# US 8,772,478 B2 · Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics

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- Number: US 8,772,478 B2
- Document ID: US8772478B2
- Status: Granted
- Kind: B2
- Application number: 13/381,237
- Filed: 2010-06-28
- Published: 2012-05-10
- Granted: 2014-07-08
- Earliest claimed: 2009-06-30
- Assignees: Galderma Research & Development
- Applicants: Laurence Clary; Sandrine Chambon; Laurent Chantalat; Pascale Mauvais; Olivier Roye; Marlène Schuppli
- Inventors: Laurence Clary; Sandrine Chambon; Laurent Chantalat; Pascale Mauvais; Olivier Roye; Marlène Schuppli
- Web page: https://patentgrep.com/patent/US8772478B2

## CPC

- C07D 295/15: to an acyclic saturated chain
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/18: for HIV
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- 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 401/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Benzenesulfonamide compounds having a structure of the following general formula (I) are described. Also described, are methods for synthesizing the compounds, and to the use thereof in pharmaceutical compositions for human or veterinary medicine and in cosmetic compositions.

## Claims

### Claim 1

A compound of formula (I) below:
in which:
R1 and R2 are identical or different and represent alkyl radicals or else they form a ring with the nitrogen atom to which they are attached, said ring being represented by the formula below:
X, m, and n having the meanings given hereinafter;
R3 is a hydrogen atom or a lower alkyl radical;
R4 is an alkyl radical, a substituted alkyl radical, an alkenyl radical, a substituted alkenyl radical, an alkynyl radical, a substituted alkynyl radical, an aryl radical, a substituted aryl radical, an aralkyl radical, a substituted aralkyl radical, a heterocyclic radical, a substituted heterocyclic radical, a cycloalkyl radical, a substituted cycloalkyl radical, a heteroaryl radical, a substituted heteroaryl radical, a heteroaralkyl radical, or a substituted heteroaralkyl radical;
X represents an oxygen atom, a —CH2— radical, a —CH—(CH2)p-NR5R6 radical, a sulfur atom, an SO radical, or an SO2 radical, with R5, R6, and p having the meanings given hereinafter;
R5 and R6, which are identical or different, represent a hydrogen atom, an alkyl radical, a substituted alkyl radical, an aryl radical, or a substituted aryl radical;
m can take the values of 0 or 1;
n can take the values of 0, 1, 2, or 3; and
p can take the values of 0, 1, or 2;
and also addition salts of the compound of formula (I) with a pharmaceutically acceptable acid, addition salts of the compound of formula (I) with a pharmaceutically acceptable base, and enantiomers of the compound of formula (I).

### Claim 2 (depends on 1)

The addition salts of the compound as claimed in claim 1, with a pharmaceutically acceptable acid, wherein the pharmaceutically acceptable acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, glycolic acid, pyruvic acid, succinic acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, para-toluenesulfonic acid, salicylic acid, picric acid, citric acid, oxalic acid, tartaric acid, malonic acid, maleic acid, camphorsulfonic acid, and fumaric acid.

### Claim 3 (depends on 1)

The addition salts of the compound as claimed in claim 1, with a pharmaceutically acceptable base, wherein the pharmaceutically acceptable base is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, methylamine, ethylamine, ethanolamine, propylamine, isopropylamine, the 4 isomers of butylamine, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, diethanolphenylamine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, isoquinoline, lysine, arginine, and ornithine.

### Claim 4 (depends on 1)

The compound as claimed in claim 1,
wherein,
R1 and R2, which are identical or different, represent alkyl radicals or else they form a ring with the nitrogen atom to which they are attached, said ring being represented by the formula below:
X, m, and n having the meanings given hereinafter;
R3 is a hydrogen atom or a lower alkyl radical;
R4 is an aryl radical, a substituted aryl radical, an aralkyl radical, a substituted aralkyl radical, a heterocyclic radical, a substituted heterocyclic radical, a heteroaryl radical, a substituted heteroaryl radical, a heteroaralkyl radical, or a substituted heteroaralkyl radical;
X represents an oxygen atom, a —CH2— radical, a —CH—(CH2)p-NR5R6 radical, a sulfur atom, an SO radical, or an SO2 radical, with R5, R6, and p having the meanings given hereinafter;
R5 and R6, which are identical or different, represent a hydrogen atom, an alkyl radical, a substituted alkyl radical, an aryl radical, or a substituted aryl radical;
m can take the values of 0 or 1;
n can take the values of 0, 1, or 2; and
p can take the values of 0, 1, or 2;
and also addition salts of the compound with a pharmaceutically acceptable acid, addition salts of the compound with a pharmaceutically acceptable base, and enantiomers of the compound.

