4-hydroxy-piperidine derivatives

Details 4-hydroxy-piperidine derivatives 4-hydroxy-piperidine derivatives

1997-11-24

2002-03-19

Morris, Patricia L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S196000, C546S200000, C546S202000, C546S205000, C546S206000, C546S210000

Reexamination Certificate

active

06359138

ABSTRACT:

BACKGROUND OF THE INVENTION
Under pathological conditions of acute and chronic forms of neurodegeneration overactivation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members of two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two subunit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 subunits result in NMDA receptors displaying different pharmaceutical properties. Possible therapeutic indications for NMDA receptor subtype specific blockers include acute forms of neurodegeneration caused, e.g., by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer,s disease, Parkinson,s disease, Hantington,s disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections.
The present invention relates to novel 4-hydroxy-piperidine derivatives, a process for their manufacture, and NMDA receptor subtype specific blocker compositions containing such 4-hydroxy-piperidine derivatives.
SUMMARY OF THE INVENTION
The present invention relates to 4-hydroxy-piperidine derivatives, exhibiting NMDA receptor subtype specific blocker activity.
The novel 4-hydroxy-piperidine derivatives of the present invention have the general formula (I),
wherein
X denotes —O—, —NH—, —CH
2
—, —CH═, —CHOH—, —CO—, —S—, —SO— or —SO
2
—;
R
1
-R
4
are, independently from each other, hydrogen, hydroxy, lower-alkyl-sulfonylamino, 1- or 2-imidazolyl or acetamido;
R
5
-R
8
are, independently from each other, hydrogen, hydroxy, lower-alkyl, halogen, lower-alkoxy, trifluoromethyl or trifluoromethyloxy;
a and b may be a double bond, provided that when “a” is a double bond, “b” cannot be a double bond;
n is 0-2;
m is 1-3;
p is 0 or 1
and to pharmaceutically acceptable addition salts thereof.
The compounds of formula I and their salts are distinguished by valuable therapeutic properties. Compounds of the present invention are NMDA(N-methyl-D-aspartate)-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of the CNS including learning and memory formation and function.
The objects of the invention are the compounds of formula I and pharmaceutically acceptable addition salts thereof, racemic mixtures and their corresponding enantiomers and the preparation of the above-mentioned compounds. Further objects of the present invention include medicaments containing the compounds and their manufacture as well as the treatment and control of illness using the compounds and medicaments set forth herein.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions of the general terms are used the present specification and apply irrespective of whether the terms appear alone or in combination.
As used herein, the term “lower alkyl” denotes a straight or branched-chain alkyl group containing from 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl and t-butyl.
The term “halogen” denotes chlorine, iodine, fluorine and bromine.
The term “lower alkoxy” denotes a group wherein the alkyl residue is as defined above.
The term “leaving group” has the meaning conventionally used, and refers to, for example, halogen, alkylsulfonyloxy, arylsulfonyloxy and the like. The most preferred leaving group in the present case is a halogen.
The term “pharmaceutically acceptable addition salts” embraces salts with inorganic and organic acids generally known to a person skilled in the art, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
Compounds of formula I wherein X is —O—, —NH—, —CHOH or —CH
2
— are preferred.
Exemplary preferred compounds in which X denotes —O—, are:
(RS)-1-(5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4-methyl-benzyl)-piperidine-4-ol,
(RS)-4-benzyl-1-(5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl)-piperidine-4-ol,
(RS)-4-(4-fluoro-benzyl)-1-(5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl)-piperidine-4-ol,
(RS)-4-(4-ethyl-benzyl)-1-(5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl)-piperidine-4-ol,
(S)-1-(5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4-methyl-benzyl)-piperidine-4-ol,
(S)-1-(5-hydroxy-2,3-dihydro-benzofuran-2-ylmethyl)-4-(4-chloro-benzyl)-piperidine-4-ol,
(RS)-N-[2-{4-hydroxy-4-(4-methyl-benzyl)-piperidine-1-ylmethyl}-2,3-dihydrobenzofuran-5-yl]-methane sulfonamide; and
(RS)-N-[2-{4-hydroxy-4-(4-methyl-benzyl)-piperidine-1-ylmethyl}-2,3-dihydrobenzofuran-5-yl]-methane sulfonamide.
Exemplary preferred compounds in which X denotes —CHOH— are:
(1RS,2RS) and (1RS,2SR)-2-[4-hydroxy-4-(4-methyl-benzyl)-piperidine-1-ylmethyl]-indan-1,5-diol,
(1RS,2RS)-1-(1,6-dihydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-4-(4-methyl-benzyl)-piperidine-4-ol; and
(1RS,2RS)-2-(4-benzyl-4-hydroxy-piperidine-1-yl-methyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-ol.
Exemplary preferred compounds in which X denotes —CH
2
— are:
(RS)-1-(5-hydroxy-indan-2-ylmethyl)-4-(4-methyl-benzyl)-piperidine-4-ol; and
(RS)-1-(6-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-4-(4-methyl-benzyl)-piperidine-4-ol.
Another exemplary preferred compound in which X denotes —NH— is:
(RS)-2-[4-hydroxy-4-(4-methyl-benzyl)-piperidine-1-ylmethyl]-2,3-dihydro-1H-indol-5-ol.
The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the processes (a-j) described below:
a) reacting a compound of the formula (II)
wherein R
1
-R
4
, X, a, b, n and m have the meaning given in general formula I and L is OH or a leaving group, for example, halogen or —O—tosyl,
with a compound of the formula (III)
wherein R
5
-R
8
and p have the meaning given in general formula I or
b) reacting a compound of the formula (IV)
wherein the substituents have the meaning given in general formula I,
with a compound of the formula (IIIA)
in the presence of paraformaldehyde to give a compound of the formula (IA)
wherein m is 1 and the other substituents have the meaning given in general formula I, or
c) dehydrating a compound of the formula (IB)
to give a compound of the formula (IC)
wherein m is 1 and the other substituents have the meaning given in general formula I, or
d) reducing a compound of the formula IA to give a compound of the formula IB, or
e) debenzylating a compound of the formula (V)
or
f) reacting a compound of formula I, wherein one of R
1
-R
4
is an amino group with a lower-alkyl-sulfonyl halogen to give a compound of formula I, wherein one of R
1
-R
4
is a lower-alkyl-sulfonyl-amino group, or
g) hydrogenating the isolated double bond in a compound of formula I, or
h) cleaving off (a) hydroxy or amino protecting group(s) present as (a) substituent(s) R
1
-R
4
or as X′=—N(protecting group)-, or
i) oxidizing a compound of formula I, wherein X represents —S— or —SO— to yield the corresponding sulfonyl (—SO
2
) compound; and
j) if desired, converting the compound of formula I obtained into a pharmaceutically acceptable addition salt.
In accordance with process variant a), a mixture of a compound of formula II and of formula III, wherein the leaving group L in formula II is, for example, bromine, was dissolved in a suitable solvent, for example in DMF and heated to about 80-90° C. This reaction was carried out in the presence of a base, preferably triethylamine. The compound of formula I is then separated in conventional manner. When one of R
1
-R
4
in formula II is a hydroxy group these groups are protected by groups conventionally used.
Examples of such groups are described in Green, T.,
Protective Groups in Organic Synthesis
, Chapter 7, John Wiley and Sons, Inc. (1981), pp 218-287. Most prefe

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