Piperidine derivatives

Details Piperidine derivatives Piperidine derivatives

2000-04-04

2001-03-06

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S166000, C514S314000

Reexamination Certificate

active

06197959

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to novel piperidine derivatives, their manufacture and use as medicaments.
SUMMARY OF THE INVENTION
The subject invention provides compounds of the formula:
wherein
R
1
is
a) —(CH
2
)
k
—N(R
3
,R
4
), wherein k is 2, 3 or 4;
b) —(CH
2
)
k
—O—R
3
, wherein k is 2, 3 or 4;
c) —(CH
2
)
m
—R
5
, wherein m is 1 or 2; or
d) —(CH
2
)
l
—R
6
, wherein l is 1, 2 or 3;
R
2
is lower cycloalkylalkyl, 1,1,1-trifluoroethyl, phenyl, benzyl, phenyl substituted independently with from one to three halogen, cyano, C
1
-C
3
-alkoxy, or nitro groups, or benzyl substituted independently with from one to three halogen, cyano, C
1
-C
3
-alkoxy, or nitro groups;
R
3
is hydrogen or C
1
-C
3
-alkyl;
R
4
is hydrogen, C
1
-C
3
-alkyl, C
1
-C
3
-alkylsulfonyl, aminosulfonyl, C
1
-C
3
-alkylaminosulfonyl, C
1
-C
3
-alkylaminocarbonyl, C
1
-C
3
-alkylcarbonyl, trifluoromethylcarbonyl, trifluoromethylsulfonyl, or aminocarbonyl;
R
5
is C
1
-C
3
-alkoxycarbonyl, aminocarbonyl, C
1
-C
3
-alkylaminocarbonyl, di-C
1
-C
3
-alkylaminocarbonyl, or cyano;
R
6
is imidazolyl or triazolyl, with the proviso that 1 must be 2 or 3 if the imidazolyl or triazolyl is bound via a C—N-bond;
and pharmaceutically acceptable salts thereof.
While the substituents are above listed collectively, all combinations of the mentioned substituents are enabled and described. For example, R
1
can be —(CH
2
)
k
—N(R
3
,R
4
), wherein k is 2, 3 or 4; or —(CH
2
)
k
—O—R
3
, wherein k is 2, 3 or 4; or —(CH
2
)
m
—R
5
, wherein m is 1 or 2; or d) —(CH
2
),
l
—R
6
, wherein l is 1, 2 or 3. A preferred example of R
1
being —(CH
2
)
2
—N(R
3
,R
4
) is ethylacetamide.
In a preferred R
1
group, R
3
is hydrogen or C
1
-C
3
-alkyl, such as methyl or ethyl. Favorably, when R
1
is —(CH
2
)
k
—O—R
3
, the specific group is —(CH
2
)
2
—O—R
3
or —(CH
2
)
3
—O—R
3
, such as methoxypropyl or hydroxypropyl.
As mentioned above, R
2
can be lower cycloalkylalkyl, 1,1,1-trifluoroethyl, phenyl, benzyl, phenyl substituted independently with from one to three halogen, cyano, C
1
-C
3
-alkoxy, or nitro groups, or benzyl substituted independently with from one to three halogen, cyano, C
1
-C
3
-alkoxy, or nitro groups. One preferred selection is where R
2
is benzyl or benzyl substituted independently with from one to three halogen, cyano, C
1
-C
3
-alkoxy, or nitro groups. Favorably, R
2
is benzyl substituted with one C
1
-C
3
-alkoxy group or benzyl substituted independently with one C
1
-C
3
-alkoxy group and from one to three halogen. Especially preferred is methoxybenzyl, and more specifically 2-methoxybenzyl
Preferred groupings of R
4
include hydrogen or C
1
-C
3
-alkyl and C
1
-C
3
-alkylsulfonyl, aminosulfonyl, C
1
-C
3
-alkylaminosulfonyl, C
1
-C
3
-alkylaminocarbonyl, C
1
-C
3
-alkylcarbonyl, trifluoromethylcarbonyl, trifluoromethylsulfonyl, or aminocarbonyl. Further preferred groupings include where R
4
is C
1
-C
3
-alkylsulfonyl, aminosulfonyl, C
1
-C
3
-alkylcarbonyl, trifluoromethylcarbonyl, trifluoromethylsulfonyl, or aminocarbonyl, or where R
4
is methanesulfonyl, aminosulfonyl, acetyl, trifluoroacetyl, trifluoromethanesulfonyl, or aminocarbonyl. Favored is where R
4
is C
1
-C
3
-alkylcarbonyl, such as acetyl.
Another preferred group is where R
5
is C
1
-C
3
-alkoxycarbonyl, aminocarbonyl, C
1
-C
3
-alkylaminocarbonyl, di-C
1
-C
3
-alkylaminocarbonyl, or cyano, or aminocarbonyl.
Another preferred group is where R
6
is imidazolyl, with the proviso that l must be 2 or 3 if the imidazolyl is bound via a C—N-bond or where R
