Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ 3 Q~152
THIOXOPYRAZOLO[1,5-c]QUINAZOLINE
DERIVATIVES AND RELATED COMPOUNDS
The present invention relates to thioxopyrazolo-
[1,5-c]quinazoline derivatives of the structure
s 5 f J/l r
wherein Rl is hydrogen or lower alkyl; R2 is carboxyl,
: 10 hydroxymethyl, lower alkanoyloxymethyl or lower alkoxy-
carbonyl; R3 is hydrogen, lower alkyl or benzyl; R4 and
R5 are the same or different and are selected from
hydrogen, alkyl of 1 to 4 carbons, alkoxy of 1 to 4
. carbons, hydroxy, lower alkanoyloxy of 1 to 4 carbons,
nitro, halogen, trifluoromethyl, benzyloxy, or benzyloxy
having a lower alkoxy, halogen, hydroxy, nitro or tri-
fluoromethyl substituent; and physiologically acceptable
salts thereof.
Throughout this specification, the symbols are as
defined above in connection with Formula I.
Preferred are those compounds of Formula I wherein
R is carboxyl or lower alkoxycarbonyl, Rl is hydrogen,
R is hydrogen, R4 and R5 are hydrogen.
Unless otherwise indicated the term "lower alkyl"
or "alkyl" as employed herein includes both straight
- and branched chain radicals of up to eight carbon
atoms, for instance~ methyl, ethyl, n-propyl, isopropyl,
~ n-butyl, t-butyl, isobutyl, n-pentyl, n-hexyl, isohexyl,
- n-heptyl, 4,4-dimethylpentyl, n-octyl, 2,2,4-trimethyl-
pentyl, and I:he like.
.
- , ~
QAl52
Unless otherwise indicated, the term "lower alkoxy"
or "alkoxy" includes s-traight and branched chain radicals
which correspond to the above lower alkyl groups
attached to an oxygen atom.
- 5 Unless otherwise indicated, the term "lower
` alkanoyl" or "alkanoyl" as employed herein includes any
of the above lower alkyl sroups linked to a carbonyl
group.
The term "benzyloxy" refers to a radical of the
structure
-,. -O-CH2{ ~ xl
:
(Xl is hydrogen, hydroxy, lower alkoxy, (1-4 carbons),
halogen, CF3 or NO2).
The compounds of Formula I of the invention may be
prepared by several methods.
One method involves preparation of compounds of the
structure
Rl COOH
II R4
~ N
R _
13
- R
wherein Rl, R3, R4 and R5 are as defined hereinbefore.
The Formula II compounds are prepared by reacting
compounds of the structure
.
:,
.~,
QA152
~'
III
. R / COOH
` 5
H
R 13
-~ with carbon disulfide in the presence of a base, such
as alkali metal hydroxide, alkaline earth metal hydroxide
or quaternary ammonium hydroxide or a heterocyclic
amine, such as pyridine, preferably at reflux under
nitrogen for periods of l to 48 hours.
The Formula III compounds may be prepared as
described in U.S. Patent No. 3,895,027 to Katner.
The Formula II acid compounds of tne invention
may be employed to prepare the ester compounds of
Formula IV of the invention, namely,
IV Rl COAlkyl
R5
R4 ~ ¦ ~ S
by reacting the Formula II acid with phosphorus penta-
chloride in the presence of an inert solvent, such as
' halogenated hydrocarbons, for example, methylene
chloride, chloroform or trichloroethylene to form the
intermediate acid chloride
': . ' , ' : ' ' ' .
.
~ QA152
`
;~ V
R COCl
R
R IN3 ~S
R
The acid chloride V is reacted with a lower alkanol
(alkyl-OII) at reflux under n:itrogen for 1 to 4 hours
to form the Formula IV esters.
The Formula IV esters may also be prepared from
the corresponding ester analog of Formula VI (disclosed
in U.S. Patent No; 3,897,434 to Katner).
VI 4 R ~ ~ COOAlkyl
R N
~ N,
~ N ~ O
R R3
The Formula VI esters are reacted with phosphorus penta-
sulfide in the presence of a base, such as pyridine or
an inorganic alkali metal or alkaline earth metal hy-
droxide as set out hereinbefore, preferably under an
inert atmosphere, for periods ranging from 0.5 to 48
hours to form the Formula IV esters of the invention.
