CA1162546A - Medicine effective for warmblooded animals comprising, as an essential ingredient, a germanium- containing organic polymer - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Germanium containing polymers of general formula ( ? Ge?H - ?H - COZ)nO1.5n (I) or (II) wherein A represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, -COOH, -COOR (wherein R is an alkyl group having 1 to 3 carbon atoms, or

Description

1 1 6~5~6 MEDICINE E~ECTIVE ~OR WARMBLOODED ANIMALS
COMPRI5ING, AS AN ESSENTIAL INGREDIENT, A GERMANIUM-CONTAINING ORGANIC POL~MER
f The present ~n~ntio~ relate~ ~o me~icines, in particular, those effective for human hyperten~ion, cardiovascular disturbances such as arrhythmia, angina pectoris, myocardial infraction, encephalomalacia, cerebral apoplexy, viral disease, tumor, cataract, chronic respiratory disease, (usually referr~d to as C. R. D ) and so called C. R. D. complex caused by mixed infection of various pathogens.
In recent years, attention has been drawn to germanium-containing organic compounds in view of their pharmacological activities, which have been disclosed in Japanese Patent Publication No 2964/74, Japanese Patent Application Laid Open No. 61431/73, Japanese Patent Publication Nos. 21855/71 and 2498/71, etc. The germanium-containing organic compound disclosed in these publications is a low molecular weight compound represented by the formula:
(GecH2cH2cooH)2o3 -As a result of extensive investigations on the synthesis of germanium-containing organic compounds other than the low mo]e-cular weight compound represented by the formula:
(GecH2cH2cooH)2o3 1 1 B25~ 6 with attention to the pharmacological activities of the germanium-containing organic compound, the present inventors have found novel germanium-containing organic polymers and the process for the production thereof as well as their use as medicines.
The present inventors have further found that the novel germanium-containing organic polymers exhibit particularly good pharmaceutical effects against hypertension, cardiovascular diseases, various cancers, cataract, viral diseases and mycoplasma diseases.
Specifically, the present germanium-containing organic polymers have advantageous features in that they show only a very low toxicity (acute toxicity: LD50 for rats by oral administration is more than 10,000 mg/kg, which is the maximum oral dose and, actually, no more amount can be applied being restricted in view of the inside volume of rat's stomach), they are both adaptible to rats of spontaneous hypertension (SHR) (as disclosed herein) and to human hypertension, as disclosed herein to reduce the blood pressure properly but not below the normal level. Further, they are also effective for the recovery from cardiovascular diseases such as arrhythmia, myocardial infraction, encephalomalacia and cerebral a~oplexy.
mc(rkecl Moreover, the present polymers have rcmar~cd therapeutic effects against various viral diseases including viral skin diseases (see Example 5 below).

~ 1 62S~6 Furthermore, it has surprisingly been confirmed also that the present germanium-containing organic polymers show distinctive anti-tumor effects against various cancers (see Example 3 below), therapeutic effects for human cataract (see Example 4 below), as well as therapeutic effects for C. R.
D. or against so called C. R. D. complex by mixed infection of other pathogens (see Example 6 below).
The germanium-containing organic polymers having the foregoing effects are represented by the following formula (I) or (II):
A B
( = GeCH - CH - CZ)nl Sn . (I) or OH A B
( - o - Ge - CH - CH - CZ)n (II) wherein A is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, -COOH, -COOR (wherein R is an alkyl group having 1 to 3 carbon atoms), ~ , ~O~ or '~ ;
N

B is hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
Z is a hydroxy group, an alkoxy group having 1 to 3 carbon 1 3 62~6 atoms or an alkyl group having 1 to 3 carbon atoms;
n i~ an integer greater than 3, inclusive.
Of the germanium-containing organic polymers represented by the formulae (I) and (II), particularly preferred are those wherein A is a hydrogen ~rhr~b~ a methyl group, -COOH, ~ ~ ~ ~ or B is a hydrogen atom or a methyl group; and Z is a hydroxy group, a methoxy group, an ethoxy group or a methyl group.
Representative examples for preparing the germanium-containing organic polymers of the present invention are illustratively shown below.

