Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-11
2003-10-28
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S212040, C514S213010, C540S519000, C540S543000, C540S576000
Reexamination Certificate
active
06638925
ABSTRACT:
The invention relates to new compounds and drugs containing the new compounds as active, pharmaceutical ingredients.
Likewise, the invention relates to the use of the new compounds for the preparation of drugs for the treatment of Alzheimer's disease and related dementia conditions, as well as for the treatment of Langdon-Down Syndrome (mongolism, trisomy 21).
The acid addition salt of galanthamine, which has the chemical structure
as well as some of its analog, are known as active pharmaceutical ingredients having an inhibitory effect on the synaptic enzyme, acetylcholine esterase. Galanthanine is therefore used pharmacologically for paralysis symptoms resulting from polio mellitus and for different diseases of the nervous system.
Galanthamine and some of its derivatives are also used for the symptomatic treatment of Alzheimer's disease and related dementia conditions (EP 236 684 B1).
Chemically, galanthamine is an alkaloid of the morphine group, which can be obtained from snowdrops (
Galanthus woronowii, G. nivalis
etc.) and other Amaryllidaceae.
Aside from obtaining galanthamine from plant sources, chemical methods of synthesizing galanthamine and its analogs, including its acid addition salts, have also become known (WO 95/27715).
The Down syndrome is attributed to a tripling of chromosome 21, that is, the patients have a set of 47 chromosomes instead of 46. This can be demonstrated relatively simply cytologically. Trisomy 21 is associated with moderate to severe mental impairment and a series of symptoms of physical dysmorphism. A causative treatment is not possible at the present time. The existing impairment can be influenced by selective therapeutic measures. However, a distress usually remains.
The new inventive compounds are new benzazepine derivatives, particularly derivatives of benzofuro[3a, 3, 2, ef] [2] benzazepine.
They are compounds of the general formula (I)
in which
R
1
, R
2
either are the same or different and represent
hydrogen, F, Cl, Br, I, CN, NC, OH, SH, N0
2
, SO
3
H, NH
2
, CF
3
or
a lower (C
1
-C
6
), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkoxy group or
an amino group, which is substituted by one or two or different lower (C
1
-C
6
), optionally branched, optionally substituted (Ar) alkyl or (Ar) alkyl carbonyl or (Ar) alkoxy carbonyl or
a COOH, COO(Ar) alkyl, CONH, CON(Ar) alkyl group or
represents —(CH
2
)
n
—Cl, —(CH
2
)
n
—Br, —(CH
2
)
n
—OH,—(CH
2
)
n
—COOH, —(CH
2
)
n
—CN, —(CH
2
)
n
—NC, in which
it is also possible to define R
1
-R
2
jointly as —CH═CH—CH═CH—, —O—, (CH
2
)
n
—O—, with n=1 to 3.
R
3
═R
1
, particularly OH and OCH
3
and furthermore
R
2
-R
3
can jointly form: —O—(CH
2
)
n
—O—, with n=1 to 3
R
4
, R
5
: either are both hydrogen or, alternatively, any combination of hydrogen or an (Ar) alkyl, (Ar) alkenyl, (Ar) alkinyl with
S—R
8
, wherein R
8
is hydrogen or a lower (C
1
-C
10
), optionally branched, optionally substituted (Ar) alkyl group
SO—R
8
, SO
2
R
8
OH, O-protective group (such as TMS, TBDMS)
O—CS—N—R
8
(thiourethanes)
O—CO—N—R
9
, wherein R
9
has the following meaning:
O—CO—R
5
(ester, R
8
see above), in particular, also esters with the substitution pattern of amino acids such as
Furthermore: R
4
, R
5
=jointly hydrazone (═N—NH—R
10
, ═N—N(R
10
, R
11
), Oximes (═N—O—R
11
), wherein R
10
is hydrogen, a lower (C
1
-C
6
), optionally branched, optionally substituted (Ar)-alkyl or (Ar)-alkyl carbonyl or (Ar)-alkyl carbonyloxy group as well as a sulfonic acid group, such as a tosyl and mesyl group and R
11
is hydrogen, a lower (C
1
-C
6
), optionally branched, optionally substituted (Ar)-alkyl or (Ar)-alkyl carbonyl group, as well as a sulfonic acid group, such as a tosyl and mesyl group.
as well as substituents of the type
Y
1
, Y
2
═O, S, NH or N—R
10
(excess valences in each case are —H)
wherein, in the event that R
4
═H, R
5
can also be OH and, in the event that R
5
═H, R
4
can also be OH.
G
1
, G
2
:jointly or separately have the meaning:
—C(R
13
, R
14
)—, wherein R
13
, R
14
can be hydrogen, OH, a lower, optionally branched, optionally substituted (Ar)-alkyl, aryl, (Ar)-alkoxy or aryloxy group or jointly an alkyl spiro group (C
3
to C
7
spiro ring).
