# US 2014/0154181 A1 · Rgd-containing peptidomimetics and uses thereof

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

- Number: US 2014/0154181 A1
- Document ID: US20140154181A1
- Status: Published application
- Kind: A1
- Application number: 14/175,302
- Filed: 2014-02-07
- Published: 2014-06-05
- Earliest claimed: 2008-10-23
- Assignees: Steba Biotech S.A.
- Applicants: Steba Biotech S.A.
- Inventors: Doron EREN; Tamar YECHEZKEL; Yoseph SALITRA; Natalia KOUDINOVA
- Web page: https://patentgrep.com/patent/US20140154181A1

## CPC

- C07K 7/64: Cyclic peptides containing only normal peptide links
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 49/0056: {Peptides, proteins, polyamino acids}
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 27/02: Ophthalmic agents
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 1/1133: {by redox-reactions involving cystein/cystin side chains}
- C07K 7/54: with at least one abnormal peptide link in the ring
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides RGD-containing cyclic peptidomimetics; conjugates of said peptidomimetics and a moiety of a payload selected from fluorescent probes, photosensitizers, chelating agents, or cytotoxic agents; and pharmaceutical compositions comprising these conjugates. The conjugates of the invention are useful both for diagnostic purposes and treatment of various diseases, disorders and conditions. More specifically, conjugates comprising fluorescent probes can be used for diagnostic purposes, e.g., visualization of organs and tissues, and diagnosis of tumors; conjugates comprising photosensitizers can be used for photodynamic therapy of both tumors and nonneoplastic tissues; conjugates comprising chelating agents can be used in radioimaging or radiotherapy; and conjugates comprising cytotoxic agents can be used for targeted chemotherapy.

## Claims

### Claim 1

An arginine-glycine-aspartic acid (RGD)-containing cyclic peptidomimetic of the general formula II:
wherein
A1 is a natural or non-natural amino acid residue bearing either an amino or carboxyl group on its side chain, linked via its α- or side chain carboxyl group to the α-amino group of the arginine residue and via its α- or side chain amino group to the backbone C═O;
A2 is a natural or non-natural amino acid residue linked via its α-amino group to the backbone C═O and via its α-carboxyl group to the α- or side chain amino group of A3; and
A3 is a natural or non-natural amino acid residue bearing an amino group on its side chain and amidated at its C-terminus, linked via one of its α- or side chain amino group to the carboxyl group of A2 and via another of its α- or side chain amino group to the α-carboxyl group of the aspartic acid residue.

### Claim 2 (depends on 1)

The RGD-containing cyclic peptidomimetic of claim 1, wherein A1 is a residue of an amino acid selected from the group consisting of lysine (Lys), diaminopropionic acid (Dap), diaminobutyric acid (Dab), ornithine (Orn), glutamic acid (Glu), aspartic acid (Asp) and aminoadipic acid; A2 is a residue of an amino acid selected from the group consisting of phenylalanine (Phe), D-phenylalanine (D-Phe), valine (Val), glycine (Gly) and Asp; and A3 is a residue of an amino acid selected from the group consisting of Dap, Dab, Orn and Lys, amidated at its C-terminus.

### Claim 3 (depends on 2)

The RGD-containing cyclic peptidomimetic of claim 2, wherein A1 is Lys, A2 is Phe, Val, D-Phe, Gly or Asp, and A3 is Dap amidated at its C-terminus.

### Claim 4 (depends on 2)

The RGD-containing cyclic peptidomimetic of claim 2, wherein A1 is Lys, A2 is Phe, and A3 is Dab, Orn or Lys amidated at its C-terminus.

### Claim 5 (depends on 1)

A conjugate of the RGD-containing cyclic peptidomimetic of claim 1 and a moiety of a payload selected from the group consisting of a fluorescent probe, a photosensitizer, a chelating agent, and a cytotoxic agent, linked to the amino acid residue A1 in the peptidomimetic, provided that when A1 has a side chain amino group, said payload moiety is linked to either the α- or side chain amino group of A1, optionally via a spacer, and when A1 is a dicarboxylic amino acid residue, said payload moiety is linked to either the α- or side chain carboxyl group of A1, optionally via a spacer.

### Claim 6 (depends on 5)

The conjugate of claim 5, wherein said spacer is selected from the group consisting of a moiety of a natural or non-natural amino acid, a moiety of a small peptide having not more than 8 amino acids, a diamine residue, a C1-C25 hydrocarbylene and a soluble polymer.

