Quinolin-4-yl derivatives

Details Quinolin-4-yl derivatives Quinolin-4-yl derivatives

2000-09-11

2002-08-27

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S313000, C514S314000, C546S153000, C546S154000, C546S159000, C546S160000

Reexamination Certificate

active

06440995

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 from 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, Huntington's disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections, and, in addition, chronic and acute pain.
SUMMARY OF THE INVENTION
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.
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.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula I:
wherein
R
1
is hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, nitro, cyano, lower alkyl-amino, di-lower alkyl-amino or halogen;
R
2
is phenyl, optionally substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl, amino, lower alkyl-amino or di-lower alkyl-amino, 2,3-dihydro-benzofuran-5-yl, chroman-6-yl, naphthalen-2-yl, indan-5-yl, lower alkenyl-phenyl, 5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-isoindol-2-yl, 1,2,3,4-tetrahydro-naphthalenyl, benzofuran-2-yl, benzo[b]thiophen-2-yl, lower alkyl-phenyl, 3,4-dihydro-1H-isoquinolin-2-yl or thiophen-3-yl;
R
3
and R
4
are independently from each other hydrogen or lower alkyl;
R
5
is hydrogen, lower alkyl, —CH
2
OH or —CH
2
NR
6
R
7
;
R
6
and R
7
are independently from each other hydrogen, lower alkyl, —(CH
2
)
n
-phenyl, cycloalkyl, —(CH
2
)
m
-morpholinyl or form together with the N-atom a saturated ring with 4-6 C-atoms;
n is 0-3;
m is 2 or 3;
X is —NR
8
— or —O—; or
X and R
5
are together >N(CH
2
)
2
—; or
X and R
3
are together >N(CH
2
)
3
—; and
R
8
is hydrogen or lower alkyl;
and to pharmaceutically acceptable acid addition salts thereof.
Not encompassed from compounds of formula I are the following specific compounds, which are described in Indian Journal of Chemistry, Vol. 35B, 1996, 871-873 and having an antibacterial activity.
(6-Chloro-2-phenyl-4-quinolinyl)-(+)-2-aminobutanol;
(6-methyl-2-phenyl-4-quinolinyl)-(+)-2-aminobutanol;
(6-methoxy-2-phenyl-4-quinolinyl)-(+)-2-aminobutanol; and
(8-methoxy-2-phenyl-4-quinolinyl)-(+)-2-aminobutanol;
The present invention embraces racemic mixtures and all their corresponding enantiomers.
The following definitions of the terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
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, butyl and the like.
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 “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, methanesulfonic acid, p-toluenesulfonic acid and the like.
Preferred compounds of formula I in the scope of the present invention are those, wherein X is —NH— and R
5
is hydrogen, —CH
2
NH
2
, —CH
3
or —CH
2
OH. These are the following compounds:
2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-4-ylamino]-ethanol,
(RS)-1-amino-3-(2-p-tolyl-quinolin-4-ylamino)-propan-2-ol,
(RS)-1-amino-3-[2-(4-methoxy-phenyl)-quinolin-4-ylamino]-propan-2-ol,
S(+)-1-[2-(4-methoxy-phenyl)-quinolin-4-ylamino]-propan-2-ol,
2-[2-(4-methoxy-phenyl)-7-methyl-quinolin-4-ylamino]-ethanol,
(S)-1-[2-(4-methoxy-3-methyl-phenyl)-quinolin-4-ylamino]-propan-2-ol,
2-(7-Methyl-2-p-tolyl-quinolin-4-ylamino)-ethanol,
(S)-1-[2-(3-chloro-4-methyl-phenyl)-quinolin-4-ylamino]-propan-2-ol,
(RS)-3-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-4-ylamino]-propane-1,2-diol,
RS)-1-amino-3-[2-(3,4-dihydro-1H-isoqulinolin-2-yl)-quinolin-4-ylamino]-propan-2-ol,
2-[7-methoxy-2-(4-methoxy-phenyl)-quinolin-4-ylamino]-ethanol,
(RS)-1-amino-3-[7-methoxy-2-(4-methoxy-phenyl)-quinolin-4-ylamino]-propan-2-ol or
(RS)-1-amino-3-(7-methoxy-2-p-tolyl-quinolin-4-ylamino)-propan-2-ol.
Compounds of the present invention, in which X is —O— and R
5
is —CH
2
NHCH
3
, —CH
2
NH
2
, —CH
2
NHCH(CH
3
)
2
or —CH
2
NH-cycloalkyl, are further preferred, for example the following compounds:
(RS)-1-(7-methoxy-2-phenyl-quinolin-4-yloxy)-3-methylamino-propan-2-ol,
(RS)-1-amino-3-(2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-isopropylamino-3-(2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-cyclopentylamino-3-(2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-isopropylamino-3-(7-methoxy-2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-methylamino-3-(2-p-tolyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-cyclobutylamino-3-(2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-[2-(4-methoxy-phenyl)-quinolin-4-yloxy]-3-methylamino-propan-2-ol,
(RS)-1-methylamino-3-(7-methyl-2-phenyl-quinolin-4-yloxy)-propan-2-ol,
(RS)-1-(7-methoxy-2-p-tolyl-quinolin-4-yloxy)-3-methylamino-propan-2-ol,
(RS)-1-[7-methoxy-2-(4-methoxy-phenyl)-quinolin-4-yloxy]-3-methylamino-propan-2-ol or
(RS)-1-[2-(4-methoxy-phenyl)-7-methyl-quinolin-4-yloxy]-3-methylamino-propan-2-ol.
The afore-mentioned compounds of formula I can be manufactured in accordance with the invention by
a) reacting a compound of formula:
 with an amine of formula:
 to a compound of formula:
 wherein R
1
-R
5
and R
8
have the significances given above, or
b) reducing a compound of formula:
 with a reducing agent to a compound of formula:
 wherein R
1
-R
4
and R
8
have the significances given above, or
c) reducing a compound of formula:
 wherein R
1
-R
4
and R
8
have the significances given above and R
6
is lower alkyl-phenyl, lower alkyl-morpholino or lower alkyl,
 to a compound of formula:
 or
(d) reacting a compound of formula:
 with a compound of formula:
 to a compound of formula:
 wherein R
1
-R
4
and R
6
have the significances given above, or,
e) reacting a compound of formula:
 with a compound of formula:
H—NR
6
 to a compound of formula:
 wherein R
1
-R
4
and R
6
have the significances given above, or,
 if desired, modifying one or more substituients within the definitions given above, or
 if desired, converting the compound of formula I obtained into a pharmaceutically acceptable salt.
In the following the pr

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