The Formula IV esters may be employed in preparing
the corresponding hydroxyl derivatives of Formula VII
~ QA152
:~ 5
~: R C~l2OH
VII R5 ~ ;
H ~S
by reducing the Formula IV esters with metal hydrides,
such as aluminum hydride; substituted me-tal hydrides,
such as diisobutyl aluminum hydride; complex metal
hydrides, such as magnesium aluminum hydride, sodium
aluminum hydride, aluminum borohydride, sodium boro-
~ hydride, li-thium borohydride r calcium borohydride and
the like J alkoxyaluminum hydrides, such as sodium
di-(2-me-thoxyethoxy)aluminum hydride and the like.
The reaction can be run in inert non-hydroxylic
oryanic solvents, such as e-ther (4-12 carbons), ~or
~- example, diethyl e-ther, diisopropyl ether, diphenyl
: ether, te-trahydrofuran, dioxane, 1~2-dimethoxyethane
and the like; saturated hydrocarbons (6-10 carbons),
such as n-hexane, cyclohexane; aromatic hydrocarbons
(6-10 carbons), such as benzene, toluene, xylene;
halogenated hydrocarbons (1-4 carbons), such as
methylene chloride, chloroform, dichloroethane, tetra-
chloroethane; or, where compatible with the less
reactive reducing agents, such as sodium borohydride,
in alkanols (1-6 carbons) such as methanol, isopropanol
: or, preferably, ethanol, at a temperature of 25C to
reflux for O.S hour to 48 hours.
.`. Compounds of Formula VIII of the invention
. .
:
QA152
VIII
.'- R1 11
4 ~CH20CA1kY1
: R~ N~l IN
1 1
~` R ~~1 ~ S
R
may be prepared by reacting compounds of Formula VII
with a lower alkanoic acid under an inert atmosphere
preferably at reflux tempera-ture.
Certain of the compounds of Formula I may form
physiologically acceptable acid-addi-tion salts or base
addition salts with inorganic and organic acids or
alkali metal or al]saline earth metal bases such as
sodium bicarbonate, sodium hydroxide or calcium
hydroxide. These salts frequently provide useful
means for isolating the products from reaction
mixtures by forming the salt in a medium in which it
is insoluble. The free base may then be obtained by
neutralization, e.~., with a base or acid. Then any
other salt may again be formed from the free base and
the appropriate inorganic acid or base. Illustrative
are the hydrohalides, especially the hydrochloride and
hydrobromide which are preferred, sulfate, nitrate,
:
phosphate, oxalate, tartrate, maleate, fumarate,
citrate, succinate, methanesulfonate, benzenesulfonate,
toluenesulfonate, and the like.
`.
'
QA152
The compounds of Formula I, and their pharmaceuti-
cally acceptable salts, are useful in -treating various
allergic conditions in mammalian species such as mice,
cats, dogs, etc., when administered in amounts ranging
from about 1 milligram to about 500 milligrams per
kilogram of body weigh-t per day. The compounds can be
used prophylactically or therapeutically to treat
various allergic and immunological disorders and in
particular to treat certain types of asthma, hay-fever,
and rhinitis. A preferred dosage regimen would be from
about 3 milligrams to about 200 milligrams per kilogram
of body weight per day administered in a single dose
or plurality of divided doses.
The compounds of Formula I, and the pharmaceuti-
cally acceptable salts thereof, are anti-allergics
which inhibit the effects of certain antigen-antibody
reactions and in particular inhibit the release of
mediators such as histamine. The anti-allergy activity
. of these compounds is determined by -the reaginic
antibody induced passive cutaneous anaphylaxis (PCA)
reaction in rats. (See Bach, Immediate Hypersensitivity:
Laboratory Models and Experimental Findings, Ann. Rep.
Med. Chem., 7:238-2~8 (1972), for a discussion of the
predictability of clinical efficacy of compounds
active in the PCA).
