Amino-benzothiazole derivatives

Details Amino-benzothiazole derivatives Amino-benzothiazole derivatives

2000-06-01

2002-06-18

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S198000

Reexamination Certificate

active

06407122

ABSTRACT:

This application is a 371 of PCT/EP98/07532 filed Nov. 23, 1998.
The present invention relates to novel aminobenzothiazole derivatives, to a process for their preparation, to pharmaceutically acceptable compositions comprising them and to the use of said compounds in the prevention and/or treatment of acute or chronic neurodegenerative disorders.
According to W. Danysz et al., DN&P 8(5), June 1995, excitatory amino acid (EAA) glutamate is a broad spectrum agonist at the major neuronal EAA receptor sites. Although glutamate is a very important element in governing physiological balance within the central nervous system (CNS), under certain conditions excessive activation of glutamate receptors is neurotoxic. It is now clear that not only exogenously given excitotoxins but also endogenous glutamate or other similar agonists can kill neurons under certain pathological conditions called “excitotoxicity”. It has been implied that excitotoxicity is involved in many types of acute neurodegenerative disorders such as, for example, ischemia, hypoglycemia or hypoxia and chronic neurodegenerative disorders such, for example, Huntington's, Parkinson's and Alzheimer's diseases, AIDS-dementia, hepatic encephalopaty, amyotrophic lateral sclerosis, epilepsy-related damage, olivopontocerebellar atrophy, Tourette's syndrome, CNS pathology related to measles virus, infection and motor neuron disease.
Agents able to modulate or antagonize the neurotoxic effect of an endogenous excitatory amino acid (EAA) or a similar compound at the CNS level can therefore be useful as neuroprotective agents for the prevention and/or treatment of an acute or a chronic neurodegenerative disease.
There is therefore a need to find pharmacological substances which exert a control of the above mentioned neuropathological processes by means of their activity as mediators or inhibitors of the effects of said neurotoxic agents.
The present invention fulfill such a need.
Accordingly, the present invention provides a 2-aminobenzothiazole derivative of formula (I)
if the case either as single isomer or as mixture of isomers,
wherein
X is CO, C═NOH, CHOH or CH
2
;
Y is CH
2
or
CHCH
2
R
2
in which
R
2
is hydrogen, hydroxy, phenoxy, amino, N(CH
3
)
2
, OCOR
4
in which R
4
is C
1
-C
6
alkyl or a group of formula (i)
wherein R
1
is hydrogen, halogen, cyano, a linear or branched C
1
-C
5
alkyl group, a linear or branched C
1
-C
5
alkoxy group or trifluoromethyl; or
R
2
is NHR
3
in which R
3
is a linear or branched C
2
-C
6
alkanoyl group, a linear or branched C
1
-C
6
alkylsulfonyl group, trifluoromethanesulfonyloxy, or a group of formula (i) or (ii)
wherein R
1
is as defined above;
Z is a (CH
2
)
n
group wherein n is zero or an integer from 1 to 4; CHOH; CO; O; S; SO
2
or a group of formula (iv)
wherein R
1
is as defined above;
provided that :
when X is CO, R
2
is not hydroxy;
or a pharmaceutically acceptable salt thereof.
Depending on the precise meaning of the substituent(s) X and/or Y, the compounds of formula(I) can have one or more asymmetric centers and therefore can exist in different stereoisomers. For example, a compound of formula (I) which possesses one asymmetric center can exist either as a pure optical isomer or as racemic mixture; and a compound of formula (I) which possesses two, not equivalent, asymmetric centers wherein one of the substituents is the same, can exist as a threo or an erithro pure optical isomer or as threo or erithro racemic mixture.
Both the racemic mixture and the pure optical isomers of a compound of formula (I) are within the scope of the invention.
The present invention further comprises pharmaceutically acceptable salts of the compounds of formula (I) with pharmaceutically acceptable inorganic acids such as, e.g., hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid and organic acids such as, e.g., malic, maleic, pamoic, succinic, gluconic, citric, tartaric, ascorbic, acetic, methanesulphonic or benzensulphonic acid.
