2-substituted 1,2-benzisothiazole derivatives and their use...

Details 2-substituted 1,2-benzisothiazole derivatives and their use... 2-substituted 1,2-benzisothiazole derivatives and their use...

2000-04-20

2002-02-12

Kifle, Bruck (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C548S214000, C548S206000, C514S373000

Reexamination Certificate

active

06346622

ABSTRACT:

The invention relates to 2-substituted 1,2-benzoisothiazole derivatives, their preparation and use for preparing active ingredients of drugs.
Classical antidepressants, and the newer selective serotonin reuptake inhibitors (SSRIs) exert their antidepressant effect inter alia by inhibiting active reuptake of the transmitter into the presynaptic nerve endings. Unfortunately, in this case the antidepressant effect has its onset only after treatment for at least 3 weeks, moreover, about 30% of patients are therapy-resistent.
Blockade of presynaptic serotonin autoreceptors increases, by abolishing negative coupling, the serotonin release and thus the instantaneous transmitter concentration in the synaptic cleft. This increase in the transmitter concentration is regarded as the principle of the antidepressant effect. This mechanism of action differs from that of previously disclosed antidepressants which activate both the presynaptic and somatodendritic autoreceptors and therefore result in a delayed onset of action only after desensitization of these autoreceptors. Direct autoreceptor blockade bypasses this effect.
It is known that although the thiazole derivatives described in DE 3620643 have affinity for 5-HT
1A
receptors they have no 5-HT
1B
affinity.
According to current knowledge, the presynaptic serotonin autoreceptor is of the 5-HT
1B
subtype (Fink et al., Arch. Pharmacol. 352 (1995), 451). Selective blockade thereof by 5-HT
1B/D
antagonists increases serotonin release in the brain: G. W. Price et al., Behavioural Brain Research 73 (1996), 79-82; P. H. Hutson et al., Neuropharmacology Vol. 34, No. 4 (1995), 383-392.
However, surprisingly, the selective 5-HT
1B
antagonist GR 127 935 reduces serotonin release in the cortex after systemic administration. One explanation might be stimulation of somatodendritic 5-HT
1A
receptors in the raphe region by the released serotonin, which inhibits the rate of firing of serotonergic neurones and thus serotonin excretion (M. Skingle et al., Neuropharmacology Vol. 34, No. 4 (1995), 377-382, 393-402).
One strategy for bypassing the autoinhibitory effects in serotonergic areas of origin thus aims at blockade of the presynaptic 5-HT1B [sic] receptors. This hypothesis is supported by the observation that the effect of paroxetine on serotonin release in the dorsal raphe nucleus of the rat is potentiated by the 5-HT
1B
receptor antagonist GR 127 935 (Davidson and Stamford, Neuroscience Letts., 188 (1995),41).
The second strategy includes blockade of both types of autoreceptors, namely the 5-HT
1A
receptors, in order to enhance neuronal firing, and the 5-HT
1B
receptors, in order to increase terminal serotonin release (Starkey and Skingle, Neuropharmacology 33 (3-4) (1994),393).
5-HT
1B/D
antagonists, alone or coupled to a 5-HT
1A
receptor antagonist component, ought therefore to cause a greater increase in serotonin release in the brain and might therefore entail advantages in the therapy of depression and related psychological disorders.
It has now been found that 2-substituted 1,2-benzoisothiazole derivatives of the formula I
where
R
1
and R
2
are, independently of one another (C
1-6
) alkyl,
R
3
and R
4
are, independently of one another, hydrogen, (C
1-6
) alkyl branched or unbranched, OH, O—(C
1-6
)-alkyl branched or unbranched, F, Cl, Br, I, trifluoromethyl, NR
5
R
6
, CO
2
R
7
, nitro, cyano, pyrrole, a phenylalkyl C
1
-C
4
radical which in turn can be substituted on the aromatic system by F, Cl, Br, I, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, trifluoromethyl, hydroxyl, amino, cyano or nitro,
R
5
and R
6
are, independently of one another, hydrogen, (C
1-6
) alkyl branched or unbranched, COPh, CO
2
tBu, CO—(C
1-4
)-alkyl or together are a 5- or 6-membered ring which may contain a second nitrogen (e.g. piperazine),
