Note: Descriptions are shown in the official language in which they were submitted.
This application is divided out of our Application Serial No. 268,164,
which relates to novel derivatives oE quinazolone having interesting pharmacol-
ogical properties.
Application Serial No. 268,164 discloses compounds of general formula
o
Il
- N ' ~
] t A ~ R (I)
and t1leir pharmaceutically acceptable salts [wherein A represents a group of
? ~ S~d/
the formula -CH=CH-, -6T.~fi~-, or -S-, Rl represents a hydrogen atom, an amino
or acetylamino group, a fused benzene ring or a carboxyl group, R2 represents a
cyano or tetrazol-5-yl group, a group of the formula -COR4 ~wherein R4 represents
a lower alkoxy, hydroxy, amino, hydroxylamino or tetrazol-5-yl-amino group) or,
when Rl represents a carboxyl group, can additionally represent a lower alkyl or
alkoxy group, or a fused benzene ring thereof.
The compounds of general formula I (as hereinbefore defined) and the
physiologically acceptable salts thereof possess interesting pharmacological
properties. In particular they show an anti-allergic effect and also a muscle-
relaxing (e.g. bronchodilating) and vasodilatory activity. The anti-allergic
properties of the compounds according to the invention make them suitable for
the prophylaxis and treatment of allergic diseases such as, Eor example, asthma,
hay-fever, conjunctivitis urticaria, eczema and atopic dermatitis. Tests which
we have conducted have shown that in the prophylaxis of asthma those compounds
of general Eormula I and physiologically acceptable salts thereo-f subjected to
testing have a longer duration of action coMpared to the known compound~cromo-
glycinic acid and also exhibit an activity when administered orally.
It will be appreciated that ~he salts of compo~mds of general formula
I (as hereinbefore defined) for use in medicine should be physiologically ac-
ceptable. Other salts however may be useful in the preparation of the compounds
according to the invention or the physiologically acceptable salts thereof.
The present application is direc-ted to compound of formula I in which
A is -CH=CI-I-, Rl is hydrogen and R2 is -COOH in the 2-position, i.e. the com-
pound ll-oxo-ll-H-pyrido[2,1-b]quinazoline-2-carboxylic acid, and its pharma-
ceutically acceptable salts.
Compounds of general formula I, including the compound of the present
invention, may be prepared according to the following processes, which processes
constitute further features of the present invention.
a) for the preparation of compounds o-f general formula I ~wherein Rl
represents a hydrogen atom, an acetylamino gro~p, a fused benzene ring, or a
carboxyl group, and R2 represents a tetrazol-5-yl or carboxyl group or, when
Rl represents a carboxyl group, R2 can additionally represent a lower alkyl or
alkoxy group or a fused benzene ring) reacting a compound of formula
A ~II)
~wherein A is as hereinbefore defined; R'l represents a hydrogen atom, an
acetylamino group, a fused benzene ring, or a carboxyl group; and X represents
a halogen atom)
with a compound of formula
Alkyl-02C ~,
Il J ;R 2 ~III)
H2N /~ /
(wherein R'2 represents a tetrazol-5 yl or carboxyl group or, when R'l represents
a carboxyl group, c~n additionally represent a lower alkyl or alkoxy group or a
fused benzene ring).
Thus, to ~btain ll-oxo-ll-H-pyrido[2,1-b]quinazoline-2-carboxylic acid
a compound oE Eormula
~ N
l~ X
is reacted with a compound of formula
Alkyl 02C "`r' COOH
H2N ~'~
In the compounds of formula II X preferably represents a fluorine,
chorine or bromine atom.
The reaction is preferably effected at an elevated temperature, and
advantageously at a temperature of from 120 to 160C. If desired it may be ef-
fected without a solvent or in a high boiling solvent, for example dimethyl-
formamide, or sulfolane. It is useful to add an acid-acceptor, for example an
excess of the compound oE formula III.
