U.S. patent application number 10/402382 was filed with the patent office on 2003-12-04 for sulfonylguanidine compounds and pharmaceutical uses thereof.
This patent application is currently assigned to Gruenenthal GmbH. Invention is credited to Chizh, Boris, Gerlach, Matthias, Haurand, Michael, Maul, Corinna, Puetz, Claudia Katharina, Uragg, Heinz.
Application Number | 20030225084 10/402382 |
Document ID | / |
Family ID | 26007237 |
Filed Date | 2003-12-04 |
United States Patent
Application |
20030225084 |
Kind Code |
A1 |
Gerlach, Matthias ; et
al. |
December 4, 2003 |
Sulfonylguanidine compounds and pharmaceutical uses thereof
Abstract
Sulfonylguanidine compounds corresponding to the tautomeric
formulas I and Ia, a method for producing them, pharmaceutical
compositions containing them, and methods of using them to prepare
medicaments and for treating various medical conditions. The
sulfonylguanidine compounds have an affinity for the gabapentin
binding site and can be used to treat conditions such as pain,
epilepsy, migraine and others.
Inventors: |
Gerlach, Matthias;
(Brachttal, DE) ; Uragg, Heinz; (Stolberg, DE)
; Haurand, Michael; (Aachen, DE) ; Puetz, Claudia
Katharina; (Dueren, DE) ; Maul, Corinna;
(Aachen, DE) ; Chizh, Boris; (Aachen, DE) |
Correspondence
Address: |
CROWELL & MORING LLP
INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON
DC
20044-4300
US
|
Assignee: |
Gruenenthal GmbH
Zieglerstrasse 6
Aachen
DE
52078
|
Family ID: |
26007237 |
Appl. No.: |
10/402382 |
Filed: |
March 31, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10402382 |
Mar 31, 2003 |
|
|
|
PCT/EP01/11245 |
Oct 1, 2001 |
|
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|
Current U.S.
Class: |
514/237.8 ;
514/252.12; 514/331; 514/408; 514/601; 514/602 |
Current CPC
Class: |
A61P 1/04 20180101; C07C
311/64 20130101; A61P 25/02 20180101; A61P 25/24 20180101; C07D
213/40 20130101; C07D 239/26 20130101; C07D 295/215 20130101; C07D
333/20 20130101; C07D 213/77 20130101; C07D 213/75 20130101; A61P
27/02 20180101; A61P 15/12 20180101; A61P 25/06 20180101; A61P
21/04 20180101; C07D 295/32 20130101; A61P 9/00 20180101; C07D
521/00 20130101; A61P 25/14 20180101; A61P 25/18 20180101; C07D
231/40 20130101; C07C 311/49 20130101; A61P 29/00 20180101; C07D
409/12 20130101; A61P 25/08 20180101; A61P 25/28 20180101; A61P
25/00 20180101; A61P 23/00 20180101; C07C 2601/14 20170501; A61P
25/22 20180101; C07D 401/12 20130101; C07D 307/52 20130101 |
Class at
Publication: |
514/237.8 ;
514/252.12; 514/331; 514/408; 514/601; 514/602 |
International
Class: |
A61K 031/537; A61K
031/495; A61K 031/445; A61K 031/40; A61K 031/18 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 30, 2000 |
DE |
100 48 716.5 |
Mar 12, 2001 |
DE |
101 12 068.0 |
Claims
What is claimed is:
1. A method of treating a condition selected from: the group
consisting of pain, epilepsy and migraine; or the group consisting
of hyperalgesia, allodynia, inflammatory pain and post-operative
pain; or the group consisting of hot flashes, post-menopausal
symptoms, amyotropic lateral sclerosis (ALS), reflex sympathetic
dystrophy (RSD), spastic paralysis, restless leg syndrome, acquired
nystagmus, psychiatric or neuropathological disorders, painful
diabetic neuropathy, symptoms and pain due to multiple sclerosis or
Parkinson's disease, neurodegenerative diseases, gastrointestinal
lesions, erythromelalgic or post-poliomyelitic pain, and trigeminal
or post-herpetic neuralgia; or a method of providing
