Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-17
2003-05-13
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S400000
Reexamination Certificate
active
06562825
ABSTRACT:
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) 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.
EP 0 903 349 (Hoffmann-La Roche) discloses compounds of general formula
that are CCR-3 receptor antagonists.
DISCLOSURE OF THE INVENTION
In accordance with the present invention, there is provided a compound of general formula
wherein:
each R
1
represents a substituent independently selected from halogen, C1 to 6 alkyl, C1 to 6 alkoxy, amino, nitro, cyano, SO
2
NH
2
, C1 to 6 haloalkyl, C1 to 6 haloalkoxy and C1 to 6 alkylsulphonyl;
m represents an integer 0 to 2;
R
2
represents hydrogen or C1 to 4 alkyl;
R
3
and R
4
independently represent hydrogen, C1 to 4 alkyl or phenyl; each phenyl group being optionally substituted by one or more substituents chosen independently from halogen, amino, nitro, cyano, C1 to 6 alkyl, C1 to 6 alkoxy, SO
3
H, SO
2
NH
2
, C1 to 6 haloalkyl, C1 to 6 haloalkoxy and C1 to 6 alkylsulphonyl;
each R
5
independently represents hydrogen or C1 to 4 alkyl;
n represents an integer 0 to 4;
X represents a bond or C1 to 4 alkyl;
Y represents C1 to 4 alkyl;
Z represents OH or NR
6
R
7
;
R
6
and R
7
independently represent hydrogen, C1 to 6 alkyl, C2 to 6 unsaturated alkyl; each alkyl group being optionally substituted by one or more substituents independently chosen from hydroxyl, C1 to 4 alkoxy, amino, NR
8
R
9
, 1-pyrrolidin-2-onyl and CO
2
R
10
;
or the group NR
6
R
7
together represents a 3 to 8 membered saturated or unsaturated azacyclic ring system optionally incorporating one or two further heteroatoms independently selected from N, O and S; said ring system being optionally further substituted by CO
2
R
11
, COR
12
, CONR
13
R
14
or C1 to 4 alkyl; said alkyl group itself being optionally further substituted by hydroxyl; and
R
8
, R
9
, R
10
, R
11
, R
12
, R
13
and R
14
independently represent hydrogen or C1 to 4 alkyl;
or a pharmaceutically acceptable salt or solvate thereof.
In one preferred embodiment, X represents a bond, R
3
represents optionally substituted phenyl and R
4
represents hydrogen.
Preferably R
1
represents halogen and m represents 1 or 2. More especially, R
1
represents chloro. Even more especially, R
1
represents chloro and m represents 1.
Preferably, Z represents NR
6
R
7
.
Preferably, each R
5
represents hydrogen.
Preferably, Y represents CH
2
.
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 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) and “C1 to 6 haloalkoxy” (for example, trifluoromethoxy) are to be interpreted analogously.
Similarly, the term “C1 to 6 alkylsulphonyl” represents such groups as methylsulphonyl, t-butylsulphonyl and cyclohexylsulphonyl.
Examples of a “3 to 8 membered saturated or unsaturated azacyclic ring system optionally incorporating one or two further heteroatoms independently selected from N, O and S” include pyrrolidine, piperidine, morpholine, piperazine, pyrroline, pyrazoline, imidazolidine, tetrahydroazepine 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:
4-chloro-2-[2-(dimethylamino)-2-oxoethoxy]-N-[2-(4-phenethyl-1-piperazinyl)ethyl]benzamide;
2-{5-chloro-2-[({2-[4-(3,4-dichlorobenzyl)-1-piperazinyl]ethyl}amino)carbonyl]phenoxy}acetic acid;
4-chloro-N-{2-[4-(3,4-dichlorobenzyl)-1-piperazinyl]ethyl}-2-[2-(dimethylamino)-2-oxoethoxy]benzamide;
4-chloro-N-{2-[4-(3,4-dichlorobenzyl)-1-piperazinyl]ethyl}-2-{2-[(2-hydroxy-1-methylethyl)amino]-2-oxoethoxy}benzamide;
4-chloro-N-{2-[4-(3,4-dichlorobenzyl)-1-piperazinyl]ethyl}-2-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-2-oxoethoxy}benzamide;
4-chloro-N-{2-[4-(3,4-dichlorobenzyl)-1-piperazinyl]ethyl}-2-[2-(methylamino)-2-oxoethoxy]benzamide;
4-chloro-N-{2-[4-(3,4-dichlorobenzyl)-1-piperazinyl]ethyl}-2-[2-oxo-2-(1-pyrrolidinyl)ethoxy]benzamide;
2-(2-amino-2-oxoethoxy)-4-chloro-N-{2-[4-(3,4-dichlorobenzyl)-1-piperazinyl]ethyl}benzamide;
4-chloro-N-(2-{4-[1-(4-chlorophenyl)ethyl]-1-piperazinyl}ethyl)-2-[2-(dimethyalmino)-2-oxoethoxy]benzamide;
4-chloro-N-{2-[4-(3,4-dichlorobenzyl)-1-piperazinyl]ethyl}-2-[2-(diethylamino)-2-oxoethoxy]benzamide;
4-chloro-N-{2-[4-(3,4-dichlorobenzyl)-1-piperazinyl]ethyl}-2-{2-[[2-(dimethylamino)ethyl](methyl)a
Baxter Andrew J G
Brough Stephen J
Kindon Nicholas D
McInally Thomas
Roberts Bryan
Astrazeneca UK Limited
Fish & Richardson P.C.
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