The starting materials used for this process are known and may be ob-
tained by conventional processes.
b) for the preparation of compounds of general formula I ~wher0in A re-
presents a group of the formula -CII-CH- or -CH~N-; Rl represents a hydrogen atom
or a carboxyl group; and R2 represents a carboxyl group or, when Rl r~presents a
carboxyl group, can additionally represent a lower alkoxy group) oxidising a com-
pound of formula
~-N 3 ~
R"l ~ ~~ R"2 (IV)
A' / N ~ \ /
Acyl
(wherein A' represents a group of the formula -CH=CH- or -CH=N-, R'll representsa hydrogen atom or a carboxyl grcup; and R"2 represents a carboxyl group or,
when Rl represents a carboxyl group, can additionally represent a lower alkoxy
group) and subsequently acidifying the compound thereby formed.
Thus, ll-oxo-ll-H-pyrido[2,1-b]quinazoline-2-carboxylic acid is ob-
tained by oxidizing a compound of formula
H3C COOH
N \ _'~
Acyl
The oxidation is generally efEected at an elevated temperature with
for example, potassium permanganate in an aqueous solution buffered with magnesi-
um sulfate. The acidification may if desired be effected with mineral acids,
for example hydrochloric acid, or with organic acids, Eor example acetic acid.
The starting materials of formula IV for use in this reaction may be
produced by conventional methods. If R"l and/or R"2 in the compound of formula
IV represent carboxyl groups, the compound may also be produced in situ from the
corresponding methyl compound or from compounds with other groups convertible,
under the reaction conditions, into the carboxyl group.
c) for the preparation of compounds of general formulaI converting a com-
pound of formula
N ~ -
A / ~ N J ~ (V)
-- 4 --
(wherein A is as hereinbefore defined, Q represents the group Rl
or a group readily converti.ble thereto and R represents the group
R2 or a group readily convertible thereto) into a compound of
formula I.
When ll-oxo-ll-H-pyrido[2,1-b]quinazoline-2-carboxylic
acid is to be obtained Q is hydrogen or a group readily convertible
thereinto and R is in the 2-position and is a carboxyl group or a
group readily convertible thereinto~
Conversion may be effected by conventional methods. For
example, compounds of general formula I (wherein Rl and/or R2
represent amido or tetrazole-5-yl-amido groups) may be prepared
from the compound of formula V wherein Q and/or R represent chloro-
carbonyl groups by reaction with ammonia or aminotetrazole.
Similarly, the corresponding hydroxamic acids and esters of the
compounds of general formula I can be prepared by reacting chloro-
carbonyl derivatives of the compound V with hydroxylamine or a
lower alcohol respectively. Reacting a compound of formula V
wherein Q and/or R represents a cyano group with sodium azide
will yield a compound of formula I wherein Rl and/or R2 represent
tetrazole-5-yl groups. Cyano compounds of formula I may be obtain-
ed by dehydration of the corresponding carbamoyl compounds of
formula V, and carboxyl compounds by the saponification of com-
pounds of formula V wherein Q and/or R represent ester or amide
groups. Carboxyl compounds may also, if desired, be obtained by
the oxidation of compounds of formula V wherein Q and/or R repre-
sent methyl groups, for example with potassium permanganate. For
the preparation of compounds of formula I (wherein Rl or R2 repre-
sents an amino group), a compound of formula V (wherein Q or R
represents an acylamino group) may, for example, be subjected to
acid or alkaline saponification.
(d) oxidizing a compound of formula
~ N ~ CH3
11 1 11
N
Acyl
Suitable conditions for the oxidation are those described in
respect of process (b) above.
The products obtained from processes (a) to (d) may be
subsequently conver-ted, if desired, into acid addition salts or,
when Rl and/or R2 represent carboxyl groups, into salts with
organic or inorganic bases. If salts of the
~ 5a -
compounds of formula I (as hereinbefore defined) are first obtained, the free
compounds can readily be liberated by conventional techniques.
