Gallium compounds

Gallium(III) complexes of general formula I, ##STR1## in which X=O.sub.2 CR.sup.2, halogen, NO.sub.3 or -OA, R.sup.1 =H, alkyl, alkoxy, halogen, NO.sub.2 or amino, R.sup.2 =alkyl, alkoxy or aryl, each of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 =H or alkyl and n=0, 1 or 2, or when n=0 and R.sup.3 and R.sup.6 both=H, then R.sup.4 and R.sup.5 together may form tetramethylene, and A=an identical gallium complex moiety to that to which the oxygen atom is linked, are well absorbed orally, and are indicated as medicaments for hypercalcemia and for cancer chemotherapy.

This invention concerns gallium compounds. More especially it concerns 
gallium compounds having increased absorption when administered by the 
oral route. 
Salts of the group 13 metal gallium have been known for some time to have 
anti-tumour activity. More recently, gallium has been shown to reduce 
serum calcium in patients with hypercalcemia of malignancy. Gallium exerts 
this latter effect by inhibiting the resorption of calcium from bone; it 
also increases bone strength so that gallium would also be useful for 
treating bone disorders associated with accelerated bone loss and 
decreased bone strength, (see e.g., U.S. Pat. No. 4,704,277 and U.S. Pat. 
No. 4,529,593 the teaching of which is incorporated herein by reference). 
In practice, gallium therapy for hypercalcemia has been difficult to 
provide. It has been reported that renal toxicity is dose-limiting when 
gallium is administered as an iv bolus. A seven day continuous iv infusion 
of gallium showed no renal toxicity for the treatment of cancer-associated 
hypercalcemia, and while this therapy is effective, it is cumbersome. In 
order to make gallium therapy more conveniently administered for both 
cancer chemotherapy and the hypercalcemia of malignancy, and in order to 
provide wider application of gallium therapy to appropriate bone diseases, 
an oral dose form of gallium is highly desirable. 
Drug absorption from the gastro-intestinal tract occurs at pH 4.5-7. In 
this pH range the gallium(III) aquo-ion is extensively hydrolysed to 
insoluble hydroxides and is very poorly absorbed. Daily oral doses of 400 
mg GaCl.sub.3 in lung cancer patients yielded mean serum gallium 
concentrations of 371.+-.142 ug/ml. However, gallium in an appropriate 
co-ordination environment is stable to hydrolysis in aqueous environment, 
at pH which is relevant biologically. 
The present invention provides novel pharmaceutical compositions comprising 
an active component which is a gallium complex as defined by formula I 
hereinafter, and methods of administering gallium to a patient comprising 
the use of said complexes and the invention has many other inventive and 
useful aspects. 
In particular, the active components according to the invention are 
gallium(III) complexes of formula I, 
##STR2## 
in which, X=O.sub.2 CR.sup.2, halogen, NO.sub.3 or --O--A, 
R.sup.1 =H, alkyl, alkoxy, halogen, NO.sub.2 or amino, 
R.sup.2 =alkyl, alkoxy or aryl, 
each of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 =H or alkyl and 
n=0, 1 or 2, or 
when n=0, and R.sup.3 and R.sup.6 both=H, then R.sup.4 and R.sup.5 together 
may form tetramethylene, and 
A=an identical gallium complex moiety to that to which the oxygen atom is 
linked. 
For ease of reference hereafter, compounds in which X=--O--A will be called 
"dimers". 
The invention further provides a process for the production of compounds of 
formula I, comprising reacting a tetradentate Schiff base of general 
formula II, 
##STR3## 
wherein R.sup.1 -R.sup.6, and n are as defined above, with a gallium(III) 
compound, 
a) which is gallium(III) hydroxide to form a dimer compound of formula I in 
which X=--O--A, and when a compound of formula I in which X=O.sub.2 
CR.sub.2 is desired, reacting said dimer with an acylating agent, 
especially an acid of formula R.sup.2 COOH, or 
b) which is gallium(III) halide or nitrate, to form the corresponding 
compound of formula I in which X is halogen or nitrate. 
