# US 2013/0281402 A1 · Hdac inhibiting derivatives of camptothecin

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- Number: US 2013/0281402 A1
- Document ID: US20130281402A1
- Status: Published application
- Kind: A1
- Application number: 13/977,413
- Filed: 2012-01-06
- Published: 2013-10-24
- Earliest claimed: 2011-01-12
- Assignees: Crystal Biopharmaceutical LLC
- Inventors: Yi Chen; Yu Chen
- Web page: https://patentgrep.com/patent/US20130281402A1

## CPC

- C07D 491/22: in which the condensed system contains four or more hetero rings
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/695: Silicon compounds
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07F 7/10: containing nitrogen {having a Si-N linkage}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The disclosure includes hydroxamic compounds of Formula I: (Formula I) wherein Z, L, R1, R2, and R3 are defined herein. Also disclosed is a method for treating a neoplastic disease or an immune disease with these compounds.

## Claims

### Claim 1

A compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein
Z is deleted, C(RaRb), (CH2)p, (CH2)pNH(CH2)q, CH═N, O, S, C(O), N(Ra), SO2, OC(O), C(O)O, OSO2, S(O2)O, C(O)S, SC(O), C(O)C(O), C(O)N(Ra), N(Ra)C(O), S(O2)N(Ra), N(Ra)S(O2), OC(O)O, OC(O)S, OC(O)N(Ra), OC(O)NH(CH2)p+1NH(CH2)q, N(Ra)C(O)O, N(Ra)C(O)S, or N(Ra)C(O)N(Rb), in which each of Ra and Rb, independently, is H, alkyl, alkenyl, or alkynyl; each of p and q, independently, is 0, 1, 2, 3, or 4;
each R1, R2, and R3, independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, —CH═NH, oxo, cyano, Si(RcRcRc), alkyl-Si(RcRcRc), alkyl-Rc, alkyl-NRcRc, —CH═NORc, ORc, OC(O)Rc, OC(O)ORc, OC(O)SRc, SRc, C(O)Rc, C(O)ORc, C(O)SRc, C(O)NRcRc, SORc, SO2Rc, NRcRc, N(Rc)C(O)Rc, in which each of Rc independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, cyano, nitro, amino, hydroxyl, alkylamino, haloalkyl, or alkoxy, or R1, R2, and the atoms to which they are attached are taken together form a ring, which is optionally substituted with Rc;
L is —(CH2)m—,
in which m is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; each of n and o, independently, is 1, 2, 3, or 4; and each W1 and W2, independently, is CH or N.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein Z is deleted, (CH2)p, (CH2)pNH(CH2)q, CH═N, O, CO, NH, SO2, OC(O), OSO2, C(O)O, C(O)S, NHC(O), C(O)NH, OC(O)NH, OC(O)NH(CH2)p+1NH(CH2)q, OC(O)O, or OC(O)S; m is 5, 6, 7 or 8; and each R1, R2, and R3, independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, nitro, oxo, halo, cyano, —CH═NH, Si(RcRcRc), alkyl-Si(RcRcRc), alkyl-Rc, alkyl-NRcRc, CH═NORc, or NRcRc.

### Claim 3 (depends on 2)

The compound or salt of claim 2, wherein Z is O, OC(O), OSO2, OC(O)NH, OC(O)O, OC(O)S, OC(O)NH(CH2)p+1NH(CH2)q; m is 6 or 7; R3 is H or F; each Rc independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, nitro, amino, hydroxyl, alkylamino, haloalkyl, or alkoxy; and W2 is N.

### Claim 4 (depends on 3)

The compound or salt of claim 3, wherein each R1 and R2, independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, nitro, Si(RcRcRc), alkyl-SnRcRcRc), alkyl-Rc, alkyl-NRcRc, CH═NORc, or NRcRc.

### Claim 5 (depends on 4)

The compound or salt of claim 4, wherein the compound is

### Claim 6 (depends on 5)

The compound or salt of claim 5, wherein the compound is

### Claim 7 (depends on 6)

The compound or salt of claim 6, wherein the compound is

### Claim 8 (depends on 6)

The compound or salt of claim 6, wherein the compound is

### Claim 9 (depends on 1)

A modified compound of a compound of claim 1 comprising a modification having improved pharmaceutical solubility, stability, bioavailability, and/or therapeutic index as compared to the unmodified compound.

### Claim 10 (depends on 9)

A compound of claim 9, in which said modified compound is a prodrug derivative, a deuterium-enriched compound, a conjugate with a polyethylene glycol, dextran, polyvinyl alcohol, carbohydrate polymer, an antibody, a biomolecule, or mixtures thereof.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound or salt of claim 1 and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

A method of treating a neoplastic disease or an immune disease, comprising administering to a subject in need thereof an effective amount of a compound or salt of claim 1.

### Claim 13

An anti-cancer agent simultaneously containing a hydroxamic acid pharmacophore capable of inhibiting histone deacetylases (HDAC) and a pharmacophore capable of inhibiting topoisomerases.

### Claim 14 (depends on 13)

An anti-cancer agent of claim 13, wherein said pharmacophore capable of inhibiting topoisomerases is a camptothecin pharmacophore.

### Claim 15 (depends on 13)

An anti-cancer agent of claim 13, wherein said topoisomerase is topoisomerase I.