# US 2019/0375787 A1 · Peptidomimetics and their use in therapy

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2019/0375787 A1
- Document ID: US20190375787A1
- Status: Published application
- Kind: A1
- Application number: 16/464,532
- Filed: 2017-11-28
- Published: 2019-12-12
- Earliest claimed: 2016-11-28
- Applicants: Instytut Homeostazy Sp. Z O.O.
- Inventors: Andrzej Wojciech LIPKOWSKI; Aleksandra MISICKA-KESIK; Piotr SOSNOWSKI; Anna Katarzyna PUSZKO; Anna LASKOWSKA; Marek DURLIK; Krzysztof RÓZYCKI
- Web page: https://patentgrep.com/patent/US20190375787A1

## CPC

- A61P 35/00: Antineoplastic agents
- C07K 5/1016: {and aromatic or cycloaliphatic}
- C07K 5/06078: {and aromatic or cycloaliphatic}
- C07K 5/0812: {and aromatic or cycloaliphatic}
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07K 7/06: having 5 to 11 amino acids
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Peptidomimetic analogs suitable for use in cancer therapy, or as antagonists of opioid drugs, and suitable application of the compounds are disclosed. The described compounds display cytostatic and cytotoxic effects toward intestinal cancer cells, and pancreatic cancer cells, display affinity to μ and δ receptors, and act as antagonists of opioid drugs. Particularly, they are intended for administration to gastrointestinal system, in the form of tablets, infusions, injections, or implants, in therapy and supporting therapy of intestinal or pancreatic cancer, and in elimination of respiratory depression triggered by opioids, and to assure appropriate intestine peristalsis during an opioid therapy.

## Claims

### Claim 1

Compound of general formula:
wherein:
R1 relates to a side chain of 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 relates to none, or to L-amino acid residue selected from Gly or Lys, or dipeptide residue L-Gly-L-Lys,
R3 relates to L-amino acid residue selected from Phe or Trp,
R4 relates to none or to L-amino acid residue Lys,
R5 relates to straight, saturated or unsaturated hydrocarbon chain of general formula CnHm, wherein n is an integer from 1 to 4, and m is an even integer from 2 to 10,
R6-10 relates independently to a substituent selected from: hydrogen, hydroxyl, methyl, formyl, carboxy, methoxycarbonyl, carbamoyl, cyano, amino, methylamino, dimethylamino, iodo, fluoro, nitro, or sulphone,
for use in therapy or prophylaxis of cancer, especially intestinal or pancreatic cancer.

### Claim 2 (depends on 1)

Compound for use according to claim 1, wherein, R2 relates to L-Gly residue, when:
a) R4 relates L-Lys residue, or
b) R5 does not relate to hydrocarbon chain of formula C2H2, or
c) at least one from R6-R10 does not relate to hydrogen.

### Claim 3 (depends on 1)

Compound for use according to claim 1, wherein it is selected from:
tyrosyl-D-alanyl-glicyl-cinnamylpiperazine,
tyrosyl-D-threonyl-glicyl-phenylalanyl-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-D-threonyl-L-tryptophyl-cinnamylpiperazine,
L-tyrosyl-D-alanyl-glicyl-L-phenylalanyl-cinnamylpiperazine,
L-tyrosyl-D-alanyl-glicyl-L-tryptophyl-cinnamylpiperazine,
L-tyrosyl-D-threonyl-glicyl-L-phenylalanyl-cinnamylpiperazine,
L-tyrosyl-D-threonyl-glicyl-L-tryptophyl-cinnamylpiperazine.

### Claim 4 (depends on 1)

Compound for use according to claim 1, wherein it is used in a form intended for oral, by injection, or intravenous administration.

### Claim 5 (depends on 1)

Compound for use according to claim 1, wherein it is used in a form of oral tablet to be administered directly into gastrointestinal tract, as intravenous infusion for peripheral administration, or injection into the tumor and its vicinity.

### Claim 6 (depends on 1)

Compound for use according to claim 1, wherein it is used in a form of multidrug pharmaceutical composition, preferably containing additionally an analgesic opioid, and/or an anticancer drug.

### Claim 7 (depends on 1)

Compound for use according to claim 1, wherein it is intended for use in classical chemotherapy of intestinal cancer, applied prior to surgery (neo-adjuvant therapy), or post-surgery (adjuvant therapy), or in chemotherapy of inoperable intestinal cancer, or as its supporting therapy, or it is intended for intestine protection from metastasis of cancer of different tissue origin.

### Claim 8 (depends on 1)

Compound for use according to claim 1, wherein it is intended for use in classical chemotherapy of pancreatic cancer, applied prior to surgery (neo-adjuvant therapy), or post-surgery (adjuvant therapy).

### Claim 9

Compound of general formula:
wherein:
R1 relates to side chain of 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 relates to none, or to L-amino acid residue selected from Gly or Lys, or dipeptide residue L-Gly-L-Lys,
R3 relates to L-amino acid residue selected from Phe or Trp,
R4 relates to none, or to L-amino acid residue Lys,
R5 relates to straight, saturated or unsaturated hydrocarbon chain of general formula CnHm, wherein n is an integer from 1 to 4, and m is an even integer from 2 to 10,
R6-10 relates independently to a substituent selected from: hydrogen, hydroxyl, methyl, formyl, carboxy, methoxycarbonyl, carbamoyl, cyano, amino, methylamino, dimethylamino, iodo, fluoro, nitro, or sulphone,
except of compound of general formula:
wherein:
R1 relates to side chain of D-amino acid selected from: D-alanine, D-threonine, D-serine, D-methionine, D-leucine, D-glutamine, D-asparagine, D-lysine, or D-arginine,
and R2 relates to none, or to residue of glycine, or a dipeptide selected from Gly-Phe or Gly-Trp.

### Claim 10 (depends on 9)

Compound according to claim 9, wherein it is selected from:
L-tyrosyl-D-alanyl-phenylalanyl-cinnamylpiperazine,
L-tyrosyl-D-alanyl-L-tryptophyl-cinnamylpiperazine,
L-tyrosyl-D-threonyl-L-phenylalanyl-cinnamylpiperazine,
L-tyrosyl-D-threonyl-L-tryptophyl-cinnamylpiperazine.

### Claim 11 (depends on 9, 10)

Compound according to claims 9-10 for use as an antagonist of opioid drugs.

### Claim 12 (depends on 11)

Compound for use according to claim 11, wherein, it is intended for oral or peripheral administration, to eliminate side effects of opioid drugs, especially intestinal disorder, constipation, or respiratory depression.

### Claim 13 (depends on 11)

Compound for use according to claim 11, wherein, it is intended for direct or indirect interaction with opioid receptors.

### Claim 14 (depends on 11)

Compound for use according to claim 11, wherein, it is used in a form of oral tablet to be administered directly into gastrointestinal tract, or as intravenous infusion for peripheral administration.

### Claim 15 (depends on 11)

Compound for use according to claim 11, wherein, it is used in a form of multidrug pharmaceutical composition, containing, preferably, an opioid used in painkilling therapy.

### Claim 16 (depends on 1, 11)

Compound for use according to claim 1, or claim 11, wherein, it is used in a form of composition containing a polymer as a carrier for the active agent.