PL238779B1 - Peptidomimetics and their application in the therapy of intestine cancer and in ensuring their proper peristalsis - Google Patents

Abstract

The subject of the application are peptidomimetics. One of the compounds concerned by the application is a compound represented by the general formula, where: R1 is the side chain of a D-amino acid selected from: D-Ala, D-Tre, D-Ser, D-Met, D-Leu, D-Glu, D- Asp, D-Lys or D-Arg, R2 is none or an L-amino acid residue selected from Gly or Lys or a dipeptide residue L-Gly-L-Lys, R3 is an L-amino acid residue selected from: Phe or Trp, R4 is none or an L-amino acid residue Lys, R5 is a linear saturated or unsaturated hydrocarbon chain of the general formula CnHm, where n is an integer from 1 to 4 and m is an even integer from 2 to 10. R6-10 are independently a substituent selected from: hydrogen, hydroxyl, methyl, formyl, carboxyl, methoxycarbonyl, carbamoyl, cyano, amine, methylamine, dimethylamine, iodide, fluoride, nitro or sulfone. The application also covers the use of the peptidomimetics in question in the treatment of intestinal cancers and ensuring their proper peristalsis. The compounds described in the application have cytostatic and cytotoxic effects on intestinal cancer cells, have affinity for μ and δ receptors and act as antagonists of opioid drugs. They are intended for administration through the digestive system, in the form of tablets, infusions, injections or implants.

Description

Description of the invention

The invention relates to peptidomimetic analogs suitable for use in the therapy of cancer as opioid antagonists and the use of these compounds in the therapy of intestinal cancer. The described compounds show a cytostatic and cytotoxic effect on intestinal cancer cells, show affinity for μ and δ receptors, and act as antagonists of opioid drugs. They are intended for administration through the digestive system, in the form of tablets, infusions, injections or implants, in the treatment and support of intestinal cancer therapy and in ensuring proper intestinal peristalsis when taking opioids.

State of the art

Fluoropyrimidines, including 5-fluorouracil (5-FU), are commonly used in the treatment of intestinal cancer and other types of cancer. This preparation is often administered with leucovorin as a bolus injection or as a continuous intravenous infusion (Humeniuk R., et. Al., 2009). 5-FU is often used in chemotherapy in combination with other drugs, such as oxaliplatin, which impairs DNA replication and induces cellular apoptosis (Raymond E., Faivre S., et. Al., 1998; Raymond E., Chaney SG, et. al., 1998), or irinotecan, which inhibits the action of topoisomerase I (Akhtar R., et. al., 2014). A popular pharmacological compound used in the treatment of intestinal cancer is also capecitabine administered orally and absorbed through the gastrointestinal mucosa (Pentheroudakis G., et. Al., 2002).

Very often, cancer treatment therapies are accompanied by painkillers, used at all stages of tumor development, the strength of which increases with the advancement of the disease. In particularly severe cases, when surgical or pharmacological treatment ceases to be effective or is not possible, the therapy is basically limited to pain relief in the last days of the patient's life. The group of the strongest opioid drugs for years has been made up of specific compounds, among which one of the most commonly used is morphine.

The strong analgesic activity of morphine makes it a commonly used agent in the treatment of all types of cancer. However, the scientific community has taken up new research topics, also examining the effects of morphine on the cancer itself. To date, the results are not clear. It was proved, inter alia, that morphine at clinically relevant doses accelerated the growth of breast cancer in murine models (Bimonte S., et. Al., 2015; Nguyen J., et. Al., 2014); this has been associated with accelerated angiogenesis, inhibition of apoptosis, and cell cycle progression (Farooqui M., et. al., 2007). Similar conclusions have been drawn from experiments in murine sarcoma and leukemia models (Ishikawa M., et. Al., 1993). Moreover, in vitro and in vivo studies have shown that tumor growth may be favored by the occasional administration of high doses of morphine or its long-term administration at low doses (Zong J., et. Al., 2000). Moreover, morphine may inhibit apoptosis of cancer cells (Lin X., et al., 2007) or induce tumor growth by increasing the expression of cyclooxygenase-2 (COX-2) (Farooqui M., et. Al., 2006; Salvemini D ., et. al., 1993; Arerangaiah R., et. al., 2007; Nedelec E., et. al., 2001) and / or stimulating angiogenesis mediated by prostaglandin E2 (Chang SH, et. al., 2004 ; Griffin RJ, et. Al., 2002; Salvemini D., et. Al., 1994; Leahy KM, et. Al., 2002).