HX HX
GeO ~ GeX2 ~ HGeX ~ --~ H + GeX .................. ..(1)

2 H3PO2 3 3 or M2HPO2 (M is a metal or ammonium ions) HGeX3 ~ A B A B

~1 ~ + CH = C - COZ X3GeCH - CHCOZ............... (2) H + GeX3 J (~) (II) - 1 1 6~5~ 6 A
,0 X GeC~ Cl-IC07, . ~ low molecular weight polymer ....... (3)

3 organlc solvent low molecular weight polymer ttl ~ high molecular weight polymer ...... (4) In the reaction schemes (l), (2) and (3), A, B and Z have the same meaninqs as defined above, X is a halogen selected from chlorine, bromine and iodine, and the low molecular weight polymer and the high molecular weight polymer shown in the reaction schemes (3) and (4) are germanium containing organic polymers represented by the formulae (I) and (II) which are objective compounds of the present invention. Whether the objective compound is of high molecular weight polymer or of low molecular weight polymer is determined by the number of n, more simply, depending upon the solubility of the compound in water.
In the accompanying drawinqs:
Fig. 1 shows an infrared absorption spectrum for one example of a polymer used in this invention;
Fig. 2 shows a powder X-ray spectrum of the ahove polymer;
Fig. 3 shows the relations between the blood pressure and the heart weight of spontaneous hypertension rats and the administration of the medicine according to this invention;

7 ~ ~7,546 Fig. 4 shows the course of the reduction in the blood pressure with time for hypertension patients by the administration of the medicine according to this invention;
Fig. 5 i9 electrocardiographs on arrhythmia patients before and after the administration of the medicine according to this invention;
Fig. 6 is electrocardiographs on angina pectoris patients before and after the administration of the medicine according to this invention;

Fig. 7 shows the survival rate of rats by the elapse of time for rat adcites liver cancer AH 66 strain with the administration of the medicine according to this invention;
Fig. 8 is a sketch showing lungs of pulmonary glandular cancer patients before and after the administration of the medicine according to this invention; and Fig. 9 is a sketch showing lungs of cutaneous-liver cancer patients before and after the administration of the medicine according to this invention.
It is apparent from the infrared absorption spectrum (Figure 1), x-ray diffraction spectrum of powders (Figure 2), and the like that the compounds in accordance with the present invention are novel compounds different from heretofore known compound: (GeCH2CH2C02H)203.

~ 1 6~5~ , The foregoing pharmacological effects of the germanium-containing organic polymers according to this invention are to be described specifically. The germanium-containing organic polymers used for the purpose are prepared by the synthetic processes described below and have such properties as shown by the infrared absorption spectrum and by the powder X-ray diffraction analysis in Fig. l and Fig. ~.

Preparatory Example Preparation of a low molecular weight polymer (A) of 3-oxygermyl-propionic acid:
In 1.3~ of acetone, a solvent miscible with water, was dissolved 252 g (l mol) of 3-trichlorogermylpropionic acid. To the solution, 1.3~ of water was added with stirring White hairy crystals were precipitated out. The reaction liquid was allowed to stand overnight. Then, crystals were collected by suction-filtration The so obtained crystals were washed with acetone sufficiently, followed by drying under reduced pressure. White needle-like low molecular weight polymer (A) was obtained in an amount of 144 g (85% in yield).
In addition, also in the case where other solvents which are miscible with water (e.g., ethanol, methanol, cellosolve, aceton~trile, tetrahydrofuran, dioxane, dimethoxyethane, diglime, dimethylsulfoxide, dimethylformamide, etc.) are employed in place of acetone, the low molecular weight polymer (A) can also be obtained likewise at high yield.
~urthermore, the low molecular weight polymer (A) can also be obtained using solvents which are immiscible with water (e.g., chloroform, methylenechloride, carbon ~ 1 6~
-- 8 ~

tetrachloride, benæene, ether~ etc.). In this case~ the low molecular weight polymer (A) was precipitated out when a solution of 3-trichlorogermylpropionic acid was throughly shaked with water. Crystals of this low molecular weight polymer (A) neither decompose nor melt at temperature below 320 C. It is found that the polymer differs from the germanium-containing organic compound prepared in accordance with the method described in Japanese Patent Publication No. 2964/71 since infrared absorption spectrum and X-ray diffraction spectrum of powders are completely different.
In addition, the low molecular weight polymer (A) was relatively easily soluble in water and the solubility in water was about 1 g/100 ml (25 C).

