# US 8,785,430 B2 · Compound that can inhibit UBC13-UEV interactions, pharmaceutical compositions and therapeutic uses

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- Number: US 8,785,430 B2
- Document ID: US8785430B2
- Status: Granted
- Kind: B2
- Application number: 13/555,804
- Filed: 2012-07-23
- Published: 2013-09-12
- Granted: 2014-07-22
- Earliest claimed: 2006-07-20
- Assignees: Consejo Superior de Investigaciones Cientificas
- Applicants: Timothy Thomson Okatsu; Johanna Scheper Sigmund; Ángel Messeguer Peypooh; Gloria Sanclimens Pérez de Rozas; Isabel Masip Masip; Alejandra Moure Fernández; Domingo González Ruiz; Antonio Morreale de León; Maria Luz Ortiz Melguizo; Ma Carmen Fabrega Claveria
- Inventors: Timothy Thomson Okatsu; Johanna Scheper Sigmund; Ángel Messeguer Peypooh; Ángel Ramirez Ortiz; Gloria Sanclimens Pérez de Rozas; Isabel Masip Masip; Alejandra Moure Fernández; Domingo González Ruiz; Antonio Morreale de León
- Web page: https://patentgrep.com/patent/US8785430B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 241/08: with oxygen atoms directly attached to ring carbon atoms
- C07D 243/08: not condensed with other rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to a compound (I) wherein R is a heterocyclyl radical; R1 and R2 are independently H or alkyl; R3 is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl; R4 and R5 are independently H or alkyl; q is a number selected from 0 and 1; and the salts, solvates, prodrugs or stereoisomers thereof having inhibitory activity for UBC13-UEV interactions and which can be used in the production of pharmaceutical compositions intended for antitumor therapy or the treatment and/or prophylaxis of diseases associated to metabolic pathways involving the UBC13 enzyme, metabolic pathways involving transcriptional factor NF-κB, or pathways involving PCNA or RAD6. R—(CR1R2)q-CO—N(R3)—C(R4R5)—CO—NH2 (I)

## Claims

### Claim 1

A method for the treatment of pathologies or diseases associated to metabolic pathways involving the UBC13 enzyme or involving the transcriptional factor NF-κB, comprising administering to a patient a therapeutically effective amount of a compound of formula (I):
R—(CR1R2)q—CO—N(R3)—C(R4R5)—CO—NH2
wherein:
R is the radical
wherein:
R6 is a radical selected from the group consisting of: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heterocyclylalkyl;
A is a radical selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
R7 and R8 are independently selected from H, methyl, ethyl, propyl and isopropyl,
o is a number selected from the group consisting of 0, 1, 2, 3 and 4,
n is a number selected from the group consisting of 0 and 1,
the line — indicates the bonding site of the radical R with the rest of the molecule of formula (I);
R1 and R2 are independently selected from the group consisting of H, methyl, ethyl, propyl and isopropyl;
R3 is a radical selected from the group consisting of: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl;
R4 and R5 are independently selected from the group consisting of H, methyl, ethyl, propyl and isopropyl; and
q is a number selected from the group consisting of 0 and 1;
or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 2 (depends on 1)

The method according to claim 1, wherein in compound of formula (I), R6 is a radical selected from the group consisting of H, substituted or unsubstituted arylalkyl and substituted or unsubstituted heterocyclylalkyl, and in that R3 is a radical selected from H, substituted or unsubstituted arylalkyl and substituted or unsubstituted heterocyclylalkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 3 (depends on 2)

The method according to claim 2, wherein in compound of formula (I) R6 is a radical selected from the group consisting of substituted or unsubstituted phenylpropyl, substituted or unsubstituted phenylethyl, substituted or unsubstituted benzyl, substituted or unsubstituted furylpropyl, substituted or unsubstituted furylethyl, substituted or unsubstituted furylmethyl, substituted or unsubstituted imidazolylpropyl, substituted or unsubstituted imidazolylethyl, substituted or unsubstituted imidazolylmethyl, substituted or unsubstituted pyridinylpropyl, substituted or unsubstituted pyridinylethyl, substituted or unsubstituted pyridinylmethyl, substituted or unsubstituted piperidinylpropyl, substituted or unsubstituted piperidinylethyl, substituted or unsubstituted piperidinylmethyl; and in that R3 is a radical selected from substituted or unsubstituted phenylpropyl, substituted or unsubstituted phenylethyl, substituted or unsubstituted benzyl, substituted or unsubstituted furylpropyl, substituted or unsubstituted furylethyl, substituted or unsubstituted furylmethyl, substituted or unsubstituted imidazolylpropyl, substituted or unsubstituted imidazolylethyl, substituted or unsubstituted imidazolylmethyl, substituted or unsubstituted pyridinylpropyl, substituted or unsubstituted pyridinylethyl, substituted or unsubstituted pyridinylmethyl, substituted or unsubstituted piperidinylpropyl, and substituted or unsubstituted piperidinylethyl, substituted or unsubstituted piperidinylmethyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 4 (depends on 3)

