This invention relates to a class of novel 4H-pyrimido[2,1-a]isoquinoline derivatives. The invention further relates to pharmaceutical compositions containing such 4H-pyrimido[2,1-a]isoquinoline-4-one derivatives and to the use of such compounds and compositions as anorectic agents. In particular, the novel 4H-pyrimido[2,1-a]isoquinoline-4-one derivatives are effective anorectic agents when administered orally.

SUMMARY OF THE INVENTION 
The present invention relates to a class of compounds of the formula 
##STR1## 
wherein R is 
##STR2## 
or --(C.sub.n H.sub.2n)--R.sub.3 wherein n is an integer of from 1 to 4; 
R.sub.1 and R.sub.2 are independently hydrogen or lower alkyl; and R.sub.3 
is a group selected from the class consisting of hydroxyl, amino, 
substituted amino, lower alkylcarboxyl, and 
##STR3## 
wherein m is an integer of from 1 to 4 and R.sub.4 and R.sub.5 are 
independently hydrogen or lower alkyl; and 
R' and R" are independently hydrogen, halo, nitro or trifluoromethyl; 
or pharmaceutically acceptable salts thereof when R.sub.3 is amino, 
substituted amino or 
##STR4## 
or when R is 
##STR5## 
The invention further relates to pharmaceutical compositions containing the 
compounds of formula (I) and to the use of such compounds and compositions 
as anorectic agents. 
DETAILED DESCRIPTION OF THE INVENTION 
The term "lower alkyl" designates those alkyl radicals having straight or 
branched chains with a total of one to four carbons such as, for example, 
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl. 
As used herein, the term "substituted amino" refers to groups represented 
by the formula --NR.sup.6 R.sup.7 wherein R.sup.6 is lower alkyl and 
R.sup.7 is hydrogen or lower alkyl. Illustrative of such substituted amino 
groups include, for example, methylamino, dimethylamino, ethylamino, 
di(isopropyl)amino, butylamino and the like. 
The term "halo" encompasses fluoro, chloro, bromo and iodo. 
As used herein, the term "lower alkylcarboxyl" refers to groups represented 
by the formula 
##STR6## 
wherein R.sup.8 is lower alkyl. Illustrative of such lower alkylcarboxyl 
groups include, for example, methylcarboxyl, ethylcarboxyl, 
isopropylcarboxyl, t-butylcarboxyl and the like. 
The term "pharmaceutically acceptable salts" refers to salts derived from 
physiologically acceptable acids. Such physiologically acceptable acids 
include but are not limited to hydrochloric, hydroiodic, hydrobromic, 
phosphoric, sulphuric, toluenesulphonic, acetic, maleic, benzoic, citric, 
fumaric, gluconic, lactic, malic, nitric, saccharic, succinic, tartaric 
and the like. 
A preferred embodiment of the present invention includes compounds of 
formula (I) wherein R' and R" are hydrogen. A more preferred embodiment 
includes compounds of formula (I) wherein R' and R" are hydrogen and R is 
--(C.sub.n H.sub.2n)--R.sub.3. It is most preferred that n is 1 and 
R.sub.3 is hydroxyl, amino or lower alkylcarboxyl. 
The compounds of the present invention may be prepared in accordance with 
one or more of the following procedures. 
Compounds of formula (I) wherein R is --(C.sub.n H.sub.2n)--OH and n is and 
integer of from 2 to 4, may be prepared by reacting a 
trisdimethylaminomethane of the formula 
##STR7## 
with a lactone of the formula 
##STR8## 
to yield an .alpha.-N,N-dimethylaminomethylenelactone of the formula 
##STR9## 
The .alpha.-N,N-dimethylaminomethylenelactone is reacted with a 
1-aminoisoquinoline of the formula 
##STR10## 
at a temperature of from 180.degree. to 200.degree. C. to yield the 
3-(hydroxyalkyl)-4H-pyrimido[2,1a]isoquindin-4-one of the formula 
##STR11## 
Preferably, to prepare compounds of the present invention wherein R is 
--CH.sub.2 OH, a pyrimido[2,1a]isoquinoline derivative of the formula 
##STR12## 
wherein Z is a cleavable ester group under nitrogen atmosphere in an 
appropriate solvent is reduced in the presence of an aluminum hydride at a 
temperature of from -70.degree. to -25.degree. C. 
The compounds of formula (VII) may be prepared in accordance with the 
procedures described in U.S. Pat. No. 4,127,720. 
The compounds of formula (I) wherein R is --(C.sub.n H.sub.2n)--R.sub.3 and 
wherein R.sub.3 is lower alkylcarboxy are prepared by reacting a compound 
of formula (VI) with an anhydride of the formula, 
##STR13## 
wherein Y and Y' are independently lower alkyl, in the presence of 
triethylamine to yield an ester of the formula 
##STR14## 
To prepare the compounds of the formula 
##STR15## 
a 4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carbonitrile of the formula 
##STR16## 
is hydrogenated under pressure in the presence of Raney nickel. 