anticonvulsant, analgesic or anxiolytic treatment; said method
comprising administering to a patient in need thereof a
pharmaceutically effective amount of a sulfonylguanidine compound
corresponding to at least one of the tautomeric formulas I and Ia,
67wherein R.sup.1 is aryl or heteroaryl, that may be unsubstituted
or singly or multiply substituted; R.sup.2 is selected from the
group consisting of: C.sub.1-10-alkyl that is branched or
unbranched, saturated or unsaturated, and singly or multiply
substituted or unsubstituted; C.sub.3-8-cycloalkyl that is
saturated or unsaturated, and singly or multiply substituted or
unsubstituted; aryl or heteroaryl, that is unsubstituted or singly
or multiply substituted; aryl, C.sub.3-9-cycloalkyl and heteroaryl,
that is bonded via saturated or unsaturated C.sub.1-3-alkyl,
S(O).sub.2 or NH, and that is unsubstituted or singly or multiply
substituted; NR.sup.4R.sup.5 where R.sup.4, R.sup.5 are
independently selected from the group consisting of H;
C.sub.1-18-alkyl that is branched or unbranched, saturated or
unsaturated, and singly or multiply substituted or unsubstituted;
C.sub.3-8-cycloalkyl that is saturated or unsaturated, and singly
or multiply substituted or unsubstituted; aryl or heteroaryl, that
is unsubstituted or singly or multiply substituted; or aryl,
C.sub.3-9-cycloalkyl or heteroaryl, bonded via saturated or
unsaturated C.sub.1-3-alkyl, and unsubstituted or singly or
multiply substituted; or R.sup.4 and R.sup.5 together form
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2N(R.sup.7)
CH.sub.2CH.sub.2--, where R.sup.7 is selected from C.sub.1-18-alkyl
that is branched or unbranched, saturated or unsaturated, and
singly or multiply substituted or unsubstituted;
C.sub.3-8-cycloalkyl that is saturated or unsaturated, and singly
or multiply substituted or unsubstituted; aryl or heteroaryl, that
is unsubstituted or singly or multiply substituted; or aryl,
C.sub.3-9-cycloalkyl or heteroaryl, that is bonded via saturated or
unsaturated C.sub.1-3-alkyl, and that is unsubstituted or singly or
multiply substituted; and SO.sub.2R.sup.6 where R.sup.6 is selected
from C.sub.1-18-alkyl that is branched or unbranched, saturated or
unsaturated, and singly or multiply substituted or unsubstituted;
C.sub.3-8-cycloalkyl that is saturated or unsaturated, and singly
or multiply substituted or unsubstituted; aryl or heteroaryl, that
is unsubstituted or singly or multiply substituted; or aryl,
C.sub.3-9-cycloalkyl or heteroaryl, that is bonded via saturated or
unsaturated C.sub.1-3-alkyl, and that is unsubstituted or singly or
multiply substituted; R.sup.3 is H or CH.sub.3; or R.sup.2 and
R.sup.3 together form --CH.sub.2(CH.sub.2).sub.nCH.sub.2--, where
n=2 or 3, --CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2N(R.sup.8)CH.- sub.2CH.sub.2 where R.sup.8 is
C.sub.1-18-alkyl that is branched or unbranched, saturated or
unsaturated, and singly or multiply substituted or unsubstituted;
optionally in the form of a racemate, a pure stereoisomer,
enantiomer or diastereomer, or a mixture of stereoisomers,
enantiomers or diastereomers; in the form of a free acid or free
base or a physiologically compatible salt, or in the form of a
solvate, or a hydrate; in both tautomeric forms corresponding to
formulas I and Ia, or exclusively in one of the tautomeric forms
corresponding to formula I or Ia, or in a mixture of the tautomeric
forms corresponding to formulas I and Ia.