Suitable acids for the preparation of acid addition salts of the com-
pounds of formula I (as hereinbefore defined) include, Eor example, hydrochloric
acid, hydrobromic acid, sulphuric acid, phosphoric acid, lactic acid, citric
acld and maleic acid. Suitable bases for the preparation of basic salts are
for example sodium hydroxide or potassium hydroxide.
In addition to the use of the novel compounds according to the inven-
tion directly in medicine, they may also serve as intermediate products for the
production of other pharmaceutically active agents.
According to a further feature of the invention there are provided
pharmaceutical compositions comprising~ as active ingredient, a compound of
formula I as hereinbefore defined or a physiologically acceptable salt thereof
in association with a pharmaceutical carrier or excipient.
The pharmaceutical compositions according to the invention can, for
example, be in a form suitable for oral, rectal, parenteral, pulmonary or topical
administration. Suitable forms of administration being~ for example, capsules~
tablets~ coated t~iblets, solutions, suspensions, aerosols, sterile isotonic solu-
tions, creams, ointments, lotions, emulsions, sprays or suppositories.
If desired, the compositions according to the invention can be in dos-
age unit form. When administered by the pulmonary route, each dosage ~mit pre-
ferably comprises 20 to 500~g/kg of the active ingredient, for oral administra-
tion 1 to 50 mg of the active ingredient and -for intravenous administration 0.2
to 10 mg of the active ingredient. For nasal or ocular administration each dos-
age unit preferably comprises 0.5 to 25 mg of active ingredient. In general,
the specific dose administered depends on the nature of the condition which is
to be treated.
Tablets may, for example, be obtained by mixing the active ingredient
with known excipients, for example with inert diluents such as calcium carbonate,
magnesium stearate or talcum and/or agents for obtaining sustained release, such
as carboxypolymethylene, carboxymethyl cellulose, cellulose acetatephthalate or
polyvinyl acetate. The tablets may, if desired, consist of several layers, for
example to obtain sustained release or to avoid incompatibilities.
Coated tablets may be obtained by coating tablet cores prepared ana-
logously to the tablets described above, with agents commonly applied for tablet
coating) for example, polyvinylpyrrolidone, shellac, gum arabic, talcum, titani-
um dioxide or sugar. To obtain sustained release or for avoiding incompatibili-
ties the core may also consist of several layers. The tablet coating may also
consist of several layers whereby the excipients mentioned above for tablets may
be used.
Capsules comprising the active ingredient according to the invention
may be produced, for example, by mixing the active ingredient with inert carriers
such as lactose or sorbitol and filling gelatin capsules with the mixture.
For pulmonary administration, the active ingredient according to the
invention may be conveniently combined with conventional aerosol formulations
and filled into spray cans, preferably cans provided with metering means. The
active ingredients may also, if desired, be made into aerosol formulations in
micronised form ~generally with a particle si~e of 2 to 6 ~m), optionally with
the addition of micronised carriers such as lactose. These formulations may be
filled into hard gelatine capsules, Conventional devices for powder inhalation
are generally used, and into each capsule preferably 2 to 40 mg of active in-
gredient and 0 to 40 mg of lactose are filled.
The following examples illustrate the inventions of this application
and Application Serial No. 268,164. It will be appreciated by those skilled in
the art that although some of the preparative examples illustrate preparation of
compounds of formula I other than the compound of the present invention~ the com-
pound of the present invention could readily be prepared by analogous methods.
Further, some compounds of formula I can be used as starting material for pre-
paration of the compound oE the invention by process (c).
Example 1
5-Oxo-5-H-thiazolo[2,3-b]quinazoline-7-ethylcarboxylate
~ N ~ COOCH2-CH3
2.4 g of 2-chlorothiazole are heated with 5.6 g of 4-amino-ethyl isophthalate in
an oil bath to 150C for 8 hours. The resulting dark brown oil is then refluxed
with 10 ml of acetonitrile for 1 hour, cooled and the crystals obtained removed
by suction filtration. By recrystallization from a little methanol the title
compound is obtained.
