Purine derivatives, medicaments containing them and methods of treating cardiac insufficiencies and irregularities with them.

The compounds of formula I, ##STR1## in free form or in salt form have cardiotonic and antiarrhythmic activity. They may be used as medicaments. They are obtained by means of appropriate 3-amino-2-hydroxy-propylation of purines.

The invention relates to the compounds of formula I, 
##STR2## 
wherein 
R signifies diphenylalkyl with 13 to 17 carbon atoms or diphenylalkyl with 
13 to 17 carbon atoms which is monosubstituted or disubstituted by the 
same or different substituents in one or both phenyl rings by alkyl with 1 
to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms and/or halogen with an 
atomic number of 9 to 35, 
R.sub.1 denotes hydrogen, halogen with an atomic number of 9 to 35, amino, 
alkylamino with 1 to 4 carbon atoms, dialkylamino with independently 1 to 
4 carbon atoms in the alkyl radicals, 1-pipe-ridino, alkanoylamino with a 
total of 2 to 5 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, 
sulphhydryl, alkylthio with 1 to 4 carbon atoms, benzoylamino or 
pyridinylcarbonylamino, 
R.sub.2 signifies hydrogen, hydroxy, amino or alkanoylamino with a total of 
2 to 5 carbon atoms and 
R.sub.3 signifies hydrogen, alkyl with 1 to 4 carbon atoms, 
trifluoromethyl, Amino or halogen with an atomic number of 9 to 35, 
in free form or in salt form. 
The compounds of formula I may exist in tautomeric form. Such tautomeric 
forms also fall within the scope of the present invention. The compounds 
of formula I are in the following also named compounds according to the 
invention. 
As can be seen from formula I, the side chain is bonded to a nitrogen atom. 
The side chain is preferably bonded in position 3, 7 or 9 of the purine 
frame, especially position 3 or 9. 
The alkylene part of diphenylalkyl preferably contains 1, 3 or 4, 
especially 1 or 4 carbon atom(s). The phenyl rings of diphenylalkyl are 
preferably unsubstituted. If they are substituted, they are each 
preferably mono-substituted, especially in meta- or para-, especially in 
para-position. If they are di-substituted, they are preferably substituted 
in meta- and para-position. If they are substituted, they are preferably 
substituted by halogen or alkoxy, especially by halogen and the 
substituents are preferably identical. 
Alkyl and/or alkoxy and/or alkylthio and/or the alkyl part of alkylamino or 
dialkylamino preferably contains 1 to 3, especially 1 carbon atom(s). 
Halogen preferably signifies fluorine or chlorine or bromine. The alkyl 
parts of dialkylamino are preferably identical. 
R preferably signifies diphenylmethyl, preferably unsubstituted. R.sub.1 
preferably denotes hydrogen, halogen, amino, benzoylamino, acetylamino, 
piperidino, alkylamino, dialkylamino, hydroxy or alkoxy, especially amino, 
alkylamino, dialkylamino or alkoxy, especially amino. R.sub.2 preferably 
denotes hydrogen. R.sub.3 preferably denotes hydrogen, alkyl, 
trifluormethyl or halogen, especially chlorine or bromine, especially 
hydrogen. 
The compounds according to the invention are obtained by appropriate 
3-amino-2-hydroxy-propylation of corresponding compounds of formula II 
##STR3## 
wherein R.sub.1 to R.sub.3 are defined as above. Especially compounds of 
formula II are reacted with corresponding compounds of formula III 
##STR4## 
wherein R is defined as above and R.sub.x denotes a group which yields a 
1-hydroxyethyl group reacting with a purine.

The process according to the invention may take place under conditions 
which are known for the production of analogous compounds, which are 
discussed in the following examples. 
The choise of the most suitable variant should of course be made whilst 
taking into consideration the reactivities of the substituents available, 
if necessary giving temporary protection of any sensitive groups and 
subsequently splitting off or converting the protecting groups. Thus e.g. 
an amino group on the purine ring can be transformed by means of 
diazotisation and subsequent boiling down into the hydroxy group; an amino 
group is position 6 of the purine ring can e.g. also be transformed into 
an alkanoylamino, benzoylamino or pyridinylcarbonylamino group by reacting 
with an alkanoyl-, benzoyl- or pyridinecarbonylchloride. 
Primary products of the compounds of formula II are compounds which can be 
reacted to form compounds of formula II, e.g. by means of appropriate 
splitting off protecting groups or by transformation. 
The process according to the invention can therefore be effected in more 
than one operation. 
