Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-13
2004-11-02
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S230800, C514S228800, C544S092000, C544S105000, C546S315000, C546S316000, C546S329000
Reexamination Certificate
active
06812226
ABSTRACT:
The present invention relates to piperidine derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
The P2X
7
receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X
7
receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-1&bgr; (IL-1&bgr;) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and L-selectin shedding (lymphocytes). P2X
7
receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells) and hepatocytes.
It would be desirable to make compounds effective as P2X
7
receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2X
7
receptor may play a role.
In accordance with the present invention, there is therefore provided a compound of formula (I):
where
A is phenyl or a 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from O, N or S; and optionally substituted by C
1-6
alkyl, halogen, nitro, amino, alkylamino, CF
3
, SO
2
Me, NHSO
2
Me or cyano;
B is C═O, NH or SO
2
;
X is C═O, CH(Me), O or (CH
2
)p where p is 0 or 1;
Y is O, CH
2
, NH or S;
Z is C═O or SO
2
, provided that when Z is C═O, then Y is O, CH
2
or S;
R is hydrogen or C
1-6
alkyl;
R
1
is hydrogen, halogen;
R
2
is phenyl optionally substituted by CO
2
H, CO
2
alkyl, CONH
2
or R
2
is OH, NHR
3
, NHCH(R
4
)(CHR
5
)
n
R
6
, NH—R
7
—R
8
, SO
2
NHalkyl, NHCOalkyl, NHSO
2
alkyl, morpholine, NR
9
R
10
, piperazine substituted by phenyl, alkoxyphenyl, pyridyl or fluorophenyl;
n is 0, 1 or 2;
R
3
is hydrogen, a bi- or tricyclic saturated ring system optionally containing a nitrogen atom, piperidinyl, alkylpyrollidine, ethynylcyclohexyl, a 5-membered aromatic ring containing 2 or 3 heteroatoms, C
4-6
cycloalkyl optionally substituted by alkyl, cyano or hydroxy, or C
1-8
alkyl optionally containing an oxygen atom in the alkyl chain and being optionally substituted by one or more substituents selected from ethynyl, cyano, fluoro, di-alkylamino, hydroxy, thioalkyl, CO
2
R
11
or CONH
2
;
R
4
is hydrogen or alkyl optionally substituted by hydroxy or alkoxy;
R
5
is hydrogen or hydroxy;
R
6
is CO
2
R
11
, NHCO
2
R
12
, CONH
2
or a 5 or 6-membered saturated ring containing an oxygen atom, a 5-membered heterocyclic ring containing one or two heteroatoms selected from O, N or S, or phenyl optionally substituted by one or more groups selected from alkyl, hydroxy, amino, alkoxy, or nitro;
R
6
is alkyl;
R
7
is a cyclopentane ring;
R
8
is phenyl;
R
9
and R
10
are independently hydrogen, benzyl, alkenyl, cycloalkyl, alkyl optionally substituted by hydroxy, alkoxy, cyano, dialkylamino, phenyl, pyridyl or CO
2
R
11
or R
9
and R
10
together form a 5- to 7-membered saturated or partially saturated ring optionally containing a further heteroaton and optionally substituted by one or more groups selected from alkyl (optionally containing an oxygen atom in the chain and optionally substituted by hydroxy), COalkyl, CO
2
R
11
, COR
13
R
14
, CHO or piperidine,
R
11
is hydrogen or alkyl;
R
12
is alkyl; and
R
13
and R
14
are independently hydrogen or alkyl, and pharmaceutically acceptable salts and solvates thereof
In the context of the present specification, unless otherwise indicated, an alkyl substituent or alkyl moiety in a substituent group may be linear or branched and may contain up to 6 carbon atoms, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl and n-hexyl.
Suitably A is phenyl or a 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from O, N or S; and optionally substituted by C
1-6
alkyl, halogen, nitro, amino, alkylamino, CF
3
, SO
2
Me, NHSO
2
Me or cyano. Examples of suitable 5- or 6-membered heterocyclic rings include. Preferably A is optionally substituted phenyl, more preferably A is phenyl substituted by a nitro group.