Melting point: 148 - 155C (pale yellow needles).
Analysis: C13HlON2S03
C % H % N % S %
calc: 56.93 3.65 10.22 11.68
found: 56.87 3.82 10.21 11.82
~xample 2
8-Oxo-8-H-isoquino~1,2-b]quina7,oline-10-ethyl carboxylate
~,J~ COOCHZ-CH3
4.97 g of l-chloroisoquinoline are mixed with 14.4 g of 4-amino-ethyl iso-
phthalate and heated slowly to 150C. The molten mixture solidifies after about
45 minutes. After addition of 50 ml of ethanol, it is refluxed for 1 hour~
cooled and the product removed by suction filtration. The hydrochloride is ob-
tained, from which the free base is liberated in water with the calculated quan-
tity of sodium bicarbonate and extracted with chloroform. After evaporating and
purifying the compound over a silica gel column, lemon-yellow crystals are ob~
tained (m.p. 205 - 210C).
AnalYsis: ClgH14~23
C % I-l % N %
calc: 71.70 4.40 8.81
found: 71.58 4.40 8.68
_ g _
Exam~le 3
12-Oxo-12-H-quino~2,1-b]quinazoline-10-ethyl carboxylate
\ ~ N ~ - COOCH2-CH3
4.1 g of 2-chloroquinoline are reacted with 11.9 g of 4-amino-ethyl iso-
phthalate, as described in Example 2, and worked up. The compound thus obtained
has a melting point of 157 - 163C.
Analysis: C19H14N2O3
C % H % N % O %
calc: 71.70 4.40 8.81 15.09
found: 71.70 4.17 8.67 15.95
Example 4
ll-Oxo-ll-H-2-methyl-pyrido L2,1-b]quinazoline-8-carboxylic acid
~!` ~
N
4.37 g of 6-chloronicotinic acid are heated with 4.53 g of 5-methyl-anthranilic
acid to 150C. After several minutes the reaction product solidifies, it is
then boiled with 5 times its volume of concentrated hydrochloric acid cooled,
-- 10 -
removed by suction filtration and washed with water and acetonitrile. The re-
sulting hydrochloride is suspended in water and dissolved with the quantity of
sodium bicarbonate calculated Eor the sodium salt. On acidi-fying this solution
with acetic acid the desired product precipitates.
AnalYsis: C14lll0N2 3
C % H % N %
calc: 66.14 3.94 11.02
found: 66.19 4.09 11.11
Example 5
_3-Oxo-13-H-benzo[g]pyrido[2,1-b~quinazoline-10-carboxylic acid
HOOC _ ~ N
~ ~ N ' ~ , ~
1.32 g of 6-chloronicotinic acid are heated with 1.8 g of ethyl 2,3-amino-
naphthoate to 160C. The melt, solidifying after a short time, is boiled with
100 ml of ethanol and the obtained crystals are heated in 20% sodium hydroxide
solution for 2 hours. After addition of ethanol the solution is filtered, acidi-
fied with glàcial acetic acid and the crystals are removed by suction filtration.
The hydrochloride (yellow crystals) is obtained from the free base by acidifying
with hydrochloric acid.
Analysis 17 10 2 3
C % H % N % Cl %
calc: 62.48 3.37 8.58 10.87
found: 62.62 3.50 8.33 10.02
Example 6
ll-Oxo-ll-H-2-methoxy-pyrido~2~l-b~quinazoline-8-carboxylic acid
HOOC ~ OCH3
1.58 g of 6-chloronicotinic acid are heated with 3.9 g of ethyl 5-methoxy-
anthranilate to 160C and processed as described in Example 5. The compound is
isolated as the hydrochloride and melts above 300C.
