HDAC inhibitor compounds and methods of treatment

Patent metadata

Field	Value
Publication number	US-10807944-B2
Application number	US-201515301508-A
Country	US
Kind code	B2
Filing date	Mar 30, 2015
Priority date	Apr 4, 2014
Publication date	Oct 20, 2020
Grant date	Oct 20, 2020

Abstract

The instant invention describes hydrazide-containing compounds having therapeutic activity, and methods of treating disorders such as cancer, tumors and cell proliferation related disorders, or affect cell differentiation, dedifferentiation or transdifferentiation.

First claim

What is claimed:

1. A compound according to Formula I, or a salt thereof:

wherein:
X is CH;
Y is C—R 3 ;
R 1 is H, halo, optionally substituted aryl, optionally substituted alkyl, haloalkyl, alkoxy, nitro, haloalkoxy,

R 2 is H, halo, optionally substituted aryl, optionally substituted alkyl, haloalkyl, alkoxy, nitro, haloalkoxy,

R 3 is optionally substituted heteroaryl, NMe 2 , t-Bu,

or aryl optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, arylsulfonyl, alkylaminocarbonyl, alkylcarbonyl, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, carbamido, carbamyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl, or sulfonylaryl;
R 4 is H or OH;
R 5 is alkyl optionally substituted with cycloalkyl; and
R 6 and R 7 are each independently H or optionally substituted alkyl.

2. The compound of claim 1 , wherein R 1 and R 4 are H.

3. The compound of claim 1 , wherein R 1 and R 4 are H; and R 5 is C 1 -C 6 alkyl or (cycloalkyl)alkyl.

4. The compound of claim 1 , wherein R 1 and R 4 are H; and R 5 is n-Pr, n-Bu, n-pentyl, n-hexyl,

5. The compound of claim 1 , wherein R 1 , R 2 , and R 4 are H; and R 5 is n-Bu,

6. The compound of claim 3 , wherein R 2 is alkoxy.

7. The compound of claim 1 , wherein the compound is selected from the group consisting of:
N′-butyl-4-(dimethylamino)benzohydrazide (RLS2-131);
N′-(cyclopentylmethyl)-4-(dimethylamino)benzohydrazide (RLS2-225);
4-(azidomethyl)-N′-butylbenzohydrazide (RLS2-312);
N′-pentylbiphenyl-4-carbohydrazide (RLS3-43)
N′-butyl-4-(pyrimidin-5-yl)benzohydrazide (SR-4369);
N′-butyl-2′,3′-difluorobiphenyl-4-carbohydrazide (SR-4370);
N′-butyl-3′-fluoro-5′-methylbiphenyl-4-carbohydrazide (SR-4372); and
ethyl 4′-(2-butylhydrazinecarbonyl)-6-fluorobiphenyl-3-carboxylate (SR-4373).

8. A pharmaceutical composition comprising the compound of formula I and a pharmaceutically acceptable carrier:

wherein:
X is CH;
Y is C—R 3 ;
R 1 is H, halo, optionally substituted aryl, haloalkyl, alkoxy, nitro, haloalkoxy,

R 2 is H, halo, optionally substituted aryl, optionally substituted alkyl, haloalkyl, alkoxy, nitro, haloalkoxy,

R 3 is optionally substituted heteroaryl, NMe 2 , t-Bu,

or aryl optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, arylsulfonyl, alkylaminocarbonyl, alkylcarbonyl, aralkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, carbamido, carbamyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl, or sulfonylaryl;
R 4 is H or OH;
R 5 is alkyl optionally substituted with cycloalkyl; and
R 6 and R 7 are each independently H or optionally substituted alkyl.

9. The pharmaceutical composition of claim 8 further comprising an anti-cancer agent, a chemotherapeutic agent, or an anti-angiogenesis agent.

10. The pharmaceutical composition of claim 9 wherein the chemotherapeutic is selected from daunorubicin, daunomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, esorubicin, bleomycin, mafosfamide, ifosfamide, cytosine arabinoside, bis-chloroethylnitrosurea, busulfan, mitomycin C, actinomycin D, mithramycin, prednisone, hydroxyprogesterone, testosterone, tamoxifen, dacarbazine, procarbazine, hexamethylmelamine, pentamethylmelamine, mitoxantrone, amsacrine, chlorambucil, methylcyclohexylnitrosurea, nitrogen mustards, melphalan, cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-azacytidine, hydroxyurea, deoxycoformycin, 4-hydroxyperoxycyclophosphoramide, 5-fluorouracil, 5-fluorodeoxyuridine, methotrexate, colchicine, vincristine, vinblastine, etoposide, trimetrexate, teniposide, cisplatin, and diethylstilbestrol.

Assignees

• Univ Florida
• Scripps Research Inst

Inventors

• Liao Daiqing
• Roush William R
• Stowe Ryan L

Classifications

• A61K31/166 Primary

  having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol · CPC title

• C07C243/38

  with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings · CPC title

• C07C247/12

  being further substituted by carboxyl groups · CPC title

• C07D239/26

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D213/86

  Hydrazides; Thio or imino analogues thereof · CPC title