DE1941942A1 - New pharmaceutical agent - Google Patents

Description

Patent attorney

HERMANN L. JUNQ 757 bathe bathe

Ludwig-Wilhelm-Strasse

^Dipl - ^Chem Telephone (07221) 23933

Telegrams: JUPAT Baden-Baden

Jg / R - »-398 August 15, 1969

"Today's pharaaseutic remedy ¹¹

The invention relates to a novel pharmaceutical agent, particularly sur treatment of neoplastic diseases, Anlteien _t Throabosytopenien \ ma XnanitionssustKnden "

New discoveries in the field of morning diseases, in particular the finding of one of the TuMorsellen Polypeptides formed which damage the healthy organs and in all probability the cause of the cachexia and the To4.es of the sick patient is »has led to that new palliative or curative agents for cancer complaints are sought after, with the previously known ones Means from cancer therapy could not be achieved

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Chemotherapy drugs in the fight against cancer a · so high Texiteit that your «application is largely restricted is and rarely leads to the desired success “But also Surgical treatment of cancer generally has the disadvantage that surgery therefore is no longer possible «because the general condition of the patient and the metastasis require an operation not allow »

The finding is therefore based on the task of “a means to find »which not only protects the healthy cells against the polypeptide of the cancer cell» but also destroys the cancer cell itself, without the normal healthy cells Cells are attacked or damaged in any way ο Furthermore, the task is to be solved, a To achieve stimulation of the bone marrow "whereby the cachexia that occurs particularly in cancer can be eliminated",

The solution to this problem is that the pharmaceutical agent according to the invention by a content on pyrimidine-deoxy-nucleosides or «» their precursors (precursors) is marked «.

The agent is advantageously characterized by a content of deoxycytidine or deoxy * thymidine.

The main advantage of the agents according to the invention is that they contain an endogenous substance which has no toxicity of any kind. Furthermore _{, the} agents according to the invention have the fundamental property that they have a very strong awakening-stimulating effect »That the clinical effects

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of the cell division-inhibiting polypeptides in cancer can be completely eliminated or at least substantially reduced »Bs vuröe d & reröe _p found that the agents according to the invention lead to a selective killing of cancer cells and a reduction in tumor volume the organism against the toxicity of the already known cytostatics is protected today, "this means that when using the compositions of this invention significantly large" doses of these known cytostatic agents can be used _o the treatment of these diseases is facilitated considerably, that the inventive means to a general strengthening of the organism. “This effect is not only due to the processes described above, but it has been experimentally proven that administration of the agents according to the invention also results in healthy people and animals e significant weight gain can be achieved ₀

It could also be found that the inventive Remedies for healing aplastic anemia and thrombocytopenia of various origins »

It has been found that deoxy-cytidine (3-3-D-2 ¹ - deoxyriboforanosido-cytosine) or deoxy-thymidine (3 - ß - D - 2 · - deoxyribofuranosidothymine) have been found to be particularly effective from the group of pyrimidine deoxy nucleosides ) is "A mixture of these two substances also has significant therapeutic effects,

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Particularly effective precursors are carbamoyl aspartic acid, dihydroorotic acid, orotic acid and oridine _o Abe £ a mixture of a pyrimidine deoxynucleoside with one or more of the precursors brings the effects according to the invention

The effect of the agents according to the invention will be described in more detail at the margin of the examples below,

example 1

25 mice received 2 ng deoxycytidine every day for 3c days injected intramuscularly in an aqueous solution o The mean weight of the meal before the attempt was 24 grams.

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The middle Gevicht of the mice increased vährend this experiment on 3o gr _o per Mausο All mice varen healthy and got no feverish visions "It vurde also found" that the general Gros se the mice to vährend the experiment had increased and no ToxiZitatserscheinungen varen occurred. All mice were still alive and perfectly healthy 3 months after the end of the experiment

Example 2

25 mice received 1 mc / deoxy-cytidine daily in physiological Saline solution injected intramuscularly »Am the third day of the experiment, each mouse was given intraperitoneally an ELD (Ehrlich - Landschütz) hyperdiploid ascites tumor. in a dose of 20 - 40 million, tumor cells transplanted

All mice had an ascites tumor _o Of the 25 mice, 21 died within 20 days after the transplantation

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4 mice survived the experiment, with the ascites tumor disappeared within the first few days of the experiment after transplantation. The 4 mice survived the experiment for at least 30 days without showing a tumor again. In these animals it was shown in particular that the cell proliferation of the cancer cells was significantly inhibited by the deoxycytidine used, so that at the end of the In the experiment, a significantly smaller number of tumor cells were found in the body.

