Substituted aromatic ethers as inhibitors of glycine transport

Details Substituted aromatic ethers as inhibitors of glycine transport Substituted aromatic ethers as inhibitors of glycine transport

2002-02-28

2003-05-20

Kumar, Shailendra (Department: 1621)

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

Organic compounds

Carboxylic acids and salts thereof

C562S443000, C514S567000

Reexamination Certificate

active

06566550

ABSTRACT:

BACKGROUND
The present invention relates to aromatic ethers containing a pendant amino acid side chain and to pharmaceutical compositions containing them and to their use in the treatment of central nervous system disorders, cognitive disorders, schizophrenia, dementia and other disorders in mammals, including humans. These compounds exhibit activity as inhibitors of the glycine type-1 transporter.
Schizophrenia, a progressive neurological disease, is manifested in its early stages as thought disorders such as hallucinations, paranoid delusions, and bizarre thought patterns, collectively known as positive symptoms. These easily recognizable symptoms gave the disease the historical name “madness”. As the disease progresses, negative symptoms, such as social withdrawal and anhedonia, and cognitive symptoms such as dementia become more apparent. Only about one-third of schizophrenic patients can be treated successfully and returned to society, while the remainder are generally institutionalized. The burden on society of this devastating illness and the toll it takes on family members of affected patients make it one of the most costly of all CNS diseases.
Pharmacological treatment for schizophrenia has traditionally involved blockade of the dopamine system, which is thought to be responsible for its positive symptoms. Such treatment, however, ignores the negative and cognitive aspects of the disease. Another neurotransmitter system believed to play a role in schizophrenia is the glutamate system, the major excitatory transmitter system in the brain. This hypothesis is based on the observation that blockade of the glutamate system by compounds such as PCP (“angel dust”) can replicate many of the symptoms of schizophrenia, including its positive, negative, and cognitive aspects. If schizophrenia involves a deficit of glutamatergic transmission, augmentation of the glutamate system, and specifically the NMDA receptor, may be beneficial. While glutamate is the principle agonist at NMDA receptors, glycine is required as a co-agonist to set the “tone” of the receptor for its response to glutamate. Enhancing this “tone” by increasing the effect of glycine would augment NMDA neurotransmission, and provide potential benefit in the treatment of schizophrenia.
A specific mechanism for augmenting the glycinergic “tone” of the NMDA receptor was disclosed recently by Bergeron, et al. (
Proc. Natl. Acad. Sci. USA,
95, 15730, (1998)). This group showed that a specific and potent inhibitor of the glycine type-1 transporter (GlyT1) responsible for removing glycine from the synapse at the NMDA receptor, termed NFPS (WO 97/45115), can enhance NMDA receptor function. For example, NFPS increased the post synaptic current driven by the NMDA receptor, an effect blocked by both a specific NMDA-site antagonist and a glycine-site antagonist. Even though glycine levels in the brain are high relative to the amount required to act as an NMDA receptor co-agonist, this work shows that GlyT1 removes glycine efficiently at the synapse, and that inhibition of GlyT1 can augment NMDA receptor function. The authors establish the feasibility of using a GlyT1 inhibitor as a treatment for schizophrenia through its augmentation of glutamatergic neurotransmission.
SUMMARY OF THE INVENTION
The present invention relates to a series of substituted aromatic ethers of the formula
wherein
ring A is phenyl, naphthyl, benzothienyl, benzofuranyl, or pyridyl; or ring A is a monocyclic aryl or heteroaryl ring containing from zero to four heteroatoms and not containing any adjacent ring oxygen atoms; or ring A is a bicyclic aryl or heteroaryl ring containing from zero to five heteroatoms and not containing any adjacent ring oxygen atoms; and
