SU1453661A1 - Antitumor preparation - Google Patents

Abstract

1428044 Ethylene diamine derivative VSESOJUZNY NAUCHNO - ISSLEDOVATELSKY KHIMIKO - FARMATSEVTICHESKY INSTITUT IMENI S ORDZHONIKIDZE 23 Aug 1973 [17 Nov 1972] 40012/73 Heading C2C [Also in Division A5] 1,2 - Bis(3 - bromo - propionylamino)ethane is obtained by reacting ethylene diamine with 3-bromopropionyl chloride.

Description

This invention relates to medicine and relates to an antitumor drug and 1,2-di- (α-bromopropionyl-amino) ethane of formula 1:

CH, -NH CHj-NH

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The specified anticancer agent is new and the decision of the pharmaceutical committee of the USSR Ministry of Health from 03.05.87 g is recommended for use in medical practice.

Dosage and administration.

The drug is taken orally after a meal in the form of tablets, 0.1 g once a day, 0.2-0.3 g daily for 25-30 days, then (when a therapeutic effect is obtained) the dose is reduced depending on the peripheral { shit During the course of treatment

use 6-10 g of the drug. With good tolerance and the absence (or insufficiency) of the therapeutic effect, the daily dose can be increased up to 0.4 g, and the course one up to 12 g. In erythremia, the compound (1) is applied at 0.1-0.2 g daily or every other day depending on the patient’s condition and peripheral blood counts. A course of up to 6 g is prescribed. Upon receipt of the therapeutic effect, repeated courses are conducted with an interval of 1.5-2 months.

A clinical study of the drug was conducted on 436 patients with various malignant tumors, including 336 patients with hemoblastosis. It has proven to be very effective in patients with myeloproliferative diseases. Of the 39 patients with chronic myeloid leukemia, in 35 there was a stage of a comprehensive clinical and hematological picture of the disease. In 4 patients, there was a stage

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Sweetener aggravation. In case of chronic KJOM myeloid leukemia in the stage of unfolded clinical and hematological picture of the disease, the drug was used at a dose of 200 mg once a day every day for 25-30 days, and then the dose was reduced individually depending on the peripheral blood indicators (the dose rate varied within 6-9.5 g). After treatment, this group of patients showed a significant improvement in the total. states, disappearance of signs of intoxication, pronounced reduction in p | sizes of the liver and spleen, statistically significant decrease in the number of lei 1 ocytes per liter of blood. So before treatment, the number of leukocytes was in the mean Ob = 7.3 ± 47.04 ± 10 / l, after the course of lefni - (23.8t2.52) (P iO, 05). This reveals a tendency to normalize leukocyte formula, which resulted in an increase in the content of heated granulocytes from 54.612.77 to 66.6411.95% (P 0.05) and a decrease in the immature elements of the granulocyte series (metamyelocytes, myelocytes and yromyelocytes ) from 31.97t2.39 to Il7.08t2,) 3% (P 0.05). In the patients of the group, there was a decrease in islet of red blood cells and hemo- lobin. So before the treatment, the number of erythrocytes was (3, 17) -10 UL

the hemoglobin content is 105.5t i5.57 g / l, and after the course of treatment with Prodimine, these indicators have increased: red blood cells to (4.02 to, 1 2)., hemoglobin to (123.32 t4.13) g / l (P 0.05), The number of trBm - 0 CYTES for treatment was (222,, 87) -10 in 1 liter of blood, after treatment - (307,, 87) 10 / l (P: 110.05).

In the treatment with compound (1) (well; | ke, as in the prescription of other cystatic agents, in particular 4 ilosan), the number of leukocytes decreases permanently after 14–35 days. However, in some patients. This decrease occurs in leaps and bounds. Thus, in a 30-year-old patient under observation, the number of leukocytes before treatment was 116 CHO / l, 15 days after the administration, the drug at a dose of 200 mg daily, the latter sharply decreased to 27.5 10 ° / l. This circumstance dictates that meticulous

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control (at least once every 5-7 days, and then more often) for indicators of peripheral blood and a decrease in the dose of the prescribed drug, if indicated. The duration of remission was 6-8 months. Four patients with chronic myeloid leukemia in the blast exacerbation stage were prescribed the drug along with corticosteroids and other cytotoxic drugs. Two patients received it in combination with corticosteroids (in the complex therapy of two other patients), in addition, cytarabine was used. It should be noted that a positive effect, although short-lived, was achieved in three out of four patients. At the same time, the size of the spleen and liver decreased significantly.

The following clinical observations can be cited as an example of the beneficial effect of complex therapy using compound (1) on the course of the disease.

Example 1, Patient M, 43 years old, was hospitalized in the hematology department for chronic myeloid leukemia in the blast exacerbation stage. On admission, the general condition of the patient was moderate, complaints of general weakness, loss of appetite, and heaviness in the left hypochondrium. It was noted hepato-and splenomegaly. The liver protruded 4–4.5 cm from under the right costal arch, the spleen 7.5–8 cm. The number of blast cells in the leukogram was 57%. The patient received complex therapy with prednisolone, compound J 100 mg. Once a day for 14 days and ditarabin (100 mg for 7 days),

As a result of the therapy, a significant improvement in the general condition of the patient, a significant decrease in the size of the liver and spleen (the liver and spleen were determined by pulpation at the costal arch) were noted.