A compound of Formula I, or a salt thereof, can be
administered by the inhalation of an aerosol or powder
as described in U.S. Pat. No. 3,772,336 (i.e., breathing
` finely divided particles of the active ingredient into
the lungs), orally, or parenterally. Powders can be
.
QA152
:
~3
prepared by comminuting the active ingredient with a
similarly comminu-ted diluent such as starch or lactose.
Suitable forms for oral administration include
capsules, tablets, and syrups, and a suitable form for
parenteral administration is a sterile injectable.
Such unit dosage forms are prepared by compounding
with a conventional vehicle, excipients, binders,
preservatives, stabilizers, flavoring agents or the
like as called for by acceptable pharmaceutical
practice. Also, -the compounds of this invention can
be formulated with other pharmaceu-tically active com-
pounds such as bronchodilators, steroids, antihistamines,
etc.
The compounds of the invention are also useful as
antiinflammatory agents as determined by the reverse
passive arthus -test [Agents & Actions, 5, 39 (1975)] and
are effective in the prevention and inhibition of granu-
- loma formation in warm blooded animals, and may be used,
for example, in a n~anner similar to phenylbutazone or
indomethacin. They may be used -to decrease joint
swelling, tenderness, pain and stiffness in mammalian
species, such as dogs and monkeys, e.g., in conditions
such as rheumatoid arthritis.
Furthermore, the compounds of the invention are
useful in mammals as inhibitors of 3',5'-cyclic adeno-
~; sine phosphodiesterase and 3',5' cyclic guanosine
phosphodiesterase and as inhibitors of platelet
aggregation in vitro and therefore of potential use in
the treatment of thrombosis.
The compounds of the present invention in the
QA152
: .
`~ described dosages may be administered orally; however,
other routcs such as intraperitoneally, subcutaneously,
intramuscularly or intravenously may be employed.
The active compounds of the present invention are
orally administered, for example, with an inert diluentor with an assimilable edible carrier, or they may be
` enclosed in hard or soft gelatin capsules, or they may
be compressed into tablets, or they may be incorporated
directly with the food of the diet. For oral thera-
peutic administration, the active compounds of this
invention may be incorporated with excipients and used
in the form of tablets, troches, capsules, elixirs,
suspensions, syrups, wafers, chewing gum, and the like.
The amount of active compound in such therapeutically
useful compositions or preparations is such that a
suitable dosage will be obtained.
The tablets, troches, pills, capsules and the like
may also contain the following: a binder such as gum
- tragacanth, acacia, corn starch or ~elatin; an excipient
such as dicalcium phosphate, a disintegrating agent sueh
as corn starch, potato starch, alginic acid and the
like; a lubricant such as magnesium stearate; and a
sweetening agent sueh as sucrose, lactose or saccharin
may be added or a ~lavoring agent sueh as peppermint,
oil of wintergreen, or cherry flavoring. When the
dosage unit form is a capsule, it may contain in
addition to materials of the above type a liquid carrier
such as a fatty oil. Various other materials may
be present as coatings or to otherwise modify the
physical form of the dosage unit, for instance, tablets,
pills or capsules may be coated with shellac, sugar,
or both. A syrup or elixir may contain the active
:
QA152
1 0
compounds, sucrose as a swcetening agent, methyl and
propyl parabens as prcservativcs, a dye and a flavorinc~
such as cherry or orange flavor. Of course, any
material used in preparing any dosage unit form should
be pharmaceutically pure ancl substan-tially non-toxic
- in the amounts employed.
The following Examples further illustrate and
represent preferred embodiments of the invention. All
temperatures are expresssed in degrees Centigrade.
The letter "(d)" following a melting point in-
dicates at least some apparent decomposition was
observed. The term "stripped" also means evaporation.
.
QA1~2
l .l
. .
Example 1
5,6-Dihydro-5-thioxopyrazolo[1,5-c]quinazoline-2-
carboxylic acid
A mixture of 600 mg (0.0025 mole) of 5-(2-amino-
phenyl)-lH-pyrazole-3-carboxylic acid hydrochloride,
1.98 ml of carbon disulfide, 3.2 ml of pyridine and
0.16 ml of water are refluxed under N2 for 40 hours.
