# US 2014/0193334 A1 · Targeted Delivery and Prodrug Designs for Platinum-Acridine Anti-Cancer Compounds and Methods Thereof

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

- Number: US 2014/0193334 A1
- Document ID: US20140193334A1
- Status: Published application
- Kind: A1
- Application number: 14/241,900
- Filed: 2012-08-30
- Published: 2014-07-10
- Earliest claimed: 2011-09-02
- Inventors: Ulrich Bierbach; Song Ding
- Web page: https://patentgrep.com/patent/US20140193334A1

## CPC

- C07F 15/0093: {without a metal-carbon linkage}
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 219/10: attached in position 9
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Acridine containing cisplatin compounds have been disclosed that show greater efficacy against cancer than other cisplatin compounds. Methods of delivery of those more effective cisplatin compounds to the nucleus in cancer cells is disclosed using one or more amino acids, one or more sugars, one or more polymeric ethers, C1-6alkylene-phenyl-NH—C(O)—R15, folic acid, αvβ3 integrin RGD binding peptide, tamoxifen, endoxifen, epidermal growth factor receptor, antibody conjugates, kinase inhibitors, diazoles, triazoles, oxazoles, erlotinib, and/or mixtures thereof; wherein R15 is a peptide.

## Claims

### Claim 1

1) A compound of Formula I:
wherein X is halo, OC(O)R9, nitrate or sulfate;
R1 and R2 are amino groups or together with the platinum atom to which they are attached, R1 and R2 form the ring —NH2—(CH2)v—NH2— wherein v is 1, 2, 3, or 4 or R1 and R2 together can be any of the following groups a-h;
wherein A is H, —CH3, —OCH3, CF3 or NO2;
R3 is —N(R6)—; wherein R6 is hydrogen or C1-C6alkyl;
R4 is independently an amino, a nitro, —NHC(O)(R10), —NHC(O)O(R10), —C(O)NHR10, —OC(O)NHR10, or halo;
R10 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, or adamantyl;
q is 0, 1, or 2;
R5 is a direct bond, —NH— or C1-C6alkylene;
or R5 and X together with the atoms to which they are attached form a 6- or 7-membered ring, wherein said 6- or 7-membered ring contains a linking group —C(O)O— or —OC(O)—;
R7 is hydrogen, methyl, or —C(O)O—R8; wherein
R8 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
R9 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
either or both of R11 and R12 contain a reactive group on to which a linker and/or one or more of compound W can be added; and if only one of R11 and R12 contains a reactive group, then the other of R11 and R12 is hydrogen;
compound W is one or more amino acids, one or more sugars, polymeric ethers, C1-6 alkylene-phenyl-NH—C(O)—R15, folic acid, αvβ3 integrin RGD binding peptide, tamoxifen, endoxifen, EGFR (epidermal growth factor receptor) antibody conjugates, kinase inhibitors, diazoles, triazoles, oxazoles, erlotinib, and mixtures thereof;
wherein R15 is a peptide;
Y is C1-C6alkyl; and
Z is one or more counterions sufficient to balance the charge of the compound.

### Claim 2 (depends on 1)

2) The compound of claim 1, wherein R11 and R12 are —OH, —N3, —COOH, —CONH2, —CH═CH2, —C≡CH, —(CH2)1-6—OH, —(CH2)1-6—N3, —(CH2)1-6—COOH, or —(CH2)1-6—CH═CH2, or —(CH2)1-6—C≡CH.

### Claim 3 (depends on 1)

3) The compound of claim 1, wherein R11 and R12 combined with the linker and compound W are —NH—R13,
—O—R13, —CH═CH—R13, —C≡C—R13, —N3, —COOH, —COOR14, —C(O)NH—R13, —NHC(O)—R13, —OC(O)NH—R13, —OC(O)O—R13, —(CH)1-6—NH—R13,
—(CH2)1-6—O—R13, —(CH2)1-6—N3, —(CH2)1-6—COOH, —(CH2)1-6—COOR14 or —(CH2)1-6—CH═CH—R13;
wherein R13 and R14 are independently selected from the group consisting of one or more amino acids, one or more sugars, polymeric ethers, C1-6alkylene-phenyl-NH—C(O)—R15, folic acid, αvβ3 integrin RGD binding peptide, tamoxifen, endoxifen, EGFR (epidermal growth factor receptor) antibody conjugates, kinase inhibitors, diazoles, triazoles, oxazoles, erlotinib, and mixtures thereof; wherein R15 is a peptide.

### Claim 4 (depends on 1)

4) The compound of claim 1, wherein R6 is hydrogen or methyl and R1 and R2 are amino groups or together with the platinum atom to which they are attached, R1 and R2 form the ring —NH2—(CH2)v—NH2— wherein v is 2 or 3.

### Claim 5 (depends on 4)

5) The compound of claim 4, wherein Y is —CH2—.

### Claim 6 (depends on 5)

6) The compound of claim 5, wherein R1 and R2 are amino groups or together with the platinum atom to which R1 and R2 are attached are —NH2—CH2—NH2—.