Analysis C14H10N2~ HCl
C % H % N % Cl %
calc: 54.81 3.59 9.14 11.58
found: 54.78 3.66 8.94 11.56
The following compounds are obtained by processes analogous to
Examples 1 to 6:
ll-oxo-ll-H-pyrido[2,1-b]quinazoline-8-carboxylic acid,
6-oxo-6-H-pyrimido[2,1-b]quinazoline-8-carboxylic acid,
12-oxo-12-H-quino[2,1-b]quinoazoline-10-carboxylic acidJ
ll-oxo-ll-H-pyrido[2,1-b]quinazoline-3-carboxylic acid.
Example 7
ll-Oxo-ll-H-pyrido[2,1-b]quinazoline-2-carboxylic acid
o
\ COOH
- 12 -
4~
Molar quantities of 2,4-dimethylaniline and 2-bromopyridine are condensed at
160 to 180C and 2,4-dimethyl-N-pryidyl-(2)-aniline (having a melting point af-
ter purification via the fumarate of 65 to 68C) is obtained. Heating it with
acetic anhydride gives N-pyridyl(2)-N-2,4-dimethylphenyl-acetamide. 60 g of
this acetamide are oxidized with 218 g of potassium permanganate and 75.5 g of
magnesium sulfate in 2 1 of water between 40 and 90C.
The manganese dioxide produced is removed by suc~ion filtration and
the mother liquor acidified with acetic acid. The compound that crystallises
out slowly is removed by suction filtration.
After stirring for one hour with 5 times its quantity of concentrated
hydrochloric acid at 60 to 70C, it is diluted with 10 times its quantity of
water. The ll-oxo-ll-H-pyrido[2,1-b]quinazoline-2-carboxylic acid precipitates
gradually, and after removal is washed with water and acetonitrile
Analysis: C13H8H203
C % H % N %
calc: 65.00 3.33 11.67
found:64.95 3.46 11.58
a)Sodium Salt
From the obtained pyrido-quinazolone carboxylic acid, the sodium salt
is obtained in water with the calculated quantity of sodium bicarbonate and sub-
sequently precipitated with ethanol.
b) Ethanolamine Salt
1.2 g of the obtained pyrido-quinazoline-carboxylic acid are suspended
in 3 ml of water, 0.31 ml of ethanolamine are added and the ethanolamine salt is
precipitated with acetonitrile.
Analysis: C15H15N304 2
- 13
C % H % N %
calc: 56.43 5.33 13.17
found: 57.25 4.96 13.46
c) Triethanolamine Salt
Erom 2.4 g of pyrido-quinazoline carboxylic acid suspended in 20 ml
of acetonitrile, the above salt is produced with 3.6 g of triethanolamine
(approx. 85%). (decomposition >200C)
Analysis: C19ll23N3O6
C % H % N %
calc: 58.61 5.91 10.80
found: 58.80 5.72 11.00
Exam~
ll-Oxo-ll-H-pyrido[2,1-bJquinazoline-3-carboxylic acid
N ~ ~ ~
~\ J ~ N / ~ /,J COOH
Analogous to Example 7, 2,5-dimethylaniline and 2-bromo-pyridine are reacted via
the N-pyridyl(2)-N-(2,5-dimethylphenyl)acetamide and oxidation with potassium
permanganate to ll-oxo-ll-H-pyrido[2,1-b]quinazoline-3-carboxylic acid.
Analysis: C13H8N2O3
C % H % N %
calc: 65.50 3.33 11.67
found: 65.24 3.21 11.79
- 14 -
Example 9
6-Oxo-6-H-pyrimido[2,1, b]quinazoline-8-carboxylic acid
o
I COOH
N N
9.5 g of 2-aminopyrimidine are heated with 18.5 g of 4-bromo-m-xyline, 13.8 g
of potassium carbonate and 0.5 g of copper powder to 180C for 5 hours. The
reaction mixture is then diluted with water, extracted with ether and after
evaporating the solvent, 2,~-dimethyl-N-pyrimidyl-~2)-aniline ~m.p. 95 - 99C)
is isola~ed.
