# US 2014/0155436 A1 · Chemical molecules that inhibit the slicing mechanism for treating diseases resulting from splicing anomalies

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- Number: US 2014/0155436 A1
- Document ID: US20140155436A1
- Status: Published application
- Kind: A1
- Application number: 14/070,799
- Filed: 2013-11-04
- Published: 2014-06-05
- Earliest claimed: 2008-01-10
- Assignees: Centre National De Recherche Scientifique; Universite Montpellier 2 Sciences Et Techniques; Institut Curie
- Applicants: Centre National De Recherche Scientifique; Universite Montpellier 2 Sciences Et Techniques; Institut Curie
- Inventors: Jamal TAZI; David GRIERSON; Florence MAHUTEAU-BETZER; Pierre ROUX
- Web page: https://patentgrep.com/patent/US20140155436A1

## CPC

- C07D 249/06: with aryl radicals directly attached to ring atoms
- A61K 31/166: having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
- A61K 31/417: Imidazole-alkylamines, e.g. histamine, phentolamine
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/4725: containing further heterocyclic rings
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/12: Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10)
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- 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 19/00: Drugs for skeletal disorders
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/06: Anabolic agents (androgens A61P5/26)
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 237/30: having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- C07D 213/56: Amides
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 213/82: in position 3
- C07D 233/61: with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention relates to a compound of one of the formulas I to XXI; a pharmaceutical composition comprising at least one such compound; and the use of at least one such compound in preparing a drug to treat, in a subject, a genetic disease resulting from at least one splicing anomaly.

## Claims

### Claim 1

A compound having the following formula:
wherein,
X2 represents a nitrogen atom or a CR16 group with R16 being a hydrogen atom or a
group;
R4 represents a hydrogen atom or a C1 to C3 alkyl group or a C(═O)NR14R15 group with R4 representing a hydrogen atom or a C1 to C3 alkyl group when R5 or R6 is different than a hydrogen atom;
R5 represents a hydrogen atom, a C(═O)NR14R15 group or a
group with R5 representing a hydrogen atom when R4 or R6 is different than a hydrogen atom;
R6 represents a hydrogen atom, or a C(═O)NR14R15 group or a
group with R6 representing a hydrogen atom when R5 is different than a hydrogen atom or when R4 is different than a hydrogen atom or a C1 to C3 alkyl group;
R7 represents a hydrogen atom, an NR11R12 or OR12 group with R11 and R12 representing independently of the other a hydrogen atom or a C1 to C3 alkyl group, with X2 representing a CH group when R7 represents an NR11R12 or OR12 group;
X1 represents a nitrogen atom, a NR11 group or a CR10 group with R10 being a hydrogen atom or an NR11R12 or OR11 group with R11 and R12 being as defined above;
R1 represents a hydrogen atom, an NR11R12 group, or OR12 group with R11 and R12 being as defined above, with X1 representing a CH group when R1 represents an NR11R12 or OR12 group;
A represents a
amide group or a
alcene group;
R14 and R15 represent independently of the other:
a hydrogen atom, or
a linear or branched C1 to C10 alkyl group, wherein one or more carbon atoms can be substituted by a nitrogen atom, said alkyl group optionally being substituted by one or more —OH and/or ═O groups and/or by:
which may be substituted or unsubstituted;
R21 and R22 represent independently of the other a hydrogen atom or a methyl group; or
being a pharmaceutically acceptable salt or isomer thereof.