### Claim 5 (depends on 1)

The compound as claimed in claim 1,
wherein,
R1 and R2 are identical or different and represent alkyl radicals or else they form a ring with the nitrogen atom to which they are attached, said ring being represented by the formula below:
X, m, and n having the meanings given hereinafter;
R3 is a hydrogen atom or a lower alkyl radical;
R4 is an aryl radical, a substituted aryl radical, an aralkyl radical, a substituted aralkyl radical, a heterocyclic radical, a substituted heterocyclic radical, a heteroaryl radical, a substituted heteroaryl radical, a heteroaralkyl radical, or a substituted heteroaralkyl radical;
X represents an oxygen atom, a —CH2— radical, or a —CH—(CH2)p-NR5R6 radical, with R5, R6 and p having the meanings given hereinafter; R5 and R6, which are identical or different, represent a hydrogen atom, an alkyl radical, a substituted alkyl radical, an aryl radical, or a substituted aryl radical;
m takes the value of 1;
n can take the values of 0, 1, or 2; and
p can take the values of 0, 1, or 2;
and also addition salts of the compound with a pharmaceutically acceptable acid, addition salts of said compound with a pharmaceutically acceptable base, and enantiomers of the compound.

### Claim 6 (depends on 1)

The compound as claimed in claim 1,
wherein,
R1 and R2 are identical or different and form a ring with the nitrogen atom to which they are attached, said ring being represented by the formula below:
X, m, and n having the meanings given hereinafter;
R3 is a hydrogen atom;
R4 is an aryl radical, a substituted aryl radical, an aralkyl radical, a substituted aralkyl radical, a heterocyclic radical, a substituted heterocyclic radical, a heteroaryl radical, a substituted heteroaryl radical, a heteroaralkyl radical, or a substituted heteroaralkyl radical;
X represents an oxygen atom, a —CH2 radical, or a —CH—(CH2)p-NR5R6 radical, with R5, R6, and p having the meanings given hereinafter;
R5 and R6, which are identical or different, represent a hydrogen atom, an alkyl radical, a substituted alkyl radical, an aryl radical, or a substituted aryl radical;
m takes the value of 1;
n can take the values of 1 or 2; and
p can take the values of 0, 1, or 2;
and also addition salts of the compound with a pharmaceutically acceptable acid, addition salts of the compound with a pharmaceutically acceptable base, and enantiomers of the compound.

### Claim 7 (depends on 1)

The compound as claimed in claim 1,
wherein,
R1 and R2 are identical or different and form a ring with the nitrogen atom to which they are attached, said ring being represented by the formula below:
X, m, and n having the meanings given hereinafter;
R3 is a hydrogen atom;
R4 is a heterocyclic radical, a substituted heterocyclic radical, a heteroaryl radical, a substituted heteroaryl radical, a heteroaralkyl radical, or a substituted heteroaralkyl radical;
X represents an oxygen atom or a —CH2 radical;
m takes the value of 1; and
n takes the value of 1;
and also addition salts of the compound with a pharmaceutically acceptable acid, addition salts of the compound with a pharmaceutically acceptable base, and enantiomers of the compound.

### Claim 8 (depends on 1)

The compound as claimed in claim 1,
wherein,
R1 and R2 are identical or different and form a ring with the nitrogen atom to which they are attached, said ring being represented by the formula below:
X, m, and n having the meanings given hereinafter;
R3 is a hydrogen atom;
R4 is a heteroaryl radical or a substituted heteroaryl radical;
X represents an oxygen atom or a —CH2 radical;
m takes the value of 1; and
n takes the value of 1;
and also addition salts of the compound with a pharmaceutically acceptable acid, addition salts of the compound with a pharmaceutically acceptable base, and enantiomers of the compound.