X and Y are each, independently, (C
1
-C
6
) alkyl optionally substituted with from one to seven fluorine atoms; (C
1
-C
6
)alkoxy optionally substituted with from one to seven fluorine atoms, wherein the number of fluorine substituents on the foregoing (C
1
-C
6
) alkyl and (C
1
-C
6
) alkoxy groups can not exceed the number of positions in such groups that are available for substitution; carboxy; carbo-(C
1
-C
6
)alkoxy; carboxamido; (C
1
-C
6
)alkyl-thio; sulfoxyl; sulfonyl; halo; nitro; cyano; amino; (C
1
-C
6
) alkylamino and di[(C
1
-C
6
) alkyl]amino;
B is (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy optionally substituted with 1 to 7 fluorine atoms, or halogen;
and the pharmaceutically acceptable salts of such compounds.
In a preferred embodiment of this invention, ring A is selected from phenyl, naphthyl benzofuranyl, benzothienyl, indanyl, tetrahydronaphthyl, dihydrobenzofuranyl, and dihydrobenzothiophenyl. In another preferred embodiment of this invention, X is para-trifluoromethyl, para-methyl or para-chloro.
The present invention also relates to a compound having the formula:
wherein Y is (C
1
-C
6
)alkyl optionally substituted with from one to seven fluorine atoms; (C
1
-C
6
)alkoxy optionally substituted with from one to seven fluorine atoms, wherein the number of fluorine substituents on the foregoing (C
1
-C
6
)alkyl and (C
1
-C
6
) alkoxy groups can not exceed the number of positions in such groups that are available for substitution; carboxy; carbo-(C
1
-C
6
)alkoxy; carboxamido; (C
1
-C
6
)alkyl-thio; sulfoxyl; sulfonyl; halo; nitro; cyano; amino; (C
1
-C
6
) alkylamino and di{(C
1
-C
6
)alkyl}amino;
wherein Z
1
and Z
2
are independently selected from O, NH, N—(C
1
-C
5
alkyl), and S; and n is an integer from 1 to about 3;
or a pharmaceutically acceptable salt thereof.
The present invention also relates to a compound having the formula:
wherein Y is (C
1
-C
6
)alkyl optionally substituted with from one to seven fluorine atoms; (C
1
-C
6
)alkoxy optionally substituted with from one to seven fluorine atoms, wherein the number of fluorine substituents on the foregoing (C
1
-C
6
)alkyl and (C
1
-C
6
) alkoxy groups can not exceed the number of positions in such groups that are available for substitution; carboxy; carbo-(C
1
-C
6
)alkoxy; carboxamido; (C
1
-C
6
)alkyl-thio; sulfoxyl; sulfonyl; halo; nitro; cyano; amino; (C
1
-C
6
) alkylamino and di{(C
1
-C
6
)alkyl}amino;
wherein Z
1
and Z
2
are independently selected from O, NH, N—(C
1
-C
5
alkyl), and S; and n is an integer from 1 to about 3;
or a pharmaceutically acceptable salt thereof.
Specific preferred embodiments of the invention include:
{Methyl-[3-(4-phenoxy-phenoxy)-3-phenyl-propyl]-amino}-acetic acid
(Methyl-{3-phenyl-3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-propyl}-amino)-acetic acid
(Methyl-{3-phenyl-3-[4-(3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-amino)-acetic acid
{Methyl-[3-phenyl-3-(4-p-tolyloxy-phenoxy)-propyl]-amino}-acetic acid
({3-[4-(4-Methoxy-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-acetic acid
({3-[4-(4-Chloro-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-acetic acid
(Methyl-{3-[4-(naphthalen-2-yloxy)-phenoxy]-3-phenyl-propyl}-amino)-acetic acid
({3-[4-(4-Isopropyl-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-acetic acid
({3-[4-(4-tert-Butyl-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-acetic acid
(Methyl-{3-phenyl-3-[4-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-phenoxy]-propyl}-amino)-acetic acid
({3-[4-(3,4-Dimethyl-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-acetic acid
({3-[4-(Indan-5-yloxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-acetic acid
({3-[4-(2,4-Difluoro-phenoxy)-phenoxy]-3-phenyl-propyl}-methyl-amino)-acetic acid
({3-(4-Fluoro-phenyl)-3-[4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-phenoxy]-propyl}-methyl-amino)-acetic acid
{[3-[4-(2,4-Dimethyl-phenoxy)-phenoxy]-3-(4-fluoro-phenyl)-propyl]-methyl-amino}-acetic acid
({3-(4-Fluoro-phenyl)-3-[4-(2,4,6-trimethyl-phenoxy)-phenoxy]-propyl}-methyl-amino)-acetic acid
(Methyl

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