The compounds of the formula 
##STR17## 
wherein n and m are independently integers of from 1 to 4, are prepared by 
reacting a 3-(hydroxyalkyl)-4H-pyrimido [2,1-a]isoquinolin-4-one of 
formula (VI) with an dialkyl aminoalkyl halide of the formula: 
##STR18## 
wherein X is halo and R.sub.4 and R.sub.5 are herein defined in the 
presence of sodium hydride. 
To prepare compounds of the formula 
##STR19## 
a pyrimido[2,1-a]isoquinolin-4-one derivative of formula (VII) is refluxed 
with an N.sub.1,N.sub.1 -dialkylalkenediamine of the formula 
##STR20## 
wherein R.sub.1 and R.sub.2 are above defined. 
The pharmaceutically acceptable acid addition salts of the compounds of the 
present invention may be prepared by conventional procedures, e.g. by 
reacting the free base in a suitable solvent in which the free base is 
soluble, e.g. acetone or ethanol, with a solution containing one 
equivalent of the desired acid in a suitable solvent, e.g. dioxane or 
ethanol. The salt generally precipitates from solution or is recovered by 
evaporation of the solvent. 
The compounds of the present invention are useful as anorectic agents. The 
anorectic utility of the compounds may be demonstrated by showing a dose 
responsive decrease in food intake and subsequent weight loss upon 
administration of the compounds to a subject. 
The compounds of the present invention may be administered by any suitable 
route, preferably in the form of a pharmaceutical composition adapted to 
such route and in a dose effective for the treatment intended. 
Accordingly, the invention provides a class of novel pharmaceutical 
compositions comprising one or more compounds of the present invention in 
association with one or more non-toxic, pharmaceutically acceptable 
carriers and/or diluents and/or adjuvants and if desired other active 
ingredients. The composition is preferably administered orally. 
For oral administration, the pharmaceutical composition may be in the form 
of, for example, a tablet, capsule, suspension or liquid. The 
pharmaceutical composition is preferably made in the form of a dosage 
unit, i.e., a tablet or capsule, containing a particular amount of the 
active ingredient. Such dosage units may contain from about 5 to 250 mg, 
preferably from about 25 to 150 mg, of the active ingredient. A suitable 
daily dose for a patient may vary widely depending on the condition of the 
patient and other factors. However, a dose of from about 0.1 to 300 mg/kg 
body weight, preferably from about 1 to 100 mg/kg body weight, may be 
appropriate. 
The active ingredient may also be administered by injection as a 
composition wherein, for example, saline, dextrose or water may be used as 
a suitable carrier. A suitable daily dose is from about 0.1 to 100 mg per 
kg body weight injected per day in multiple doses depending on the disease 
being treated. A preferred daily dose would be from about 1 to 30 mg/kg 
body weight per day. 
As indicated, the appropriate dose adminstered and the treatment regimen 
will be dependent, for example, on the severity of the condition thereof, 
on the route of administration, on the patient being treated and his 
response to treatment, and therefore may be widely varied. 
For therapeutic purposes, the compounds of this invention are ordinarily 
combined with one or more adjuvants appropriate to the indicated route of 
administration. If per os, they may be admixed with lactose, sucrose, 
starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, 
talc, stearic acid, magnesium stearate, magnesium oxide, sodium and 
calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium 
alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and thus 
tableted or encapsulated for convenient administration; alternatively, 
they may be dissolved in water, polyethylene glycol, propylene glycol, 
ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, 
sodium chloride, and/or various buffers. Other adjuvants and modes of 
administration are well and widely known in the pharmaceutical art; see, 
for example, F. W. Martin et al., Remington's Pharmaceutical Sciences, 
14th ed., Merck Publishing Co., Eaton, Pa., 1965.

The following examples describe in detail compounds illustrative of the 
present invention and methods which have been devised for their 
preparation. It will be apparent to those skilled in the art that many 
modifications, both of materials and of methods, may be practiced without 
departing from the purpose and intent of this disclosure. 