The dimer compounds thus serve two functions, as active compounds according 
to the invention, and as intermediates for those compounds of formula I in 
which X=O.sub.2 CR.sub.2. 
Where substituents R.sup.1 to R.sup.6 are alkyl or alkoxy, they preferably 
have from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms. 
Where substituent R.sup.1 is amino, it is preferably dialkylamino, in which 
each alkyl has from 1 to 6 carbon atoms. 
Preferred compounds of formula I are those in which R.sup.3 and R.sup.4 are 
H and n is 0. Preferably, when X is halogen, it is chlorine. 
The compound of formula I in which R.sup.1 and R.sup.3 to R.sup.6 are 
hydrogen, and X is chlorine, has been reported in the academic literature. 
(Can J Chem, 59, 94, 1980). No utility is suggested for this compound, and 
it could not be expected that it would exhibit high oral absorption 
according to the tests described hereinafter. The remaining compounds of 
formula I are believed to be novel. 
In the preparation of the compounds of formula I, the starting materials 
are known and may be prepared according to known methods, or may be 
purchased from specialist laboratory chemical suppliers. The 
gallium-containing starting materials are suitably salts such as 
GaCl.sub.3, Ga(NO.sub.3).sub.3 or freshly precipitated Ga(OH).sub.3. The 
tetradentate Schiff base is prepared by condensation of a primary diamine 
with two equivalents of a 2-hydroxybenzaldehyde, in alcohol. 
The reaction of the Schiff base with the gallium compound is suitably 
carried out in a solvent such as an alcoholic medium, boiling ethanol is 
preferred for many compound preparations. The process is more particularly 
described in specific compound preparations described in the Examples 
hereinafter. It will readily be appreciated that it may be desirable to 
use a salt form of the Schiff base, or to carry out the reaction in the 
presence of a base, as exemplified in the preparation of compounds of 
formula I in which X is chlorine or nitrate respectively. The product 
complexes may be isolated and purified using conventional techniques. 
The complexes of the invention provide good oral absorption of gallium 
compared to commercially-available preparations which are currently used 
to treat cancer-related hypercalcemia, when assessed by in vivo tests in 
rats, as described hereinafter. The complexes of the invention are also 
indicated for the treatment of excessive loss of calcium from bone tissue 
and for inhibiting bone resorption, and are therefore indicated for the 
treatment of a patient having an excessive calcium loss and bone 
resorption disorder. 
The active complexes according to the present inventions may be 
administered to a patient in the form of pharmaceutical compositions 
formulated according to well known principles. Thus, the composition 
comprises the active ingredient, preferably in a unit dose, in admixture 
with a pharmaceutically acceptable diluent or carrier. The active 
complexes of the invention are assessed to have particular activity when 
taken orally, and therefore, preferred compositions are those formulated 
in the form of capsules, tablets, dragees or other solid compositions, or 
as a solution or suspension, for example, as a syrup, for oral 
administration. Suitable pharmaceutically acceptable diluents and 
carriers, and other components, including colouring and flavouring agents, 
and methods for formulation, are generally known. 
Although the active complexes of the invention have particular utility for 
oral administration, the invention is not to be regarded as limited to 
methods of treatment and compositions solely for oral administration. 
Thus, compositions for injections, suppositories, sustained release forms 
of such or for implantation and the like, may be formulated in 
conventional manner, and may provide advantages for particular courses of 
treatment or for combined therapy. 
Dosage rates may suitably lie in the range of 0.1 to 100 mg/kg body weight. 
Preferably, the dosage is sufficient to maintain a level of 1 to 1.5 .mu.g 
gallium per ml of blood, and the dose may suitably be in the range 0.5 to 
1.5 g of gallium compound per day. Such a dose may be administered as a 
single unit dose or in a number of smaller unit doses. Other active 
compounds may be administered separately or together with the gallium 
complex, or supplemental therapy may be included in a course of treatment 
for a patient. 