### Claim 9

A compound, addition salts of the compound with a pharmaceutically acceptable acid, addition salts of the compound with a pharmaceutically acceptable base, and enantiomers of the compound, wherein the compound is selected from the group consisting of:
1) (S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-piperidin-1-ylpropionamide;
2) (S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-pyrrolidin-1-ylpropionamide;
3) (S)-3-[4-(4-fluorobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-piperidin-1-ylpropionamide;
4) (S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-piperidin-1-ylpropionamide;
5) (S)—N-hydroxy-3-[4-(naphthalen-2-ylmethoxy)benzenesulfonylamino]-2-piperidin-1-ylpropionamide;
6) (S)-3-[4-(3,4-dichlorobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-piperidin-1-ylpropionamide;
7) (S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-morpholin-4-ylpropionamide;
8) (S)—N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino)-2-piperidin-1-ylpropionamide;
9) (S)-3-(4-(3,5-dichlorobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-piperidin-1-ylpropionamide;
10) (S)—N-hydroxy-2-piperidin-1-yl-3-(4-propoxybenzenesulfonylamino)propionamide;
11) (S)-3-(4-cyclopropylmethoxybenzenesulfonylamino)-N-hydroxy-2-morpholin-4-ylpropionamide;
12) (S)-3-[4-(4-tert-butylbenzyloxy)benzenesulfonylamino]-N-hydroxy-2-morpholin-4-ylpropionamide;
13) (S)—N-hydroxy-2-morpholin-4-yl-3-(4-phenethyloxybenzenesulfonylamino)propionamide;
14) (S)—N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-morpholin-4-ylpropionamide;
15) (S)—N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-piperidin-1-ylpropionamide;
16) (R)—N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-pyrrolidin-1-ylpropionamide;
17) (R)—N-hydroxy-3-(4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino-2-piperidin-1-yl-propionamide;
18) (S)—N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-thiomorpholin-4-yl-propionamide;
19) (S)-2-(1,1-dioxothiomorpholin-4-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide;
20) (S)-2-diethylamino-N-hydroxy-3-[4-(2-methylpyridin-4-ylmethoxy)benzenesulfonylamino]-propionamide;
21) (S)-3-[4-(2,6-dimethylpyridin-4-ylmethoxy)benzenesulfonylamino]-2-(ethylpropylamino)-N-hydroxy-propionamide;
22) (S)-2-azepan-1-yl-N-hydroxy-3-[4-(3-methylbenzyloxy)benzenesulfonylamino]propionamide;
23) (S)-2-azepan-1-yl-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-propionamide;
24) (S)—N-hydroxy-2-piperidin-1-yl-3-[4-(pyrazolo[1,5-a]pyridin-3-ylmethoxy)benzenesulfonylamino]-propionamide;
25) (S)—N-hydroxy-3-[4-(2-methylpyrazolo[1,5-a]pyridin-3-ylmethoxy)benzenesulfonylamino]-2-piperidin-1-ylpropionamide;
26) (S)—N-hydroxy-2-piperidin-1-yl-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propionamide;
27) (S)—N-hydroxy-2-morpholin-4-yl-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propionamide;
28) (S)—N-hydroxy-3-{propyl[4-(quinolin-4-ylmethoxy)benzenesulfonyl]amino}-2-pyrrolidin-1-yl-propionamide;
29) (S)-2-diethylamino-N-hydroxy-3-[4-(quinolin-4-ylmethoxy)benzenesulfonylamino]propionamide;
30) (S)—N-hydroxy-3-[4-(3-methylbenzyloxy)benzenesulfonylamino]-2-[1,4]-oxazocan-4-yl-propionamide;
31) (S)-2-azocan-1-yl-N-hydroxy-3-[4-(pyrimidin-4-ylmethoxy)benzenesulfonylamino]propionamide;
32) (S)—N-hydroxy-2-morpholin-4-yl-3-[4-(pyrazolo[1,5-a]pyridin-3-ylmethoxy)benzenesulfonylamino]-propionamide;
33) (S)—N-hydroxy-3-[4-(pyrazolo[1,5-a]pyridin-3-ylmethoxy)benzenesulfonylamino]-2-thiomorpholin-4-ylpropionamide;
34) (S)—N-hydroxy-2-piperidin-1-yl-3-[4-(4-propoxybenzyloxy)benzenesulfonylamino]propionamide;
35) (R)—N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-morpholin-4-yl-propionamide;
36) (S)-2-(4-ethylaminopiperidin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide;
37) (S)-2-(3-aminopyrrolidin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide;
38) (S)-2-(3-dimethylaminomethylpyrrolidin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide;
39) (S)-2-(4-benzylaminopiperidin-1-yl)-N-hydroxy-3-[4-(2-methylpyridin-4-ylmethoxy)benzenesulfonylamino]propionamide;
40) (S)—N-hydroxy-3-[4-(2-methyl-1H-indol-3-ylmethoxy)benzenesulfonylamino]-2-piperidin-1-yl-propionamide;
41) (S)—N-hydroxy-3-[4-(2-isopropylbenzofuran-3-ylmethoxy)benzenesulfonylamino]-2-morpholin-4-yl-propionamide; and
42) (S)-2-azetidin-1-yl-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-propionamide.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, addition salts of the compound with a pharmaceutically acceptable acid, addition salts of the compound with a pharmaceutically acceptable base, or enantiomers of the compound, and a pharmaceutically acceptable carrier.