The method according to claim 3, wherein in compound of formula (I) R6 is a radical substituted with one or more of fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, alkoxyl, alkylcarbonyl, alkylamino and sulfonamino, cyano, nitro, nitrite, nitrate, thionitrate, carboxamido or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 5 (depends on 3)

The method according to claim 3, wherein in compound of formula (I) R3 is a radical substituted with one or more of fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, alkoxyl, alkylcarbonyl, alkylamino and sulfonamino, cyano, nitro, nitrite, nitrate, thionitrate, carboxamido or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 6 (depends on 1)

The method according to claim 1, wherein in compound of formula (I) R6 is the radical p-fluorophenylethyl or 2,4-dichlorophenylethyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 7 (depends on 1)

The method according to claim 1, wherein in compound of formula (I) A is a phenyl substituted with chlorine, fluorine and/or bromine, and o is a number selected from 1, 2 and 3, or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 8 (depends on 1)

The method according to claim 1, wherein in compound of formula (I) R7 and R8 are both H, o is 2, and A is p-fluorophenyl or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 9 (depends on 1)

The method according to claim 1, wherein in compound of formula (I) R3 is 2-pyridylethyl, 2,4-dichlorophenylethyl or 4-methoxyphenylethyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 10 (depends on 1)

The method according to claim 1, wherein in compound of formula (I) n is 1 or 0, or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 11 (depends on 1)

The method according to claim 1, wherein in compound of formula (I) q is 0 or 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 12 (depends on 1)

The method according to claim 1, wherein compound of formula (I) has formula Ia (N-aminocarbonylmethyl-N-(2′-(2″pyridyl)ethyl)-1,4-bis[2′-(4″-fluorophenyl)ethyl]-3,7-dioxo-[1,4]diazepane-5-carboxamide):
or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 13 (depends on 1)

The method according to claim 1, wherein compound of formula (I) has formula Ib (1,4-bis[2′-(4″-fluorophenyl)ethyl]-2-[N-aminocarbonylmethyl-N-(2′-(2″pyridyl)ethyl)amino-carbonylmethyl]piperazine-3,6-dione):
or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 14 (depends on 1)

The method according to claim 1, wherein compound of formula (I) has one of the following formulas:

### Claim 15 (depends on 1)

The method according to claim 1, for the treatment of pathologies or diseases associated to metabolic pathways involving the UBC13 enzyme, which are inflammatory disease autoimmune disease, cancer or neoplasia.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the method is for treatment of inflammatory disease or autoimmune disease, and the inflammatory disease or autoimmune disease is: inflammatory bowel disease, inflammatory joint pathologies, atopic dermatitis and other inflammatory dermatological pathologies, neuritis, encephalitis, encephalomyelitis and inflammatory pathologies affecting the central or peripheral nervous system, myositis, vasculitis, systemic lupus erythematosus, infectious diseases presenting inflammation, host versus graft rejection reactions, conjunctivitis and inflammatory oculopathies, otitis or mucositis, or
wherein the method is for treatment of cancer or neoplasia, and the cancer or neoplasia is prostate, breast, lung, pancreatic, colorectal, gastric, esophageal, laryngeal, thyroid, hepatic, urinary bladder, renal, uterine and cervical carcinoma; osteosarcoma, soft tissue sarcoma and angiosarcoma; hematopoietic tumor including leukemias and lymphomas, neuroblastomas, glioblastomas and astrocytomas, melanoma, basal cell dermal carcinoma or squamous cell dermal carcinoma.

### Claim 17 (depends on 1)

A method for the treatment of a tumor by antagonism or inhibition of the genotoxic damage tolerance pathway mediated by PCNA and RAD6 causing chemo- or radiosensitizing effects, increasing the sensitivity of a prostate or cervical cell tumor in a patient to doxorubin or etoposide, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.