As representatives of compounds of the invention, the following compounds 
of formula I may be mentioned: 
______________________________________ 
(R.sub.3 = H) 
Preparative 
R.sup.1 R.sup.4 
R.sup.5 R.sup.6 
X n Example 
______________________________________ 
H H H H O-Gasalen 
0 1 
H H H H Cl 0 2 
H H H H NO.sub.3 
0 3 
H H H H OAc 0 4 
H H H H O.sub.2 CEt 
0 5 
H H H H O.sub.2 CC.sub.7 H.sub.15 
0 6 
H H H H O.sub.2 CC.sub.6 H.sub.5 
0 7 
3-OMe H H H OAc 0 8 
5-Cl H H H OAc 0 9 
5-Me H H H OAc 0 10 
H Me H H OAc 0 11 
H --(CH.sub.2).sub.4 -- 
H OAc 0 12 
4-NMe.sub.2 
H H H OAc 0 13 
5-OMe H H H OAc 0 14 
H H Me Me OAc 0 15 
H H H H OAc 1 16 
______________________________________

The invention will now be described in the following examples, which 
illustrate but are not intended to limit the scope of the invention. 
EXAMPLES 
A typical preparation of freshly precipitated Ga(OH).sub.3 used in the 
following examples is as follows: 
20 ml 1.1M aqueous GaCl.sub.3 was hydrolysed with aqueous NaOH to a final 
pH of 8.35 and a final volume of 100 ml. The suspension was centrifuged at 
5000 rpm for 10 minutes, the supernatant liquor was decanted and the 
Ga(OH).sub.3 resuspended in deionised water three times. The Ga(OH).sub.3 
was washed once more in this manner with absolute ethanol and finally 
resuspended in absolute ethanol for use in preparation of the complexes. 
In a typical preparation of the Schiff base tetradentate ligand, two 
equivalents of aldehyde in methanol was added slowly to one equivalent of 
diamine in methanol. In most instances a crystalline solid precipitated 
and was used without further purification. 
In a typical preparation of a gallium complex where X of formula I is 
carboxylate, a suspension of Ga(OH).sub.3 in ethanol was added to a 
boiling solution of the tetradentate Schiff base in ethanol and boiled for 
approximately half an hour. The suspension was then cooled, filtered 
through celite and stripped of solvent to yield, in most instances, a 
mixture of compounds as a yellow solid. The yellow solid was then 
dissolved in methanol and stirred with excess carboxylic acid. 
Concentration of the solution often caused precipitation of analytcially 
pure LGaO.sub.2 CR (L=tetradentate Schiff base). 
Abbreviations 
SalenH.sub.2 ; N,N'-ethylenebis(salicylideneamine); 
3-MeOsalenH.sub.2 ; N,N'-ethylenebis(3-methoxysalicylideneamine); 
5-ClsalenH.sub.2 ; N,N'-ethylenebis(5-chlorosalicylideneamine); 
5-MesalenH.sub.2 ; N,N'-ethylenebis(5-methylsalicylideneamine); 
Sal-1,2-pnH.sub.2 ; N,N', 1,2-propylenebis(salicylideneamine); 
SalachH.sub.2 ; N,N', trans-1,2-cyclohexanebis(salicylideneamine); 
SalmpnH.sub.2 ; N,N'-1,2-diamine-2-methylpropanebis(salicylidene amine); 
Sal-1,3-pnH.sub.2 ; N,N'-1,3-propylenebis(salicylideneamine; 
4-Me.sub.2 NsalenH.sub.2 ; 
N,N'-ethylenebis(4-N,N-dimethylaminesalicylideneamine); 
5-MeOsalenH.sub.2 ; N,N'-ethylenebis(5-methoxysalicylideneamine) 
EXAMPLE 1 
(Gasalen).sub.2 O 
A 100 ml suspension of Ga(OH).sub.3 in ethanol prepared from 20 ml 1.1M 
GaCl.sub.3, was added to a hot suspension of 4 g salenH.sub.2 in 100 ml 
ethanol and heated at boiling point for about 15 minutes. The bright 
yellow suspension was cooled, filtered through diatomaceous earth and the 
filtrate stripped of solvent to leave 3.5 g of solid. 1.5 g yellow solid 
was recrystallised from 20 ml hot DMSO, washed with diethyl ether and 
dried. 
