Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-26
2002-01-15
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S314000, C546S144000, C546S159000, C546S171000, C546S176000
Reexamination Certificate
active
06339093
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 present invention relates to compounds of the formula
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 hydrogen, lower alkyl, amino, pyrrolidin-3-ol, pyrrolidin-2-yl-methanol or —NHCH
2
CH(OH)R;
R
3
is hydrogen or halogen;
R is hydrogen, lower alkyl or —CH
2
OH;
n is 1 or 2;
and to pharmaceutically acceptable acid 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. NMDA receptors 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 function. However when overactive, NMDA receptors contribute to neurodegeneration. Therefore compounds which block NMDA receptor activation are therapeutically important. The compounds of this invention are NMDA receptor blockers, thus have activity in reducing neurodegeneration related to NMDA activity. Such conditions include stroke or brain trauma, 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. These conditions can result in NMDA mediated neurodegeneration, which neurodegeneration can be treated or prevented by compounds which block NMDA receptors such as the compounds of this invention.
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 present invention embraces racemic mixtures and all their corresponding enantiomers.
DETAILED DESCRIPTION OF THE INVENTION
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 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and the like.
The term “lower alkyl-amino” denotes an amino group which is substituted by one lower alkyl group. Examples are methylamino, ethylamino and the like.
The term “di-lower alkyl-amino” denotes an amino group which is substituted by two lower alkyl groups which may be the same or different. Examples are dimethylamino, diethylamino, methylethylamino, and the like.
The term “lower alkoxy” denotes a group linked via an oxygen wherein the alkyl residue is as defined above.
The term “halogen” denotes chlorine, iodine, fluorine and bromine.
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, former 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 n is 2 and R
1
and R
3
are hydrogen. These are the following compounds:
(RS)-3-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-propane-1,2-diol,
(S)-1-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-propan-2-ol,
4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamine and
4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin.
Compounds of the present invention, in which n is 1, R
1
is hydrogen and R
3
is hydrogen or halogen, are further preferred, for example the following compounds:
4-(5-chloro-1,3-dihydro-isoindol-2-yl)-quinoline and
4-(1,3-dihydro-isoindol-2-yl)-quinoline.
In other compounds, R
1
and R
3
are hydrogen and R
2
is —NHCH
2
CH(OH)R or amino, and preferably n is 2. In yet other compounds, R
1
and R
3
are hydrogen, and preferably n is 1. In other compounds, R
1
is lower alkoxy (especially methoxy) and R
3
is hydrogen, and n is preferably 2.
The afore-mentioned compounds of formula I can be manufactured in accordance with the invention by
a) reacting a compound formula
with an amine of formula
to a compound of formula
wherein R
1
—R
3
and n have the significances given above, or
or
b) reacting a compound of formula
with a compound of formula
HR
2
V,
wherein R
1
to R
3
and n have the significances given above with the exception that R
2
is not hydrogen, lower alkyl or amino, to give a compound of formula I, and
if desired, modifying one or more substituents within the definitions given above, or
if desired, converting the compound of formula I obtained into a pharmaceutically acceptable salt.
In the following the preparation of compounds of formula I are described in more detail: In accordance with the process variants, described above, and with the scheme 1, described below, compounds of formula I may be prepared by known procedures, for example the following
by reaction at 150-160° C. of a 2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl) or a 2-chloro-4-(1,3-dihydro-isoindol-2-yl)-quinoline with a primary or secondary amine using the neat amine as solvent, or
by reaction of 140-150° C. of a 4-chloro-quinoline with a 1,2,3,4-tetrahydroisoquinoline or a 2,3-dihydro-1H-isoindole in a stoechiometric fashion.
2-Chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolines and 2-chloro-4-(1,3-dihydro-isoindol-2-yl)-quinolines were prepared using known methods (Curd, F. H. S.; Raison, C. G.; Rose, F. L.; J. Chem. Soc. 1947, 899) by reacting a 2,4-dihydroxy-quinoline with a 1,2,3,4-tetrahydroisoquinoline or a 2,3-dihydro-1H-isoindole at 200° C. followed by a treatment with a chlorinating agent like phosphorous oxychloride.
4-Chloro-quinolines were prepared using known methods by reacting the corresponding quinolin-4-ones with a chlorinating agent like phosphorous oxychloride (scheme 1)
Pharmaceutically acceptable salts can be manufactured according to methods which are known per se and familiar to any person skilled in the art. The acid addition salts of compounds of formula I are especially well suited for pharmaceutical use.
In scheme 1 are described process for preparation of compounds of formula I, starting from known compounds, from commercial products or from compounds, which can be prepared in conventional manner.
The preparation of compounds of formula I are described in more detail in working examples 1-18.
As mentioned earlier, the compounds of formula I and their pharmaceutical
Alanine Alexander
Buettelmann Bernd
Burner Serge
Heitz Neidhart Marie-Paule
Jaeschke Georg
Covington Raymond
Hoffmann-la Roche Inc.
Johnston George W.
Rotman Alan L.
Tramaloni Dennis P.
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