The group R.sub.x employed is for example the group 
##STR5## 
The reaction is performed preferably in the presence of a solvent. The 
solvent used is preferably methanol, ethanol or a suitable ether, e.g. 
dioxane. Suitable temperatures are about 20.degree. to 150.degree. C. It 
is convenient to operate at reflux temperature if a solvent is present. 
The process is preferably effected under alkaline conditions e.g. in 
presence of caustic soda. 
The compounds according to the invention can be isolated from the reaction 
mixture and purified by known methods, e.g. by chromatography. 
The compounds according to the invention may exist in free form, i.e. 
normally as a base, or in salt form. Salts, e.g. acid addition salts, e.g. 
with hydrochloric, malonic, maleinic or fumaric acid, may be obtained in 
known manner from the compounds in free form, and vice versa. 
In the compounds according to the invention, the propanol side chain is 
chiral; they may therefore appear in racemic form or in the form of the 
corresponding enantiomers. Should a further centre of chirality exist, the 
compounds may appear in the form of stereoisomer mixtures or the 
corresponding pure enantiomers. Should they appear in optically active 
form, preference is given to those optically active forms in which the 
S-configuration is present on the asymmetrically substituted carbon atom 
of the side chain which bears the hydroxy group. The individual 
enantiomers or resp. diastereoisomeric mixtures of the compounds according 
to the invention may be obtained in known manner, e.g. by using the 
corresponding enantiomers or resp. racemates of the starting compounds, or 
by means of fractionated crystallisation of salts of individual, 
optionally diastereoisomeric racemates with optically active acids. 
Insofar as the production of the required starting materials is not 
described, these are known or may be produced by known processes, or 
analogously to the processes described here or analogously to known 
processes. 
In the following examples, all temperatures are given in degrees celsius 
and are uncorrected. 
EXAMPLES 1 TO 3 
6-amino-.alpha.-[(4-diphenylmethyl-1-piperazinyl)-methyl]-3H-purine-3-ethan 
ol (Example 1), 
6-amino-.alpha.-[(4-diphenylmethyl-1-piperazinyl)-methyl]-9H-purine-9-ethan 
ol (Example 2) and 
6-amino-.alpha.-[(4-diphenylmethyl-1-piperazinyl)-methyl]-7H-purine-7-ethan 
ol (Example 3) 
13.5 g of adenine and 30.8 g of 
1-diphenylmethyl-4-(2,3-epoxy-propyl)-piperazine are refluxed for 1 hour 
in 100 ml of 1N caustic soda and 100 ml of dioxane. After cooling the 
reacting mixture, it is diluted with 100 ml of water and extracted several 
times with ethyl acetate. The combined organic phases are dried over 
sodium sulphate, filtered and evaporated under vacuum to dryness. The 
crude reaction mixture is chromatographed over a column of 10 times the 
quantity of silica gel with methylene chloride/5% saturated methanolic 
ammonia. The first product to be eluted is 
6-amino-.alpha.-[(4-diphenylmethyl-1-piperazinyl)-methyl]-9H-purine-9-etha 
nol (foam) (=example 2). The second product to be eluted is 
6-amino-.alpha.-[(4-diphenylmethyl-1-piperazinyl)methyl]-3H-purine-3-ethan 
ol (m.p. from methanol/methylene chloride: 239.degree.-240.degree.) 
(=Example 1). The third product obtained is 
6-amino-.alpha.-[(4-diphenyl-methyl-1-piperazinyl)methyl]-7H-purine-7-etha 
nol (m.p. 220.degree.-222.degree. [ from methano]) (=example 3). 
The epoxide used as the starting product is obtained as follows: 
100 g of 1-diphenylmethylpiperazine and 250 ml of epichlorohydrin are 
dissolved in 250 ml of methylene chloride, and then 26 g of 
tetrabutylammonium bromide in 120 ml of 50% caustic soda are added. The 
reaction mixture (2 phases) is stirred for 15 hours at room temperature. 
Then, the methylene chloride is removed in a vacuum, ether is added to the 
reaction mixture, and the organic phase is extracted several times with 
water. 1-diphenyl-methyl-4-(2,3-epoxypropyl)-piperazine (m.p. 
101.degree.-102.degree.) is obtained from the organic phase. 
The following compounds of formula I are obtained analogously to Example 1 
(if not otherwise stated, by reacting the corresponding compounds of 
formula II with corresponding compounds of formula III, in which R.sub.x 
denotes 
##STR6## 
__________________________________________________________________________ 
position of 
side chain 
Example on the 
configu- 
m.p. and possible 
no. R.sub.1 R.sub.2 
R.sub.3 
R purine ring 
ration* 
optical 
__________________________________________________________________________ 
rotation 
4.sup.2 
NHCH.sub.3 H H Diphenylmethyl 
9 rac. b 97-98.degree. 