Example 2, In the second patient C, 28 years old, suffering from chronic myeloid leukemia in the blast exacerbation stage, when admitted to the hematology department, there were complaints of severe general weakness, headache, dizziness. With an objective

In the investigation, there was a pronounced splenomegaly (the spleen reached the umbilical line with the lower edge). The liver protruded 3–3.5 cm from under the right costal arch. In the study of peripheral blood, there was a pronounced anemia, thrombocytopenia, leukocytosis was moderate 18-10 / l, in the leukogram the number of blast cells was 19%. The patient underwent complex therapy with the use of corticosteroids of compound (X) (100 mg per day for 10 days) with hemotransfusion, symptomatic agents.

As a result of the above therapy, the general condition of the patient significantly improved, almost completely eliminated the effects of intoxication, dizziness, headache, general weakness disappeared, the size of the spleen significantly decreased, the lower edge of which was determined

22%, monocytes 5%, bacillus 7%, segmental-borne 60%, hematocrit 80. Diagnosis - polycythemia PA-stage. A course of treatment with compound (I) and hemoexfusions was performed. Blood analysis at discharge: hemoglobin 140 g / l, erythrocytes 4,6-X10 / l, leukocytes 4 ,, color index 1.07, ROE 4 mm / h, platelets 230x10 7l, eosinophils 2%, lymphocytes 23%, mono-rib arc . The number of leukocytes decreased by 25 9%, segmented blood pressure 66%, hematomas from 18-10 to 5 ,, blastCrit 50. A blood test 2 months after discharge: hemoglobin 140 g / l, erythrocytes 4.8x10 / l, leukocytes 4 , ROE - 5 mm / h;

Leucogram cells were not detected.

Compound (I) was used in the treatment of 18 patients with polycythemia of the A – A stage. The age of patients ranged from 36-60 years, dominated by people over 45 years. The duration of the disease during the treatment period was up to 4 years. All patients had a typical clinical picture. The number of erythrocytes and hemoglobin was on average (6, 90iO, 17) and 190, OtO, 14 g / l. The treatment was carried out with compound (I), 200-300 mg per day without the appointment of other cytostatics. Considering that in the treatment of cytostatitis. Kami patients with polycythemia clinical effect does not occur immediately, in order to reduce plethori, all patients underwent hemoexfusion in a total volume of 1.5-2.5 l. In the process of treating adverse events, including cytopenia, it was not revealed.

Immediately after the course of treatment, an improvement in the subjective state of the patients was noted. The gnatural pains, the severity in the head, the lethargy disappeared. The clinical effect was evaluated, as a rule, after 2 months. Against the background of maintenance therapy with the drug 100 mg per day by this period, in all patients the plethorus disappeared

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hematocrit and hemogram indices normalized.

PRI me R 3. Patient E., 51 years old, was admitted to the clinic with complaints of Gog: pain, weakness, brown-bluish complexion, skin itching after a warm shower, bath, and hard legs. Analysis of blood on admission: hemoglobin 200 g / l, red blood cells 6.6x10 / l, leukocytes 8, color index 0.93, ROE 1 mm / h, platelets 360x10 / l, reticulocytes 1.8%, eosi - nofila 4%, basophils 2%, lymphocytes

22%, monocytes 5%, bacillus 7%, segmental-borne 60%, hematocrit 80. Diagnosis - polycythemia PA-stage. A course of treatment with compound (I) and hemoexfusions was performed. Blood analysis at discharge: hemoglobin 140 g / l, erythrocytes 4,6-X10 / l, leukocytes 4, color index 1.07, ROE 4 mm / h, platelets 230x10 7l, eosinophils 2%, lymphocytes 23%, mono5 9 % segmented

5 9%, segmental-borne 66%, hematopoietic

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Crete 50. Blood test 2 months after discharge: hemoglobin 140 g / l, erythrocytes 4.8x10 / l, leukocytes 4 ,, ROE - 5 mm / h;

The duration of clinical and hematological remission in patients remained 8–16 months, with an average of P months. The use of maintenance-supporting remission therapy with compound (J) (100 mg 2–3 times a week) prolonged its duration by 6–8 months. Side effects of the drug on the body is not installed.