Furthermore, G
1
and G
2
jointly represent
with m=1 to 7
G
3
: represents CH
2
or ═CO
R
6
represents a group —(G
4
)
p
—(G
5
)
q
—G
6
with p, q=0 to 1, in which G
4
satisfies the following definition
—(CH
2
)
r
—, —C(R
15
,R
16
)—(CH
2
)
r
—, with R=1 to 6 and R
15
, R
16
=hydrogen, lower, optionally branched or optionally substituted (Ar)-alkyl, cycloalkyl, aryl groups
—O— or —NR
15
with s=1 to 4, t=0 to 4
that is an ortho, meta or para disubstituted aromatic
wherein G
7
═NR
15
, O or S,
G
5
can be identical with or different from G
4
and, in the event that P=1, additionally represents —S—,
G
6
fulfills the following definition:
with
R
17
, R
18
, R
19
and R
20
individually or jointly are the same or different, hydrogen, lower, optionally branched, optionally substituted (Ar)-alkyl, cycloalkyl or aryl groups, wherein R
17
and R
18
and R
19
and R
20
can jointly form a cycloalkyl group (with a ring size of 3-8)
G
8
═O, S, NH, NR
21
—(CH
2
)
n
—,
R
21
═CHO, COOR
17
or a heteroaryl group, which is unsubstituted or substituted identically or differently by one or several F, Cl, Br, I, NO
2
, NH
2
, OH, alkyl, alkyloxy, CN, NC or CF
3
, CHO, COOH, COOalkyl, SO
3
H, SH or S-alkyl groups, (heteroaryl being, in particular, 2-pyridyl, 4-pyridyl, 2-pyrimidinyl) or
a methyl group, which is substituted by 1-3 phenyl groups, which are unsubstituted or substituted identically or differently by one or more F, Cl, Br, I, NO
2
, NH
2
, alkyl, alkyloxy, CN, NC or CF
3
groups,
Furthermore, G
6
can be:
—CHO, COOR
17
, —CONR
17
a lower, optionally branched, optionally substituted (Ar)-alkyl, (Ar)-alkenyl, (Ar)-alkinyl, cycloalkyl or aryl groups,
—O—R
17
, —NR
17
R
18
, phthalamido, —CN or —NC.
R
7
is identical with R
6
or represents —O—
(−)
(N-oxide) or a free electron pair (e-pair), wherein R
6
and R
7
can also form a common ring, 3 to 8 carbon atoms in size and
[X] exists only if, and represents an ion of a pharmacologically usable inorganic or organic acid, when R
5
and R
6
are present and the nitrogen atoms thus carries a positive charge.
Z═N or N
+
in the event that R
6
and R
7
are present jointly and R
7
is not O
−
.
A special case of the new compounds of the general formula (I) are the compounds of the general formula (II)
wherein the groups have the meanings described for formula (I). This formula arises formally out of formula (I), in that the bond from C
1
to the furan oxygen is broken and, instead, a bond between C
1
and Z is formed directly.
Furthermore, the invention comprises the new, substituted, bridged bases of the general formula (III) and their synthesis, and particularly to 2,5-diazabicyclo [2.2.1]heptane:
wherein R
22
is a (hetero) aryl group, which is unsubstituted or substituted identically or differently by one or several F, Cl, Br, I, NO
2
, NH
2
, OH, alkyl, alkoxy, CN, NC or CF
3
, CHO, COOH, COOalkyl, SO
3
H, SH or S-alkyl groups or
a methyl group, which is substituted by two phenyl groups, which are substituted identically or differently by one or more F, Cl, Br, I, NO
2
, NH
2
, OH, alkyl, alkoxy, CN, NC or CF
3
, CHO, COOH, COOalkyl, SO
3
H, SH or S-alkyl groups,
R
17
, R
18
, n, s having the meanings given for the general formula (I) and
R
23
=—(G
5
)
q
—(G
4
)
p
—G
9
wherein G
4
and G
5
have the meanings given for the general formula (I) and G
9
is defined as:
Hydrogen, F, Cl, Br, I, OH, O-ts, O-ms, O-triflate, COOH, COCl CHO, —O—R
17
, —NR
17
R
18
, phthalimido, —CN or —NC or by other groups suitable for nucleophilic substitutions, addition reactions, condensation reactions, etc.
Examples of these types of compounds are:
These compounds o
Czollner Laszlo
Frohlich Johannes
Jordis Ulrich
Kuenburg Bernhard
Kifle Bruck
Sanochemia Ltd.
Young & Thompson
LandOfFree
Benzazepine derivatives, medicaments containing the same and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Benzazepine derivatives, medicaments containing the same and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzazepine derivatives, medicaments containing the same and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3162057