Pharmacolo~ical Effects of the Germanium-Containin~ Compound A
This invention is to be described in more details by way of the following Examples which illustrate the pharmacological effects of the germanium-containing compound A prepared in the Preparatory Example mentioned above.

Example 1: Effects on Rats with Spontaneous Hypertension ~ he compounds were orally given to rats with spontaneous hypertension over 4 consecutive months at a daily dosage of 100 mg/kg. Blood pressure was examined 7 months after. Then, the rats were sacrified to weigh the heart.
The results are shown below (see Table 1 and Fig. 3).

~ ~9 ~3 p) c9 ~
~ , o '1 ~ o ~ 1 1 6 2 5 ~ 6 ~ ~ W ~ ~ O ~O ~ C ~ ~ n ~ W t~ t ~D
. ~ ~ o ~D ~ O

= = = = = = == = ,~ I
~D

= = =, =
~D

P~ o~ o , ~, ~, , ~ ~ , , , ~ t~
' 3 ~D
00 ~ O W ~ W O

1'~
1~ ~ ~+
~O ~ ~ O O ~ ~ ~ ~ D ~ ~D
~ O C~ ~n O ~n O O W O O 0~ a~ o ~n ~
~3 r~
t' I' )~ y ~ ~ ~ ~D
o ~ ~o o~ ~ ~ ~~ o~ ~ o ~ ~ ~o o ~ ~
o a~
U) I' 1- 1' 1' ~ 1' 1-- 1-1- 1' 1-- ~ 1' 1' 1- ~ ~t ~ O~ ~n ~ Oo ~ OC~ W ~D ~O ~ 3 (D
~ O ~ 0~ ~ ~\) 00CX) ~ I' a~ o ~ co \J~ ~
~D

I' 1- 1- ~ 1' 1' 1' 1-1- 1' 1' ~1' 1' 1-~ ~ O~ ~ ~ ~ ~ W~ O 1~ O ~ 1- ~ tD
O~ O ~ ~ O ~D 1' 0 W~ ~
U

w~ ~ ~o ~D O 1~ ~ ~D 00 0 P.
0~ ~ 0~ W O C~ O ~ n ~
ID
N ~
. 0 1- 11 ~ ~ ~D
n ~O O ~O 1' ~ ~ ~ O ~ 11 CO O W C~ ~ t\) W ~ ~ 00 ~ ~ W 1~ `C
. ~D
WWW~WWWW ~WWWWWWW
W ~ W Go W W ~n ~~ ~ ~ n W ~J W ~D O 1'-W 00 ~ ~o 1_ o o~ IJ0~ Co O ~ ~ ~ ~ ~ IJ.~, ~
aq ~ ,_ ~ i- Y ~ I' ~ ~ ~ 1-..... ,.......... ........ ~D
n ~ W O~ 00 co 00 ~ Go ~ 0~ ~ ~n ~
~ ~o co ~ w (O o~ ~ ~ ~ ~
a~ ~t ~ 1 B2~8 It can be seen from the Table 2 and Fig, 3:
~1) No difference in blood pressure between the control group and the medicated group was noted before the initiation of the test, (2) Blood pressure in the medicated group was obviously lower than that of the control group after administration for 126 days.
(3) Comparing heart weight at the 126th day, the heart weight of the medicated group was clearly lighter than that of the control group~

Example 2: Therapeutic Effects on Human Cardiovascular Diseases ~ lood pressure reducing effect was observed for hypertension at a daily dose of 10 mg - 90 mg/adult (50 kg body weight) or more amount depending on the symptoms.
Fig, 4 shows specific examples. This example shows the course of the improvement in the maximum blood pressure of a 52 years old man with hypertension by a daily dose of 40 mg/adult (50 kg body weight) for consecutive 40 days, Apparent improvements were also observed on ECG findings for angina pectoris, cardiodisfunction and arrhythmia by a daily dose of 10 mg - 90 mg/adult (50 kg body weight) or more depending on the symptoms, Specific findings are shown for arrhythmia in Fig, 5 and for angina pectoris in Fig, 6, Fig. 5 shows ECG findings on a 60 years old man patient with arrhythmia for the case (a) before 11 1 1 625~6 administration and for the case (b) after consecutive 10 day's administration at a daily dose of 30 mg/adult (50 kg body weight). As can be seen from the figure, distinctive improvement was attained in the arrhythmia.
Fig. 6 shows ST wave findings on a 63 years old woman patient with angina pectoris for the case (a) before administration and for the case (b) 15 minutes after the administration at a daily dose of 40 mg/adult (50 kg body weight), in which pulse normalization is shown Furthermore, antihemorrhagic activity, promotion for blood circulation~ improvements in neurocirculatory osthenia and in plumonary edema were also observed after one month at the shortest and after more than six months at the longest by a daily dose of 10 mg - 90 mg/adult (50 kg body weight) or by a more amount depending on the symptoms.