Suitably B is C═O, NH or SO
2
. Preferably B is C═O.
Suitably X is C═O, CH(Me), O or (CH
2
)p where p is 0 or 1, Y is O, CH
2
, NH or S and Z is C═O or SO
2
. Examples of groups formed by X, Y and Z include benzoxazinone and dihydroquinoline. Preferably X is CH
2
, Y is O and Z is C═O such that X, Y and Z together form part of a benzoxazinone ring which can be optionally substituted by methyl.
Suitably R is hydrogen or C
1-6
alkyl, preferably R is hydrogen.
Suitably R
1
is hydrogen or halogen, preferably R
1
is hydrogen.
Suitably R
2
is phenyl optionally substituted by CO
2
H, CO
2
alkyl, CONH
2
or R
2
is OH, NHR
3
, NHCH(R
4
)(CHR
5
)
n
R
6
, NH—R
7
—R
8
, SO
2
NHalkyl, NHCOalkyl, NHSO
2
alkyl, morpholine, NR
9
R
10
, piperazine substituted by phenyl, alkoxyphenyl, pyridyl or fluorophenyl. Preferably R
2
is NR
9
R
10
where one of R
9
or R
10
is hydrogen and the other is alkyl such as CH(CH
3
)
2
.
Particularly preferred compounds of the invention include those exemplified herein both in free base form as well as all pharmaceutically acceptable salts and/or solvates thereof
According to the invention there is further provided a process for the preparation of a compound of formula (I) which comprises reaction of a compound of formula (II):
where R, R
1
, X, Y and Z are as defined in formula (I) or a protected derivative thereof, with a compound of formula (III):
where B and R
2
are as defined in formula (I) or a protected derivative thereof, and L is a leaving group, and optionally thereafter in any order:
converting one or more functional groups into further functional groups
removing any protecting groups
forming a pharmaceutically acceptable salt or solvate.
Examples of suitable leaving groups L include halogen, OMs and OTs. Preferably L is halogen, in particular chloro.
The reaction of compounds of formula (II) and (III) is preferably carried out in the presence of an organic amine such as a trialkylamine, for example triethylamine. The reaction is preferably carried out in an inert solvent such as NMP, DMF or dioxan preferably at elevated temperature, for example at the reflux temperature of the reaction mixture.
Compounds of formulae (II) can be prepared as follows:
(a) by reacting a compound of formula (IV):
in which X, Y and Z are as defined in formula (II) or are protected derivatives thereof, with a compound of formula (V):
in which R
20
is a leaving group or an activated hydroxy group, or
(b) by reacting a compound of formula (VI):
in which P a protecting group, with a compound of formula (VII):
in which the groups L are leaving groups.
Compounds of formulae (IV) and (V) can be reacted under Mitsonobu conditions when R
20
in compound (V) is an activated hydroxy group. For the reaction of compounds (VI) and (VII), examples of suitable leaving L groups include halogen, in particular chloro, or imidazole. Alternatively triphosgene can be used. Suitable protecting groups for compounds (V) and (VI) include t-butoxy carbonyl (Boc).
Compounds of formula (III), (IV), (V) and (VII) are prepared using Iterature procedures or are commercially available.
Functional groups can be converted into further functional groups using procedures known in the art. For example a carboxylic acid group can be converted into an ester or amide using standard chemistry.
Protecting groups can be added and removed using known reaction conditions. The use of protecting groups is fully described in ‘Protective Groups in Organic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 2nd edition, T W Greene & P G M Wutz, Wiley-Interscience (1991).
Deprotection can be carried out using methods generally known in the art.
All
Baxter Andrew
Kindon Nicholas
Pairaudeau Garry
Roberts Bryan
Thom Stephen
AstraZeneca AB
Morgan & Lewis & Bockius, LLP
Patel Sudhaker B.
Raymond Richard L.
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