The aim of the invention is to provide new compounds that are useful in the treatment and prevention of intestinal cancer and, at the same time, displace opioids from opioid receptors in the gastrointestinal tract and restore / maintain intestinal motility during morphine administration.

A particular aim of the invention was the simultaneous reduction of negative side effects in patients taking morphine as part of analgesic therapy during antitumor treatment as well as treatment of neoplasms in the intestinal area. For these diseases, approximately 75% of patients require continued analgesic treatment. Moreover, the treatment of chronic pain is associated with the rapid development of tolerance to the drug, which makes it necessary to increase the doses of analgesics, and this in turn may intensify the side effects of their use [Hiliger M. Contemporary oncology 2001; 5 (4): 168-174]. Some opioid analgesics, ie morphine, also have tumor proliferation stimulating activity [Farooqui M, Li Y, Rogers T et al., British Journal of Cancer 2007; 97 (11): 1523-1531] which reduces the effectiveness of the applied anti-cancer therapy.

PL 238 779 B1

The essence of the invention

The invention relates to a compound selected from:

tyrosyl-D-alanyl-glycyl-phenylalanyl-cinnamylpiperazin (TyrDAlaGlyPheCyn), tyrosyl-D-alanyl-glycyl-tryptophyl-cinnamylpyparizine (TyrDAlaGlyTrpCyn), tyrosyl-D-threonyl-threlyl-glycyl-Tyrinyl-tyrosyl-phenyl-phenicyl-tyrosine -glycyl-tryptophyl-cinnamylpyparizine (TyrDThrGlyTrpCyn), or a pharmaceutically acceptable salt thereof.

Another object of the invention is a compound as defined above for use in the treatment or prevention of a cancer of the intestine.

Preferably, the compound for use according to the invention is administered in a form intended for oral, injection or intravenous administration. Preferably, in the form of an oral tablet for administration directly into the digestive system or intravenous infusion for peripheral administration or injection for injection of the tumor and its vicinity.

Preferably, the compound to be used according to the invention is used in the form of a multi-drug pharmaceutical composition, especially containing additionally an opioid analgesic and / or an anti-cancer drug.

Preferably, the compound for use according to the invention is intended for use in classical chemotherapy for intestinal cancer either preoperatively (neo-adjuvant therapy) or postoperatively (adjuvant therapy) or in the chemotherapy or adjunct to inoperable colorectal cancer or is intended for use in the treatment of other cancers for the treatment of intestinal cancer. protecting the intestines against tumor metastasis originally from another tissue.

Another object of the invention is a compound as defined above for use in analgesic therapy as an antagonist of opioid drugs.

Preferably, it is intended for oral or peripheral administration to eliminate constipation caused by opioid drugs. Equally preferably, it is intended to act on opioid receptors. Equally preferably, it is used in the form of an oral tablet for direct administration into the gastrointestinal tract, or an intravenous infusion for peripheral administration. Equally preferably, it is used in the form of a multi-drug pharmaceutical composition, preferably containing an opioid for analgesic therapy. Equally preferably, it is used in the form of a composition containing a polymer supporting the active ingredient.