### Claim 11 (depends on 10)

A method of treating a disease or disorder involving TNF-α production, wherein the method comprises administering the pharmaceutical composition as claimed in claim 10), to a subject to inhibit the production of TNF-α in the subject, wherein the disease or disorder is selected from the group consisting of septic shock, hemodynamic shock, malaria, inflammatory bowel disease (IBD), inflammatory bone disease, mycobacterial infections, meningitis, fibrotic disease, ischemic attack, transplant rejection, atherosclerosis, obesity, disease involving angiogenesis phenomena, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, juvenile chronic arthritis, multiple sclerosis, HIV, non-insulin-dependent diabetes mellitus, allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), ocular inflammation, inflammatory skin disease, psoriasis, atopic dermatitis, psoriatic arthritis, Crohn's disease, and ulterative colitis.

### Claim 12 (depends on 10)

A method of treating a disease or disorder involving TNF-α production, wherein the method comprises administering the pharmaceutical composition as claimed in claim 10, to a subject to inhibit the production of TNF-α in the subject, wherein the disease or disorder is selected from the group consisting of Parkinson's disease, amyotrophic lateral sclerosis, autoimmune diseases of the nervous system, autonomic diseases of the nervous system, dorsal pain, cerebral edema, cerebrovascular disorders, dementia, nervous system nerve fiber demyelinating autoimmune diseases, diabetic neuropathies, encephalitis, encephalomyelitis, epilepsy, chronic fatigue syndrome, giant cell arteritis, Guillain-Barre syndrome, headaches, multiple sclerosis, neuralgia, peripheral nervous system diseases, polyneuropathies, polyradiculoneuropathy, radiculopathy, respiratory paralysis, spinal cord diseases, Tourette's syndrome, central nervous system vasculitis, Huntington's disease, and stroke.

### Claim 13 (depends on 11)

The method of claim 11, wherein the subject is a human or an animal.

### Claim 14 (depends on 10)

A method of inhibiting the activity of TACE, comprising contacting a TACE with the pharmaceutical composition of claim 10.

### Claim 15 (depends on 10)

A method of inhibiting the production of TNFα, comprising contacting a cell producing TNF-α with the pharmaceutical composition of claim 10.

### Claim 16 (depends on 10)

A method of inhibiting a MMP, wherein the method comprises contacting the MMP with the pharmaceutical composition of claim 10.

### Claim 17 (depends on 16)

The method of claim 16, wherein the MMP is MMP1 or MMP3.

### Claim 18 (depends on 1)

The compound of claim 1, addition salts of the compound with a pharmaceutically acceptable acid, addition salts of the compound with a pharmaceutically acceptable base, and enantiomers of the compound, wherein the compound is (S)—N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-piperidin-1-ylpropionamide or (S)—N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-morpholin-4-yl-propionamide.

### Claim 19 (depends on 18)

A pharmaceutical composition comprising the compound of claim 18, addition salts of the compound with a pharmaceutically acceptable acid, addition salts of the compound with a pharmaceutically acceptable base, or enantiomers of the compound, and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 12)

The method of claim 12, wherein the subject is a human or an animal.