2. A method according to claim 1, wherein said condition is
selected from: the group consisting of neuropathic, chronic or
acute pain; or the group consisting of thermal hyperalgesia,
mechanical hyperalgesia and allodynia, and cold-induced allodynia,
or the group consisting of bipolar disorders, anxiety, panic
attacks, mood fluctuations, manic behavior, depression, and
manic-depressive behavior; or the group consisting of Alzheimer's
disease, Huntington's disease, Parkinson's disease and
epilepsy.
3. A method according to claim 1, wherein R.sup.2 is selected from
the group consisting of: C.sub.1-10-alkyl that is branched or
unbranched, saturated or unsaturated, and that is singly or
multiply substituted or unsubstituted; C.sub.3-8-cycloalkyl that is
saturated or unsaturated, and singly or multiply substituted or
unsubstituted; aryl or heteroaryl, that is singly or multiply
substituted or unsubstituted; and aryl, C.sub.3-9-cycloalkyl and
heteroaryl, that is bonded via saturated or unsaturated
C.sub.1-3-alkyl, and that is unsubstituted or singly or multiply
substituted.
4. A method according to claim 1, wherein R.sup.2 is selected from
the group consisting of aryl and heteroaryl bonded via saturated or
unsaturated C.sub.1-3-alkyl group, and that may be unsubstituted or
singly or multiply substituted.
5. A method according to claim 4, wherein said aryl or heteroaryl
is bonded via a CH.sub.2 group.
6. A method according to claim 4, wherein said aryl or heteroaryl
is singly or multiply substituted by at least one substituent
selected from the group consisting of F, Cl, Br, I, OH, NO.sub.2,
SH, NH.sub.2, C.sub.1-4-alkyl and O--C.sub.1-4-alkyl.
7. A method according to claim 4, wherein R.sup.2 is a heteroaryl
group bonded via saturated or unsaturated C.sub.1-3-alkyl, and that
may be unsubstituted or singly or multiply substituted.
8. A method according to claim 7, wherein R.sup.2 is selected from
the group consisting of pyridinyl, thiophenyl, furanyl and
pyrimidinyl, bonded via saturated or unsaturated C.sub.1-3-alkyl,
and that may be unsubstituted or singly or multiply
substituted.
9. A method according to claim 8, wherein R.sup.2 is pyridinyl.
10. A method according to claim 7, wherein said aryl or heteroaryl
is bonded via a --CH.sub.2-- group and is singly substituted in the
para position.
11. A method according to claim 1, wherein said sulfonylguanidine
compound is selected from the group consisting of:
N-{amino-[pyridin-2-yl-methyl)--
amino]-methylene}-4-methylbenzenesulfonamide (1)
N-[amino-(benzylaminometh- ylene)]-4-methylbenzene-sulfonamide (2)
N-(aminomorpholin-4-yl-methylene)-- 4-methylbenzene-sulfonamide (3)
N-(aminocyclohexylaminomethylene)-4-methyl- benzene-sulfonamide (4)
N-(aminophenylaminomethylene)-4-methylbenzene-sulf- onamide (5)
N-[(amino-4-methoxybenzylamino)-methylene]-4-methylbenzene-sul-
fonamide (6)
N-[amino-(naphthalin-2-yl-amino)-methylene]-4-methylbenzenesu-
lfonamide (7)
N-[amino-(4-methylpiperazin-1-yl-amino)-methylene]-4-methylb-
enzenesulfonamide (8)
N-[amino-(1-pyridin-2-yl-hydrazino)-methylene]-4-met-
hylbenzenesulfonamide (9)
N-[aminopropylaminomethylene]-4-methylbenzene-su- lfonamide (10)
N-(aminobutylaminomethylene)-4-methylbenzene-sulfonamide (11)
N-[aminobutylaminomethylene]-4-methylbenzene-sulfonamide (12)
N-[aminobutylaminomethylene]-4-methylbenzene-sulfonamide (13)
N-[aminophenethylaminomethylene]-4-methylbenzene-sulfonamide (14)
N-[amino-sec-butylaminomethylene]-4-methylbenzene-sulfonamide (15)
