Heterocyclic compounds useful as NMDA receptor selective...

Details Heterocyclic compounds useful as NMDA receptor selective... Heterocyclic compounds useful as NMDA receptor selective...

2001-04-12

2002-09-17

Chang, Ceila (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S208000, C548S556000, C514S424000

Reexamination Certificate

active

06451819

ABSTRACT:

FIELD OF INVENTION
The present invention is generally related to heterocyclic compounds and more particularly to substituted heterocyclics useful as NDMA receptor selective subtype blockers for modulation neuronal activity and plasticity.
BACKGROUND
The present invention relates to compounds of the general formula
wherein
Ar
1
is pyridyl or phenyl, substituted by hydroxy, lower alkyl, halogen, amino, nitro. benzyloxy or lower alkoxy-lower alkoxy, or is the group
 wherein
Z
1
is a five membered heterocyclic ring, which contains one or two heteroatoms, selected from N or O;
R
1
is hydrogen, hydroxy or an oxo group;
Ar
2
is pyridyl or phenyl, optionally substituted by hydroxy, lower alkyl, halogen, amino, nitro, benzyloxy or lower alkoxy-lower alkoxy, or is the group
 wherein
Z
2
is a five or six membered ring, which optionally contains one or two heteroatoms, selected from N or O; and
Q is —S—, —S(O)— or —S(O)
2
—;
X is a bond, —CH(OH)— or —(CH
2
)
n
—;
A is a bond or —(CHR)
m
—;
R is hydrogen, halogen or hydroxy, independently from each other if m is 2 or 3;
Y is —(CR
2
)
m
—, —O—, —C═C—, —C≡C—, piperidin-1-yl, pyrrolidin-1-yl or C
4
-C
6
-cycloalkyl, which rings are optionally substituted by hydroxy;
B is a bond, —O— or —(CHR)
m
;
n is 1 or 2; and
m is 1, 2 or 3;
and to pharmaceutically acceptable acid addition salts thereof.
Excluded from the scope of formula I are those compounds, wherein A and B are simultaneously a bond and Y is —CHR—. These compounds have been described in EP 160 436, useful as antiarrhytmic agents.
The present invention embraces racemic mixtures and all their corresponding enantiomers.
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 CNS as well as learning and memory formation.
Under pathological conditions of acute and chronic forms of neurodegeneration over-activation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members from two sub-unit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two sub-unit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 sub-units 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, Huntington's disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections, and, in addition, chronic and acute pain.
Objects of the invention are the compounds of formula I and pharmaceutically acceptable acid addition salts thereof, the preparation of the compounds of formula I and salts thereof, medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, the manufacture of such medicaments and the use of the compounds of formula I and their pharmaceutically acceptable salts in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier, and, respectively, for the manufacture of corresponding medicaments.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term “lower alkyl” denotes a straight- or branched-chain alkyl group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and the like. Preferred are groups from 1 to 4 carbon atoms.
The term “halogen” denotes chlorine, iodine, fluorine and bromine.
The term “lower alkoxy” denotes a group wherein the alkyl residue is as defined above.
A “five membered heterocyclic ring, which contains one or two heteroatoms, selected from N or O” denotes, for example, oxazolyl, isoxazolyl, furyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolidinyl or pyrazolinyl.
A “five or six membered ring, which optionally contains one or two heteroatoms, selected from N or O” are, for example; cyclopentyl, cyclohexyl, oxazolyl, isoxazolyl, furyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidyl, piperazinyl or morpholinyl.
The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, 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.
Preferred compounds of formula I in the scope of the present invention are those, wherein Ar
1
is phenyl, substituted by hydroxy, Q is —S—, Ar
2
is phenyl and X is —CH
2
. These are the following compounds:
(S)-4-[1-(4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(RS)-4-[1-(4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(R)-4-[1-(4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(2R,3S) or (2S,3S)-4-[1-(2-hydroxy-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(2S,3S) or (2S,3S)-4-[1-(2-hydroxy-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(RS)-4-[1-(3-phenyl-propyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(3RS,3RS) and (3RS,3SR)-4-[1-(3-hydroxy-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(2S,3R) or (2R,3R)-4-[1-(2-hydroxy-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(2RS,3S)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol or
(2RS,3R)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol.
Compounds of the present invention, in which Ar
1
is phenyl, substituted by hydroxy, Q is —S(O)—, Ar
2
is phenyl and X is —CH
2
— are further preferred, for example the following compound:
(3RS,S-oxide RS) and (3RS,S-oxide SR)-4-[1-(4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol,
(2R,3R,S-oxide R)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol,
(2S,3S,S-oxide R)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol,
(2R,3S,S-oxide R)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol or
(3S,S-oxide S) or (3S,S-oxide R)-4-[1-(2,2-difluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol.
Further preferred are compounds, in which Ar
1
is phenyl, substituted by hydroxy, Q is —S(O)
2
—, Ar
2
is indanyl or phenyl, optionally substituted by methyl and X is —CH
2
— or —CH(OH)—, for example the following compounds:
(S)-4-[1-(4-phenyl-butyl)-pyrrolidine-3-sulfonyl]-phenol,
(RS)-4-[1-(4-phenyl-butyl)-pyrrolidine-3-sulfonyl]-phenol,
(2R,3S) and (2S,3S)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidine-3-sulfonyl]-phenol,(3RS,cis) and (3RS,trans)-4-[1-(3-benzyl-cyclobutyl)-pyrrolidine-3-sulfonyl]-phenol,
(3RS,cis)-4-[1-(4-phenyl-cyclohexyl)-pyrrolidine-3-sulfonyl]-phenol,
(3RS,4RS)-4-(4-hydroxy-benzenesulfonyl)-1-(4-phenyl-butyl)-pyrrolidin-3-ol,
(RS)-4-[1-(4-m-tolyl-butyl)-pyrrolidine-3-sulfonyl]-phenol,
(S)-4-[1-(3-phenyl-propyl)-pyrrolidine-3-sulfonyl]-phenol,
(R)-4-[1-(4-phenyl-butyl)-pyrrolidine-3-sulfonyl]-phenol,
(RS)-4-[1-(1-phenyl-piperidin-4-yl)-pyrrolidine-3-sulfonyl]-phenol or
(2R,3S) or (2S,3S)-4-[1-(2-hydroxy-4-phenyl-butyl)-pyrrolidine-3-sulfonyl]-phenol.
The afore-mentioned compounds of formula I can be manufactured in accordance with the invention by
a) reacting a secondary amine o

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