Example 3: Anti-Tumor Effect (1) Therapeutic E~fects on Ehrlich Cancer 7.5 x 10 cells of Erhlich cancer were app]ied to each of 10 mice through intravenous injection and, after 72 hours~

the germanium polymer was given orally for lO consecutive days.
at a daily dose of 100 mg/kg. The results are shown in Table 2.

- lZ 1 1 625~ 6 Tabel 2 Experiment Dose Days of Number of group (mg/kg/day survival survived mice oral: 3 days at 40th day after cancer (mice survi~ed/
cell innocula- total mice) Control 0 21 22 23 24 25 (not-treated) 0/10 .. _ _ _ , Treated 21 22 25 28 31 with germanium 100 36 survival polymer (A) of the survival 4/10 preparatory Example survival survival As can be seen from the Table 2, the number of surviving days was evidently prolonged and the number of survived mice was also increased.

(2) Effects against Lewis Lung Cancer 1 x lO cells of Lewis lung cancer were inoculated subcutaneously to each of a group of mice and, from the next day of the inoculation, the germanium-containing organic polymer (A) (obtained by the Preparatory Example) was given once per day through oral administration for consecutive 5 days. The decrease in the weight of the tumor was observed. The results are shown in Table 3.

~ ~ fi2~

Table ~ . _ - - _ Administration Weight of solid Inhibi-schedule tumor at 14th tion for Experiment periods route dose per (average value tumor grouponce g + standard (o~) (day (mg/kg) deviation) ControlI ~ 1 71 ~ 0.804 Ge-organic 1 - 5th oral 100 1.67 + 1.211 2,3 polymer from days preparatory after 300 1.29 + 0.453 Z4.6 Example inocula-tion of 500 1.40 + 0.517 18.1 cealnlSer _ , (3) Effects on Rats with Ascite~s Liver Cancer AH 66 Strain 107 cells of AH-66 strain of ascites liver cancer were inoculated m travenously to each of a group of Donryu rats and, from after the third day, the germanium~containing low molecular weight organic polymer (A) prepared as in the Preparatory Example was applied through oral adminis-tra-tion once per day for consecutive 10 days at a dose of 100 mg/kg.
As the results, the survival days were prolonged and the number of survived rats were increased as shown in ~ig. 7~

(4) Effects on Human Cancer The germanium-containing organic polymers according 1 1 ~2546 to this invention are effective against various human cancers such as stomach cancer, lung cancer, uteru3 cancer and prostatic cancer, and their therapeutic effects are shown here for pulmonary glandular cancer and skin cancer metastasized from liver.
(A) Therapy for Pulmonary Glandular Cancer The germanium-containing polymer was applied to a 71 years old woman patient with pulmonary glandular cancer at the upper right pulmonary lobe for three months consecutively at a daily dose of 30 mg. As shown in Fig. 3, most of cancer focuses disappeared. In the figure, (a) schematically represents the lung having the cancer focus (c) before the administration and (b) schematically represents the lung after three month's administration.
~B) Therapy for Liver Metastasized Cutaneous Cancer The germanium-containing organic polymer was applied to a 69 years old man patient with liver-metastasized cutaneous cancer at the cervical region for two months at a daily dose of 90 mg. The patient was almost completely healed as shown :in Fig. 9. In the figure, (a) schematically represents the liver having liver-metastasized cutaneous cancer (c) before the administration and (b) schematically represents the liver after the two months~ administration.