Surprisingly, it was found that the compounds according to the invention, apart from opioid antagonistic properties, have a cytostatic and cytotoxic effect on intestinal neoplastic cells. They have also been shown to exhibit cytostatic and cytotoxic effects on intestinal neoplastic cells, and have affinity for opioid receptors as antagonists of opioid drugs. Thus, the invention combines the effect of protecting the intestines against the unfavorable influence of opioids on motor skills and is also helpful in the treatment of intestinal tumors or the prevention of their development, e.g. as a result of metastasis to the intestines.

Detailed Description of the Invention

In general, the invention relates to peptidomimetics useful in the treatment and prophylaxis of intestinal cancer.

While searching for new opioid peptidomimetics that should exhibit high affinity for opioid receptors, especially mu opioid receptors, and at the same time act as an antagonist to opioid drugs such as morphine, fentanyl or opioid peptides such as enkephalin or biphalin, it was surprisingly found that the obtained peptide opioid analogs also exhibit cytotoxic activity against intestinal cancer cells. This action manifests itself both through the cytostatic effect and the killing of neoplastic cells as well as by relaxing the tumor structures and facilitating the penetration of other active substances inside the tumor.

The following examples illustrate the cytostatic and cytotoxic effect on intestinal cancer cells produced in accordance with the invention. Examples of interaction with opioid receptors are also presented.

The peptidomimetics according to the invention can be obtained by methods known from the state of the art, in particular by the method described in the content of the Polish patent application no. P.402324. The following descriptions of the synthesis of exemplary peptidomimetics can be readily adapted by one skilled in the art to obtain any compound of the invention.

PL 238 779 B1

a) Tyrosyl-D-alanyl-glycyl-cinnamonylpiperazine hydrochloride

Trans-1-cinnamonyl piperazine was acylated with t-Boc-Tyr-D-Ala-Gly with N, N-dicyclohexylcarbodiimide by the N-hydroxysuccinimide coupling method in N, N-dimethylformamide solution. After filtering off the N, N'-dicyclohexylurea, the crude intermediate was precipitated with water. The pellet was washed three times with water and dried. The t-butyloxycarbonyl protecting group was removed with 5% hydrogen chloride in ethyl acetate. The crude end product as a salt (hydrochloride) was precipitated with diethyl ether. The crude product was purified by preparative HPLC with a 0.5% hydrochloric acid / ethanol gradient.

Tyrosyl-D-alanyl-glycyl-cinnamonylpiperazine hydrochloride was isolated as a pure product.

b) tyrosyl-D-threonyl-glycyl-phenylalanyl-cinnamonylpiperazine hydrochloride

Trans-1-cinnamonyl piperazine was acylated with t-Boc-Tyr-D-Thr-Gly-Phe with N, N-dicyclohexylcarbodiimide by the N-hydroxysuccinimide coupling method in N, N-dimethylformamide solution. After filtering off the N, N'-dicyclohexylurea, the crude intermediate was precipitated with water. The pellet was washed three times with water and dried. The t-butyloxycarbonyl protecting group was removed with 5% hydrogen chloride in ethyl acetate. The crude end product as a salt (hydrochloride) was precipitated with diethyl ether. The crude product was purified by preparative HPLC with a 0.5% hydrochloric acid / ethanol gradient. Tyrosyl-D-threonyl-glycyl-phenylalanyl-cinnamonylpiperazine hydrochloride (referred to as peptidomimetic 2) was isolated as a pure product.

c) tyrosyl-D-arginyl-cinnamonylpiperazine dihydrochloride

Trans-1-cinnamonylpiperazine was acylated with t-Boc-Tyr-D-Arg with N, N-dicyclohexylcarbodiimide by the N-hydroxysuccinimide coupling method in N, N-dimethylformamide solution. After filtering off the N, N'-dicyclohexylurea, the crude intermediate was precipitated with water. The pellet was washed three times with water and dried. The t-butyloxycarbonyl protecting group was removed with 5% hydrogen chloride in ethyl acetate. The crude end product as a salt (hydrochloride) was precipitated with diethyl ether. The crude product was purified by preparative HPLC with a 0.5% hydrochloric acid / ethanol gradient. Tyrosyl-D-arginyl-cinnamonylpiperazine dihydrochloride was isolated as a pure product.

