Naphthalenyl piperidines as renin inhibitors

Details Naphthalenyl piperidines as renin inhibitors Naphthalenyl piperidines as renin inhibitors

2001-12-18

2004-01-06

Chang, Ceila (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S210000, C514S316000, C514S326000

Reexamination Certificate

active

06673931

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 naphthyl or naphthyl substituted by one to three C
1
-C
5
-alkoxy groups;
R
2
is phenyl; phenyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C
1
-C
3
-alkoxy, and nitro; benzyl; or benzyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C
1
-C
3
-alkoxy, and nitro;
R
3
is hydroxymethyl, imidazolylmethyl, triazolylmethyl, H—[CH(OR
4
)]
2
—CH
2
—, H—[CH(OR
4
)]
2
—CH
2
—O—CH
2
—, or R
3a
—(CH
2
)
k
—[CH(OR
4
)]
1
—CH
2
—O—;
R
3a
is hydrogen, hydroxy, imidazolyl, triazolyl, C
1
-C
3
-alkoxy, C
1
-C
3
-alkoxy-C
2
-C
3
-alkoxy, hydroxy-C
2
-C
3
-alkoxy, C
1
-C
3
-alkylamino or C
1
-C
3
-dialkylamino;
R
4
is hydrogen or C
1
-C
3
-alkyl;
k is 1 or 2, when R
3a
is hydrogen, k is 0;
1 is 1 or 2; or
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 naphthyl or naphthyl substituted by one to three C
1
-C
5
-alkoxy groups, preferably one C
1
-C
3
-alkoxy group, such as methoxy, and in particular 4-methoxy-naphthalen-2yl.
Similarly, R
2
can be phenyl, or benzyl, or phenyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C
1
-C
3
-alkoxy, and nitro, or benzyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C
1
-C
3
-alkoxy, and nitro. Preferred R
2
s include phenyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C
1
-C
3
-alkoxy, and nitro, and benzyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C
1
-C
3
-alkoxy, and nitro. More preferred R
2
groups include phenyl substituted by one to three C
1
-C
3
-alkoxy groups or by one to three C
1
-C
3
-alkoxy groups in combination with one to three halogens. Favorably, R
2
is phenyl substituted by one to three C
1
-C
3
-alkoxy groups or phenyl substituted by one to three C
1
-C
3
-alkoxy groups in combination with one to three halogens. More preferred is where the C
1
-C
3
-alkoxy group is methoxy and the halogen is fluorine. Favored situations include R
2
being 2-methoxy benzyl, 3-fluoro-2-methoxy-benzyl, 4-fluoro-2-methoxy-benzyl, 5-fluoro-2-methoxy-benzyl, 3,5-difluoro-2-methoxy-benzyl, and 4,5-difluoro-2-methoxy-benzyl.
R
2
can also be benzyl substituted by one to three C
1
-C
3
-alkoxy groups or by one to three C
1
-C
3
-alkoxy groups in combination with one to three halogens. Of these, it is preferred that benzyl be substituted by one to three C
1
-C
3
-alkoxy groups or one to three C
1
-C
3
-alkoxy groups in combination with one to three halogens, for example 2-methoxybenzyl and fluoro-2-methoxybenzyls, such as. It is especially preferred where C
1
-C
3
-alkoxy group is methoxy and the halogen is fluorine.
Preferred R
3
s include hydroxymethyl, imidazolylmethyl, triazolylmethyl, H—[CH(OR
4
)]
2
—CH
2
—, and H—[CH(OR
4
)]
2
—CH
2
—O—CH
2
—. Any of these groups can be used. It is preferred, however, when R
4
is hydrogen. Also preferred is when R
3
is R
3a
—(CH
2
)
k
—[CH(OR
4
)]
1
—CH
2
—O—. In such situations it is preferred that R
3a
is hydroxy or C
1
-C
3
-alkoxy, or imidazolyl or triazolyl, C
1
-C
3
-alkoxy-C
2
-C
3
-alkoxy, or R
3a
is hydroxy-C
2
-C
3
-alkoxy, or C
1
-C
3
-alkylamino or C
1
-C
3
-dialkylamino. A favored R
3a
is 2-methoxy-ethoxy. Another is methylamino.
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 general formula I
wherein
R
1
is naphthyl optionally substituted by one to three C
1
-C
5
-alkoxy groups;
R
2
is phenyl or benzyl, optionally substituted by substituents independently selected from one to three halogen, cyano, C
1
-C
3
-alkoxy and nitro groups;
R
3
is hydroxymethyl, imidazolylmethyl, triazolylmethyl, H—[CH(OR
4
)]
2
— CH
2
—, or H—[CH(OR
4
)]
2
—CH
2
—O—CH
2
—, or R
3a
—(CH
2
)
k
—[CH(OR
4
)]
1
—CH
2
—O—;
R
3a
is hydrogen, hydroxy, imidazolyl, triazolyl, C
1
-C
3
-alkoxy, C
1
-C
3
-alkoxy-C
2
-C
3
-alkoxy, hydroxy-C
2
-C
3
-alkoxy, C
1
-C
3
-alkylamino or C
1
-C
3
-dialkylamino;
R
4
is hydrogen or C
1
-C
3
-alkyl;
k is 1 or 2, when R
3a
is hydrogen, k is 0;
1 is 1 or 2; 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. Accordingly, they can be used for the treatment of disorders which are associated restenosis, glaucoma, cardiac infarct, high blood pressure and end organ damage, e.g. cardiac insufficiency and kidney insufficiency. In addition, 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 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 of similar structure. However, these compounds display a high lipophilicity.
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 alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms, unless otherwise indicated. 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 “halogen” refers to fluorine, chlorine, bromine and iodine, with chlorine and fluorine being preferred.
The term “alkoxy-” refers to the group R′—O—, wherein R′ is alkyl.
The term “alkylamino-” refers to the group HR′N—, wherein R′ is alkyl.
The term “di-alkylamino” refers to the group R′R″N—, wherein R′ and R″ are alkyl.
The term “pharmaceutically acceptable salts” embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non-toxic to living organisms.
In detail, the present invention refers to compounds of formula (I)
wherein
R
1
is naphthyl optionally substituted by one to three C
1
-C
5
-alkoxy groups;
R
2
is phenyl or benzyl, optionally substituted by substituents independently selected from one to three halogen, cyano, C
1
-C
3
-alkoxy and nitro groups;
R
3
is hydroxymethyl, imidazolylmethyl, triazolylmethyl, H—[CH(OR
4
)&rsq

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