Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-03
2003-11-04
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S255030
Reexamination Certificate
active
06642240
ABSTRACT:
The present invention relates to piperazine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use.
In particular the invention relates to novel compounds which are potent and specific antagonists of tachykinins, including substance P and other neurokinins.
The present invention provides compounds of formula (I)
wherein
R represents a halogen atom or a C
1-4
alkyl group;
R
1
represents hydrogen or a C
1-4
alkyl group;
R
2
represents hydrogen or a C
1-4
alkyl group;
R
3
represents a trifluoromethyl, a C
1-4
alkyl, a C
1-4
alkoxy, a trifluoromethoxy or a halogen group;
R
4
represents hydrogen, a (CH
2
)qR
7
or a (CH
2
)rCO(CH
2
)pR
7
group;
R
5
represents hydrogen, a C
1-4
alkyl or a COR
6
group;
R
6
represents hydrogen, hydroxy, amino, methylamino, dimethylamino, a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected independently from oxygen, sulphur and nitrogen or a 6 membered heteroaryl group containing 1 to 3 nitrogen atoms;
R
7
represents hydrogen, hydroxy, or NR
8
R
9
wherein R
8
and R
9
represent independently hydrogen or C
1-4
alkyl optionally substituted by hydroxy or by amino;
R
10
represents hydrogen;
m is zero or an integer from 1 to 3; n is zero or an integer from 1 to 3; both p and r are independently zero or an integer from 1 to 4; q is an integer from 1 to 4;
and pharmaceutically acceptable salts and solvates thereof.
A further embodiment of the invention provides compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein
R represents a halogen atom or a C
1-4
alkyl group;
R
1
represents hydrogen or a C
1-4
alkyl group;
R
2
represents hydrogen, a C
1-4
alkyl, C
2-6
alkenyl_or a C
3-7
cycloalkyl group; or R
1
and R
2
together with nitrogen and carbon atom to which they are attached respectively represent a 5 to 6 membered heterocyclic group;
R
3
represents a trifluoromethyl, a C
1-4
alkyl, a C
1-4
alkoxy, a trifluoromethoxy or a halogen group;
R
4
represents hydrogen, a (CH
2
)qR
7
or a (CH
2
)rCO(CH
2
)pR
7
group;
R
5
represents hydrogen, a C
1-4
alkyl or a COR
6
group;
R
6
represents hydrogen, hydroxy, amino, methylamino, dimethylamino a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen or a 6 membered heteroaryl group containing 1 to 3 nitrogen atoms;
R
7
represents hydrogen, hydroxy or NR
8
R
9
wherein R
8
and R
9
represent independently hydrogen or C
1-4
alkyl optionally substituted by hydroxy or by amino;
R
10
represents hydogen, a C
1-4
alkyl group or R
10
together with R
2
represents a C
3-7
cycloalkyl group;
m is zero or an integer from 1 to 3; n is zero or an integer from 1 to 3; both
p and r are independently zero or an integer from 1 to 4; q is an integer from 1 to 4; provided that, when R
1
and R
2
together with nitrogen and carbon atom to which they are attached respectively represent a 5 to 6 membered heterocyclic group, i) m is 1 or 2:ii) when m is 1, R is not fluorine and iii) when m is 2, the two substituents R are not both fluorine.
Suitable pharmaceutically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable organic or inorganic acids, for example hydrochlorides, hydrobromides, sulphates, alkyl- or arylsulphonates (e.g. methanesulphonates or p-toluenesulphonates), phosphates, acetates, citrates, succinates, tartrates, fumarates and maleates.
The solvates may, for example, be hydrates.
References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable acid addition salts together with pharmaceutically acceptable solvates.
It will be appreciated by those skilled in the art that the compounds of formula (I) contain at least one chiral centre.
Further asymmetric carbon atoms are possible in the compounds of formula (I).