As described in Example 7 for the analogous pyridyl compound, it is
acetylated, oxidized with po~assium permanganate, cyclized and the 6-oxo-6-H-
pyrimido[2,1-b]quinazoline-S-carboxylic acid hydrochloride is obtained.
nalysis C12 7 3 3 Cl
C % H % N %
calc: 51.89 2.88 15.33
found: 51.89 3.03 15.87
From the hydrochloride, the sodium salt is obtained in water wi~.h
2 mol of sodium bicarbonate and precipitating with ethanol.
Analogously to Examples 7 to 9, 11-oxo-11-H-2-methoxypyrido[2,1-b]-
quinazoline-8-carboxylic acid ~which may be converted into its salts) may be
obtained.
Example 10
8-Acetamido-ll-H-ll-oxo-pyrido[2,1-b]quinazoline-2-carboxylic acid
By reacting 23.8 g of 2-chloro-5-nitropyridine with 19 g of 2,~-
- 15 -
dimethylaniline at 160C, 2,4-dimethyl-N-5-nitropyridyl-~2)-aniline is ob-
tained, from which after reduction with 76 g of tin-(II)-chloride and acetylat-
ing with 210 ml oE acetic anhydride, N-(5-diacetylaminopyridyl-(2))-N-(2~4-
dimethylphenyl)acetamide is obtained. 9.5 g of this compound are stirred with
26.5 g oE potassiu]n permanganate c~ld 3.5 g of magnesium sulfate in a water-
butanol mixture (2:1) for 4 hours at 80 to 85C. After suction filtration and
evaporating, the residue is heated with dilute acetic acid for 1 hour, whereby
8-acetamido-11-H-ll-oxo-pyrido[2,1-b]quinazoline-2-carboxylic acid gradually
crystallises out. It is removed by suction filtration and washed with acetoni-
trile and ether.
Analysis: ClsHllN3O4 2
C % H % N % H2O %
calc: 57.14 4.76 13.33 5.7
found: 57.68 4.69 13.15 4.1
Example 11
Methyl ll-oxo-ll-H-pyrido[2,1-b]quinazoline-2-carboxylate
~ COOCH3
6.2 g of the 11-oxo-11-H-pyrido[2,1-b]quinazoline-2-carboxylic acid produced in
Example 7 are refluxed in ten times its quantity of thionyl chloride for 1 hour.
The insoluble carboxylic acid chloride is sucked off and refluxed in 10 to 20
times its quantity of methanol until complete solution. After cooling~ the
methyl ll-oxo-ll-H-pyrido[2,1-b]quinazoline-2-carboxylate hydrochloride crystal-
lizes out with one mol. of methanol (decomposition point 254C).
- 16 -
~ ~ 9~
AnalysisC14H10N23 HCl . CH3
C % H % N % Cl %
calc:55.81 4.65 8.68 11.01
found:55.53 4.35 8.32 11.29
Example 12
ll-Oxo~ll-H-pyrido~2,1-b]-N-(l-H-tetrazole-5-yl)quinazoline-2-carboxamide
o
N ~ - C - NH ~
/ ~ N ~ N - N
5.53 g of the 11-oxo-11-H-pyricdo[2,1-b]quinazoline-2-carboxylic acid chloride
hydrochloride procluced as in Example 11 are dissolved with 2.1 g of amino-
tetrazole hydrate, 6.1 g of triethylamine and 200 ml of dimethylformamide at
0 to 10C and stirred for 3 hours. Afterwards acetic acid is added to the re-
action mixture until acid and the product removed by suction filtration ~de-
composition point 330C).
Analysis: C14HgN702
C % H % N %
calc: 54.72 2.93 31.92
found: 54.93 3.17 31.63
Example 13
ll-Oxo-ll-H-pyrido[2,1-b]quinazoline-2-carboxamide
o
;
As in Example 11, the carboxylic acid chloride is produced from 10 g of ll-oxo-
ll-H-pyrido[2,1-b]quinazoline-2-carboxylic acid. It is then stirred in a mixture
of 200 ml of dioxan and 50 ml of conc. ammonia for 5 hours at room temperature.