The reaction mixture is stripped to dryness and the
solid obtained is taken up in 175 ml methanol and
filtered while hot. The clear light-yellow filtrate
is concentrated down to a volume of 80 ml and cooled.
The cotton-like precipitates are filtered and dried
in vacuo over a 72 hour period at 80. Yield:
394.8 mg, m.p. 272-273, 64.4% recryst. yield.
Example 2
5,6-Dihydro-5-thioxopyrazolo~1,5-c~quinazoline-2-
carboxylic acid, ethyl ester
1.5 g (0.006 mole) o~ 5,6-dihydro-5-thioxopyrazolo-
~1,5-c]quinazoline-2-carboxylic acid (prepared as
described in Example 1) and 1.26 g (1 equivalent) of
phosphorus pentachloride are heated together in 50 ml
of methylene chloride at 60 for 30 minutes. The
reaction mixture is cooled and the solvent stripped off
and replaced with 50 ml of dry pyridine. The solution
is treated with 1.1 ml of absolute ethanol and refluxed
- under N2 for 2 hours.
The reaction mixture is stripped to dryness and
the solid obtained is evaporated once from benzene.
The crude mixture is then taken up in a mixture of
.: .
. ~ . :
QA152
12
methanol (100 ml) and chloroform (75 ml) and impreg-
nated onto silica gel. The product is chromatographed
on a silica gel column (45 g), eluting the column
successively witll methylene chloride (150 ml) and
CH2C12:EtOAc (8:2, 1.0 1.). The fractions containing
the desired product are combined to give 900 mg of
the product plus a trace of an impurity at the solvent
front. Percent yield from column = 54.9~ (theor. -
1.64 g).
The material obtained from the column is recrystal-
lized from benzene (25 ml) and the precipitates obtained
are dried overnight in vacuo at 100. Yield: 617 mg,
m.p. 258-259 .
Example 3
.:
5,6-Dihydro-5-tilioxopyrazolo[1,5-c]quinazoline-2-
carboxylic acid, ethyl ester
5.9 g (2.3mmole) of 5,6-dihydro-5-oxopyrazolo-
[1,5-c]quinazoline-2-carboxylic acid, ethyl ester and
13.1 g (2.6 equivalents) of P2S5 are refluxed in
pyridine (650 ml) under nitrogen for 19 hours. The
reaction mixture is cooled down to room temperature
and the precipitates that form are filtered off and
washed with pyridine. The clear filtrate and washings
are then poured onto 700 ml ice-water, stirred for 30
minutes and the precipitates that form are filtered
off. The precipitates are taken up in 1.1 of CH30H:
CHC13 (1:1) and the solution is stripped to dryness.
Yield: 10.0 g of an amorphous reddish solid. The
crude product is impregnated onto silica gel and
3 ~
Q~152
13
chromatographed on a silica gel column (250 g),
eluting the coluMn successively with CHC13 (250 ml)
and CHC13:CH30H (9:1, 1.5 1.). The first 650 ml
collected is discarded and the next 600 ml containing
a mixture of the star-tin~ material and desired product
is collected and stripped to dryness. Yield: 4.5 g.
800 mg of the crude mixture is taken up in 20
ml of CH2C12:CH3OH (1:1) and applied to 5 pre-
- parative silica gel plates. The plates are eluted with
CHC13:EtOAc (6:4) and the desired band extracted with
three 150 ml portions of CH2C12 CH3OH (5 1). The
extracts are evaporated down to give 350 mg of the
desired product. Recrystallization from EtOAc (25 ml)
gives two crops: 110.3 mg, m.p. 242-243; 73.5 mg,
m.p. 243-244 . Both crops are single spots with Rf
0.6 (silica gel; CHC13:EtOAc-6:4).
Example 4
5,6-Dihydro-5-thioxopyrazolo[1,5-c]quinazoline-2-
carboxylic acid, sodium salt
1.5 g (0.006 mole) of 5,6-dihydro-5-thioxo-
pyrazolo~l.5-c]quinazoline-2-carboxylic acid (prepared
as described in Example 1) is suspended in 150 ml of
water, treated with 513.3 mg of sodium bicarbonate
(1 equivalent) and stirred overnight at room temperature.