Thus, for example, when R
2
is a C
1-4
alkyl, a C
2-6
alkenyl or a C
3-7
cycloalkyl group, and R
5
and R
10
are hydrogens, the compounds of formula (I) possess two asymmetric carbon atoms and these may be represented by the formulae (1a, 1b, 1c and 1d)
The wedge shaped bond indicates that the bond is above the plane of the paper. The broken bond indicates that the bond is below the plane of the paper.
The configuration shown for the chiral carbon atom indicated as * in formulae 1b and 1d is hereinafter referred to as the &bgr; configuration and in formulae 1a and 1c as &agr; configuration. In general, in the specific compounds named below, the &bgr; configuration at the chiral carbon atom indicated as * corresponds to the S isomer and the &agr; configuration corresponds to the R isomer.
The configuration of the two chiral carbon atoms shown in formulae 1a and 1b is hereinafter referred to as anti configuation and in formulae 1c and 1d as the syn configuration.
Furthermore, when R
2
is a C
1-4
alkyl, a C
2-6
alkenyl or a C
3-7
cycloalkyl group or R
10
is a C
1-4
alkyl group and R
5
is a C
1-4
alkyl or a COR
6
group, the compounds of the invention possess three asymmetric carbon atoms.
The assignment of the R and S configuration of the asymmetric carbon atoms of the compounds of the invention has been made according to the rules of Chan, Ingold and Prelong 1956, 12, 81.
It is to be understood that all enantiomers and diastereisomers and mixtures thereof are encompassed within the scope of the present invention.
The term alkyl as used herein as a group or a part of the group refers to a straight or branched alkyl group containing from 1 to 4 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, or tert butyl.
The term halogen refers to a fluorine, chlorine, bromine or iodine atom.
The term C
2-6
alkenyl defines straight or branched chain hydrocarbon radicals containing one double bond and having from 2-6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl.
The term C
3-7
cycloalkyl group means a non aromatic monocyclic hydrocarbon ring of 3 to 7 carbon atom such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The term C
1-4
alkoxy group may be a straight or a branched chain alkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy.
When R
1
and R
2
together with nitrogen and carbon atom to which they are attached respectively represent a 5 to 6 membered heterocyclic group this group is saturated or contains a single double bond. This may be a 3,6-dihydro-2H-pyridin-1yl, a piperidin-1-yl or a pyrrolidin 1-yl group. When R
6
is a 5 or 6 membered heteroaryl group according to the invention they include furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridyl or pyrimidinyl.
The group R
5
may be in position 3, 5 or 6 of the piperazine ring of compounds of formula (I)
When R represents halogen this is suitably chlorine or more preferably fluorine or when R is C
1-4
alkyl this is suitably methyl or ethyl wherein m is 0 or an integer from 1 to 2.
Suitable values for R
1
include hydrogen, a methyl, an ethyl or a propyl group.
Suitable values for R
2
include hydrogen, a methyl, an ethyl a propyl, an isopropyl, a 2-propenyl or a cyclopropyl group.
Suitable values for R
3
include a methyl, an ethyl or a trifluoromethyl group.
When R
4
is (CH
2
)
q
R
7
or (CH
2
)
r
CO(CH
2
)
p
R
7
, R
7
is suitably hydrogen, hydroxy, NR
9
R
8
e.g. NH
2
, NH(C
1-4
alkyl) e.g. NH methyl or N(C
1-4
alkyl)
2
e.g. N(methyl)
2
, NH(C
1-4
alkyl)NH
2
e.g. NH(ethyl)NH
2
, NH(C
1-4
alkyl) wherein q is 1 or 2 and both p and rare independently zero or an integer from 1 to 2.
Suitable values for R
5
include hydrogen or a C
1-4
alkyl (e.g. methyl) group.
R is preferably a halogen atom (e.g. fluorine or chlorine) and/or a C
1-4
alkyl (e.g. methyl) group and m is preferably an integer from 1 to 2.
Suitable values for R
10
include hydrogen, a C
1-4
alkyl (e.g. methyl) grou
Alvaro Giuseppe
Di Fabio Romano
Giovannini Riccardo
Guercio Giuseppe
St-Denis Yves
Jones Dwayne C.
Morgan Lorie Ann
SmithKline Beecham Corporation
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