In patients with chronic lymphocytic leukemia (38 patients), the drug was used in patients with severe lymphadenopathy in Stage II-III after the disease. Average the daily dose was 0.1–0.2 g, the course dose was 4.0–5.0 g. In most cases, the drug was used together with glucocorticoids and some other cytotoxic drugs. From 6-8 days after its introduction into the scheme of polychemotherapy, there was a tendency to decrease the size of the lesion of the lymph nodes; and by the end of the course, their size decreased by 1.5-2 times. At the same time, the general condition of the patients improved, the occurrence of general intoxication decreased. There was a decrease in the number of leukocytes in the hematocrit 2-4 times. So in patient S. 65 Years with chronic lymphocytic leukemia III degree.

after a course of chemotherapy: preyisolone + compound (I) (4 g), the following changes were observed in the hemogram: before treatment - hemo-100. g / l, erythrocytes 3,3.XX, leukocytes 28x10E / l, color; indicator 0.94, ROE 13 mm / h, trobic cells 13Oh reticulocytes Os9 |%, lymphocytes 96%, segmented

after treatment - hemoglobin g / l, erythrocytes 3,7x10, lei

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KOUjHTM 3751x10 ° / L5 color index 1.06, ROE 12 mm / h, platelets, reticulocytes 1%, lymphocytes 97%, segmented 3% „

In some cases, during the first week of taking Prodimin, there was an increase in the number of leukocytes, but with continued treatment, their regular decrease occurred. No noticeable selective effect of the drug on lymphopoiesis was observed. After discharge from the hospital, patients continued taking the drug at a maintenance dose of 0.1 g / day or 0.1 g every other day. The total dose depended on the hemogram indices and varied within 4–8 g. Such a maintenance regimen allowed an increase in the duration of somatic combination up to 8–12 months.

Effective use of the drug. Appeared in lymphosarcoma, Of the 7 bolok NY5 SSh

In two, a complete remis- sion was noted, in two, partial remission was noted, and in von patients stabilization of the ix process was observed. Thus, the TejibHbtti objective effect (complete and partial remissions) was noted in 4 out of 7 free. It should be emphasized that before the treatment with the drug, Bcsfe repeatedly received various schemes of combined chemotherapy, vko} 1uch nitrosomethylurea, cshklofosfan, methotrexate, vincristine ad || iamycin, prospidin, and with compound (I) became the most resistant rerara-

As an example of the effectiveness of the application of the claimed agent in lymphosarcoma, here is a brief extract from the case history of one patient.

Example 4. Ill, G., 66 years old. Diagnosis: lymphosarcoma with affection of all groups of peripheral lymph nodes. Condition after multiple courses of chemotherapy. Diagnosis of lymphosarcoma

was installed in February 1982 after a biopsy of the cervical lymph node. During 1982-1983 the patient received 4 courses of combined chemotherapy, including HMM, cyclophosphane, vincristine, methotrexate, dexamethasone, and 3 courses of combined chemotherapy, including adria - blastin vinblastine, prospidin, and dect Sametazon. A complete remission was achieved, which lasted about 1.5 years. In December 1983, the process progressed due to the appearance of a large conglomerate of lymph nodes in the inguinal and iliac region. After a course of treatment with prodimine in a total dose of 5.2 g, complete regression of the nodes was achieved. The treatment was accompanied by deep and long-term leukotromytopenia (the minimum number of leukocytes was 2 00 / mm, platelets was 3140 / mm). Remissi lasted for 13 months, after which enlarged lymph nodes appeared in the parotid region, fully regressed after the repeated course of the compound (I.). At the repeated course the drug was applied in reduced doses (100 mg daily, totally 3.5 d) however, this course was also accompanied by a pronounced depression of hemopoiesis (the minimum leukocyte count was 1,800 / mm 5 platelets 36,100 / mm), Remissi after the second course lasted 1 g and, thus, the total full remission of the two courses lasted 25 months, It should be noted what is oppressing Hemopoiesis was most often observed in patients with lymphosarcoma (in 5 out of 7 patients). Partial remission (reduction in the size of recurrent angiosarcoma mezosalpinksa) with a duration of 205 Ås was observed in one patient.

Based on the analysis of the presented clinical materials, it can be said that Prodimin is an effective drug for chronic myeloid leukemia (including blast crises), spectra, chronic lymphocytic leukemia, idiopathic myelobrosis, thrombocytosis and lymphosarcoma. All clinics that conducted clinical trials of a compound (1) recommend it for medical use. It is well tolerated by the patient and its suitability.

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for outpatient practice (low toxicity, convenience dosage form).

The features of the claimed agent and its advantages over known cytostatics include the following: lack of cross-resistance in erythremia with other anti-leukemic drugs (myeloshan, myelobromol); compared with myeloshan, the drug (1) in erythremia is more rapid reduction in liver size and spleen and improved peripheral blood; its effectiveness in blast crises of CML that are resistant to modern anti-lethal drugs. With pain medication

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erythremia with thrombocytosis norm

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Platelet counting occurs much faster than using known anti-leukemic drugs. The drug is effective in hemorrhagic thrombocytemia and secondary thrombocytosis (post-splenectomy syndrome) resistant to other treatment methods. Compound (I) does not cause sexual dysfunction (one of the side effects of the main drug in CML mielosan), which justifies its use at a young age.

Claims (1)

Formula inventions ki "Amipa ethane in to left sredsgaa. The use of 1,2-di (/ e-bromopropionyl-amiko) ethane as an antitumor