Particularly preferred compounds according to the invention selected from among:

Preferably, the compound of the invention is selected from the group consisting of: tyrosyl-D-alanyl-glycyl-cinnamylpiperazine, tyrosyl-D-threonyl-glycyl-phenyl-cinnamylpiperazine, tyrosyl-D-arginyl-cinnamylpiperazine, and tyrosyl-D-threonyl- cinnamylpiperazine, L-tyrosyl-D-alanyl-L-phenylalanyl-cinnamylpiperazine, L-tyrosyl-D-alanyl-L-tryptophyl-cinnamylpiperazine, L-tyrosyl-D-threonyl-L-phenylalanyl-cinnamylpiperazine, L-tyrosyl-cinnamylpiperazine threonyl-L-tryptophyl-cinnamylpiperazine,

The above-mentioned compounds are first obtained by the synthesis of Boc-L-Tyr-D-Ala or Boc-L-Tyr-D-Thr or Boc-L-Tyr-D-Ala-Gly or Boc-L-Tyr-D-Thr- Gly using a 2-chlorotrityl resin using Fmoc-protected amino acids and the HATU / DIPEA method during coupling and 20% piperidine in DMF during deprotection. After removing from the resin with the AcO: TFE: DCM mixture, the obtained products are used to quote phenylalanyl-trans-1-cinnamylpiperazine and tryptophyl-trans-1-cinnamylpiperazine using the TBTU / DIPEA method. The t-butyloxycarbonyl group is removed with TFA: DCM.

To better illustrate the activity of the present invention as a compound showing a cytostatic and cytotoxic effect on intestinal cancer cells, an example of effective action on intestinal cancer cell lines is presented below. Examples of interaction with opioid receptors are also presented.

P r z k ł a d 1

Assessment of migration inhibition was performed using 24-well plates equipped with PET (polyethylene terephthalate) membrane inserts. The experiment was performed for the IC50 concentrations of the compounds tested, observing the inhibition of cell migration, i.e. the number of cells migrating / passing to the lower side of the membrane. After passing through the membrane, cells were stained with crystal violet and counted.

PL 238 779 B1

A) TyrDAlaGlyPheCyn

Phenylalanyl-trans-1-cinnamylpiperazine was acylated with t-Boc-Tyr-D-Ala-Gly using the TBTU / DIPEA method. The reaction product was precipitated with 10% NaHCQ3 and separated from the reaction mixture by filtration. The precipitate was washed 3 times with water until the filtrate had a neutral pH. The t-butyloxycarbonyl group was removed with TFA: DCM (1: 1). The crude product was purified by preparative HPLC on a water / methanol gradient system with 0.1% trifluoroacetic acid. The counterion was replaced with Cl- using a Dowex ion exchange resin. Purified product Tyrosyl-D-alanyl-glycyl-phenylalanyl-cinnamylpiperazin hydrochloride, hereinafter referred to as TyrDAlaGlyPheCyn. The compound was used in cell research:

- For HT29 cells (intestinal cancer), migration inhibition to approx. 70% at 150 μΜ was determined.

- For Colo205 cells (intestinal cancer), migration inhibition to approx. 60% at 170 μmol was determined.

- For SW480 cells (intestinal cancer), migration inhibition was determined to approx. 62% at 304 μmol

- For SW620 cells (intestinal cancer), migration inhibition was determined to approx. 40% at 400 μmol

B) TyrDAlaGlyTrpCyn

Tryptophyl-Trans-1-cinnamylpiperazine was acylated with t-Boc-Tyr-D-Ala-Gly using the TBTU / DIPEA method. The reaction product was precipitated with 10% NaHCQ ₃ and separated from the reaction mixture by filtration. The precipitate was washed 3 times with water until the filtrate had a neutral pH. The t-butyloxycarbonyl group was removed with TFA: DCM (1: 1). The crude product was purified by preparative HPLC on a water / methanol gradient system with 0.1% trifluoroacetic acid. The counterion was replaced with Cl- using a Dowex ion exchange resin. The purified product tyrosyl-D-alanyl-glycyl-tryptophylcinnamylpyparizine hydrochloride is hereinafter referred to as TyrDAlaGlyTrpCyn. The compound was used in cell studies: - For HT29 cells (intestinal cancer), migration inhibition was determined to approx. 50% at 300 μΜ.

