CA1111033A - Thioxopyrazolo[1,5-c]quinazoline derivatives and related compounds - Google Patents

Abstract

Abstract THIOXOPYRAZOLO[1,5-c]QUINAZOLINE DERIVATIVES AND RELATED COMPOUNDS New compounds, useful as anti-allergics, have the structure wherein R1 is hydrogen or lower alkyl; R2 is carboxyl, 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 trifluoro-methyl substituent; and physiologically acceptable salts thereof.

Description

~ 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

~ N
R _ - R
wherein Rl, R3, R4 and R5 are as defined hereinbefore.
The Formula II compounds are prepared by reacting compounds of the structure .
:, .~, ~' III
. R / COOH

` 5 H

-~ 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 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

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 . .

:

VIII
.'- R1 11 4 ~CH20CA1kY1 : R~ N~l IN

~` 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.

`.

' 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 .

:
~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 : .
`~ 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 :

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 .: .

. ~ . :

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 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~

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-.

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.

:' :' ~ 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 . . .

:, ` 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 :
` :.
' 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 .:
.~`, :` 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 .:

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.

:
, .
:

- .

- ' ~ -. ' : .

=~ ~}: ~

' ; ' '~)~' H ~
~ ~ V
_ X
O

~ o O N ~ N D
N ~ b ``:`

. - . . . .
. - , . .
. ~. .. ,.' ' ' ' ' ., ' '. . ' . , ~ ~

3~3 `~ ~ QA152 } ~ 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.~ ~

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.

., , .

Claims (12)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for the preparation of a compound of the structure I:
I

wherein R1 is hydrogen or lower alkyl; R2 is carboxyl, hy-droxymethyl, lower alkanoyloxymethyl or lower alkoxycarbonyl;
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 trifluoromethyl substituent; or a physiologically accep-table salt thereof, which comprises either:
a) reacting a compound of the structure III:

III

with carbon disulfide in the presence of a base to form a compound of the structure II:

II

wherein R1, R2, R3, R4 and R5 have the meaning stated above;
or b) reacting an acid chloride of the structure V:

V

with a lower alkanol to form a compound of the structure IV:

IV

wherein R1, R2, R3, R4 and R5 have the meaning stated above;
or c) reacting an ester of the structure VI:
VI

with phosphorus pentasulfide in the presence of a base to form a compound of the structure IV:

IV

wherein R1, R2, R3, R4 and R5 have the meaning stated above;
or d) reducing a compound of the structure IV:
IV

to form a compound of the structure VII:

VII

wherein R1, R2, R3, R4 and R5 have the meaning stated above;
or e) reacting a compound of the structure VII:

VII

with a lower alkanoic acid to form a compound of the structure VIII:

VIII

wherein R1, R2, R3, R4 and R5 have the meaning stated above.

2. The process as in claim 1 wherein R1 is hydrogen.

3. The process as in claim 1 wherein R2 is carboxyl.

4. The process as in claim 1 wherein R2 is hydroxy-methyl.

5. The process as in claim 1 wherein R2 is lower al-kanoyloxymethyl.

6. The process as in claim 1 wherein R2 is lower al-koxycarbonyl.

7. The process as in claim 1 wherein R3 is hydrogen.

8. The process as in claim 1 wherein R4 is hydrogen.

9. The process as in claim 1 wherein R5 is hydrogen.

10. The process as in claim 1 wherein the compound thus prepared has the name 5,6-dihydro-5-thioxopyrazolo-[1,5-c]quinazoline-2-carboxylic acid.

11. The process as in claim 1 wherein the compound thus prepared has the name 5,6-dihydro-5-thioxopyrazolo[1,5-c]quinazoline-2-carboxylic acid, ethyl ester.

12. The process as in claim 1 wherein the compound thus prepared has the name 5,6-dihydro-5-thioxopyrazolo[1,5-c]quinazoline-2-carboxylic acid, sodium salt.

13. A compound of the structure I:
I

wherein R1 is hydrogen or lower alkyl; R2 is carboxyl, hy-droxymethyl, lower alkanoyloxymethyl or lower alkoxycarbonyl;
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 trifluoromethyl substituent; or a physiologically accep-table salt thereof, when prepared by the process of claim 1.

14. A compound as defined in claim 13 wherein R1 is hydrogen, when prepared by the process of claim 2.

15. A compound as defined in claim 13 wherein R2 is carboxyl, when prepared by the process of claim 3.

16. A compound as defined in claim 13 wherein R2 is hydroxymethyl, when prepared by the process of claim 4.

17. A compound as defined in claim 13 wherein R2 is lower alkanoyloxymethyl, when prepared by the process of claim 5.

18. A compound as defined in claim 13 wherein R2 is lower alkoxycarbonyl, when prepared by the process of claim 6.

19. A compound as defined in claim 13 wherein R3 is hydrogen, when prepared by the process of claim 7.

20. A compound as defined in claim 13 wherein R4 is hydrogen, when prepared by the process of claim 8.

21. A compound as defined in claim 13 wherein R5 is hydrogen, when prepared by the process of claim 9.

22. The compound as defined in claim 13 having the name 5,6-dihydro-5-thioxopyrazolo[1,5-c]quinazoline-2-car-boxylic acid, when prepared by the process of claim 10.

23. The compound as defined in claim 13 having the name 5,6-dihydro-5-thioxopyrazolo[1,5-c]quinazoline-2-car-boxylic acid, ethyl ester, when prepared by the process of

claim 11.

24. The compound as defined in claim 13 having the name 5,6-dihydro-5-thioxopyrazolo[1,5-c]quinazoline-2-car-boxylic acid, sodium salt, when prepared by the process of

claim 12.