The insoluble precipitates are filtered off and the
clear filtrate stripped to dryness. The solid obtained
is triturated with 12 ml of 50~i aqueous methanol and
filtered, washing the precipitates with a small amount
of aqueous methanol. The product is dried ln vacuo
over P2O5 for 5 hours at 100 and then overnight
.
3~
QA152
14
at 80 (without P2O5). Yield: 1.35 g, m.p.~350
dec. Per cent yield: 82.8% (theor. yield = 1.63 g).
Example _
2-(Hydroxymethyl)pyrazolo[1,5-c]quinazoline~5(6H)-thione
1.37g (0.005 mole) of 5,6-dihydro-5-thioxo-
pyrazolo~l,5-c]quinazoline-2-carboxylic acid ethyl ester
prepared as described in Example 2 is suspended in 100
ml of dichloromethane and treated with 8 ml (0.011 mole)
of 20% diisobutylaluminum hydride (Dibal). The
resultant yellow solution is stirred at room temperature
for 45 minutes, 2.0 ml (0.003 M) of Dibal solution
--~ is added and stirring continued for 17 hours.
An additional 2.0 ml (0.003 mole) of Dibal solution
is added and the reaction stirred for 2 hours (total
reaction time 20 hours). The reaction mixture is
stripped to an oil, triturated ard suspended in 1 N
hydrochloric acid. The solid is filtered off and dried
to give the product.
Example 6
2-[(Acetyloxy)methyl]pyrazolo[1,5-c]quinazoline-5(6H)-
thione
` 3 23 g (0.014 mole) of the product of Example 5
[2-(hydroxymethyl)pyrazolo[1,5-c]quinazoline-5(6H)-
thione] is refluxed with 250 ml of glacial acetic acid
for 20 hours under nitrogen. The solution is cooled
and stripped to a solid residue which is dissolved in
a mixture of ethyl acetate-absolute ethanol. The volume
of solution is reduced and the concentrated solution
set aside at 5. The precipitate is filtered off to
give the product. Recrystallization from ethyl acetate-
.
QA1515
absolute ethanol gives the title compound.
Examples 7 to 25
Following the procedure of Example 1, except
substituting the compounds indicated in Column I of
Table I set out below for 5-(2-aminophenyl)-lH-pyra-
zole-3-carboxylic acid hydrochloride, the compounds
indicated in Column II are obtained.
:'
:'
QA152
16
~ H
. ~; Ic4 ~
~' ~
; " O ~ H
I ~c~i
~4'~ O
H ~ ~ W U
., I .
:- ~;
~ W
--N
H~
~> ~ ~ X
~;~4')~ l
f') ~ o, ~
C O O U~ O O O 1`
x o ¦ o j N ~r 117
17 Q~152
'`"
~ } ~ O
O ) H
.. H O ~ D. E~ _
. ~ ~ D~ J O t'7
,'
_ ~1 .
, . 1~ v .~ ~ o _ _ _
t) D~ ~ ~ ~ O-lJ~
., ~ ~:~ m ~ ~ X
~ .. ~
.' ~
U~ U~
1~; 5: ~ IN D~5N
o .
~1 o
o ¦ ~ ' ~
-I
v ¦ 'r N Ul
C _ -- 1 ~Ul _ ~D -- ,1~ ~
~: ~ m
X Z I ~ ~1 ~ NN N N N N
~ QA152
:
': 1.
'.
E:x~ , to ~
Following the procedure of ~xample 2, except
substituting the compounds indicated in Column I of
Table II set out below for 5,6-dihydro-5-thioxo-
pyrazolo[l,5-c]quinazoline-2-carboxylic acid, and
- substituting for ethanol, the alcohols se-t out in
: Column II, the compounds indicated in Column III
are obtained.
'"
:
:'`
~ ` :
,~
QAl5;~
1 (3
... , ~` ~1
o I ~
J
o~ N ~ a ~ o~ ~
. I --- --- .
ô~
o, ô ô ~" O O O o
x ol ~ ~ ~ -I ~ ~ ~
: :
~ QA152
. .
~ }
~ o
:, r'xl
~ ~v J
. g
U H
H U X U U rl U U C U U ~ U
~: .
