# US 8,569,297 B2 · 1-benzyl-3-hydroxymethylindazole derivatives and use thereof in the treatment of diseases based on the expression of MCP-1 and CX3CR1

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- Number: US 8,569,297 B2
- Document ID: US8569297B2
- Status: Granted
- Kind: B2
- Application number: 13/618,948
- Filed: 2012-09-14
- Published: 2013-01-10
- Granted: 2013-10-29
- Earliest claimed: 2008-03-07
- Assignees: Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.p.A.
- Applicants: Angelo Guglielmotti; Guido Furlotti; Giorgina Mangano; Nicola Cazzolla
- Inventors: Angelo Guglielmotti; Guido Furlotti; Giorgina Mangano; Nicola Cazzolla
- Web page: https://patentgrep.com/patent/US8569297B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- 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 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 13/00: Drugs for disorders of the urinary system
- A61P 13/12: of the kidneys
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 231/54: condensed with carbocyclic rings or ring systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel 1-benzyl-3-hydroxymethylindazole derivatives according to formula (I) described in the claims, and to a pharmaceutical composition comprising them, together with a pharmaceutically acceptable vehicle. In addition, the present invention relates to the use of novel 1-benzyl-3-hydroxymethylindazole derivatives for the preparation of a pharmaceutical composition that is active in the treatment of diseases based on the expression of MCP-1 and CX3CR1, and to their use in a method for treating or preventing diseases based on the expression of MCP-1 and CX3CR1.

## Claims

### Claim 1

A method for treating a disease based on the expression of MCP-1 or CX3CR1, comprising administering an effective amount of a compound represented by formula (I):
wherein:
A is —X1— or —X1—O—X2—, in which
X1 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms, and
X2 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms,
Y is hydrogen, —OH, —N(R11)(R12), or —N(R11)O(R12), wherein
R11 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, or an alkoxy group having from 1 to 3 carbon atoms, or R11 together with R12 forms a 4- to 7-membered heterocycle,
R12 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an aryl group, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, —COR′, —COOR′, or —CON(R′)(R″), wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R12 together with R11, forms a 4- to 7-membered heterocycle,
R1 and R2, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R3, R4 and R8, which may be identical or different from each other, are each independently hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, —CN, CONR′R″, —SO2NR′R″, —SO2R′, nitro or trifluoromethyl; wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R5 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, nitro or trifluoromethyl, or R5 together with one of either R6 or R7 forms a ring having 5 or 6 carbon atoms; wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R6 and R7, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R6 and R7 together form a group C═O, or one of either R6 or R7, together with R5, forms a ring having 5 or 6 carbon atoms,
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, to a subject in need thereof.

### Claim 2

A method for treating a disease based on the expression of MCP-1 or CX3CR1, comprising administering an effective amount of a pharmaceutical composition, which comprises a compound represented by formula (I):
wherein:
A is —X1— or —X1—O—X2—, in which
X1 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms, and
X2 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms,
Y is hydrogen, —OH, —N(R11)(R12), or —N(R11)O(R12), wherein
R11 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, or an alkoxy group having from 1 to 3 carbon atoms, or R11 together with R12 forms a 4- to 7-membered heterocycle,
R12 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an aryl group, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, —COR′, —COOR′, or —CON(R′)(R″), wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R12 together with R11, forms a 4- to 7-membered heterocycle,
R1 and R2, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R3, R4 and R8, which may be identical or different from each other, are each independently hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, —CN, —CONR′R″, —SO2NR′R″, —SO2R′, nitro or trifluoromethyl; wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R5 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, nitro or trifluoromethyl, or R5 together with one of either R6 or R7 forms a ring having 5 or 6 carbon atoms; wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R6 and R7, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R6 and R7 together form a group C═O, or one of either R6 or R7, together with R5, forms a ring having 5 or 6 carbon atoms,
a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, and at least one pharmaceutically acceptable vehicle, to a subject in need thereof.