5.sup.2 
NHCH.sub.3 H H Diphenylmethyl 
3 rac. b 196-197.degree. 
6.sup.3 
N(C.sub.2 H.sub.5).sub.2 
H H Diphenylmethyl 
9 rac. b foam 
7.sup.3 
N(C.sub.2 H.sub.5).sub.2 
H H Diphenylemthyl 
3 rac. b foam 
8.sup.4 
H H Diphenylmethyl 
9 rac. b foam 
9.sup.4 
##STR7## H H Diphenylemthyl 
3 rac. b 141-142.degree. 
10.sup.5 
OH H H Diphenylmethyl 
9 rac. b 196-197.degree. 
11.sup.1 
OCH.sub.3 H H Diphenylmethyl 
9 rac. b 134-136.degree. 
12.sup.1 
OCH.sub.3 H H Diphenylmethyl 
7 rac. b 114-115.degree. 
13.sup.6 
NHCOCH.sub.3 
H H Diphenylmethyl 
9 rac. b 135-136.degree. 
14.sup.7 
NH.sub.2 H H Diphenylmethyl 
9 (R) tch 228-230.degree. 
[.alpha.].sub.D.sup.20 = 
+7.degree. 
(c = 1 in H.sub.2 O) 
15.sup.8 
NH.sub.2 H H Diphenylmethyl 
9 (S) tch 220.degree. 
[.alpha.].sub.D.sup.20 = 
-6,8.degree. 
(c = 1 in H.sub.2 O) 
16.sup.6 
##STR8## H H Diphenylmethyl 
9 rac. b 198-199.degree. 
17 NH.sub.2 H H Diphenylmethyl 
7 (S) b 150-151.degree. 
[.alpha.].sub.D.sup.20 = 
+30,8.degree. 
(c = 1 in Methanol) 
18 NH.sub.2 H H Diphenylmethyl 
3 (S) zfu 181-185.degree. 
[.alpha.].sub.D.sup.20 = 
+26,6.degree. 
(c = 0,5 in Methanol) 
19 NH.sub.2 H H Diphenylmethyl 
3 (R) zfu 185.degree. 
[.alpha.].sub.D.sup.20 = 
-27,6.degree. 
(c = 0,5 in Methanol) 
20.sup.2 
NHCH.sub.3 H H Diphenylmethyl 
9 (S) bmo 127-128.degree. 
[.alpha.].sub.D.sup.20 = 
-2,9.degree. 
(c = 2 in Methanol) 
21.sup.2 
NHCH.sub.3 H H Diphenylmethyl 
9 (R) zfu 175-177.degree. 
[.alpha.].sub.D.sup.20 = 
+1,4.degree. 
(c = 0,5 in Methanol) 
22 NH.sub.2 H H 
##STR9## 9 rac. zfu 180-183.degree. 
23.sup.9 
##STR10## H H Diphenylmethyl 
9 rac. b 137-138.degree. 
24.sup.9 
##STR11## H H Diphenylmethyl 
3 rac. b 193-195.degree. 
25.sup.1 
OCH.sub.3 H H Diphenylmethyl 
9 (S) b 153-154.degree. 
[.alpha.].sub.D.sup.20 = 
-8,9.degree. 
(c = 1 in Methanol) 
26.sup.1 
OCH.sub.3 H H Diphenylmethyl 
7 (S) b 166-167.degree. 
[.alpha.].sub.D.sup.20 = 
-5,4.degree. 
(c = 1 in Methanol) 
27.sup.10 
NHC.sub.2 H.sub.5 
H H Diphenylmethyl 
9 rac. b foam 
28.sup.10 
NHC.sub.2 H.sub.5 
H H Diphenylmethyl 
3 rac. b 162-164.degree. 
29 H H H Diphenylmethyl 
9 rac. zml 142-144.degree. 
30 H H H Diphenylmethyl 
7 rac. b 145-147.degree. 
31 Cl H H Diphenylmethyl 
9 rac. dch 217-220.degree. 
32 Cl H H Diphenylmethyl 
7 rac. b foam 
33.sup.11 
NH.sub.2 H CF.sub.3 
Diphenylmethyl 
9 rac. b 157-158.degree. 
34.sup.12 
NH.sub.2 H CH.sub.3 
Diphenylmethyl 
9 rac. zfu 189-191.degree. 
35 NH.sub.2 H NH.sub.2 
Diphenylmethyl 
9 rac. b 141-142.degree. 