AEterwards, dilute acetic acid is added to the reaction mixture until acid and
the crystals removed by suction filtration.
Analysis: C13H9N3O2
H % N %
calc: 65.27 3.77 17.57
found: 65.00 3.6~ 17.38
Example 14
_Cyano-ll-oxo-ll-H-pyrido[2,1-b~uinazoline
N ~ -- ~ CN
~ N ~
4.8 g of 11-oxo-11-H-pyrido[2,1-b]quinazoline-2-carboxamide (Example 13) are
suspended in 150 ml of dimethylformamide and 3.3 ml of thionyl chloride are
added drop~ise. When the addition is completed the reaction mixture is stirred
at 90 to 110C for 10 hours. It is then neutralized with dilute sodium carbonate
solution and suction filtered.
By recrystallization from dimethylformamide, 2-cyano ll-oxo-ll-H-
pyrido[2,1-b]quinazoline is obtained. ~decomposition 268 - 271C).
Analysis: C13H7N30
C % H % N %
calc: 70.59 3.17 19.00
found: 70.42 3.04 19.00
Example 15
ll-Oxo-ll-H-pyrido[2,1-b]-2-(lH tetrazole-5-yl)quinazoline
\ N - N
5.2 g of 2-cyano-11-oxo-11-H-pyrido[2,1-b~quinazoline ~Example 1~), 1.8 g of
sodium azide and 1.5 g of ammonium chloride are heated in 60 ml of dimethyl-
formamide for 10 hours to 90 to 110C.
The mixture is acidified with diluted acetic acid and the tetrazo]yl-
quinazoline product is removed by suction filtration.
Analysis: C13H8N6O
C % H % N %
calc: 59.09 3.03 31.82
found: 58.88 3.26 31.96
Example 16
ll-Oxo-ll-H-pyrido[2,1-b]-quinazoline-2-hydroxamic acid
o
Jl
N I C - NH - OH
~ N ~
5.9 g of 11-oxo-11-H-pyrido[2,1-b]quinazoline-2-carboxylic acid chloride hydro-
chloride produced according to Example 11 are dissolvsd in 2.08 g o hydroxyl-
amine hydrochloride, 9.8 ml of diisopropylamine and 100 ml of dimethyl formamide
- 19 -
at 20C and stirred for 5 hours. After acidification with dilute acetic acid
the product is removed by suction filtration.
Analysis: C13H9N3 1/2 ~12
C % 11 % N %
calc:59.09 3.79 15.91
found:59.20 3.70 15.49
Example 17
12-Oxo-12-H-quino~2,1b~quinazoline-10-carboxylic acid
~ ~ N i ~ COOH
2.8 g of 12-oxo-12-H-quino[2,1-b]quinazoline-10-ethyl carboxylate, produced as
described in Example 3, are refluxed in 20 ml of 10 % sodium hydroxide solution
or 30 minutes. The solution is heated with 5 times its quantity of semi-
concentrated hydrochloric acid for half an hour in a boiling water-bath. After
diluting with water the precipitated yellow crystals are removed by suction
filtration and washed with water and acetonitrile.