### Claim 3

A method for treating a disease based on the expression of MCP-1 or CX3CR1, comprising administering an effective amount of a compound represented by formula (I):
wherein:
A is —X1—O—X2—, in which
X1 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms, and
X2 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms,
Y is hydrogen, —OH, —N(R11)(R12), or —N(R11)O(R12), wherein
R11 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, or an alkoxy group having from 1 to 3 carbon atoms, or R11 together with R12 forms a 4- to 7-membered heterocycle,
R12 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an aryl group, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, —COR′, —COOR′, or —CON(R′)(R″), wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R12 together with R11, forms a 4- to 7-membered heterocycle,
R1 and R2, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R3, R4 and R8, which may be identical or different from each other, are each independently hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, —CN, —CONR′R″, —SO2NR′R″, —SO2R′, nitro or trifluoromethyl; wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R5 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, nitro or trifluoromethyl, or R5 together with one of either R6 or R7 forms a ring having 5 or 6 carbon atoms; wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R6 and R7, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R6 and R7 together form a group C═O, or one of either R6 or R7, together with R5, forms a ring having 5 or 6 carbon atoms,
a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, to a subject in need thereof.

### Claim 4

A method for treating a disease based on the expression of MCP-1 or CX3CR1, comprising administering an effective amount of a pharmaceutical composition, which comprises a compound represented by formula (I):
wherein:
A is —X1—O—X2—, in which
X1 is an alkylene grout having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms, and
X2 is an alkylene group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms,
Y is hydrogen, —OH, —N(R11)(R12), or —N(R11)O(R12), wherein
R11 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, or an alkoxy group having from 1 to 3 carbon atoms, or R11 together with R12 forms a 4- to 7-membered heterocycle,
R12 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an aryl group, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, —COR′, —COOR′, or —CON(R′)(R″), wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R12 together with R11, forms a 4- to 7-membered heterocycle,
R1 and R2, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R3, R4 and R8, which may be identical or different from each other, are each independently hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, —CN, —CONR′R″, —SO2NR′R″, —SO2R′, nitro or trifluoromethyl; wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R5 is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, —OH, —N(R′)(R″), —N(R′)COR″, nitro or trifluoromethyl, or R5 together with one of either R6 or R7 forms a ring having 5 or 6 carbon atoms; wherein R′ and R″, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms,
R6 and R7, which may be identical or different from each other, are each independently hydrogen or an alkyl group having from 1 to 5 carbon atoms, or R6 and R7 together form a group C═O, or one of either R6 or R7, together with R5, forms a ring having 5 or 6 carbon atoms,
a pharmaceutically acceptable salt thereof, or a pharmaceutically ester thereof, and at least one pharmaceutically acceptable vehicle, to a subject in need thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein said method is a method for treating a disease based on the expression of MCP-1 in a subject in need thereof.

### Claim 6 (depends on 5)

The method of claim 5, wherein said disease based on the expression of MCP-1 is selected from the group consisting of rheumatoid arthritis, arthritis induced by viral infections, psoriatic arthritis, arthrosis, lupus nephritis, diabetic nephropathy, glomerulonephritis, polycystic kidney disease, interstitial lung disease, fibrosis, multiple sclerosis, Alzheimer's disease, HIV-associated dementia, atopic dermatitis, psoriasis, vasculitis, restenosis, atherosclerosis, myocardial infarction, angina, and acute coronary disease.

### Claim 7 (depends on 5)

The method of claim 5, wherein said disease based on the expression of MCP-1 is a metabolic disease or complication following a surgical intervention selected from the group consisting of angioplasty, arterectomy, a circulation recovery technique, transplant, organ replacement, tissue replacement, and prosthesis implant.

### Claim 8 (depends on 1)

The method of claim 1, wherein said method is a method for treating a disease based on the expression of CX3CR1 in a subject in need thereof.

### Claim 9 (depends on 8)

The method of claim 8, wherein said disease based on the expression of CX3CR1 is selected from the group consisting of rheumatoid arthritis, lupus nephritis, diabetic nephropathy, Crohn's disease, ulcerative colitis, restenosis, atherosclerosis, myocardial infarction, and angina.

### Claim 10 (depends on 8)

The method of claim 8, wherein said disease based on the expression of CX3CR1 is a complication following a surgical intervention selected from the group consisting of angioplasty, arterectomy, and a circulation recovery technique.

### Claim 11 (depends on 2)

The method of claim 2, wherein said method is a method for treating a disease based on the expression of MCP-1 in a subject in need thereof.

### Claim 12 (depends on 11)

The method of claim 11, wherein said disease based on the expression of MCP-1 is selected from the group consisting of rheumatoid arthritis, arthritis induced by viral infections, psoriatic arthritis, arthrosis, lupus nephritis, diabetic nephropathy, glomerulonephritis, polycystic kidney disease, interstitial lung disease, fibrosis, multiple sclerosis, Alzheimer's disease, HIV-associated dementia, atopic dermatitis, psoriasis, vasculitis, restenosis, atherosclerosis, myocardial infarction, angina, and acute coronary disease.