6
is triazolyl, with the proviso that l must be 2 or 3 if the triazolyl is bound via a C—N-bond.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The invention relates to novel piperidine derivatives of formula I
wherein
R
1
is
a) —(CH
2
)
k
—N(R
3
,R
4
) and wherein k is 2, 3 or 4;
b) —(CH
2
)
k
—O—R
3
, wherein k is 2, 3 or 4;
c) —(CH
2
)
m
—R
5
, wherein m is 1 or 2; or
d) —(CH
2
)
l
—R
6
, wherein l is 1, 2 or 3;
R
2
is lower cycloalkylalkyl, 1,1,1-trifluoroethyl, phenyl or benzyl, wherein the phenyl or benzyl groups optionally are independently substituted with 1-3 halogen, cyano, C
1
-C
3
-alkoxy or nitro;
R
3
is hydrogen or C
1
-C
3
-alkyl;
R
4
is hydrogen, C
1
-C
3
-alkyl, C
1
-C
3
-alkylsulfonyl, aminosulfonyl, C
1
-C
3
-alkylaminosulfonyl, C
1
-C
3
-alkylaminocarbonyl, C
1
-C
3
-alkylcarbonyl, trifluoromethylcarbonyl, trifluoromethylsulfonyl, aminocarbonyl;
R
5
is C
1
-C
3
-alkoxycarbonyl, aminocarbonyl, C
1
-C
3
-alkylaminocarbonyl, di-C
1
-C
3
-alkylaminocarbonyl or cyano;
R
6
is imidazolyl or triazolyl; with the proviso that l is 2 or 3 if imidazolyl or triazolyl is bound via a C—N-bond;
and pharmaceutically acceptable salts thereof.
The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant.
The piperidine derivatives of the present invention have an inhibitory activity on the natural enzyme renin. They can accordingly be used for the treatment of disorders which are associated with restenosis, glaucoma, cardiac infarct, high blood pressure and end organ damage, e.g. cardiac insufficiency and kidney insufficiency. Accordingly, the present invention relates to a method for the prophylactic and/or therapeutic treatment of diseases which are associated with restenosis, glaucoma, cardiac infarct, high blood pressure and end organ damage, e.g. cardiac insufficiency and kidney insufficiency, which method comprises administering a compound of formula (I) to a human being or an animal. Furthermore, the present invention relates to the use of such compounds for the preparation of medicaments for the treatment of disorders which are associated with restenosis, glaucoma, cardiac infarct, high blood pressure and end organ damage, e.g. cardiac insufficiency and kidney insufficiency.
The present invention also relates to processes for the preparation of the compounds of formula (I).
WO 97/09311 discloses piperidine derivatives. However, these tetrahydroquinoline compounds display low in vitro potencies.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term “lower” is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term “alkyl” refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms.
The term “lower alkyl” refers to a branched or straight chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
The term “cycloalkyl” refers to a monovalent carbocyclic radical of 3 to 10 carbon atom(s), preferably 3 to 6 carbon atoms.
The term “cycloalkylalkyl” refers to a branched or straight chain monovalent saturated aliphatic carbon radical of 1 to 5, preferably 1 to 4 carbon atom(s) having a monovalent carbocyclic radical of 3 to 10 carbon atom(s), preferably 3 to 6 carbon atoms.
The term “halogen” refers to fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.
The term “alkoxy” refers to the group R′—O—, wherein R′ is an alkyl.
The term “alkylsulfonyl” refers to the group —SO
2
—R′, wherein R′ is lower alkyl.
The term “aminosulfonyl-” refers to the group NH
2
—SO
2
—.
The term “alkylaminosulfonyl” refers to the group R′—NH—SO
2
—wherein R′ is alkyl.
The term “alkylaminocarbonyl” refers to the group R′—NH—C(O)—, wherein R′ is alkyl.
The “term alkylcarbonyl” refers to the group R′—C(O)—, wherein R′ is alkyl.
The term “aminocarb

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