# US 10,118,901 B2 · Therapeutic agents

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- Number: US 10,118,901 B2
- Document ID: US10118901B2
- Status: Granted
- Kind: B2
- Application number: 14/374,995
- Filed: 2013-01-31
- Published: 2015-03-26
- Granted: 2018-11-06
- Earliest claimed: 2013-01-31
- Assignees: Purdue Pharmaceutical Products L.P.
- Applicants: Purdue Pharmaceutical Products L.P.
- Inventors: Yu Chen; Yi Chen
- Web page: https://patentgrep.com/patent/US10118901B2

## CPC

- C07D 235/30: Nitrogen atoms not forming part of a nitro radical
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07D 235/14: Radicals substituted by nitrogen atoms (by nitro radicals C07D235/10)
- C07D 235/18: with aryl radicals directly attached in position 2
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to a class of hydroxamic acid compounds of Formula (I), which act as alkylating agents and/or inhibitors of the HDAC pathway, having potential utility in the treatment of a neoplastic disease and immune diseases.

## Claims

### Claim 1

A compound of Formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt of said compound of formula (I) or N-oxide thereof:
wherein
Z is (CRaRb)pN(Ra)(CRaRb)q;
X1 and X2 are each independently selected from halo and OSO2Rc;
P is
Q is benzimidazolyl, which is optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, halo, nitro, oxo, cyano or ORe;
Ra, Rb, Rd and Re are each independently selected from H, alkyl, alkenyl and alkynyl;
Rc is selected from alkyl, alkenyl and alkynyl; and
p and q are each independently selected from 1, 2, 3 and 4.

### Claim 2 (depends on 1)

The compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1 and q is 2; or p is 2 and q is 1; or p and q are both 2.

### Claim 3 (depends on 1)

The compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein Z is (CH2)pNH(CH2)q.

### Claim 4 (depends on 3)

The compound according to claim 3 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein Z is (CH2)2NH(CH2).

### Claim 5 (depends on 1)

The compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are each independently selected from chloro, bromo and iodo.

### Claim 6 (depends on 5)

The compound according to claim 5 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are both chloro.

### Claim 7 (depends on 1)

The compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein Q is benzimidazolyl substituted by one or more alkyl groups.

### Claim 8 (depends on 7)

The compound according to claim 7 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is represented by Formula(II):

### Claim 9 (depends on 8)

The compound according to claim 8 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof wherein the compound of Formula (I) is represented by Formula (III):

### Claim 10 (depends on 9)

The compound according to claim 9, which is
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

The compound according to claim 10, which is the hydrochloride salt thereof.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising a compound of formula (I) or an N-oxide thereof as defined in claim 1, or a pharmaceutically acceptable salt of said compound of formula (I) or an N-oxide thereof, and a pharmaceutically acceptable diluent or carrier.

### Claim 13 (depends on 1)

A combination comprising a compound of formula (I) or an N-oxide thereof as defined in claim 1, or a pharmaceutically acceptable salt of said compound of formula (I) or N-oxide thereof, together with one or more other therapeutic agents.

### Claim 14 (depends on 13)

The combination according to claim 13 wherein the one or more other therapeutic agents is selected from: proteasome inhibitors, IMIDs, platinum agents, folate antagonists, CD30 antibodies and conjugates, antibodies or conjugated antibodies to treat haematological malignancies, anti-CD20 antibodies, B-cell receptor antagonists, PI3K antagonists, BTK inhibitors, taxanes, antibodies or conjugated antibodies—to treat ovarian cancer, antibodies to treat multiple myeloma, anthracyclines, nucleoside analogues, purine antagonists, PNP antagonists, Bcr-abl tyrosinekinase blockers, mTor antagonists, Agents influencing the CD40 activation, multi tyrosine kinase antagonists, and bifunctional antibodies.

### Claim 15 (depends on 1)

A product containing a compound of formula (I) or an N-oxide thereof as defined in claim 1, or a pharmaceutically acceptable salt of said compound of formula (I) or N-oxide thereof, and one or more other therapeutic agents, as a combined preparation for simultaneous, separate or sequential use in treating a neoplastic disease or an immune disease, wherein said one or more other therapeutic agents is selected from: proteasome inhibitors, IMIDs, platinum agents, folate antagonists, CD30 antibodies and conjugates, antibodies or conjugated antibodies to treat haematological malignancies, anti-CD20 antibodies, B-cell receptor antagonists, PI3K antagonists, BTK inhibitors, taxanes, antibodies or conjugated antibodies to treat ovarian cancer, antibodies to treat multiple myeloma, anthracyclines, nucleoside analogues, purine antagonists, PNP antagonists, Bcr-abl tyrosinekinase blockers, mTor antagonists, Agents influencing the CD40 activation, multi tyrosine kinase antagonists, and bifunctional antibodies.

### Claim 16 (depends on 13)

The combination according to claim 13, wherein the one or more other therapeutic agents is selected from: bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, cisplatin, carboplatin, pemetrexed, pralatrexate, brentuximab, vendotin, ofatumumab, rituximab, GA101, ibrutinib, GS1101, IPI145, taxol, paclitaxel, alpha folate receptor monoclonal antibodies, CA125 antibodies, elotuzumab, anti CD38 monoclonal antibodies, doxorubicin, idarubicin, cytarabine, fludarabine, gemcitabine, cytarabine, fludarabine, gemcitabine, forodesine, imatinib, dasatinib, ponatinib, nilotinib, temsirolimus, everolimus, CD40 antagonists, CD40 gene medicines, sorafenib, axitinib, CD19/CD3 bifunctional antibodies, conjugated bifunctional antibodies, and bifunctional antibodies recognizing CD epitopes.

### Claim 17 (depends on 15)

The product according to claim 15, wherein said one or more other therapeutic agents is selected from: bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, cisplatin, carboplatin, pemetrexed, pralatrexate, brentuximab, vendotin, ofatumumab, rituximab, GA101, ibrutinib, GS1101, IPI145, taxol, paclitaxel, alpha folate receptor monoclonal antibodies, CA125 antibodies, elotuzumab, anti CD38 monoclonal antibodies, doxorubicin, idarubicin, cytarabine, fludarabine, gemcitabine, cytarabine, fludarabine, gemcitabine, forodesine, imatinib, dasatinib, ponatinib, nilotinib, temsirolimus, everolimus, CD40 antagonists, CD40 gene medicines, sorafenib, axitinib, CD19/CD3 bifunctional antibodies, conjugated bifunctional antibodies, and bifunctional antibodies recognizing CD epitopes.