### Claim 13 (depends on 11)

The method of claim 11, wherein said disease based on the expression of MCP-1 is a metabolic disease or complication following a surgical intervention selected from the group consisting of angioplasty, arterectomy, a circulation recovery technique, transplant, organ replacement, tissue replacement, and prosthesis implant.

### Claim 14 (depends on 2)

The method of claim 2, wherein said method is a method for treating a disease based on the expression of CX3CR1 in a subject in need thereof.

### Claim 15 (depends on 14)

The method of claim 14, wherein said disease based on the expression of CX3CR1 is selected from the group consisting of rheumatoid arthritis, lupus nephritis, diabetic nephropathy, Crohn's disease, ulcerative colitis, restenosis, atherosclerosis, myocardial infarction, and angina.

### Claim 16 (depends on 14)

The method of claim 14, wherein said disease based on the expression of CX3CR1 is a complication following a surgical intervention selected from the group consisting of angioplasty, arterectomy, and a circulation recovery technique.

### Claim 17 (depends on 3)

The method of claim 3, wherein said method is a method for treating a disease based on the expression of MCP-1 in a subject in need thereof.

### Claim 18 (depends on 17)

The method of claim 17, wherein said disease based on the expression of MCP-1 is selected from the group consisting of rheumatoid arthritis, arthritis induced by viral infections, psoriatic arthritis, arthrosis, lupus nephritis, diabetic nephropathy, glomerulonephritis, polycystic kidney disease, interstitial lung disease, fibrosis, multiple sclerosis, Alzheimer's disease, HIV-associated dementia, atopic dermatitis, psoriasis, vasculitis, restenosis, atherosclerosis, myocardial infarction, angina, and acute coronary disease.

### Claim 19 (depends on 17)

The method of claim 17, wherein said disease based on the expression of MCP-1 is a metabolic disease or complication following a surgical intervention selected from the group consisting of angioplasty, arterectomy, a circulation recovery technique, transplant, organ replacement, tissue replacement, and prosthesis implant.

### Claim 20 (depends on 3)

The method of claim 3, wherein said method is a method for treating a disease based on the expression of CX3CR1 in a subject in need thereof.

### Claim 21 (depends on 20)

The method of claim 20, wherein said disease based on the expression of CX3CR1 is selected from the group consisting of rheumatoid arthritis, lupus nephritis, diabetic nephropathy, Crohn's disease, ulcerative colitis, restenosis, atherosclerosis, myocardial infarction, and angina.

### Claim 22 (depends on 20)

The method of claim 20, wherein said disease based on the expression of CX3CR1 is a complication following a surgical intervention selected from the group consisting of angioplasty, arterectomy, and a circulation recovery technique.

### Claim 23 (depends on 4)

The method of claim 4, wherein said method is a method for treating a disease based on the expression of MCP-1 in a subject in need thereof.

### Claim 24 (depends on 23)

The method of claim 23, wherein said disease based on the expression of MCP-1 is selected from the group consisting of rheumatoid arthritis, arthritis induced by viral infections, psoriatic arthritis, arthrosis, lupus nephritis, diabetic nephropathy, glomerulonephritis, polycystic kidney disease, interstitial lung disease, fibrosis, multiple sclerosis, Alzheimer's disease, HIV-associated dementia, atopic dermatitis, psoriasis, vasculitis, restenosis, atherosclerosis, myocardial infarction, angina, and acute coronary disease.

### Claim 25 (depends on 23)

The method of claim 23, wherein said disease based on the expression of MCP-1 is a metabolic disease or complication following a surgical intervention selected from the group consisting of angioplasty, arterectomy, a circulation recovery technique, transplant, organ replacement, tissue replacement, and prosthesis implant.

### Claim 26 (depends on 24)

The method of claim 24, wherein said method is a method for treating a disease based on the expression of CX3CR1 in a subject in need thereof.

### Claim 27 (depends on 26)

The method of claim 26, wherein said disease based on the expression of CX3CR1 is selected from the group consisting of rheumatoid arthritis, lupus nephritis, diabetic nephropathy, Crohn's disease, ulcerative colitis, restenosis, atherosclerosis, myocardial infarction, and angina.

### Claim 28 (depends on 26)

The method of claim 26, wherein said disease based on the expression of CX3CR1 is a complication following a surgical intervention selected from the group consisting of angioplasty, arterectomy, and a circulation recovery technique.