N-[amino-(N'-tosyl-2-yl-hydrazino)-4-methylbenzene-sulfonamide (16)
N-[amino-(2H-pyrazol-3-yl-amino)-methylene]-4-methylbenzenesulfonamide
(17) N-(aminopyrrolidin-1-yl-methylene)-4-methylbenzene-sulfonamide
(18)
N-[amino-(naphthalin-1-yl-amino)-methylene]-4-methyl-benzenesulfonamide
(19)
N-[amino-(morpholin-4-yl-amino)-methylene]-4-methyl-benzenesulfonami-
de (20)
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-4-chlorobenzenes-
ulfonamide (21)
N-{amino-[(pyridin-4-yl-methyl)-amino]-methylene}-4-methyl-
benzenesulfonamide (22)
N-{amino-[(pyridin-3-yl-methyl)-amino]-methylene}--
4-methylbenzenesulfonamide (23)
N-[amino-(pyridin-3-yl-amino)-methylene]-4-
-methyl-benzenesulfonamide (24)
N-(aminopyrrolidin-1-yl-methylene)-4-chlor- obenzene-sulfonamide
(25) N-(aminopyrrolidin-1-yl-methylene)-benzenesulfon- amide (26)
N-(aminopyrrolidin-1-yl-methylene)-2-nitrobenzene-sulfonamide (27)
N-[amino-(morpholin-4-yl-amino)-methylene]-4-chlorobenzenesulfonamid-
e (28)
N-[amino-(morpholin-4-yl-amino)-methylene]-benzenesulfonamide (29)
Naphthalene-1-sulfonic acid amino-(morpholin-4-yl-amino)-methylene
amide (30)
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-C-phenylmethanesul-
fonamide (31)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-bromobenz-
enesulfonamide (32)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3,4-d-
ichlorobenzenesulfonamide (33)
N-{amino[(pyridin-2-yl-methyl)-amino]-methy-
lene}-4-isopropylbenzenesulfonamide (34)
N-{amino[(pyridin-2-yl-methyl)-am-
ino]-methylene}-4-iodobenzenesulfonamide (35)
N-{amino[(pyridin-2-yl-methy-
l)-amino]-methylene}-benzenesulfonamide (36) Naphthalene-2-sulfonic
acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (37)
1-methyl-1H-imidazole-4-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]- -methylene amide (38)
N-[4-({amino-[(pyridin-2-yl-methyl)-amino]-methylene-
}-sulfamoyl)-phenyl]-acetamide (39)
N-{amino[(pyridin-2-yl-methyl)-amino]--
methylene}-4-fluorobenzenesulfonamide (40)
N-{amino[(pyridin-2-yl-methyl)--
amino]-methylene}-2,4,6-trimethylbenzenesulfonamide (41)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfonami-
de (42)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-methoxybenzenes-
ulfonamide (43) Naphthalene-1-sulfonic acid
amino-[(pyridin-2-yl-methyl)-a- mino]-methylene amide (44)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene-
}-3-methylbenzenesulfonamide (45) Thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (46)
Quinoline-8-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (47)
5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (48)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulf-
onamide (49)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-butylbenze-
nesulfonamide (50)
N-{amino[(pyrimidin-2-yl-methyl)-amino]-methylene}-4-te-
rt.-butylbenzenesulfonamide (51)
N-{amino[(furan-2-yl-methyl)-amino]-methy-
lene}-4-butylbenzenesulfonamide (52)
N-{amino[(furan-2-yl-methyl)-amino]-m-
ethylene}-4-methylbenzenesulfonamide (53)
N-{amino[(furan-2-yl-methyl)-ami-
no]-methylene}-4-isopropylbenzenesulfonamide (54)
N-{amino[(furan-2-yl-met-
hyl)-amino]-methylene}-4-propylbenzenesulfonamide (55)
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulfon-
amide (56)
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-butylbenzen-
esulfonamide (57)
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-prop-
ylbenzenesulfonamide (58)
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene-