- For Colo205 cells (intestinal cancer), migration inhibition to approx. 40% at 280 μmol was determined.

- For SW480 cells (intestinal cancer), migration inhibition was determined to approx. 33% at 291 μmol

- For SW620 cells (intestinal cancer), migration inhibition was determined to approx. 28% at 452 μmol

C) TyrDThrGlyPheCyn

The phenylalanyl-trans-1-cinnamylpiperazine was acylated with t-Boc-Tyr-D-Thr-Gly using the TBTU / DIPEA method. The reaction product was precipitated with 10% NaHCQ3 and separated from the reaction mixture by filtration. The precipitate was washed 3 times with water until the filtrate had a neutral pH. The t-butyloxycarbonyl group was removed with TFA: DCM (1: 1). The crude product was purified by preparative HPLC on a water / methanol gradient system with 0.1% trifluoroacetic acid. The counterion was replaced with Cl- using a Dowex ion exchange resin. Purified product Tyrosyl-D-threonyl-glycyl-phenylalanyl-cinnamylpiperazin hydrochloride, hereinafter referred to as TyrDThrGlyPheCyn. The compound was used in cell research:

- For SW480 cells (intestinal cancer), migration inhibition was determined to approx. 45% at 430 μmol

D) TyrDThrGlyTrpCyn

Tryptophyl-Trans-1-cinnamylpiperazine was acylated with t-Boc-Tyr-D-Thr-Gly using the TBTU / DIPEA method. The reaction product was precipitated with 10% NaHCQ3 and separated from the reaction mixture by filtration. The precipitate was washed 3 times with water until the filtrate had a neutral pH. The t-butyloxycarbonyl group was removed with TFA: DCM (1: 1). The crude product was purified by preparative HPLC on a water / methanol gradient system with 0.1% trifluoroacetic acid. The counterion was replaced with Cl- using a Dowex ion exchange resin. The purified product Tyrosyl-D-threonyl-glycyl-tryptophylcinnamylpyparizine hydrochloride is hereinafter referred to as TyrDThrGlyTrpCyn. The compound was used in cell studies: - For SW480 cells (intestinal cancer), migration inhibition was determined to approx. 39% at 426 μmol

- For SW620 cells (intestinal cancer), migration inhibition was determined to approx. 33% at 552 μmol

P r z k ł a d 2

The effect of the test compounds on cell growth was assessed by the colorimetric method with the use of MTT or XTT reagents by determining the IC50. The tests were based on salt reduction under the influence

Of mitochondrial dehydrogenase, metabolically active cells. The color of the reduction product was determined spectrophotometrically and the number of viable cells was thus determined.

A) TyrDAlaGlyPheCyn (compound obtained according to the scheme shown in Example 1)

- For HT29 cells (intestinal carcinoma), the IC50 of 150 μΜ was determined.

- For Colo205 cells (intestinal cancer), the IC50 for 170 μταΙ was determined.

- For HCT116 cells (intestinal cancer), the IC50 was determined for 284 μταΙ.

- For SW480 cells (intestinal cancer), the IC50 was determined for 304 μταΙ

- For SW620 cells (intestinal cancer), the IC50 of 400 μταΙ was determined

B) TyrDAlaGlyTrpCyn (compound obtained according to the scheme shown in Example 1)

- For HT29 cells (intestinal carcinoma), the IC50 of 300 μΜ was determined.

- For Colo205 cells (intestinal cancer), the IC50 was determined for 280 μταΙ.