36 NH.sub.2 H Cl Diphenylmethyl 
3 rac. b 155-157.degree. 
37 NH.sub.2 H Br Diphenylmethyl 
3 rac. b 185-186.degree. 
38.sup.13 
NHCOCH.sub.3 
NHCOCH.sub.3 
H Diphenylmethyl 
9 rac. b 225-227.degree. 
__________________________________________________________________________ 
* = on the carbon atom of the side chain which bears the hydroxy 
rac. = racemic 
b = in free form as a base 
tch = in salt form as a trihydrochloride 
zfu = bishydrogenfumarate 
bmo = bismalonate 
zml = bishydrogenmaleinate 
dch = dihydrochloride 
.sup.1 The 6methoxypurine (m.p. 198.degree.) used as the starting product 
is obtained by reacting 6chloropurine with sodium methylate in methanol 
.sup.2 The 6methylaminopurine (m.p. 300.degree., decomp.) used as the 
starting product is obtained by reacting 6chloropurine with methylamine 
.sup.3 The 6diethylaminopurine (m.p. 210-212.degree. ) used as the 
starting product is obtained by reacting 6chloropurine with diethylamine 
.sup.4 The 6piperidinopurine (m.p. 232-234.degree.) used as the starting 
product is obtained by reacting 6chloropurine with piperidine 
.sup.5 By reacting the compound of example 2 with sodium nitrite in 
diluted sulphuric acid at 70.degree.- 
.sup.6 By means of acetylation of the compound of example 2 
.sup.7 The adenine is reacted with 
R2,2-dimethyl-4-tosyloxymethyl-1,3-dioxolane, then the isopropylidene 
protecting group is split off with acetic acid, the product (m.p. 
202.degree.; [.alpha.]D.sup.20 = -45.7.degree. in H.sub.2 O) is tosylated 
and the tosylate obtained (m.p. 150.degree., indefinite) is reacted with 
1diphenylmethylpiperazine 
.sup.8 The adenine is reacted with Sbenzyloxymethylethylene oxide 
([.alpha.]D.sup.20 = -9.6.degree.), then the benzyl protecting group is 
split off by means of hydrogenation in presence of palladium on charcoal, 
the diol obtained (m.p. 203-204.degree.; [.alpha.]D.sup.20 = +45.8.degree 
in H.sub.2 O) is tosylated and the toslyate obtained (m.p. 150.degree., 
indefinite) is reacted with 1diphenylmethylpiperazine. 
.sup.9 The 6isopropylaminopurine (m.p. 193-194.degree.) used as the 
starting product is obtained by reacting 6chloropurine with isopropylamin 
.sup.10 The 6ethylaminopurine (m.p. 221-223.degree.) used as the starting 
product is obtained by reacting 6chloropurine with ethylamine 
.sup.11 The 8trifluoromethyladenine (m.p. &gt;300.degree.) used as the 
starting product is obtained by reacting 4,5,6triaminopyrimidine with 
trifluoroacetamide 
.sup.12 The 8methyladenine (m.p. &gt;340.degree.) used as the starting 
product is obtained by reacting 4,5,6triaminopyrimidine with acetanhydrid 
.sup.13 The 2,6bis-acetaminopurine (m.p. 280-285.degree.) used as the 
starting product is obtained by reacting 2,6diaminopurine with 
acetanhydride 
The (S)-1-diphenylmethyl-4-(2,3-epoxypropyl)piperazine used as starting 
product in examples 17, 18, 20, 25 and 26 is prepared as follows: 
1-diphenylmethylpiperazine is heated together with an equimolar amount of 
R-glyzerineglycide in isopropanol during 2 hours to 50.degree.. The formed 
(S)-1-diphenylmethyl-4-(2,3-dihydroxypropyl)piperazine is reacted at 
-10.degree. to -20.degree. with p-toluenesulfochloride in 
methylenechloride in the presence of triethylamine, then a methanolic 
sodiummethylat solution is added. 
The above reaction product crystallises from ether/hexane in the form of 
white needles, m.p.=84.degree. to 85.degree., [.alpha.]D.sup.20 
=-14,6.degree. (c=2 in methanol). 
The compounds according to the invention in free form or in the form of 
their physiologically acceptable salts are notable for their interesting 
pharmacodynamic properties. They can be used as medicaments. 
This can be shown in standard tests. 
The compounds according to the invention have cardiotonic properties. On 
the rat which has been anaesthetised with Inactin(R) at a dosage of about 
0.03 mg/kg to 3 mg/kg i.v., they effect an increase in the contractile 
force of the left ventricle. When using the compound of example 20, the 
increase is 12% and 61% at dosages of 0.1 and 1.0 mg/kg i.v. The 
corresponding values for amrinone are 7% and 29%. 