R
7
is hydrogen and (C
1-6
) alkyl branched or unbranched,
A is branched or unbranched (C
1-10
)-alkylene or straight-chain or branched (C
2-10
)-alkylene, which comprises at least one group Z which is selected from O, S, NR
7
, cyclopropyl, CHOH, a double or a triple bond,
B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine and the corresponding cyclic compounds enlarged by one methylene group, the linkage to A taking place by one nitrogen atom of B, and
Ar is phenyl which is unsubstituted or substituted by (C
1-6
) alkyl branched or unbranched, O—(C
1-6
)-alkyl branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR
5
R
6
, CO
2
R
7
, cyano or phenyl or is tetralin, indan, fused aromatic systems such as naphthalene which is unsubstituted or substituted by (C
1-4
) alkyl or O(C
1-4
) alkyl, or anthracene or 5- or 6-membered aromatic heterocycles having 1 or 2 heteroatoms which are selected, independently of one another, from O and N and which may also be fused to other aromatic radicals, for example quinoline, isoquinoline, phthalazine, indole and quinazoline, which in turn may be substituted by phenyl,
and their salts with physiologically tolerated acids, have valuable pharmacological properties.
Preferred compounds of the formula I are those where
R
1
and R
2
is [sic], independently of one another, methyl or ethyl,
R
3
and R
4
are, independently of one another, hydrogen, O—(C
1-4
)-alkyl branched or unbranched, F, Cl, Br, trifluoromethyl, NR
5
R
6
, nitro, cyano and phenyl,
R
5
and R
6
are, independently of one another, hydrogen, COPh, CO
2
tBu, (C
1-6
) alkyl branched or unbranched and CO—(C
1-4
)-alkyl,
A is branched or unbranched (C
2-5
) alkylene or straight-chain or branched (C
2-5
) alkylene, which comprises a group Z which is selected from CHOH, cyclopropyl, a double or a triple bond,
B is 4-piperidine, 4-tetrahydro-1,2,3,6-pyridine, 4-piperazine or homopiperazine, the linkage to A taking place by one nitrogen atom of B, and
Ar is phenyl which is unsubstituted or substituted by (C
1-6
) alkyl branched or unbranched, O—(C
1-6
)-alkyl branched or unbranched, F, Cl, Br, I, trifluoromethyl, NR
5
R
6
, CO
2
R
7
, cyano and phenyl, or tetralin, indan, fused aromatic systems such as naphthalene which is unsubstituted or substituted by (C
1-4
) alkyl or O(C
1-4
) alkyl, or anthracene and 5- or 6-membered aromatic heterocycles having 1 or 2 heteroatoms which are selected, independently of one another, from O and N, and which may be fused to other aromatic radicals.
Particularly preferred compounds of the formula I are the compounds listed in claim
3
.
The compounds of the formula I may have one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The invention also includes the respective tautomeric forms.
The novel compounds of the formula I can be prepared by reacting a compound of the formula II
where R
1
to R
4
and A have the meanings stated above, and Q is a group which can be eliminated (e.g. Cl, Br, I, alkanesulfonyloxy or arylsulfonyloxy), with a secondary amine of the formula III,
H—B—Ar  III
where B and Ar have the meanings stated above, in a manner known per se, and converting the compound obtained in this way where appropriate into the addition salt with a physiologically tolerated acid. It is likewise possible to react a compound of the formula IV
with a compound of the formula V
Q—A—B—Ar  V
in a manner known per se. Another synthetic variant is linkage of a compound of the formula VI
to a compound of the formula III by a reductive amination known per se.
Compounds of the formula III can be synthesized by
1. linking compounds of the formula VII
W—B
1
  (VII)
 where B
1
is piperazine or homopiperazine and W is hydrogen or one of the usual amino protective groups (e.g. Boc or Cbz), with a compound of the formula VIII
P—Ar  (VIII),
 where P is B(OH)
2
, SnR
3
, OTf, Br, Cl, or I and R is C
1
-C
4
-alkyl, in a known manner; or
2. linking compounds of the formula IX
W—B
2
—P
1
  (IX)
 where B
2
is 4-tetrahydro-1,2,3,6-pyridine and the corresponding cyclic compounds enlarged by one methylene group, and P
1
is

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