Example 4: Effects on Cataract .. . . _ _ _ _ It has been found that the germanium-containing organic polymers (A) according to this invention are also 1 ~ 6 2 ~ 4 ~
.

effective agai.nst cataract, which is considered as one of most refractory ophthalmologic diseases.
An eye-lotion with pH at 7.2 was prepared by dissolving the germanium-containing ~ow molecular weight polymer as 1/~ strength into Politzer~s solution (containing 10 ml of 0.2% boric acid solution + 90 ml of 0~05% borax solution, at pH 2.11). A cup f`illed with the eye-lotion was contacted to the eye and an electric current was applied by the Itoh~s ionophoresis. ~s one course of the ionophoretic therapy, 1.0 - 1.2 mA of current was applied each time in

5 - 6 minutes for 10 times on every other day.and for further lO times. Approximately the same effects w0re also obtained by the consecutive oral admini.stration of the germanium-containing low molecular weight organic polymers at a daily dose of 10 - 150 mg/adult (50 kg body weight) although it takes a longer tIme than that in the ionophoretic therapy.
The results of the ionophoretic therapy are as shown in Table 4.

S ~ fi (A) Found much effective Treated patient ~ much effective (o/O) 1 initial cataract 3/3 100 2 immature cataract 8/11 (72) _ _ ' (B) Found a little T t d ti t a litt e effective effective (o/o) .
1 immature cataract 3/11 (27) 2 mature cataract 5/5 (100) 3 capsular cataract 4/4 (100) Example 5: Effects on Viral Diseases (1) Effects on DNA Type Viral Disease It was confirmed that the germanium-containing low molecular weight organi.c polymer (A) obtained in the Preparatory Example was markedly effective to viral cutaneous diseases.
The dose of the polymer is as below:

Infants: 10 mg (divided in twice on every day) Children older than 7 years old: 20 mg (divided in twice on every day) Adults: 30 mg (divided in three times on every day) Effects for various viral cutaneous diseases are shown below in Tables 5, 6 and 7.

2~ 6 - 17 ~

Herpes Group Virus . _ . I
PatientNumber of Consecutive period Number and percentage I
patient for therapy of patients showing rapid administration (day) ( / ) Water pox 8 2 - 5 7 (87.5) Herpes11 2 - 7 ll (100 !
zoster _ 1 J 62~4.6 - 18 ~

Table 6: Herpes Group Virus Juvenile Verruca Planu~
. ~
Period from less than 1 - 3 3 ~ 5 more~than more than onset to 1 year years years 5 years 10 years therapy total Avera6e days till the polymer 5 days 34 days _ 90 days 90 days found effective _ _ _ .. .__.
Average days till complete 17 days 63 days _ 180 days ?
elimination Tatseals 7 cases 1 2 3 ~ s ~ases .
Hasaesed 5 cases 2 _ 2 _ 9 _ Effective 2 cases 2 _ _ 2 cases 6 cases (inter- (inter-rupted) rupted) _ _ Although verruca became partially eliminated for 6 effective cases, complete healing cou]d not be observed since the administration was interrupted.

1 1 6~6 Table 7: Pox Group Virus Infectious Molluscum Contagiosum (1) Effects_on_Atopic Dermatitis Period from onset to administration 1 month 2 months Average administration day till the polymer found effective 3 days 9 days Total I

Total administration period 14 days 45 days (average) Total cases 3 4 7 ~ _ _ .
Cases healed 3 3 6-Cases effective -In effective cases partial elimination was shown although the administration was interrupted after 21 days In addition, the organic germanium compound of the present invention is efficacious widely for DNA type virus diseases of warm-blooded animals, for example infectious bovine rhinotracheitis, feline rhinotracheitis, infectious canine hepatitis, human molluscum contagiosum and condyloma accuminatum and young men's plane wart.

