aminonicotinamide in place of 6,7-
dimethoxy-2-aminoquinoline-3-carboxamide produces the follow-
ing compounds:
R ~ HCH3
R2 R3 R4
CH3 SC7H7 H
CH3 SC7H7 CH3
CH3 SOc7H7* H
CH3 SOc7H7* CH3
CH3 OC7H7 H
OC7H~ H H
*Produced by oxidation of the corresponding
thioethers according to the procedure of Example XIV.
The benzyl ethers and benzylthio ethers listed
above are debenzylated by treatment with trifluoroacetic acid
to afford the corresponding hydroxy and thiol compounds ac-
0 cording to the procedure of Example VII.EX~MPLE XXIX
2-Ethylpyridot2,3-dl-pyrimidin-4(3H)-ones.
Concentrated sulfuric acid (0.5 ml.) is added to a
mixture of 2-aminonicotinamide ~0.24 g., 0.002 mole) in
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propionic anhydride (10 ml.) at 60~C. and the resulting mix-
ture stirred for one hour. It is then cooled to room tem-
perature and poured into water (25 ml.). The aqueous mix-
ture i5 stirred, made basic with 6N sodium hydroxide and
stirred overnight. Upon acidification to pH 5.0 with 10%
hydrochloric acid the desired product precipitates. It is
filtered off and dried.
The following compounds are prepared in like manner
from appropriate reactants:
l2
~ H
~ N ~ N ~ 2H5
R2 R3 R4
CH3 SC7H7 H
CH3 SC7H7 CH3
CH3 SOC7H7 H
~Prepared by oxidation of the corresponding thio
compound according to the procedure of Example XIV.
Debenzylation of the benzyl ethers and benzylthio
ethers by treatment with trifluoroacetic acid according to
the procedure of Example VII affords the corresponding
hydroxy and thiol compounds.
EXAMPLE XXX
2-Acetyl pyrimido[2,3-d]-pyrimidin-4~3H)-ones.
The products of Example XXIX are oxidized by
selenium dioxide substantially according to the procedure
of Example XIX to provide compounds of the formula:
1053674
R2 R
R3~H
N ~ CO-CH3
EXAMPLE XXXI
Repetition of the procedure of Example XXV but
using appropriate reactants produces the following compounds:
R2 Pl
R ~ NH
4~N~\NlcoRo
R R R3 R4
OC2H5 CH3 SC7H7 H
OCH3 CH3 SC~H7 CH3
OCH3 CH3 OC7H7 H
C2H5 OC7H7 H H
- ~ OC2H5 CH3 SC7H7* H
OCH3 CH3 SOC7H7 CH3
*Prepared by oxidation according to the procedure
of Example XIV.
Hydrolysis of the ester by the method of Example
XV-D produces the acid and disodium salt derivatives. De-
benzylation of benzyl ethers and benzylthio ethers in the
manner of Example VII affords the corresponding hydroxy and
thiol compounds.
EXAMPLE XXXII
The hydroxy and thiol compounds of Examples XXVIII-
XXXI are converted to acyloxy derivatives by the procedure
of Example XI. In this manner the formyloxy, acetoxy,
butyryloxy and benzyloxy derivatives are prepared.
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.
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EXAMPLE XXXIII
Pyrido[2,3-d] pyrimidin-4(3~)-one-2-carboxamides.
The procedure of Example V is repeated but using
the appropxiate 2-aminonicotinamide as reactant in place of
2-aminonaphthalene-3-carboxamide to produce the amides corre-
8ponding to the e8ters of Example XXXI.
EXAMPLE XXXIV
Pyrido[2!3-d] pyrimidin-4(3H)-one-2-hydroxamic acids.
The esters of Example XXXI are converted by the
procedure of Example VI to hydroxamic acids of the formula:
~2
N ~ ONHOH
EXAMPLE XXXV
The ester products of the preceding Examples are
converted to the corresponding acids by the procedure of
Example II-D and to the disodium, dipotassium and diammonium
~alt8 by the procedure of Example XXIV-D and XXIV-E.
The acids are converted to the calcium, magnesium,
aluminum, triethylamine, tri-n-butylamine, piperidine, tri-
ethanolamine, diethylaminoethylamine, N,N'-dibenzylethylene-
diamine and pyrrolidine by reaction with an equivalent amountof the appropriate base (Ca(OH)2, Mg(OH)2, Al(OH)3) or amine
in water or ethanol followed by filtration of the salt if
insoluble or by evaporation of the solvent if the salt iS
soluble therein.
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