Substituted amino-furan-2-yl-acetic acid and...

Details Substituted amino-furan-2-yl-acetic acid and... Substituted amino-furan-2-yl-acetic acid and...

2003-05-30

2004-09-28

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S275000, C514S336000, C514S403000, C514S438000, C514S471000, C546S280400, C546S283400, C546S284700, C544S331000, C544S405000, C548S364100, C549S076000, C549S486000, C549S473000, C549S496000

Reexamination Certificate

active

06797712

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to substituted amino-furan-2-yl-acetic acid derivatives and substituted amino-thien-2-yl-acetic acid derivatives, to processes for their preparation, to medicaments containing them, to the use of those compounds in the preparation of medicaments for the treatment of, inter alia, pain and migraine, and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
The treatment of chronic and non-chronic pain is of great importance in medicine. There is a worldwide need for highly effective therapies for the targeted treatment of chronic and non-chronic pain in a manner that is fair to the patient, which is understood to mean the successful and satisfactory treatment of pain for the patient.
Conventional opioids such as morphine are highly effective in the therapy of severe to the most severe pain. However, their use is limited by the known side-effects, such as respiratory depression, vomiting, sedation, constipation and tolerance. In addition, they are less effective in neuropathic or incidental pain, from which tumor patients in particular suffer.
Opioids develop their analgesic action by binding to receptors in the cell membrane which belong to the family of the so-called G-protein-coupled receptors. In addition, there are further receptors and also ion channels which are substantially involved in the system of pain formation and pain transmission, for example the N-methyl-D-aspartate ion channel (NMDA ion channel), via which a substantial part of the communication of synapses proceeds and through which the calcium ion exchange between a neuronal cell and its surroundings is controlled (see, for example, P. D. Leeson, L. L. Iversen,
J. Med. Chem.
37 (1994) 4053-4067).
Important findings regarding the physiological importance of ion-channel-selective substances have been made possible by the development of the “patch-clamp” technique, by means of which the action of NMDA antagonists (i.e. antagonists of the NMDA ion channel) on the metabolism of calcium inside the cell can be demonstrated.
DESCRIPTION OF THE INVENTION
The object underlying the present invention is to provide novel compounds suitable for the therapy of pain. In addition, it is desirable that these substances have only minimal, if any, of the side-effects that usually occur with the use of opioids such as morphine, such as nausea, vomiting, dependence, respiratory depression or constipation.
That object is achieved by compounds having the general structure (I) and by their pharmaceutically acceptable salts:
wherein
A represents oxygen or sulfur,
R
1
represents aryl, (C
1-6
-alkyl)-aryl, heterocyclyl or (C
1-6
-alkyl)-heterocyclyl,
R
2
represents H, C
1-12
-alkyl, C
3-8
-cycloalkyl, (C
1-6
-alkyl)-C
3-8
-cycloalkyl, aryl, (C
1-6
-alkyl)-aryl, heterocyclyl or (C
1-6
-alkyl)-heterocyclyl,
R
3
, R
4
and R
5
each independently of the others represents H, OH, SH, F, Cl, Br, I, —CN, NO
2
, C
1-2
-alkyl, C
3-8
-cycloalkyl, (C
1-6
-alkyl)-C
3-8
-cycloalkyl, aryl, (C
1-6
-alkyl)-aryl, heterocyclyl, (C
1-6
-alkyl)-heterocyclyl, —SiR
6
R
7
R
8
, —(CH
2
)
n
—O—(CH
2
)
m
—R
9
wherein n=1, 2, 3 or 4 and m=0, 1, 2, 3 or 4, —(CH
2
)
o
—S
p
—(CH
2
)
q
—R
10
wherein o=1, 2, 3 or 4, p=1 or 2 and q=0, 1, 2, 3 or 4, —(CH
2
)
r
—CO
2
R
11
wherein r=0, 1, 2, 3 or 4, —(CH
2
)
s
—OCOR
12
wherein s=0, 1, 2, 3 or 4, or —COR
13
,
R
6
, R
7
and R
8
each independently of the others represents C
1-6
-alkyl or phenyl,
R
9
and R
10
each independently of the other represents H, CH
3
, aryl, heterocyclyl or —C(═O)—C
1-6
-alkyl, —C(═O)—(C
1-6
-alkyl)-aryl or —C(═O)-aryl,
R
11
represents H, C
1-6
-alkyl or CH
2
-phenyl,
R
12
represents C
1-6
-alkyl or aryl,
R
13
represents H, C
1-6
-alkyl, aryl, heterocyclyl or NR
14
R
15
,
R
14
and R
15