- 20 - 13~25~6 (2) Effect9 on RNA Type Virus The effects of the germanium-containing low molecular organic polymer on mouse influenza, which is one of the RNA
type viral diseases were studied~
Virus of influenza A2/Adachi Strain was infected through noses of d d.Y mice with 10 - 12 g body weight.
The amount of inoculation, oral administration of the germanium-containing low molecular weight organic polymer was started and it was consecutively given for 5 days at a daily dose of 100 mg/kg and 300 mg/kg. 25 mice were used for a group of experiments At 14th day~ they were anatomi~ed for det~rrnining (1) rate of mortality, (2) visual pathogenic changes in lung and (3) amount of the virus in the lung.
The pathogenic changes in the lung was estimated by scores Specifically, 0 MeanS no pathogenic changes at all, 1 means that pathogenic changes were observed in 1/4 region of the lung, 2 means that pathogenic changes were observed in about one-half region of the lung, 3 means that pat`hogenic changes were observed in about 2/3 region of the lung and 4 means that pathogenic changes were observed in the entire region of the lung, in which each score was obtained by dividing the to,tal number of the pathogenic changes in each of the mice with 20. Estimation 4 was also allocated to such a case where distinctive consol~ation was observed for a mouse~within 14 days. Contents of the virus in the lung were then examined in the following procedures: Five out of twenty five mice were sampled at random, homogenated and then inoculated 1 1 ~2546 on a petri-dish in which a single layer of fowl fibroblast was formed. They were cultivated at 37 C for 3 days and, thereafter, the resulted pathogenic changes were tinted with neutral red, and the numbers were counted for the contents of the virus.
The results of the experiment are shown below.

Experiment Dose Mortality Lung Virus content group mg/kg/daY rate hypermia in lung (%) (score) *reduction in the content Control 73.0 3.7 _ Germanium- lC0 60.0 1.9 90%
containing ~ow molecular 300 40 0 1.5 ggc/~
polymer .

* Reduction rate based on the virus content in the control group as lO0.
It can be seen from the above results that the germanium-containing low molecular weight polymer is also effective against influenza diseases.

1 1 ~2~6 ; 22 -(3) Effect Against Sialodacrvoadenitis in Rats Among coronaviruses that spontaneously infect rats, one cau3es severe inflammation and necrosis of salivary and Harderian glands. The enlargement of the glands is transient and usually subsides in 3 to 7 days, and the infection itself is not fatal and Dften occurs in breeding stocks The viral agent has an antigenic relationship to mouse hepatitis virus (MHV) and, therefore, antibodies reacting with MHV'in rat serum have been attributed to infection by this coronavirus. The virus has been reported to be extensively distributed in rat breeding colonies and in wild rats. In infant rats, ocular symptoms are more frequently prominent than enlargement of salivary glands~
and the infection tends to cause substantial damage to laboratory animal production.
Four pregnant rats at comparable gestational stage from a stock colony maintained in a quarter with a widespread infection by the virus, where consistently 60 to 70% of animals had been found seropositive for antibody to MHV with a morbidity rate (ocular) of about 20 to 30% over the past 2 years, were transferred to an isolated animal room. They were divided into two groups, of which one received -the'low molecular wei'ght polymer"(A) in drinking water~ 0.5 g/l~000 ml~ ad lib. daily for a period of 50 days beginning the 15th day of pregnancy. The other group of 2 litters (10 sucklings) was maintained 1 :11 6 2 ~
: - 23 -without medication~
After conclusion of the ~0-day treatment, all rats were tested for serum antibody titer to MHV b~
the microtitration techniG of complement fixation (Kolmer's modification). None of the rats in the treated group was found po9itive and had ocular manifactations, whereas in the untreated group, 7 animals demonstrated significant serum antibody titers and 3 had symptoms of the eye (Table 8).

Table 8: Serum titers of antibody+ to MHV
in untreated and the low molecular weight polymer (A) treated rats .... .
¦ Control group 20 - 10 20 40 10 10 - 40 Treated group - - ~ - ~ ~ ~ ~ ~ ~

+Reciprocal titer.
~ urthermore, the organic germanium compound of the present invention is efficacious wide]y for the RNA type virus diseases of warm blooded animals, for example, parainfluenza, mumps, intestinal disturbances of warm blooded animals due to the presence of rotavirus or corovirus and so forth.

Example 6: Effects on C. R. D. or C0 R. D. Com~lex No satisfactory methods have not yet been established for surely healing C. R C. or C. R. D~ complex. The 1 ~ 6~6 present inventors have found that the germanium~containing low molecular weight polymer is markedly effective against the above diseases.

