Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-15
2003-04-22
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253010, C514S254020, C514S254030, C514S254050, C514S254100, C514S252130, C514S254090, C514S254110, C514S255030, C514S331000, C544S357000, C544S360000, C544S367000, C544S369000, C544S370000, C544S372000, C544S373000, C544S377000, C544S379000, C544S393000, C546S230000, C546S234000
Reexamination Certificate
active
06552022
ABSTRACT:
CROSS-REFERENCES TO RELATED APPLICATIONS
This application is a Rule 371 Application of PCT Application No. EP99/09320, filed Dec. 1, 1999, which claims priority to GB Application Serial No. 9826412.0, filed Dec. 3, 1998.
This invention relates to novel compounds which inhibit hepatic production of apoprotein B-100 (apoB-100), and to processes for their preparation, pharmaceutical compositions containing them and their medical use.
ApoB-100 is the main protein component of low density lipoprotein-cholesterol (LDL-C). High LDL-C plasmatic levels are a major risk factor for atherosclerosis and coronary, artery diseases. ApoB-100 plasmatic levels correlate with LDL-C plasmatic levels and also constitute a cardiovascular risk factor in themselves. ApoB-100 is exclusively produced by hepatocytes and reducing hepatic production of ApoB-100 should induce a decrease of LDL-C plasmatic levels.
Compounds having ApoB-100 inhibition properties have been described in WO96/40640, which is incorporated herein by reference.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a compound of formula (I)
wherein
A represents N or CH;
X is selected from the following groups:
(i) —C
1-6
alkylene-, optionally containing one or two double bonds and optionally substituted by one or more hydroxy, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
acyl or C
1-6
acyloxy groups,
(ii) oxo, sulfonyl, thioxo,
(iii) —C
1-6
alkylenecarbonyl-,—C
1-6
alkylenesulfonyl-,—C
1-6
alkylenethioxo-,
(iv) —C
2-6
alkyleneoxy-, —C
2-6
alkylenethio-, —C
2-6
alkylene(N—H or N—C
1-6
alkyl)amino-,
(v) —C
1-6
alkylenecarboxy-, —C
1-6
alkylenethioamido-, —C
1-6
alkylene(N—H or N—C
1-6
alkyl)carboxamido-, and
(vi) —C
2-6
alkyleneoxycarbonyl-, —C
2-6
alkylenethiocarbonyl-, —C
2-6
alkylene(N—H or N—C
1-6
alkyl)aminocarbonyl-;
Z represents a direct link or —C
1-6
alkylene-, optionally containing one double bond and optionally substituted by one or more hydroxy, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
acyl or C
1-6
acyloxy groups;
R
1
is selected from the following groups:
(i) hydrogen, C
1-3
perfluoroalkyl,
(ii) C
6-10
aryl, C
3-8
cycloalkyl and fused benz derivatives thereof, C
7-10
polycycloalkyl, C
4-8
cycloalkenyl, C
7-10
polycycloalkenyl,
(iii) a heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, wherein said, radicals contain a total of from 5-14 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated, or aromatic, and
(iv) where either X is C
1-6
alkylene and Z is a direct link, or Z is C
1-6
alkylene, R
1
additionally may represent a halogen, cyano, nitro or C
1-6
acyl group,
wherein, when R
1
contains one or more rings, said rings may each independently bear 0 to 4 substituents independently selected from
(i) halogen, hydroxy, cyano, nitro, formyl, C
1-6
alkylsulfonylamino,
(ii) C
1-6
alkyl, C
3-8
cycloalkyl, C
1-3
perfuoroalkyl,
(iii) C
1-6
alkoxy, methylenedioxy, C
1-3
perfuoroalkoxy, C
1-6
alkylthio,
(iv) amino, C
1-6
alkylamino, di-C
1-6
alkylamino,
(v) phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy,
(vi) hydroxycarbonyl,C
1-6
alkoxycarbonyl,
(vii) aminocarbonyl, C
1-6
alkylaminocarbonyl, di-C
1-6
alkylaminocarbonyl, di-C
1-6
alkylaminocarbonylC
1-6
oxy, C
1-3
perfluoroalkylaminocarbonyl,
(viii) C
1-6
acyl, C
1-6
acyloxy, C
1-6
acyloxyC
1-6
alkyl, C
1-6
acylamino, and
(ix) an aromatic heterocyclyl consisting of monocyclic radicals, wherein said radicals contain 5-6 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and where each of the said heterocyclyl groups is optionally substituted by one or more groups independently selected from halogen, C