Example 3

A 48-year-old patient was operated on for a highly malignant ovarian carcinoma, although the carcinoma was already generalized in the abdominal cavity ο After the operation, the patient received extensive radiation with radio-cobalt in a relatively very good condition until she developed large amounts of ascites fluid about 3 years after the operation. Large abdominal metastases were now also found. Despite treatment with cytostatics, the patient's condition did not improve she was moribuad.Bs could only 1.1 million red blood cells _0, 1 5oo leukocytes and platelets 24 ooo be found.

At this point, treatment with the present agent started. The patient received the first two Days «each 1/2 gram of deoxy-cytidine in physiological saline solution was injected intramuscularly the dose was reduced to 1/2 gr every other day »7 days after the start of the experiment, the number of platelets had already increased to 12,000. 14 days after the start of the experiment, the number of red blood cells was increased to 4 million.

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1941S42

Within Io days, the total Ascites fluid disappeared and body weight the patient increased by several kilograms connected was a significant improvement in the general condition of the patient, so that this even “During the first 3 weeks of the experiment, all skin metastases also disappeared and the improvement in the general condition of the patient went so far that she could leave the hospital and can lead a normal life.

Example 4

In a 45-year-old, previously healthy woman, a Ovarian tumor detected. His radical surgery failed not performed, veil abdominal and pleural metastases were found. The cytological examination showed Metastasis from adenocarcinoma originating from the right OvariuBtoBine treatment with cytostatics and extensive irradiation with Kadio-Cobalt brought no improvement, The patient had severe cachexia and severe thrombosytopenia due to the tumor disease and treatment.

The patient received i / 2 gr (corresponding to 9.8 mg per cg of body weight) desoocy-cytidine in the peysiolofieomer Kooms * lsl5sunf intramuscular eiaffespritit every day for one week. For 7 days a significant improvement of the general condition and the blood count of the patient suddenly set in .Daraufhin vurde the dose mat i / 2 gr deoxy-cytidine any "broad day redusiert.Blnen month after the start of the experiment was sterile pleural effusion and no more Ascitesflüsslgkeit found a grundliebea ümtersnekvmf n 'oh 3 Konaten

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found that not only the large primary tumor but also the previously detectable metastases had completely disappeared patient also injected twice in a Abstnd 1 month a known under the trade name Alkeran cytostatic, once mg in a dose of 0.8 per Tg törpergevicht and once in a dose of o, 9 mg per Xg body weight ₀ Although both doses far are above the normally tolerable Quantmm, there were no side effects ο

I _n another Verscuhen showed that the precursors had (precursor) a similarly good effect, but in part, the dose may be increased something had "In other cases, the active ingredients of the new pharmaceutical agent were transferred into compounds of Xörper in the active substances could be broken down or broken down _e This also made it possible to achieve a certain depot effect. In addition, it is advantageous to add cytostatics to the agent, the amount of which can be greater than the previously known doses "

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Claims (1)

-β- 19-4 1S42 PATENT CLAIMS 1.) Pharmaceutical agent, especially for treatment of neoplastic diseases, anemia, thrombocytopenia and states of inanition, characterized by a content of pyriraidine-deoxy-nucleosides _or their precursors <, Ψ 2 ») means according to claim 1, characterized by a content of deoxy-cytidine or ₀ deoxy-thymidine _e 3o) means according to claim 1, characterized by a content of carbamoylaspartic acid or dihydroorotic acid bsv ₀ orotic acid or uridine ₀ 4o) means according to claim 2, characterized by a mixture of deoxy-cytidine and deoxy-thyraidin ο ) 5o) means according to claim 2 and 3, characterized by a mixture of a pyrimidine deoxy nucleoside and one or more precursors _o 6.) Means according to claim 1 to 5, characterized by a dose of at least 1, ο mg per kilogram of body weight and per day 7.) Means according to claim 1 to 6, characterized by connections, velche from the body in the active substances are broken down or broken down. 10 9 8 10/2085 194 I. 8o) means according to claim 1 to 7, characterized by an additional content of Cytostatics. 9o) means according to claim 8, characterized in that the cytostatics in ralativ there is a large proportion " Ioο) means according to claim 1 to 9, characterized in that the release of the virksamen Substances are protracted to the body " 109810/208