### Claim 7 (depends on 6)

7) The compound of claim 6, wherein the one or more counter ions of Z comprise NO3.

### Claim 8 (depends on 7)

8) The compound of claim 7, wherein R5 is —NH— or —CH2—.

### Claim 9 (depends on 8)

9) The compound of claim 8, wherein R6 is hydrogen.

### Claim 10 (depends on 9)

10) The compound of claim 9, wherein the compound is Example 1

### Claim 11 (depends on 7)

11) The compound of claim 7, wherein the compound is Example 2:

### Claim 12

12) A method of treating cancer comprising administering to a subject in need thereof an effective amount of the compound of Formula I:
wherein X is halo, OC(O)R9, nitrate or sulfate;
R1 and R2 are amino groups or together with the platinum atom to which they are attached, R1 and R2 form the ring —NH2—(CH2)v—NH2— wherein v is 1, 2, 3, or 4 or R1 and R2 together can be any of the following groups a-h;
wherein A is H, —CH3, —OCH3, CF3 or NO2;
R3 is —N(R6)—; wherein R6 is hydrogen or C1-C6alkyl;
R4 is independently an amino, a nitro, —NHC(O)(R10), —NHC(O)O(R10), —C(O)NHR10, —OC(O)NHR10, or halo;
R10 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, or adamantyl;
q is 0, 1, or 2;
R5 is a direct bond, —NH— or C1-C6alkylene;
or R5 and X together with the atoms to which they are attached form a 6- or 7-membered ring, wherein said 6- or 7-membered ring contains a linking group —C(O)O— or —OC(O)—;
R7 is hydrogen, methyl, or —C(O)O—R8; wherein
R8 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
R9 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
either or both of R11 and R12 contain a reactive group on to which a linker and/or one or more of compound W can be added; and if only one of R11 and R12 contains a reactive group, then the other of R11 and R12 is hydrogen;
compound W is one or more amino acids, one or more sugars, polymeric ethers, C1-6alkylene-phenyl-NH—C(O)—R15, folic acid, αvβ3, integrin RGD binding peptide, tamoxifen, endoxifen, EGFR (epidermal growth factor receptor) antibody conjugates, kinase inhibitors, diazoles, triazoles, oxazoles, erlotinib, and mixtures thereof,
wherein R15 is a peptide;
Y is C1-C6alkyl; and
Z is one or more counterions sufficient to balance the charge of the compound.

### Claim 13 (depends on 12)

13) The method of claim 12, wherein the cancer is selected from the group consisting of lung cancer, testicular cancers, ovarian carcinomas, head and neck cancers, leukemias and lymphomas.

### Claim 14 (depends on 13)

14) The method of claim 13, wherein R6 is hydrogen or methyl and R1 and R2 are amino groups or together with the platinum atom to which they are attached, R1 and R2 form the ring —NH2—(CH2)v—NH2— wherein v is 2 or 3.

### Claim 15 (depends on 14)

15) The method of claim 14, wherein Y is —CH2—.

### Claim 16 (depends on 15)

16) The method of claim 15, wherein R1 and R2 are amino groups or together with the platinum atom to which R1 and R2 are attached are —NH2—CH2—CH2—NH2—.

### Claim 17 (depends on 16)

17) The method of claim 16, wherein the one or more counter ions of Z comprise NO3.

### Claim 18 (depends on 17)

18) The method of claim 17, wherein R5 is —NH— or —CH2—.

### Claim 19 (depends on 18)

19) The method of claim 18, wherein R6 is hydrogen.

### Claim 20

20) A pharmaceutical composition comprising the compound of Formula I:
wherein X is halo, OC(O)R9, nitrate or sulfate;
R1 and R2 are amino groups or together with the platinum atom to which they are attached, R1 and R2 form the ring —NH2—(CH2)v—NH2— wherein v is 1, 2, 3, or 4 or R1 and R2 together can be any of the following groups a-h;
wherein A is H, —CH3, —OCH3, CF3 or NO2;
R3 is —N(R6)—; wherein R6 is hydrogen or C1-C6alkyl;
R4 is independently an amino, a nitro, —NHC(O)(R10), —NHC(O)O(R10), —C(O)NHR10, —OC(O)NHR10, or halo;
R10 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, or adamantyl;
q is 0, 1, or 2;
R5 is a direct bond, —NH— or C1-C6alkylene;
or R5 and X together with the atoms to which they are attached form a 6- or 7-membered ring, wherein said 6- or 7-membered ring contains a linking group —C(O)O— or —OC(O)—;
R7 is hydrogen, methyl, or —C(O)O—R8; wherein
R8 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
R9 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
either or both of R11 and R12 contain a reactive group on to which a linker and/or one or more of compound W can be added; and if only one of R11 and R12 contains a reactive group, then the other of R11 and R12 is hydrogen;
compound W is one or more amino acids, one or more sugars, polymeric ethers, C1-6alkylene-phenyl-NH—C(O)—R15, folic acid, αvβ3 integrin ROD binding peptide, tamoxifen, endoxifen, EGFR (epidermal growth factor receptor) antibody conjugates, kinase inhibitors, diazoles, triazoles, oxazoles, erlotinib, and mixtures thereof;
wherein R15 is a peptide;
Y is C1-C6alkyl; and
Z is one or more counterions sufficient to balance the charge of the compound;
and a pharmaceutically acceptable diluent, carrier, or excipient.