- For HCT116 cells (intestinal cancer), the IC50 of 321 μταΙ was determined.

- For SW480 cells (intestinal cancer), the IC50 was determined for 291 μταΙ

- For SW620 cells (intestinal cancer), the IC50 was determined for 452 μταΙ

C) TyrDThrGlyPheCyn (compound obtained according to the scheme shown in Example 1) - IC50 for 557 μταΙ was determined for HCT116 cells (intestinal cancer).

- For SW480 cells (intestinal cancer), the IC50 was determined for 430 μταΙ

- For SW620 cells (intestinal cancer), the IC50 for 634 μταΙ was determined

D) TyrDThrGlyTrpCyn (compound obtained according to the scheme shown in example 1)

- An IC50 of 500 μΜ was determined for HT29 cells (intestinal cancer).

- For Colo205 cells (intestinal cancer), the IC50 of 610 μταΙ was determined.

- For HCT116 cells (intestinal cancer), the IC50 of 403 μταΙ was determined.

- For SW480 cells (intestinal cancer), the IC50 was determined for 426 μταΙ

- For SW620 cells (intestinal cancer), the IC50 for 552 μταΙ was determined

P r z k ł a d 3

Tryptαfylα-Trans-1-tinτylαpiperazine was quoted with t-Bαc-Tyr-D-Ala-Gly using the TBTU / DIPEA method. The reaction product was precipitated with 10% NaHCO3 and the αdseparate αd of the reaction mixture by filtration. The precipitate was washed 3 times with water until the filtrate had a neutral pH. The t-butyloxycarbonyl group was removed with TFA: DCM (1: 1). Crude product αcleanαnα using a preparative HPLC system in a wαda / τetanαl gradient system with dαdatkieτ 0.1% trifluαrααctαwegα acid. The counterjαn of the transformation of αnα to O- using the Dowex ion exchange resin. The purification product of the hydrochthore tyrαzylα-D-alanylα-glycylα-tryptαfylαcynaτylαpiperazine is hereinafter referred to as TyrDAlaGlyTrpCyn. Tryptαfylα-Trans-1-tinτylαpiperazine was quoted with t-Bαc-Tyr-D-Thr-Gly using the TBTU / DIPEA method. The reaction product was precipitated with 10% NaHCO3 and the αseparate αd of the α-reaction mixture by filtration. The sediment was washed three times with water until the filtrate had a neutral pH. The t-butylαxycarbαnyl group was removed with TFA: DCM (1: 1). The crude product was purified on a preparative HPLC system in a gradientαwyτ wαda / τetanαl system with dαdatkieτ 0.1% trifluαrααctαwegα acid. The counterjαn of the transformation of αnα to O- using the Dowex ion exchange resin. The purified product hydrochtorek tyrαzylα-D-treαnylα-glycylα-tryptαfylα-cynaτylαpiperazine is hereinafter referred to as TyrDThrGlyTrpCyn. Phenylalanylα-trans-1-cinnamylpiperazine was acylated with t-Bαc-Tyr-D-Ala-Gly using the TBTU / DIPEA method. The reaction product was precipitated with 10% NaHCO3 and the αs separated from the reaction mixture by filtration. The precipitate was washed 3 times with water until the filtrate had a neutral pH. The t-butyloxycarbonyl group was removed with TFA: DCM (1: 1). The crude product was purified on a preparative HPLC system in a gradientαwyτ wαda / τetanαl system with dαdatkieτ 0.1% trifluαrααctαwegα acid. Counterjαn of the emergence of αnα on O with the Dowex ion exchange resin. The purified product tyrosyl-D-alanylα-glycylα-phenylαalanylα-tinτylαpiperayin hydrochloride is called TyrDAlaGlyPheCyn.