### Claim 2

A compound selected from the group consisting of:
N-(3-Dimethylamino-propyl)-3-(4-trifluoromethoxy-phenylamino)-benzamide;
4-(4-Methoxy-phenylamino)-3-methyl-N-(3-methyl-butyl)-benzamide;
3-Methyl-N-(3-methyl-butyl)-4-(4-trifluoromethoxy-phenylamino)-benzamide;
N-(2-Dimethylamino-ethyl)-2-(4-trifluoromethoxy-phenylamino)-benzamide;
N-(2-Diethylamino-ethyl)-2-(4-trifluoromethoxyphenylamino)-benzamide;
N-(2-Diethylamino-propyl)-2-(4-trifluoromethoxy-phenylamino)-benzamide;
(N-Diethylamino)-{1-[4-(4-Methoxy-phenylamino)-phenyl]-1H-1,2,3-triazol-4-yl}-methylamine;
(N-Diethylamino)-{1-[4-(4-trifluoromethoxyphenylamino)-phenyl]-1H-1,2,3-triazol-4-yl}-methylamine;
(N-Diethylamino)-{1-[4-(4-N-dimethylamino-phenylamino)-phenyl]-1H-1,2,3-triazol-4-yl}-methylamine;
N-(3-Imidazol-1-yl-propyl)-2-(4-methoxy-phenylamino)-benzamide;
N-(3-Imidazol-1-yl-propyl)-2-(4-trifluoromethoxy-phenylamino)-benzamide;
2-(4-Dimethylamino-phenylamino)-N-(3-imidazol-1-yl-propyl)-benzamide;
N-(4-Diethylamino-1-methyl-butyl)-2-(4-dimethylaminophenylamino)-benzamide;
N-(2-Dimethylamino-ethyl)-4-(4-trifluoromethoxy-phenylamino)-benzamide;
N-(2-Dimethylamino-ethyl)-4-(4-dimethylamino-phenylamino)-benzamide;
N-(2-Dimethylamino-ethyl)-4-(4-methoxy-phenylamino)-3-methyl-benzamide;
N-(3-Diethylamino-propyl)-4-(4-methoxy-phenylamino)-benzamide;
N-(3-Diethylamino-propyl)-4-(4-methoxy-phenylamino)-3-methyl-benzamide;
N-(3-Diethylamino-propyl)-3-methyl-4-(4-trifluoromethoxy-phenylamino)-benzamide;
N-(3-Diethylamino-propyl)-4-(4-dimethylamino-phenylamino)-3-methyl-benzamide;
N-(2-Dimethylamino-ethyl)-3-methyl-4-(4-trifluoromethoxy-phenylamino)-benzamide;
3-{1-[4-(4-Methoxy-phenylamino)-phenyl]-1H-1,2,3-triazol-4-yl}-propan-1-ol;
(N-diethylamino)-{1-[3-(4-Methoxy-phenylamino)-phenyl]-1H-1,2,3-triazol-4-yl}-methylamine;
[4-(5-Chloro-1H-imidazol-2-yl)-2-methyl-phenyl]-(4-methoxy-phenyl)-amine;
N-(2-Diethylamino-ethyl)-4-(4-methoxy-phenylamino)-benzamide;
N-(2-Dimethylamino-ethyl)-2-(4-methoxy-phenylamino)-benzamide;
4-(4-Methoxy-phenylamino)-N-(3-methyl-butyl)-benzamide;
N-(3-Imidazol-1-yl-propyl)-4-(4-trifluoromethoxy-phenylamino)-benzamide;
[3-(4-Diethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-(4-dimethylamino)-phenylamine;
N-(2-Diethylamino-ethyl)-2-(4-methoxy-phenylamino)-benzamide;
3-{1-[3-(4-Trifluoromethoxy-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-yl}-propan-1-ol;
3-{1-[3-(4-Dimethylamino-phenylamino)-phenyl]-1H-[1,2,3]triazol-4-yl}-propan-1-ol; and
pharmaceutically acceptable salts thereof.

### Claim 3 (depends on 1)

A pharmaceutical composition, comprising at least one compound of claim 1 and a pharmaceutically acceptable support.

### Claim 4 (depends on 1)

A method of treating a disease related to the process of splicing pre-messenger RNAs cells comprising administering to a subject in need thereof the compound according to claim 1, said disease being selected from the group consisting of Frasier syndrome, frontotemporal dementia related to chromosome 17, Parkinson's, Leigh syndrome, encephalopathy, atypical cystic fibrosis, neuropathologies, Alzheimer's relating to a mutation of the Tau protein, amyotrophy which affects the SMN (survival motor neuron) gene, depression related to dysregulation of serotonin splicing, metastatic cancers in which the overall splicing process is affected, epithelial cancer, and a cancer.

### Claim 5 (depends on 4)

The method of claim 4, wherein said disease is a cancer selected from the group consisting of breast cancer, colon cancer, pancreas cancer, liver cancer, prostate cancer, and uterus cancer.

### Claim 6 (depends on 1)

A method of treating a disease related to the process of splicing pre-messenger RNAs in cells comprising administering to a subject in need thereof the compound of claim 1, said disease being selected from the group consisting of atherosclerosis, insulin resistant type II diabetes, cataracts, osteoporosis and aging of the skin.

### Claim 7 (depends on 1)

A method of treating a disease related to the process splicing pre-messenger RNAs in cells comprising administering to a subject in need thereof the compound of claim 1, wherein said disease is a disease of viral origin.

### Claim 8 (depends on 1)

A method of treating a disease associated with a gene mutation and that can be treated by exon skipping, comprising administering to a subject in need thereof the compound of claim 1.

### Claim 9 (depends on 8)

The method of claim 8, wherein the disease is Duchenne muscular dystrophy (DMD).