______________________________________ 
Analysis for C.sub.32 H.sub.28 N.sub.4 O.sub.5 Ga.sub.2.H.sub.2 O 
% C % H % N % Ga 
______________________________________ 
Calc: 54.44 4.28 7.94 19.75 
Found 54.25 4.33 7.94 19.40 
______________________________________ 
EXAMPLE 2 
GasalenCl 
This compound was prepared from 2 g salen according to a published 
procedure with slight modifications (K S Chong et al, Can J Chem, 59, 94, 
1980). The crude product was only slightly soluble in the reaction solvent 
THF, and benzene extraction according to the published procedure was 
inefficient. Thus the THF insoluble residue from the reaction was stirred 
briefly in water to remove NaCl, filtered and dried under vacuum. This 
material was then extracted with boiling acetone, gravity filtered hot and 
the solvent volume reduced with gentle boiling. 
Crystallisation was allowed to proceed first at room temperature and then 
at 0.degree. C. The crystalline solid was filtered and dried to yield 0.6 
g. 
______________________________________ 
Analysis for C.sub.16 H.sub.14 N.sub.2 O.sub.2 GaCl 
% C % H % N 
______________________________________ 
Calc: 51.73 3.80 7.54 
Found 51.67 3.84 7.56 
______________________________________ 
EXAMPLE 3 
GasalenNO.sub.3 
To a stirred hot solution of 1.26 g H.sub.2 salen and 0.3 g LiOH in 60 ml 
methanol was added a suspension of 2 g (Ga(NO.sub.3).sub.3.9H.sub.2 O in 
60 ml methanol. The mixture was heated for a few minutes. The clear, pale 
yellow solution was concentrated to about 50 ml and chilled to -20.degree. 
C. for 16 hours. Precipitated LiNO.sub.3 was filtered off, the filtrate 
was concentrated to about 25 ml and about 40 ml acetone was added. The 
mixture was chilled to -20.degree. C. for 2 hours. A pale yellow solid was 
filtered off and the volume of filtrate was reduced. A crystalline solid 
formed in the viscous yellow solution. This was filtered off, carefully 
washed with small volumes of very cold (T&lt;0.degree. C.) methanol, then 
with room temperature acetone, before being vacuum dried to leave 0.92 g 
pale yellow solid. 
______________________________________ 
Analysis for C.sub.16 H.sub.14 N.sub.3 O.sub.5 Ga.2H.sub.2 O 
% C % H % N 
______________________________________ 
Calc: 44.27 4.18 9.68 
Found 44.12 4.37 9.42 
______________________________________ 
EXAMPLE 4 
GasalenOAc 
2.93 g (salenGa).sub.2 O (Example 1) was stirred in 150 ml methanol and 20 
ml glacial acetic acid for 5 minutes. The volume was reduced by about 50% 
on the "rotovap" and the product precipitated. The mixture was allowed to 
stand for 3 hours at 20.degree. C., the yellow solid filtered, washed with 
acetone and ether and dried to yield 2 g yellow solid. 
______________________________________ 
Analysis for C.sub.18 H.sub.17 N.sub.2 O.sub.4 Ga 
% C % H % N 
______________________________________ 
Calc: 54.72 4.34 7.09 
Found 54.73 4.37 7.11 
______________________________________ 
EXAMPLE 3 
GasalenO.sub.2 CEt 
This was prepared by a procedure similar to Example 4 from 2 g 
(Gasalen).sub.2 O and 4 ml propionic acid in 150 ml MeOH. After addition 
of propionic acid the solvent was removed under vacuum and the resulting 
yellow oil recrystallised from 20 ml acetone by adding hexane to the cloud 
point (70 ml) and allowing crystallisation to proceed, 1.36 g. 