On the isolated, acutely insufficient rabbit's heart, increases in 
conctractile force could be established at dosages of about 0.1 .mu.g/min 
to 100 .mu.g/min. For the compound of example 20, increases of 7% and 47% 
are established at dosages of 10 and 100 .mu.g/min. With amrinone, the 
increase in contractile force is 3% at 100 .mu.g/min and 15% at 2000 
.mu.g/min. 
This test is effected as follows: 
The test is concerned with a method by LANGENDORFF (1895) in which the 
apparatus is modified, but the principle is unchanged. Male rabbits (2.2 
to 2.5 kg) are given 5 mg/kg heparin by an i.v. injection, and are killed 
10 minutes later by a blow to the neck, and drained of blood by opening 
the carotid artery. After opening the chest cavity, a cannula is connected 
to the aorta and is perfused with oxygenated (95% O.sub.2 and 5% CO.sub.2) 
Tyrode's solution of 37.degree. C. The Tyrode's solution has the following 
composition (g/liter): NaCl 8 g; KCl 0.2 g; CaCl.sub.2 0.2 g; MgCl.sub.2 
0.1 g; NaHCO.sub.3 1 g; NaH.sub.2 PO.sub.4 0.05 g; glucose 1 g. After the 
heart has been exposed, it is suspended from the perfusion apparatus. The 
heart is perfused at a constant pressure of 60 cm H.sub.2 O (44 mm Hg). A 
strain-gauge is fixed into the left ventricular wall without putting too 
much strain on the coronary vessels. The active electrodes for electric 
stimulation are placed in the right atrium and connected to a 
Grass-Stimulator Type S5. The left-ventricular contractile force, measured 
isometrically in grams with a strain-gauge, is recorded on a Schwarzer 
stenographer. In order to raise the sensitivity of the heart, the organs 
are damaged with high concentrations of isoprenaline. 10 minute infusions 
of 0.5 or 1 .mu.g/min isoprenaline repeated two to three times, lead, 
subsequently, to a reduction in contractile force. A criterion for an 
acutely insufficient heart is a reduction in contractile force of ca. 40%. 
The test substance is respectively infused for 10 minutes. 
Because of this activity, the compounds according to the invention can be 
used as cardiotonics, e.g. in the therapy of cardiac insufficiency. 
For the above-mentioned use as cardiotonics, the dosage to be used varies 
according to the substance used, the type of administration and the 
desired treatment. In general however, satisfactory results are obtained 
with a daily dosage of approximately 0.01 to 10 mg per kg body weight; if 
necessary, administration may take place in 2 to 4 parts or even in 
sustained release form. For larger mammals, the daily dosage is in the 
region of approximately 1 to 500 mg; suitable dosage forms for e.g. oral 
or non-oral administration generally contain about 0.25 to 250 mg, 
together with solid or liquid carrier substances. 
In addition, the compounds according to the invention possess 
anti-arrhythmic properties. They effect a prolonging of the functional 
refractory period in the left guniea-pig atrium at bath concentrations of 
about 10.sup.-7 M to 10.sup.-4 M (R. Hof and G. Scholtysik, J. Cardiovasc. 
Pharm. 5 [1983] 176-183). 
They can therefore be used as anti-arrhythmics, e.g. in the treatment of 
cardiac irregularities, such as supraventricular tachycardia or 
fibrillation. 
For the above-mentioned use as anti-arrhythmics, the dosage to be used 
varies according to the substance used, the type of administration and the 
desired treatment. In general however, satisfactory results are obtained 
with a daily dosage of approximately 0.01 to 10 mg per kg body weight; if 
necessary, administration may take place in 2 to 4 parts or even in 
sustained release form. For larger mammals, the daily dosage is in the 
region of approximately 0.1 to 500 mg; suitable dosage forms for e.g. oral 
or non-oral administration generally contain about 0.025 to 250 mg, 
together with solid or liquid carrier substances. 
The compound of Example 20 is preferred. 
The compounds according to the invention in free form or in the form of 
their physiologically acceptable salts may be administered alone or in a 
suitable dosage form. The medicinal forms, e.g. solution or a tablet, may 
be produced analogously to known methods. 
The invention thus relates also to medicaments which contain the compounds 
according to the invention in free form or in the form of their 
physiologically acceptable salts, as well as the use of the compound 
according to the invention for the production of these medicaments that 
are useful in the treatment of cardiac insufficiency and cardiac 
irregularity. The conventional pharmaceutical adjuvants and carriers may 
be used in their production.