### Claim 7 (depends on 6)

The conjugate of claim 6, wherein said amino acid is selected from the group consisting of glycine (Gly), β-alanine (β-Ala), phenylalanine (Phe), D-phenylalanine (D-Phe), 1-naphthylalanine (1-Nal), D-1-naphthylalanine (D-1-Nal), γ-aminobutiric acid (GABA) and 3-(aminomethyl) benzoic acid; said diamine residue is —HN—(CH2)2—NH— or —HN—(CH2)4—NH—; said C1-C25 hydrocarbylene is a C1-C10 alkylene or phenylene, substituted by two end functional groups selected from the group consisting of OH, COOH, SO3H, COSH and NH2, thus forming ether, ester, amide, thioamide or sulfonamide groups; and said soluble polymer is selected from the group consisting of linear or branched polyethylene glycol (PEG) or copolymers thereof, polylactide (PLA) or copolymers thereof, polyesters having suitable functional groups based on PLA, polyglycolide (PGA), polycaprolactone (PCL), or their copolymers, and polyamides based on polymethacrylamide or their copolymers, said polymers having functional groups.

### Claim 8 (depends on 5)

The conjugate of claim 5, wherein said fluorescent probe is BPheide taurine amide (BTA), fluorenyl isothiocyanate (FITC), dansyl, rhodamine, eosin or erythrosine; said photosensitizer is a porphyrin, a chlorophyll or a bacteriochlorophyll; said chelating agent is DTPA or DOTA; and said cytotoxic agent is an anthracycline chemotherapeutic agent selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin and mitoxantrone, a mitotic inhibitor, a topoisomerase I inhibitor, or a topoisomerase II inhibitor.

### Claim 9 (depends on 8)

The conjugate of claim 8, wherein the payload is BTA, linked directly to A1, A1 is Lys, and:
(i) A2 is Phe, Val, D-Phe, Gly or Asp, and A3 is Dap amidated at its C-terminus (conjugates 41, 42, 43, 44 and 45, respectively); or
(ii) A2 is Phe, and A3 is Dab, Orn or Lys amidated at its C-terminus (conjugates 46, 47 and 48, respectively).

### Claim 10 (depends on 5)

A pharmaceutical composition comprising a conjugate as defined in claim 5, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 11 (depends on 10)

The pharmaceutical composition of claim 10, wherein the payload is a fluorescent probe; a photosensitizer; a chelating agent; or a cytotoxic agent.

### Claim 12 (depends on 11)

The pharmaceutical composition of claim 11, wherein the payload is a fluorescent probe, and the pharmaceutical composition comprises a conjugate selected from the group consisting of the herein identified conjugates 41-48.

### Claim 13 (depends on 11)

The pharmaceutical composition of claim 11, wherein:
(i) the payload is fluorescent probe, suitable for diagnostic purposes;
(ii) the payload is a photosensitizer, suitable for photodynamic therapy (PDT);
(iii) the payload is a chelating agent, suitable for use in radio imaging or radiotherapy; or
(iv) the payload is a cytotoxic agent, suitable for use in targeted chemotherapy.

### Claim 14 (depends on 13)

The pharmaceutical composition of claim 13:
(i) consisting of the pharmaceutical composition of 14(i), and suitable for visualization of organs and tissues, or for diagnosis of tumors; or
(ii) consisting of the pharmaceutical composition of 14(ii), and suitable for PDT of tumors or normeoplastic tissue.

### Claim 15 (depends on 14)

The pharmaceutical composition of claim 14,
(i) consisting of the pharmaceutical composition of 15(i), and suitable for tumor diagnosis by dynamic fluorescence imaging, radiodiagnostic technique or molecular magnetic resonance imaging (MRI);
(ii) consisting of the pharmaceutical composition of 15(ii), wherein said tumor is a primary tumor or a metastasis from melanoma, colon, breast, lung, prostate, brain or head and neck cancer; or for treatment of age-related macular degeneration; or for treatment of obesity by limiting vascular supply to adipose tissue.

### Claim 16 (depends on 5)

A method of diagnosis which comprises contacting a diagnostic target with the conjugate of claim 5, said target being specifically bound by the RGD-containing cyclic peptidomimetic, and detecting said binding.

### Claim 17 (depends on 16)

The method of claim 16, wherein said contacting occurs inside the body of a patient.