EXAMPLE 1 
To 12.0 g of ethyl 4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (44.7 
mmole) dissolved in 600 ml dry methylene chloride cooled to -50.degree. to 
-70.degree. C. under nitrogen was added dropwise over 15 minutes 92 ml of 
diisobutylaluminum hydride (1M in hexane, 92.0 mmole). The reaction 
mixture was stirred for 1 hour, then allowed to slowly warm to room 
temperature. After hydrolyzing in the cold (-70.degree. C.) with 40 ml of 
methanol the mixture was again allowed to warm to room temperature with 
stirring overnight, when the solids were separated by filtration and 
extracted with hot methanol. The filtrates were combined and concentrated 
in vacuo to give a crude product which was crystallized from 
chloroform/hexane. The crude product was dissolved in 300 ml of methanol, 
treated with decolorizing charcoal at reflux and filtered hot. The 
resulting solution was reduced to one-third initial volume. The solution 
was cooled to 25.degree. C., ether was added and the resulting mixture was 
cooled to -20.degree. to -50.degree. C. until 
3-(hydroxymethyl)-4H-pyrimido [2,1-a]isoquinolin-4-one crystallized as 
white needles (2.55 g, 28% yield) having the formula: 
##STR21## 
and a melting point of 198.degree. C. and the following elemental 
analysis: 
C.sub.13 H.sub.10 N.sub.2 O.sub.2 (MW=226.23): Calculated: C, 69.02; H, 
4.46; N, 12.38. Found: C, 68.88; H, 4.40; N, 12.36. 
EXAMPLE 2 
To 3.0 g of 3-(hydroxymethyl)-4H-pyrimido [2,1-a]isoquinolin-4-one (13.3 
mmole) suspended in 100 ml chloroform with 10 ml of triethylamine and a 
trace of 4-dimethylaminopyridine was added 5.0 g of acetic anhydride (50.0 
mmole). The reaction mixture was refluxed for 2 hours, then cooled to room 
temperature and washed twice with water. The organic layer was dried and 
concentrated in vacuo to give a crude solid which was crystallized from 
methylene chloride/hexane to yield 
3-(hydroxymethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one acetate as yellow 
crystals (2.09 g, 59% yield) of the formula: 
##STR22## 
having a melting point of 173.3.degree. C. and the following elemental 
analysis: 
C.sub.15 H.sub.12 N.sub.2 O.sub.3 (MW=268.27): Calculated: C, 67.15; H, 
4.51; N, 10.44. Found: C, 66.98; H, 4.48; N, 10.39. 
EXAMPLE 3 
22.6 g of 4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carbonitrile (102.2 mmole) 
dissolved in 400 ml of THF and 52.8 g of ammonia was hydrogenated for 5 
hours at a pressure of 60 psi at room temperature, using 2.26 g of Raney 
nickel as the catalyst. The solution was concentrated in vacuo to yield a 
residue which was suspended in methanol and treated with 25 ml. of 
isopropanolic hydrochloric acid solution to yield 6.37 g of a crude 
product as a light brown solid. 2.7 g of this solid was suspended in 
ethanol/methanol and treated with 20 ml. of isopropanolic hydrochloric 
acid solution while heating on a steam bath. Cooling and filtering 
afforded 3-(aminomethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one, 
dihydrochloride (1.6 g; 28% yield) of the formula: 
##STR23## 
having a melting point of 291.1.degree. C. and the following elemental 
analysis: 
C.sub.13 H.sub.11 N.sub.3 O.2HCl (MW=298.17): Calculated: C, 52.36; H, 
4.39; N, 14.09; Cl, 23.78. Found: C, 52.02; H, 4.32; N, 13.86; Cl, 23.01. 
EXAMPLE 4 
To 0.7 g of sodium hydride (14.5 mmol) stirred in 40 ml of dry 
dimethylformamide under nitrogen was added dropwise over a 15 minute 
period a solution of 2.0 g of 
3-(hydroxymethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one (8.3 mmol) in 40 ml 
of warm dimethylformamide. After stirring for 1 hour, 1.58 g of 
diethylaminoethyl chloride (11.6 mmol) was added dropwise over a 15 minute 
period. The reaction mixture was stirred for 3 hours, then poured onto 
ice-water and extracted 3 times with 500 ml of methylene chloride. The 
extracts were dried and concentrated in vacuo to yield a semi-solid, to 
which 15 ml of isopropanolic hydrochloric acid solution and diethyl ether 
were added. The crystalline solid which formed was collected and washed 
with ether to yield 
3-[[2-(diethylamino)ethoxy]methyl]-4H-pyrimido[2,1-a]isoquinolin-4-one 
dihydrochloride (0.973 g; 28% yield) of the formula: 
##STR24## 
having a melting point of 128.7.degree. C. and the following elemental 
analysis: 
C.sub.19 H.sub.23 N.sub.3 O.sub.2.2HCl.H.sub.2 O (MW=416.34): Calculated: 
C, 54.81; H, 6.54; N, 10.09; Cl, 17.03. Found: C, 54.98; H, 6.96; N, 
10.05; Cl, 16.88. 