Analysis: C17HloN203
C % H % N % O %
calc:70.34 3.45 9.66 16.55
found: 70.23 3.50 9.53 17.02
Analo~ously with Examples 11 to 17, the following compounds are ob-
tained:-
- 20 -
5-oxo-5-H-thiazoloL2,3-b]quinazoline-7-ethyl carboxylate;
8-oxo-8-H-isoquino[1,2-b]quinazoline-10-ethyl carboxylate;
12-oxo-12-H-quino[2,1-b]quinazoline-10-ethyl carboxylate;
ll-oxo-ll-H-2-methyl-pyrido[2,1-b]quinazoline-8-carboxylic acid;
13-oxo-13-H-benzo~glpyrido[2,1-b]quinazoline-10-carboxylic acid;
ll-oxo-ll-H-2-methoxy-pyrido[2,1-b]quinazoline-8~carboxylic acid;
ll-oxo-ll-H-pyrido[2,1-b]quinazoline-3-carboxylic acid;
6-oxo-6-H-pyrimido[2,1-b]quinazoline-8-carboxylic acid;
5-oxo-5-H-thiazolo[2,3-b3quinazoline-7-carboxylic acid;
8-oxo-8-H-isoquino[1,2-b]quinazoline-10-carboxylic acid;
ll-oxo-ll-H-pyrido[2,1-b]quinazoline-2,8-dicarboxylic acid.
I`he above compounds may also be isolated as their acid addition salts
preferably with strong acids. Those containing a carboxyl group may also be
converted into the corresponding basic addition salts e.g. with alkalis or with
alkyl amines.
Example 18
8-Amino-ll-H-ll-oxopyrido-[2,1-b]quinazoline-2-carboxylic acid
3.4 g of 8-acetamido-11-H-ll-oxopyrido[2,1-b]-2--carboxylic acid pro-
duced as in Example 10 are heated in a boiling water-bath with 30 ml of a mix-
ture of water with concentrated sulfuric acid ~2:3) for 30 minutes. The reaction
mixture is diluted with water, cooled and suction filtered. The 8-amino-11-H-
ll-oxopyrido-[2,1-b~quinazoline-2-carboxylic acid thus obtained is purified by
dissolving in soda solution, precipitated with glacial acetic acid, suction
filtered and washed with acetonitrile and ether.
Analysis: C13HgN33 H2
C % H % N % H2O %
calc: 57.14 4.03 15.38 6.6
found: 56.95 4.09 15.29 7.1
- 21 -
Example I: Tablets
Composition:
a) ll-oxo-ll-H-pyrido[2,1-b]quinazoline-
2-carboxylic acid 0.100 g
stearic acid 0.010 g
glucose 1.890 g
2.000 g
b) active ingredient according to the invention 0.200 g
stearic acid 0.020 g
glucose _780 g
2.000 g
The components are processed in the conventional way to produce
tablets of the composition indicated above.
Example II: Ointments
Composition: g/100 g ointment
active ingredient acc. to invention 2.000
fuming hydrochloric acid 0.011
sodium pyrosulfite 0.050
mixture of equal parts of cetyl alcohol
and stearyl alcohol 20.000
white vaseline 5.000
artificial Bergamotte oil 0.075
distilled water a~ lOO.00
The components are processed to produce an ointment in the usual way.
- ~2 -
Example III: Inhalation Aerosol
Composition:
sodium salt of ll-oxo-ll-H-pyrido-
[2,1-b]quinazoline 2-carboxylic acid 1.00 parts
soya lecithin 0.20 parts
propellant gas mixture
(Frigene* 11, 12 and 114)ad 100.00 parts
The preparation is filled into aerosol containers with metering means
in such a way that a dose of 5 mg of active ingredient is released. For higher
doses preparations with a higher content of active ingredient are used.
Example IV: Ampoules (Injection Solutions)
Composition:
13-oxo-13-H-benzo[g]pyrido~2,1-b]-
quinazoline-10-carboxylic acid10.0 parts by weight
sodium pyrosulfite1.0 parts by weight
disodium salt of ethylene diamine-
tetraacetic acid0.5 parts by weight
sodium chloride8.5 parts by weight
doubly distilled waterad 1000.0 parts by weight
The active ingredient and excipients are dissolved in a sufficient
quantity of water and brought to the desired concentration with the required
quantity of water. The solution is filtered and filled into 1 ml ampoules
under aseptic conditions. The ampoules are sterilized and sealed. Each
ampoule contains 10 mg of active ingredient.