______________________________________ 
Analysis for C.sub.19 H.sub.19 N.sub.2 O.sub.4 Ga.1/4H.sub.2 O 
% C % H % N 
______________________________________ 
Calc: 55.18 4.75 6.77 
Found 55.25 4.47 6.70 
______________________________________ 
EXAMPLE 6 
Gasalenoctanoate 
This compound was made from 2 g (Gasalen).sub.2 O (Example 1) and 1.83 ml 
octanoic acid in 75 ml methanol. Precipitation was induced by adding ether 
to yield 1.7 g of fluffy off-white solid. 
______________________________________ 
Analysis for 
% C % H % N 
______________________________________ 
Calc: 60.15 6.10 5.85 
Found 60.16 6.10 5.83 
______________________________________ 
EXAMPLE 7 
Gasalenbenzoate 
This compound was prepared from 0.50 g (Gasalen).sub.2 O (Example 1) and 
0.18 g benzoic acid in 50 ml methanol. After stirring the reaction mixture 
for 3 hours, 0.27 g yellow solid was filtered off, washed with ether and 
dried. 
______________________________________ 
Analysis for C.sub.23 H.sub.19 N.sub.2 O.sub.4 Ga 
% C % H % N 
______________________________________ 
Calc: 60.43 4.19 6.13 
Found 60.41 4.01 6.04 
______________________________________ 
EXAMPLE 8 
3-MeOsalenGaOAc 
3-MeOsalenH.sub.2 was prepared from 5 g o-vanillin in 50 ml absolute 
ethanol and 1 g ethylenediamine in 50 ml absolute ethanol. 5 g of 
yellow-orange crystalline solid formed which was filtered, washed with 
ethanol and dried. 
Ga(OH).sub.3 in 100 ml ethanol, from 8.3 ml 1.1M aqueous GaCl.sub.3, was 
boiled for about 1 hour in a solution of 2 g 3-MeOsalen in 100 ml ethanol, 
to yield 2.4 g bright yellow solid. 
To 1.8 g of this solid, stirred as a suspension in 250 ml methanol, was 
added 5.3 ml glacial acetic acid. The clear, bright yellow solution was 
reduced in volume on the "rotovap" to about 60 ml during which a yellow 
solid formed. This was allowed to stand at -20.degree. C. for 1 hour, the 
solid filtered, washed and dried to yield 1.4 g yellow solid. 
______________________________________ 
Analysis for C.sub.20 H.sub.21 N.sub.2 O.sub.6 Ga.11/2H.sub.2 O 
% C % H % N 
______________________________________ 
Calc: 49.82 5.02 5.68 
Found 49.69 4.94 5.68 
______________________________________ 
EXAMPLE 9 
Ga5-chlorosalen 
5-chlorosalenH.sub.2 was prepared from 14 g 5-chlorosalicylaldehyde and 3 
ml ethylene-diamine in a total of 150 ml methanol. The product 
precipitated without reducing the volume, with a yield of 13 g. 
A 120 ml ethanol suspension of Ga(OH).sub.3 from 21.3 ml 0.84M aqueous 
GaCl.sub.3 was added to a solution of 4 g 5-chlorosalen in 700 ml ethanol 
at boiling point. The suspension was boiled for half an hour, left to cool 
and centrifuged at 9000 rpm for 10 minutes. The supernatant liquor was 
decanted and stripped of solvent to leave 3 g of pale yellow solid. 1 g of 
this solid was dissolved in 200 ml absolute ethanol and 2.8 ml glacial 
acetic acid was added. After precipitation was complete, the pale yellow 
powder was filtered, washed and dried to yield 560 mg. 
______________________________________ 
Analysis for C.sub.18 H.sub.15 N.sub.2 O.sub.4 Cl.sub.2 Ga 
% C % H % N 
______________________________________ 
Calc: 46.60 3.26 6.04 
Found 46.88 3.81 5.75 
______________________________________ 
EXAMPLE 10 
Ga5-methylsalenOAc 
5-methylsalicylaldehyde was prepared from p-cresol by the Duff reaction. 