### Claim 21 (depends on 20)

21) The pharmaceutical composition of claim 20, wherein Y is —CH2—, wherein R1 and R2 are amino groups or together with the platinum atom to which R1 and R2 are attached are —NH2—CH2—CH2—NH2—, and wherein the one or more counter ions of Z comprise NO3.

### Claim 22 (depends on 21)

22) The pharmaceutical composition of claim 21, wherein R5 is —NH— or —CH2—, wherein R6 is hydrogen or methyl and R1 and R2 are amino groups or together with the platinum atom to which they are attached, R1 and R2 form the ring —NH2—(CH2)v—NH2— wherein v is 2 or 3.

### Claim 23 (depends on 20)

23) The pharmaceutical composition of claim 20, further comprising one or more compounds selected from the group consisting of HERCEPTIN™ (trastuzumab), RITUXAN™ (rituximab), ZEVALIN™ (ibritumomab tiuxetan), LYMPHOCIDE™ (epratuzumab), GLEEVAC™, BEXXAR™ (iodine 131 tositumomab), ERBITUX™ (IMC-C225), KDR inhibitory agents, AVASTIN™, VEGF-TRAP™, ABX-EGF (panitumumab), IRESSA™ (gefitinib), TARCEVA™ (erlotinib), Campath, IL-8, B-FGF, Tek antagonists, anti-TWEAK agents, anti-PDGF-BB antagonists, SD-7784, cilengitide; pegaptanib octasodium; Alphastatin, M-PGA; ilomastat, emaxanib, vatalanib, 2-methoxyestradiol, TLC ELL-12, anecortave acetate, alpha-D148 Mab, CEP-7055, anti-Vn Mab, DAC:antiangiogenic, Angiocidin, KM-2550, SU-0879, CGP-79787, YIGSR-Stealth, fibrinogen-E fragment, TBC-1635; SC-236, ABT-567, Metastatin, maspin, ER-68203-00, Benefin, Tz-93, TAN-1120, FR-111142, platelet factor 4, vascular endothelial growth factor antagonist, bevacizumab (pINN), XL 784, XL 647, MAb, alpha5beta3 integrin, enzastaurin hydrochloride (USAN), CEP 7055, BC 1, VEGF antagonist, rBPI 21 and BPI-derived antiangiogenic, PI 88, cilengitide (pINN), cetuximab (INN), AVE 8062, AS 1404, SG 292, Endostatin, ATN 161, ANGIOSTATIN, ZD 6474, ZD 6126, PPI 2458, AZD 9935, AZD 2171, vatalanib (pINN), pegaptanib (Pinn), xanthorrhizol, SPV5.2, SDX 103, PX 478, METASTATIN, troponin I, SU 6668, OXI 4503, o-guanidines, motuporamine C, CDP 791, atiprimod (pINN), E 7820, CYC 381, AE 941, urokinase plasminogen activator inhibitor, oglufanide (pINN), HIF-lalfa inhibitors, CEP 5214, BAY RES 2622; Angiocidin, A6, KR 31372, GW 2286, EHT 0101, CP 868596, CP 564959, CP 547632, compound 786034 from GlaxoSmithKline, KRN 633, anginex, ABT 510, AAL 993, VEGI, tumor necrosis factor-alpha inhibitors, SU 11248, ABT 518, YH16, S-3APG, KDR, GFB 116, CS 706, combretastatin A4 prodrugs, chondroitinase AC, BAY RES 2690, AGM 1470, AG 13925, Tetrathiomolybdate, GCS 100, CV 247, CKD 732, irsogladine (INN), RG 13577, WX 360, squalamine (pIN), RPI 4610, heparanase inhibitors, KL 3106, Honokiol, ZK CDK, ZK Angio, ZK 229561, XMP 300, VGA 1102, Vasostatin, Flk-1, TZ 93, TumStatin, truncated soluble FLT 1 Tie-2 ligands and thrombospondin 1 inhibitor.

### Claim 24 (depends on 1)

24) A system of delivering a compound of formula I as claimed in claim 1 to a patient in need thereof, wherein said system employs directly or indirectly binding said compound of formula I to one or more members selected from the group consisting of one or more amino acids, one or more sugars, one or more polymeric ethers, C1-6alkylene-phenyl-NH—C(O)—R15, folic acid, αvβ3 integrin RGD binding peptide, tamoxifen, endoxifen, EGFR (epidermal growth factor receptor) antibody conjugates, kinase inhibitors, diazoles, triazoles, oxazoles, erlotinib, and mixtures thereof; wherein R15 is a peptide.