EXAMPLE 5 
1.27 g of ethyl 4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (4.73 
mmol) and 4.1 ml of N,N-dimethylethylenediamine (3.13 g 35.5 mmol) were 
refluxed with stirring for 24 hours. The excess amine was then distilled 
off, yielding a beige solid which was dissolved in methylene chloride and 
filtered through silica gel. Concentration of the eluent in vacuo yielded 
3-[(dimethylamino)methyleneiminocarbonyl]-4H-pyrimido[2,1-a]isoquinolin-4- 
one (1.137 g; 73% yield) of the formula: 
##STR25## 
having a melting point of 162.degree.-166.degree. C. and the following 
elemental analysis: 
C.sub.17 H.sub.18 N.sub.4 O.sub.2.H.sub.2 O (MW=328.37): Calculated: C, 
62.17; H, 6.14; N, 17.06. Found: C, 62.24; H, 6.33; N, 17.88. 
EXAMPLE 6 
A heterogenous mixture containing 14.4 g of 1-isoquinolinamine (0.1 m) and 
14.12 g of dihydro-3-[(dimethylamino)methylene]-2(3H)-furanone was heated 
to 200.degree. C. for 4 hours to yield a homogenous yellow orange solution 
which solidified upon cooling to ambient temperature. The solidified 
reaction mixture was titurated with methanol and ethyl acetate to yield 
3-(2-hydroxyethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one as a tan solid 
(18.0 g; 75% yield) of the formula 
##STR26## 
having a melting point of 185.2.degree.-187.0.degree. C. and the following 
elemental analysis: 
C.sub.14 H.sub.12 N.sub.2 O.sub.2 (MW=240.25): Calculated: C, 69.98; H, 
5.04; N, 11.66. Found: C, 69.87; H, 5.00; N, 11.52. 
EXAMPLE 7 
Male Sprague-Dawley derived rats, Charles River Breeders (Portage, MI), 
weighing between 200-400 grams at the time of testing, were employed in 
the food intake studies and water intake studies. The rats were housed 
individually and kept on a 12 hour light-dark-light cycle. The room 
temperature ranged between 23.degree.-25.degree. C. 
Food Intake Studies 
The rats employed in food intake testing were food deprived on the day 
preceding testing and were divided into experimental groups that were 
matched on the basis of average daily food intake and body weight. At 
approximately 24 hour post-deprivation, the rats were administered a test 
sample containing as the active ingredient a compound of the present 
invention. All test samples employed herein were prepared and homogenized 
in a vehicle of normal saline (to which a few drops of PG/Tween 80 was 
added). The test samples were administered at an injection volume of 2 
ml/kg, unless otherwise stated. Thirty minutes following administration of 
the test samples, pre-weighed food jars containing ground meal were placed 
in the rats' cages. (Prior to testing the rats were given ground meal for 
a minimum of 3 days to familiarize the rats with this food.) After 1, 2 
and 6 hours of food access, the jars were removed, weighed and returned to 
the rats' cages providing a 1, 2 and 6 hours intake measurement. Controls 
were simultaneously run in accordance with the above procedures except 
that the test samples administered to the control rats did not contain any 
active ingredient. The results obtained are represented in Table I as a 
percent of control values. A student t test was used for making 
statistical comparisons, and the p-values are based upon two-tailed 
comparisons. The compound employed as the active ingredient on the test 
sample is indicated by the example number which describes its preparation. 
TABLE I 
______________________________________ 
Food Intake Test Results 
Food Intake 
Active % of control 
Ingredient 
Dose & Route n 1 Hr. 2 Hr. 
6 Hr. 
______________________________________ 
Example 1 
32.0 mg/kg i.g. 
12 61.8.sup.1 
77.4.sup.3 
90.4 
Example 2 
32.0 mg/kg i.g. 
12 51.4.sup.1 
67.1.sup.2 
89.8 
Example 3 
32.0 mg/kg i.g. 
12 51.3.sup.1 
71.4.sup.2 
92.3 
Example 4 
32.0 mg/kg i.g. 
9 70.8.sup.3 
80.8.sup. 
90.9 
Example 5 
32.0 mg/kg i.g. 
12 82.4.sup.2 
87.5.sup. 
88.3 
______________________________________ 
.sup.1 p &lt; .01 compared with saline control 
.sup.2 p &lt; .05 compared with saline control 
.sup.3.05 &lt; p &lt; .09 compared with saline control 
The above results indicate that certain compounds of the present invention 
are effective anorectic agents. In addition, compounds of the present 
invention possess oral appetite suppressant activity. Furthermore, in 
addition to the above illustrated anorectic activity, the compounds of the 
present invention also possess other pharmaceutical activity, such as for 
example, the compounds are benzodiazepine antagonists. 
Although this invention has been described with respect to specific 
modification, the details thereof are not to be construed as limitations, 
for it will be apparent that various equivalents, changes and modification 
may be resorted to without departing from the spirit and scope thereof and 
it is understood that such equivalent embodiments are intended to be 
included therein.