The Schiff base (5-Mesalen) was prepared in 100 ml methanol from 1.2 ml 
ethylenediamine and 5.03 g 5-methylsalicylaldehyde to yield 2.75 g 
product. 
Ga(OH).sub.3, prepared from 12 ml 0.84M GaCl.sub.3 in ethanol was added to 
a solution of 2 g 5-methylsalen in 400 ml boiling ethanol. The suspension 
was boiled for half an hour, allowed to cool, filtered through celite and 
stripped of solvent under vacuum. The yellow solid was dissolved in 300 ml 
methanol and 3 ml glacial acetic acid was added. After stirring for 11/2 
hours the solution was stripped to dryness and the yellow solid 
recrystallised from acetone. The crystalline material contained acetone 
not removed under vacuum. The solid was recrystallised from ethylacetate 
to yield 1.16 g yellow solid. 
______________________________________ 
Analysis for C.sub.20 H.sub.21 N.sub.2 O.sub.4 Ga 
% C % H % N 
______________________________________ 
Calc: 56.77 5.00 6.62 
Found 56.74 4.99 6.55 
______________________________________ 
EXAMPLE 11 
Ga(Sal-1,2-pn)OAc 
Sal-1,2-pnH.sub.2 was made from 3 ml.+-.1,2-propanediamine and 7.54 ml 
salicylaldehyde in 130 ml methanol as a yellow oil, yielding 9.7 g. 4 g 
Sal-1,2-pnH.sub.2 was allowed to react with Ga(OH).sub.3 from 6.39 ml 
0.84M GaCl.sub.3 m, in 250 ml boiling methanol for half an hour. The 
mixture was allowed to cool, filtered through celite and stripped of 
solvent to leave 5.61 g yellow solid. A solution of 5.5 g of the yellow 
solid in 100 ml MeOH, was stirred with 9 ml glacial acetic acid for 1 hour 
and stripped of solvent to leave a yellow oil which solidified on 
standing. This was recrystallised from 250 ml hot acetone to yield 1.2 g 
pale yellow solid. 
______________________________________ 
Analysis for C.sub.19 H.sub.19 N.sub.2 O.sub.4 Ga 
% C % H % N % Ga 
______________________________________ 
Calc: 55.78 4.68 6.85 17.04 
Found 55.81 4.63 6.85 16.48 
______________________________________ 
EXAMPLE 12 
GasaldachOAc 
To a stirred solution of 3 g trans-1,2-diaminocyclohexane in 75 ml methanol 
was added slowly 6.41 g salicylaldehyde in 25 ml methanol. SaldachH.sub.2, 
obtained as 7.23 g yellow granular product, was filtered, washed and 
dried. 
A methanol suspension of Ga(OH).sub.3 from 16.6 ml 0.84M GaCl.sub.3 was 
added to 3 g saldachH.sub.2 in 200 ml boiling absolute ethanol. The 
suspension was boiled for half an hour and filtered through celite. Little 
material was extracted into the ethanol. The celite was extracted with 
CH.sub.2 Cl.sub.2 and the solvent evaporated from the extract under vacuum 
to leave 3.31 g yellow solid. 
0.5 g of this yellow solid was dissolved in 400 ml 50:50 CH.sub.2 Cl.sub.2 
/MeOH and about 1 ml glacial acetic acid was added. After 3 hours, the 
volume of the mixture was reduced to 75 ml and then chilled to -20.degree. 
C. 0.49 g of white solid was filtered off, washed with ether and dried. 
______________________________________ 
Analysis for C.sub.22 H.sub.23 N.sub.2 O.sub.4 Ga.H.sub.2 O 
% C % H % N 
______________________________________ 
Calc: 56.56 5.39 6.00 
Found 56.74 5.68 5.79 
______________________________________ 
EXAMPLE 13 
4-Me.sub.2 NsalenGaOAc 
4-N,N-dimethylaminosalicylaldehyde was prepared according to a published 
procedure (Baird and Shriner, J Am Chem Soc 1964, 68, 3142). 