A linear or branched C
2
-C
6
alkyl group may be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl sec-butyl, tert-butyl or n-pentyl; preferably it is methyl, ethyl or n-propyl.
A linear or branched C
1
-C
5
alkoxy group may be, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy or sec-butoxy; preferably, it is methoxy or ethoxy.
A linear or branched C
2
-C
4
alkanoyl group may be, for example, acetyl, propanoyl, isobutirroyl, valeroyl; preferably, it is acetyl or propanonyl.
A linear or branched C
1
-C
6
alkylsulfonyl group may be, for example, methanesulphonyl, ethanesulphonyl or propanesulphonyl; preferably, it is a linear C
1
-C
3
alkylsulfonyl group, in particular methanesulphonyl ot ethanesulphonyl.
In a group of formula (i), (ii), (iii) or (iv), the substituent R
1
, which may be in position orto, meta, or para of the phenyl ring is, preferably, in position para.
Preferably, R
1
is hydrogen or halogen, in particular fluorine.
A preferred class of compounds of the invention are compounds of formula (I), if the case either as singie isomers or as mixture of isomers, wherein
X is CO, CHOH or CH
2
;
Y is CH
2
or CHCH
2
R
2
wherein R
2
is hydrogen, hydroxy, phenoxy, N(CH
3
)
2
or wherein R
2
is NHR
3
in which R
3
is a linear C
1
-C
3
alkylsulfonyl group, a group of formula (ii) or (iii) as defined above in which R
1
is hydrogen;
Z is a (CH
2
)
n
group wherein n is 1, CO, O, S or a group of formula (iv) as defined above in which R
1
is hydrogen or halogen;
R
1
is as defined above;
provided that:
when X is CO, Y is not hydroxy; and the pharmaceutically acceptable salts thereof.
Examples of specific compounds of the invention are:
1)1-Hydroxymethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
2)1-Phenoxymethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
3)1-Dimethylaminomethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
4)1-Benzoylaminomethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
5)1-Methanesulphonylaminomethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
6)1-Phenylsulphonylaminomethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
7)1-(2-Amino-benzothiazol-6-yl)-2-(4-benzyl-piperidin-1-yl)-propan-1-ol;
8)1-(2-Amino-benzothiazol-6-yl)-2-(4-benzyl-piperidin-1-yl)-propane;
9)1-(2-Amino-benzothiazol-6-yl)-2-(4-benzyl-piperidin-1-yl)-ethane;
10)1-(2-Amino-benzothiazol-6-yl)-2-(4-phenoxy-piperidin-1-yl)-ethane;
11)1-(2-Amino-benzothiazol-6-yl)-2-(4-phenylthio-piperidin-1-yl)-ethane;
12)1-(2-Amino-benzothiazol-6-yl)-2-(4-benzoyl-piperidin-1-yl)-ethane;
13)1-(2-Amino-benzothiazol-6-yl)-2-(4-(4,4′-difluorodiphenylmethyl-piperidin-1-yl)-ethane;
14)1-(2-Amino-benzothiazol-6-yl)-3-phenoxy-2-(4-benzyl-piperidin-1-yl)-propan-1-one;
15)1-(2-Amino-benzothiazol-6-yl)-3-dimethylamino-2-(4-benzyl-piperidin-1-yl)-propan-1-one;
16)1-(2-Amino-benzothiazol-6-yl)-3-benzoylamino-2-(4-benzyl-piperidin-1-yl)-propan-1-one;
17)1-(2-Amino-benzothiazol-6-yl)-3-methanesulphonylamino-2-(4-benzyl-piperidin-1-yl)-propan-1-one;
18)1-(2-Amino-benzothiazol-6-yl)-3-phenylsulphonylamino-2-(4-benzyl-piperidin-1-yl)-propan-1-one;
19)2-(4-Benzylpiperidin-1-yl)-1-(2-amino-benzothiazol-6-yl)-propan-1-one;
20)2-(2-Benzoylpiperidin-1-yl)-1-(2-aminobenzothiazol-6-yl)-propan-1-one;
21)1-(2-Aminobenzothiazol-6-yl)-2-(4-benzyl-piperidin-1-yl)-ethanone;
22)1-(4-Benzoylpiperidin-1-yl)-2-(2-amino-benzothiazol-6-yl)-ethanone;
23)1-(4-Phenoxypiperidin-1-yl)-2-(2-amino-benzothiazol-6-yl)-ethanone;
and their pharmaceutically acceptable salts;
if the case,when one asymmetric center is present on the molecule, either as a pure optical isomer or as racemic mixture; or when two, not equivalent, asymmetric centers wherein a substituent is the same, are present on the molecule, either as a threo or an erithro pure optical isomer or as threo or erithro racemic mixture.
A compound of formula (I), if the case, either as pure optical isomer or as racemic mixture,

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