1-4
alkyl, C
1-4
alkoxy, C
1-3
perfuoroalkyl and C
1-3
perfuoroalkoxy;
Y represents a direct or oxy link, —C
1-6
alkylene-, -oxyC
1-6
alkylene- or a heterocyclyl consisting of monocyclic radicals, wherein said radicals contain 5 ring atoms, and wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur and wherein the ring may be independently saturated, partially unsaturated, or aromatic;
R
2
represents phenyl, C
3-8
cycloalkyl, or a heterocyclyl consisting of monocyclic radicals, wherein said radicals contain a total of from 5-6 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein the ring may be independently saturated, partially unsaturated, or aromatic, and where each R
2
is optionally substituted by one or more groups independently selected from halogen, C
1-4
alkyl, C
1-4
alkoxy, C
3-8
cycloalkyl, C
1-3
perfuoroalkyl, C
1-3
perfuoroalkoxy, hydroxycarbonyl, C
1-6
alkoxycarbonyl, cyano, nitro, C
1-4
alkylaminosulfonyl;
R
3
represents hydrogen or one or more groups independently selected from halogen, C
1-4
alkyl, C
1-4
alkoxy, C
1-3
perfluoroalkyl or C
1-3
perfluoroalkoxy;
or a physiologically acceptable salt, solvate or derivative thereof.
Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable organic and inorganic acids for example, citrates, hydrochlorides, hydrobromides, or sulphates. Particularly preferred salts are citrates or hydrochloride salts.
The solvates may, for example, be hydrates.
References hereinafter to a compound according to the invention include both compounds of formula (I) and their physiologically acceptable salts together with physiologically acceptable solvates.
Referring to the general formula (I), alkyl, alkylene and alkoxy include both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl and ethyl groups, examples of alkylene groups include methylene and ethylene groups, whilst examples of alkoxy groups include methoxy and ethoxy groups.
Referring to general formula (I), a halogen atom may be a fluorine, chlorine, bromine or iodine atom.
Referring to the general formula (I), reference to heterocyclyl, unless otherwise defined, means any single ring or fused ring system containing at least one ring heteroatom independently selected from O, N and S. Thus, a polycyclic fused ring system containing one or more carbocyclic fused saturated, partially unsaturated, or aromatic rings (usually benz rings) is within the definition of heterocyclyl so long as the system also contains at least one fused ring which contains at least one of the aforementioned heteroatoms. As a substituent, such heterocyclyls may be attached to the remainder of the molecules from either a carbocyclic (e.g. benz) ring or from a heterocyclic ring.
Referring to the general formula (I), reference to R
1
as containing one or more rings is intended to mean any single or fused cyclic moiety or moieties attached to Z. The rings may be carbocyclic or heterocyclic, saturated or partially unsaturated, and aromatic or non-aromatic.
Reference to a polycyclic ring system or radical means that all rings in the system are fused.
Referring to the general formula (I), aryl means that the ring or substituent is carbocyclic and includes phenyl and naphthyl.
Referring to the general formula (I), acyl refers to aliphatic or cyclic hydrocarbons attached to a carbonyl group through which the substituent bonds.
Referring to the general formula (I), methylenedioxy refers to a x,x+1-methylenedioxy group, where x and x+1 are integers which represent the substitiution pattern on the ring, e.g. 3,4-methylenedioxy.
Referring to the general formula (I), C
1-3
perfuoroalkyl or C
1-3
perfuoroalkoxy includes compounds such as trifluoromethyl and trifluoromethoxy.
Suitably, the piperazine or piperidine group in formula (I) is substituted meta or para, most suitably para substituted. Preferably, A represents N.
X is suitably —C
1-6
alkylene-, optionally containing by one double b
Bernhardt Emily
Deppenbrock Bonnie L.
SmithKline Beecham Corporation
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