Phenylalanylα-trans-1-cinnamylpiperazine was acylated with t-Bαc-Tyr-D-Thr-Gly using the TBTU / DIPEA method. The reaction product was precipitated with 10% NaHCO3 and the αseparate αd of the reaction mixture by filtration. The sediment was washed 3 times with water until the filtrate had a neutral pH. The t-butyloxycarbonyl group was removed with TFA: DCM (1: 1). The crude product was purified on a preparative HPLC gradient system

The mixture was water / methanol containing 0.1% trifluoroacetic acid. The counterion was replaced with Cl- using a Dowex ion exchange resin. The purified product tyrosyl-D-threonyl-glycyl-phenylalanyl-cinnamylpiperazine hydrochloride is hereinafter referred to as TyrDThrGlyPheCyn.

The study of the receptor affinity of the analyzed compounds was investigated by the radioisotope method consisting in the competitive binding of 0.5 nM of a selective radioactive agonist of the opioid receptor μ: [3H] DAMGO and δ: [3H] DELT in the presence of increasing concentrations of the tested compounds in unlabeled form (10-10.5 - 10- 6) showed the following values:

TyrDAlaGlyPheCyn - for the μ receptor less than 1.7 and for the δ receptor less than 11 TyrDAlaGlyTrpCyn - for the μ receptor less than 76 and less than 250 for the δ receptor TyrDThrGlyPheCyn - less than 1.7 for the μ receptor and less than 1.4 for the δ receptor TyrDThrGlyTrpCyn - for the μ receptor below 4.5 and for the δ receptor below 56, which proves the ability of the tested compounds to bind to the receptors used.

Claims (12)

Patent claims 1.Compound selected from: tyrosyl-D-alanyl-glycyl-phenylalanyl-cinnamylpiperazine (TyrDAlaGlyPheCyn), tyrosyl-D-alanyl-glycyl-tryptophyl-cinnamylpiperazine (TyrDAlaGlyTrpCyn), tyrosyl-glycyl-phenylamine-Thrly-phenylamine) , tyrosyl-D-threonyl-glycyl-tryptophyl-cinnamylpiperazine (TyrDThrGlyTrpCyn), or a pharmaceutically acceptable salt thereof. 2. A compound as defined in claim 1 for use in treating or preventing a cancer of the intestine. 3. The compound for use according to claim 1 A method according to claim 2, characterized in that it is used in a form intended for oral, injection or intravenous administration. 4. The compound for use according to claim 1 A method according to claim 2, characterized in that it is used in the form of an oral tablet for administration directly into the gastrointestinal tract or intravenous infusion for peripheral administration or injection for injection of the tumor and its vicinity. 5. The compound for use according to claim 1 A pharmaceutical composition according to claim 2, characterized in that it is used in the form of a multi-drug pharmaceutical composition, preferably additionally containing an opioid with analgesic effect and / or an anti-cancer drug. 6. The compound for use according to claim 1 A method according to claim 2, characterized in that it is intended for use in classical chemotherapy of colorectal cancer conducted preoperatively (neo-adjuvant therapy) or postoperatively (adjuvant therapy) or in the chemotherapy of inoperable colorectal cancer or in its support or is intended for use in protecting the intestine against metastasis to the intestine. cancer from another tissue. 7. A compound as defined in claim 1 for use in analgesic therapy as an opioid antagonist. 8. The compound for use according to claim 1 The method of claim 7, for the purpose of oral or peripheral administration for the elimination of constipation induced by opioid drugs. 9. The compound for use according to claim 1 The method of claim 7, which is designed to act on opioid receptors. 10. The compound for use according to claim 1 7. The method of claim 7 for use in the form of an oral tablet for direct administration into the gastrointestinal tract, or an intravenous infusion for peripheral administration. 11. The compound for use according to claim 1 A pharmaceutical composition according to claim 7, characterized in that it is used in the form of a multi-drug pharmaceutical composition, preferably containing an opioid for analgesic therapy. 12. The compound for use according to claim 1 1 or claim The method of claim 7, for use in the form of a composition containing an active substance carrier polymer.