Inhibitorv Effect a~ainst Chromic Respiratorv Disease (CRD) in Chickens, Pi~s, Rats and the like l. Rats Randomized ~0 male Wistar rats from the con-sistently CRD-affected breeding colonies maintained at this Laboratory were divided into three groups of 30 each and transferred to an isolated, sterilized animal room. One group received the low molecular weight polymer (A), 40 mg/kg/day, and another group tylosin tartrate, 20 mg/kg/day in drinking water for a period of 10 days beginning 21 days of age immediately after weaning, the dosage of the latter being such that would not be rejected by the rats when administered in the manner described The third group served as a control.
All rats in the three groups were sacrificed at 80 days of age and examined for CRD at autopsy. No significant difference in morbidity was observed between the tylosin-treated group and the control group whereas there was practically no case of CRD in the low molecular weight polymer (A) treated group (Table 9) 1 1 6~5~ 1 Table ~: Effect of the Polymer (A) against CRD in rats No~ of Rats No of Rats No. of Rats Studied with CRD+ CRD

Control group 30 8 (++~: 6~ 1 ( ++: 2) Tylosin-treated group 3 7 (+++: 6) 2 ( ++: 1) The polymer (A) treated group 30 l ( +: 1) 0 +Gross pathologic pulmonary lesions: +++, lesions involving more than one pulmonary lobe; ++, lesions limited within a single lobe;
+, petechiae and/or a small lesion or lesions involving only one lobe.
2. Swine Enzootic Pneumonia (SEP) Two groups of 10 piglets, consisting o~ 5 each from two farrows of lO each, were admitted to the clinical trial at a sw:inery consistently infested with SEP All males were castrated at 25 days of age. One group (8 males and 2 females) received the low molecular weight polymer (A), 300 mg/animal/day, in water daily ~or a period of 40 days beginning at 30 days of age while the other group (6 males and 4 females) served as a control. At 120 days of age all shotes were sacrificed and examined for CRD at necropsy, with the - 26 ~ 1~6 re~ults indicating a marked suppression of CRD in the low molecular weight polymer (A) treated group, compared to the control group (Table 10).

Table 10: Effect of the low molecular weight polymer (A) against swine enzootic pneumonia , I
No. of Piglets No, of Piglets No. of Piglets Studied with CRD+ Succumbed . . _ _ Control group 10 7 (++ 3) 0 ( +: 4) Polymer (A) 10 0 (+: 1) 0 _ Pulmonary lesions: ++, bilateral pl.euritis with pleural adhesions, complicated by bronchiectasis; +, circumscribed lesion of pneumonia invo]ving a single lobe; -, only an îndex finger ti~-sized scar from healed pneumonia.

Claims (7)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process of preparing germanium-containing polymers of general formula ( ? Ge?H - ?H - COZ)nO1.5n (I) or (II) wherein A is hydrogen, an alkyl group of 1-3 carbon atoms, -COOH, -COOR (where R is an alkyl group of 1-3 carbon atoms), or , B is hydrogen or an alkyl group of 1-3 carbon atoms;
Z is a hydroxy group, an alkoxy group of 1-3 carbon atoms, or an alkyl group of 1-3 carbon atoms;
and n is an integer equal to 3 or greater, which comprises treating a monomeric germanium compound of general formula X3Ge?H - ?HCOz (III) in which A,B and Z have the meanings given above and X is.
selected from chlorine, bromine and iodine, with water and organic solvent to form a polymer thereof, represented by the general formula I or general formula II.

2. The process of claim 1 in whichthe monomeric germanium compound of formula (III) is prepared by reaction of a halo-germanium acid of formula H GeX3 with a compound of formula (IV) wherein A, B, X and Z have the meanings given in claim

3. The process of claim 1 including the subsequent step of treating the polymer of general formula (I) or (II) so obtained with further amounts of water and allowing the mixture to settle, so as to form a polymer of formula (I) or formula (II).

4. Germanium containing polymers of formula (I) or formula (II) given in claim 1, whenever prepared by a process according to claim 1 claim 2 or claim 3, or an obvious chemical equivalent thereof.

5. A process according to claim 1 wherein 3-trichlorogermylpropionic acid is treated with water and organic solvent to form a polymer thereof.

6. The process of claim 5 wherein the organic solvent is selected from acetone, ethanol, methanol, cellosolve, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, diglime, dimethylsulfoxide, dimethylformamide, chloroform, methylenechloride, carbon tetrachloride, benzene and ether.

7. Polymeric 3-trichlorogermylpropionic acid whenever prepared by a process according to claim 5 or claim 6 or an obvious chemical equivalent thereof.