U7 U~
` ~7 :C~
U ~ U :~ U U U !T
H
:` ~ ~;.1'
O D O
_ ô
O
~ _ ~ o
.. U~ o -- --o~ o ~ _ _
O O O ~ -- _ _ ,_, ~ U o ~,
_ r~ ~ U ~ r~
Ir ~ 2 U ~ U ~4 ~ r
I . . . . . . . ~ . .
,. ~ x Z~ o
:
.
':
3~ QA152
. . .
21
:,
` Examples 45 to 63
::~Following the procedure of Example 5 or Example
83, except substitutin~ the compcunds indic~ted in
Colu~n I of Table III set out below for 5,6-dihydro-
!'5 5-thioxopyrazoloLl,5-c]quinazoline-2-carboxylic acid
ethyl ester, the compounds i.ndicated in Column II
:are obtained.
:
QAl 5 2
22
:
` :.
' I
ol
: ~ 'o
_ _
H ¦ 1 3 U ~ U
u~ 3
: o
H ~_1 D 5~
u o~ ~ 1
~ ~ ~ O ~ ~ O ~ ~ ~ O
1~( Z--~; Dl O O ~U~ O O O 1`
~ U~U~
. _~ I~
:C ~ 1~
~: ~ U~ U~ ~ U~ U~ ~ UN VC
C ~!
X O ~ \ 01 0 ~i N
" '
-
.
,
.~ ' '' ' ' ' ' .
.:
' ' '
.,
': ' ' -
`''' ' ' . , : ' "
. ', . '
3~ QA15 2
23
.:
.~`,
:` I H ~
~. ~D O
!wu~=wu~w~u~uw~ww
~.,,
~ ~ H ¦ Q~ 1~ 35~ X X :r:
.~`. o ~ . o
~ ~ o ~ o ~ ~
.~ o ~ ,o u
... ,,
~ . ~
~ U C.\ ~g U ~J
x o ~ w 1` CO G~ o ~i N ')
1~1 Z U~ ~ ~ U~
`;
''`
.''
~ *
.
,,
~ QA152
.:
24
Examples 64 to 82
~- Following the procedure of Examp~e 6, except
substituting the compounds indicated in Column I
of Table IV set out below for 2-(hydroxymethyl)-
pyrazolo[l,5-c~quinazoline-5(6H)-thione, and sub-
stituting for acetic acid, the acid indicated in
Column II, the compounds indicated in Column III
are obtained.
:
, .
:
- .
- ' ~ -. ' : .
QA152
=~ ~}: ~
' ; ' '~)~'
H ~
~ ~ V
_ X
O
~ o O N ~ N D
N ~ b
``:`
. - . . . .
. - , . .
. ~. .. ,.' ' ' ' ' ., '
'. . ' . , ~ ~
3~3
`~ ~ QA152
26
} ~ H~
~1
~1 o ~
~J ~I I H
O _l
P U
o ¦ h
Q) ~;-.1 1
~ O
~ D
O H
~ 1:: ~1 r~
6 X "~
t~~'S r~ X U c; N 1 5~ U
`' E'
~)
$~
r~7 U ~ r-
~ N ')
., U ~ U U U
,' q
~1oq
., _lU~ O
8DO ~ U
1:: ô
,0 ~ a~ O
~Q o ~ -- ô ~ ~
D _ _ ~ o r~ U o--8
_ ~ ,, U O
.. . . . . . . . . .
~ Z~
.
. . : ~ . .
.
..
,
.
. -
.
..
- .:
r.~ ~
QA152
27
Example 83
2-(Hydroxymethyl)pyrazolo[1,5-c]quinazoline-5(6H)-thione
0.519 g (0.0019 mole) of 5,6-dihydro-5-thioxopyra-
zolo~l,5-c]quinazoline-2-carboxylic acid ethyl ester
is suspended in 10 ml distilled tetrahydrofuran and
treated with 0.1 g (0.004 mole) of 85% lithium
borohydride at room temperature. After 20 hours of
stirring, the reaction mixture is cooled to 0 , 4.5
ml of lN hydrochloric acid is added and stirring is
continued for 30 minutes. 25 ml of water is added and
the product is filtered off after 10 minutes and dried.
.,
,
.