4-Me.sub.2 NsalenH.sub.2 was prepared from the reaction of ethylenediamine 
with two equivalents of 4-N,N-dimethylaminosalicylaldehyde in methanol. 
The product was filtered from the reaction mixture after standing at 
-20.degree. C. overnight and used as is. 
Ga(OH).sub.3 in about 40 ml ethanol, from 10.1 ml 0.84 M aqueous 
GaCl.sub.3, was boiled for about 1/2 hour in a solution of 2 g 4-Me.sub.2 
NsalenH.sub.2 in 250 ml ethanol. During the reaction, solvent boiled away 
to leave a volume of 75 ml. When the reaction mixture cooled to room 
temperature a solid formed. This solid product was removed by filtration 
and washed with ether to leave 1.25 g fluffy solid. This solid was 
dissolved in 150 ml methanol, filtered and the filtrate allowed to react 
with acetic acid. Reduction of solvent volume caused a precipitate to form 
which was filtered, washed with ether and dried to yield two crops of 
crystalline solid with a combined weight of 0.9 g. 
______________________________________ 
Analysis for C.sub.22 H.sub.27 N.sub.4 Ga 
% C % H % N 
______________________________________ 
Calc. 54.91 5.66 11.64 
Found 54.96 5.64 11.64 
______________________________________ 
EXAMPLE 14 
5-MeOsalenGaOAc 
5-MeOsalenH.sub.2 was prepared in the same manner as the free ligand in 
Example 8. 
A suspension of Ga(OH).sub.3 in 50 ml ethanol, from 13.5 ml 0.84 M aqueous 
GaCl.sub.3, was boiled with a solution of 3 g 5-MeOsalenH.sub.2 in 400 ml 
absolute ethanol for 1/2 hour to yield 3.3 g yellow solid. The solid was 
stirred with two equivalents acetic acid in methanol and stripped of 
solvent to leave a solid. The solid was recrystallised from 
methanol/toluene. 
______________________________________ 
Analysis for C.sub.20 H.sub.21 N.sub.2 O.sub.6 Ga 
% C % H % N 
______________________________________ 
Calc. 52.78 4.65 6.16 
Found 52.83 4.71 5.96 
______________________________________ 
EXAMPLE 15 
SalmpnGaOAc 
SalmpnH.sub.2 was synthesised from 2 g 1,2-diamino-2-methylpropane and 5.54 
g salicylaldehyde in 100 ml methanol. The solvent volume was reduced by 
evaporation and 4 g yellow solid product was filtered off, washed with 
hexane and dried. 
A suspension of Ga(OH).sub.3 in 50 ml absolute ethanol, from 18.1 ml 0.84 M 
aqueous GaCl.sub.3, was boiled with a solution of 3 g SalmpnH.sub.2 and 
200 ml boiling absolute ethanol, centrifuged and stripped of solvent to 
leave 3.9 g yellow solid. The solid was stirred in methanol with two 
equivalents of acetic acid and the reaction mixture stripped to dryness to 
leave a yellow solid product which was recrystallised from 1:1 
acetone/hexane. 
______________________________________ 
Analysis for C.sub.20 H.sub.21 N.sub.2 O.sub.4 Ga 
% C % H % N 
______________________________________ 
Calc. 56.77 5.00 6.62 
Found 56.76 5.05 6.64 
______________________________________ 
EXAMPLE 16 
Sal-1,3-pnGaOAc 
Sal-1,3-pnH.sub.2 was prepared in 61% yield from 1,3-diaminopropane and two 
equivalents of salicylaldehyde in 300 ml methanol to yield 18 g 61% yellow 
solid. This product was used as is. 
