Diphenyl-piperidine derivative

Details Diphenyl-piperidine derivative Diphenyl-piperidine derivative

2000-09-08

2003-05-20

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S218000, C514S235500, C514S255030, C514S316000, C514S318000, C540S525000, C544S129000, C544S370000, C546S187000, C546S193000, C546S208000, C546S209000, C546S210000, C546S211000

Reexamination Certificate

active

06566376

ABSTRACT:

This application is a 371 of PCT/GB00/02756 filed Jul. 8, 2000.
FIELD OF THE INVENTION
The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
BACKGROUND OF THE INVENTION
Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) is families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1&agr; and 1&bgr; (MIP-1&agr; and MIP-1&bgr;).
Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
DISCLOSURE OF THE INVENTION
In accordance with the present invention, there is provided a compound of formula (I)
wherein:
R
1
and R
2
independently represent phenyl optionally substituted by halogen, C1 to 6 alkyl, nitro, cyano, hydroxy, methylenedioxy, C1 to 6 alkoxy, C1 to 6 haloalkyl, C1 to 6 haloalkoxy or C1 to 6 alkylsulphonyl;
each R
3
independently represents halogen, nitro, C1 to 6 alkyl, cyano, C1 to 6 haloalkyl, hydroxy or C1 to 6 alkoxy; each alkoxy group being optionally further substituted by halogen, NR
5
R
6
, CO
2
R
7
, CONR
8
R
9
, pyrazolidinone, or a five membered heteroaromatic ring incorporating one to three heteroatoms independently selected from N, O and S; said heteroaromatic ring being optionally further substsituted by one or more C1 to 4 alkyl groups;
n represents an integer 0 to 3;
R
4
represents hydrogen, hydroxy or NR
10
R
11
;
A represents —CO—, —CH
2
— or a bond;
Q represents C1 to 4 alkylene;
U, W and X independently represent carbon, optionally substituted by C1 to 4 alkyl, or nitrogen;
V represents nitrogen, optionally substituted by C1 to 4 alkyl, or oxygen;
Y represents C1 to 4 alkylene or —CO—;
R
5
, R
6
, R
7
, R
8
, R
9
independently represent hydrogen or C1 to 6 alkyl;
R
10
and R
11
independently represent hydrogen, C2 to 6 unsaturated alkyl or C1 to 6 alkyl; each alkyl group being optionally further substituted by CO
2
R
12
, hydroxy, C1 to 6 alkoxy, CONH
2
, NR
13
R
14
, OCH
2
CH
2
OH, or a five or six membered saturated or unsaturated heterocyclic ring containing one or two heteroatoms selected from N, O and S; said ring optionally comprising one ring carbon atom that forms a carbonyl group; and said ring being optionally further substituted by C1 to 4 alkyl;
or the group NR
10
R
11
together represents a 4 to 8 membered saturated azacyclic ring system; said ring optionally comprising one additional ring heteroatom selected from N, O and S; said ring optionally comprising one ring carbon atom that forms a carbonyl group; and said ring being optionally further substituted by C1 to 6 alkyl, C1 to 6 hydroxyalkyl, hydroxy, CO
2
R
15
, CONH
2
, CHO or COCH
3
;
R
12
and R
15
independently represent hydrogen or C1 to 4 alkyl; and
R
13
and R
14
independently represent hydrogen, C1 to 4 alkyl or C1 to 4 alkanoyl;
or a pharmaceutically acceptable salt or solvate thereof.
In one preferred embodiment, V represents nitrogen.
Preferably, R
3
represents halogen. More preferably, R
3
represents chlorine.
The term “C1 to 6 alkyl” referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms and/or a cyclic alkyl group having from 3 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopentyl, methylcyclopentyl and cyclohexyl.
The term “C1 to 4 alkyl” is to be interpreted analogously.
The term “C2 to 6 unsaturated alkyl” referred to herein denotes a straight or branched chain alkyl group having from 2 to 6 carbon atoms and including one double bond or one triple is bond or a cyclic alkyl group having from 3 to 6 carbon atoms and including one double bond. Examples of such groups include ethenyl, ethynyl, 1- and 2-propenyl, 1- and 2-propynyl, 2-methyl-2-propenyl, 2-butenyl, 2-butynyl, cyclopentenyl and cyclohexenyl.
The term “C1 to 6 alkoxy” referred to herein denotes an oxygen atom bonded to a straight or branched chain alkyl group having from 1 to 6 carbon atoms or an oxygen atom bonded to a cyclic alkyl group having from 3 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, cyclopropyloxy and cyclohexyloxy.
The term “halogen” referred to herein denotes fluorine, chlorine, bromine and iodine.
The terms “C1 to 6 haloalkyl” (for example, chloromethyl, 2-fluoroethyl and trifluoromethyl), “C1 to 6 haloalkoxy” (for example, trifluoromethoxy) and “C1 to 6 hydroxyalkyl” (for example, hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl) are to be interpreted analogously.
Similarly, the term “C1 to 6 alkylsulphonyl” represents such groups as methylsulphonyl, t-butylsulphonyl and cyclohexylsulphonyl.
The term “C1 to 4 alkanoyl” referred to herein denotes a carbonyl group bonded to a straight or branched chain alkyl group having from 1 to 3 carbon atoms. Examples of such groups include acetyl and propionyl.
Examples of a “five membered heteroaromatic ring incorporating one to three heteroatoms independently selected from N, O and S” include furan, thiophene, imidazole, isoxazole, thiazole and triazole.
Examples of a “five or six membered saturated or unsaturated heterocyclic ring containing one or two heteroatoms selected from N, O and S; said ring optionally comprising one ring carbon atom that forms a carbonyl group” include morpholine, pyrrolidine, pyridine, tetrahydrofuran, imidazole, pyrrolidone, piperidone and piperazine.
Examples of a “4 to 8 membered saturated azacyclic ring system optionally incorporating one further heteroatom independently selected from N, O and S” include pyrrolidine, piperidine, morpholine, piperazine, pyrazolidine, imidazolidine, and perhydroazepine.
The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
Examples of particular compounds of the invention include:
1-[(1-benzyl-1H-pyrazol-3-yl)methyl]-4,4-diphenylpiperidine;
1-{[1-(3-chlorobenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
1-{[1-(3,4-dimethylbenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
1-{[1-(4-methylbenzyl)-1H-pyrazol-3-yl]methyl}-4,4-diphenylpiperidine;
4,4-diphenyl-1-({1-[4-(trifluoromethyl)benzyl&

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