each independently of the other represents H, C
1-6
-alkyl, C
3-8
-cycloalkyl, (C
1-6
-alkyl)-C
3-8
-cycloalkyl, aryl, (C
1-6
-alkyl)-aryl, heterocyclyl or (C
1-6
-alkyl)-heterocyclyl, or R
14
and R
15
together form —(CH
2
)
k
— wherein k=4, 5 or 6,
wherein
alkyl represents a non-cyclic hydrocarbon radical which is straight-chain or branched and is saturated or unsaturated and is unsubstituted or is monosubstituted or polysubstituted by identical or different substituents,
cycloalkyl represents an alicyclic hydrocarbon radical which is saturated or unsaturated and is unsubstituted or is monosubstituted or polysubstituted by identical or different substituents,
aryl is a radical selected from the group of
heterocyclyl represents a monocyclic or polycyclic organic radical in which at least one ring contains one hetero atom or 2, 3, 4 or 5 identical or different hetero atoms selected from the group of N, O and S, the radical being saturated or unsaturated and being unsubstituted or monosubstituted or polysubstituted by identical or different substituents,
R
16
, R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
24
, R
25
, R
26
and R
27
each independently of the others represents H, OR
28
, S(O)
t
R
29
wherein t=0, 1 or 2, SO
2
OR
30
, F, Cl, Br, I, —CN, NO
2
, C
1-12
-alkyl, C
3-8
-cycloalkyl, (C
1-6
-alkyl)-C
3-8
-cycloalkyl, phenyl or (C
1-6
-alkyl)-phenyl, wherein phenyl is unsubstituted or is monosubstituted or polysubstituted by identical or different substituents, heterocyclyl, (C
1-6
-alkyl)-heterocyclyl, —CO
2
R
31
or —NR
32
R
33
,
R
28
, R
29
, R
30
and R
31
each independently of the others represents H, C
1-12
-alkyl, C
3-8
-cycloalkyl, (C
1-6
-alkyl)-C
3-8
-cycloalkyl, phenyl or (C
1-6
-alkyl)-phenyl, wherein phenyl is unsubstituted or is monosubstituted or polysubstituted by identical or different substituents, heterocyclyl, (C
1-6
-alkyl)-heterocyclyl or —NR
34
R
35
,
and
R
32
and R
33
each independently of the other represents H, C
1-6
-alkyl, C
3-8
-cycloalkyl, (C
1-6
-alkyl)-C
3-8
-cycloalkyl, phenyl, (C
1-6
-alkyl)-phenyl, heterocyclyl or (C
1-6
-alkyl)-heterocyclyl, or R
32
and R
33
together form —(CH
2
)
h
— wherein h=4, 5 or 6,
and
R
34
and R
35
each independently of the other represents H, C
1-6
-alkyl, C
3-8
-cycloalkyl, (C
1-6
-alkyl)-C
3-8
-cycloalkyl, phenyl, (C
1-6
-alkyl)-phenyl, heterocyclyl or (C
1-6
-alkyl)-heterocyclyl, or R
34
and R
35
together form —(CH
2
)
g
— wherein g=4, 5 or 6.
Accordingly, the compounds according to the invention having the general structure (I) are either amino-furan-2-yl-acetic acid derivatives having the general structure (I-A) or amino-thien-2-yl-acetic acid derivatives having the general structure (I-B):
It has been found that the compounds having the general structure (I-A) or (I-B) bind selectively to the glycine binding site of the NMDA ion channel and accordingly are suitable for the treatment of pain. The same is also true of (4-methoxy-phenylamino)-thien-2-yl-acetic acid, which is known as such from the prior art (N. A. Petasis et al.,
Tetrahedron
(1997), 16463-16470) but for which no medicinal indication is disclosed in the prior art. The present invention therefore relates also to that compound, in so far as its use in a medicament, for the preparation of a medicament, especially for the treatment of pain, and a pharmaceutical composition containing it are concerned.
Within the scope of this invention, the term “aryl” means phenyls and naphthyls. Each aryl radical may be unsubstituted or mono- or poly-substituted, it being possible for the aryl substituents to be identical or different and to be at any desired and possible position of the aryl. Aryl is advantageously an unsubstituted or substituted phenyl. Particularly preferred aryl radicals for the purposes of the invention are mono- or di-substituted phenyl.
Within the scope of this invention, the terms “C
1-12
-alkyl” and “C
1-6
-alkyl” include acyclic saturated or unsaturated hydrocarbon radicals which may be branched- or straight-chain and may be unsubstituted or mono- or poly-substituted, having from 1 to 12 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) and from 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) carbon a

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