A suspension of Ga(OH).sub.3 in 50 ml ethanol, from 10.6 ml 0.84M aqueous 
GaCl.sub.3 was boiled with 2.5 g Sal-1,3-pn in 200 ml absolute ethanol for 
1/2 hour. The mixture was stripped of solvent and the residue taken up in 
CH.sub.2 Cl.sub.2. This suspension was centrifuged, the supernate filtered 
through celite and the filtrate stripped of CH.sub.2 Cl.sub.2 to leave 2 g 
yellow solid. 
0.74 g of this solid was stirred with two equivalents acetic acid, stripped 
of solvent and the yellow mass triturated with ether to leave a yellow 
solid. 
______________________________________ 
Analysis for C.sub.19 H.sub.19 N.sub.2 O.sub.4 Ga 
% C % H % N 
______________________________________ 
Calc. 55.78 4.68 6.85 
Found 55.61 4.80 6.88 
______________________________________ 
According to the invention, compounds were tested for oral absorption in 
rats. Male Sprague Dawley rats weighing 150-225 g were purchased from 
Harlan Sprague Dawley, Inc., (Indianapolis, Ind.). The gallium standard 
solution is from Aldrich Chemical Co. (Milwaukee, Wis.). Metofane is a 
product from Pitman-Moore (Mundelein, Ill.), and all other Chemicals are 
commercially available. Gallium test compounds were dissolved in 18 
megaohm water (Millipore, Bedford, Mass.) or suspended in 0.5% 
carboxymethyl cellulose in 5% ethanol, if the compound was not water 
soluble. The suspensions were sonicated at room temperature for about 5 
minutes. 
For stomach and intestine administrations, rats were anaesthetised with 
metofane, and a one-inch incision made to expose the stomach and a portion 
of the small intestine. A ligation was made immediately below the pylorus, 
and a second ligation was made 1 cm below to assure no leakage. For oral 
gavage administrations, 18-gauge ball-tipped animal feeding needles 
(Popper & Sons, Inc, New Hyde Park, N.J.) were used. For stomach 
injections, needles were inserted in the middle of the pyloric part of the 
stomach which has an opaque thick muscular wall, and intestinal injections 
were made about 0.5 cm below the second ligation with the needle pointed 
down and away from the stomach. 
Sutures were made with 3-4 stitches with 3-0 silk surgical thread (Ethicon 
Inc, Somerville, N.J.). The tail vein was used for intravenous injections. 
With the exception of oral gavage administrations, all injections were 
made with 30-gauge needles to minimise the possibility of leakage. The 
dose was 0.067 mmol/kg. Approximately 300 .mu.l blood samples were 
collected at 0.17, 0.5, 1.0, 2.0, 4.0 hours following compound 
administration. The blood was placed in 1 ml Eppendorf tubes pre-coated 
with 50 .mu.l heparin (1000 U/ml and air dried, so there was no blood 
dilution involved. The plasma was recovered after the blood was 
centrifuged for 2 minutes in a Fischer Micro-centrifuge, Model 235B, and 
its gallium content measured by a Varian Flameless Atomic Absorption 
Spectrometer. The standard curve was linear in the gallium concentrations 
of 5-100 ng/ml. The area under the concentration (AUC) versus time curve 
for 0-4 hours was estimated. 
______________________________________ 
Four-Hour Area Under Curve 
4h-AUC 
Compound Example (ng/ml)h 
______________________________________ 
GasalenCl 2 15852 
(Gasalen).sub.2 O 
1 14942 
GasalenOAc 4 10000 
Ga(NO.sub.3).sub.3 
prior art 
897 
compound 
______________________________________ 
The 4-hour AUC's indicate that good oral absorption of gallium occurs from 
the intestine and that appropriate formulation of the gallium compounds of 
formula I will yield a convenient dose form of gallium for the treatment 
of cancer, the hypercalcemia of malignancy and other diseases 
characterised by excessive bone loss and bone weakening. The difference in 
the above tests between the prior art compound gallium nitrate, and the 
compounds of formula I, is extremely marked.