}-4-isopropylbenzenesulfonamide (59)
N-{amino[(thiophen-2-yl-methyl)-amino-
]-methylene}-4-tert.-butylbenzenesulfonamide (60)
N-{amino[(thiophen-2-yl--
methyl)-amino]-methylene}-4-chlorobenzenesulfonamide (61)
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonam-
ide (62), and
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-chlorobenze-
nesulfonamide (63), optionally in the form of their racemates,
their pure stereoisomers, in particular enantiomers or
diastereomers, or in the form of mixtures of the stereoisomers, in
particular of the enantiomers or diastereomers, in an arbitrary
mixture ratio; in the represented form or in the form of their
acids or their bases; or in the form of their salts, in particular
the physiologically compatible salts, preferably the hydrochloride
or sodium salt; or in the form of their solvates, in particular the
hydrates; in both tautomeric forms according to formulas I and Ia,
exclusively in one of the tautomeric forms according to formulas I
or Ia or also in mixtures of both forms according to formulas I and
Ia.
12. A method according to claim 1, wherein the sulfonylguanidine
compound is present entirely or substantially in the tautomeric
form corresponding to formula I.
13. A method according to claim 1, wherein the sulfonylguanidine
compound is present entirely or substantially in the tautomeric
form corresponding to formula Ia.
14. A method according to claim 1, wherein the sulfonylguanidine
compound is present as a pure diastereomer, a pure enantiomer, a
non-equimolar mixture of the diastereomers or enantiomers, or
exclusively in one of the tautomeric forms corresponding to
formulas I and Ia.
15. A method according to claim 1, wherein the sulfonylguanidine
compound is present as a racemate or an equimolar mixture of
diastereomers or enantiomers, or in a mixture of the tautomeric
forms corresponding to formulas I and Ia.
16. A sulfonylguanidine compound selected from the group consisting
of:
N-{amino-[pyridin-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonami-
de (1) N-[amino-(benzylaminomethylene)]-4-methylbenzene-sulfonamide
(2)
N-[(amino-4-methoxybenzylamino)-methylene]-4-methylbenzene-sulfonamide
(6) N-[aminophenethylaminomethylene]-4-methylbenzene-sulfonamide
(14)
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfonam-
ide (21)
N-{amino-[(pyridin-4-yl-methyl)-amino]-methylene}-4-methylbenzene-
sulfonamide (22)
N-{amino-[(pyridin-3-yl-methyl)-amino]-methylene}-4-methy-
lbenzenesulfonamide (23)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}--
4-bromobenzenesulfonamide (32)
N-{amino[(pyridin-2-yl-methyl)-amino]-methy-
lene}-3,4-dichlorobenzenesulfonamide (33)
N-{amino[(pyridin-2-yl-methyl)-a-
mino]-methylene}-4-isopropylbenzenesulfonamide (34)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-iodobenzenesulfonamide
(35)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-benzenesulfonamide
(36) Naphthalene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-meth- ylene amide (37)
1-methyl-1H-imidazole-4-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (38)
N-[4-({amino-[(pyridin-2-yl-methyl)-amino]-methylene}-sulfamoyl)-phenyl]--
acetamide (39)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-fluorobe-
nzenesulfonamide (40)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-2,4-
,6-trimethylbenzenesulfonamide (41)
N-{amino[(pyridin-2-yl-methyl)-amino]--
methylene}-4-propylbenzenesulfonamide (42)
N-{amino[(pyridin-2-yl-methyl)--
amino]-methylene}-4-methoxybenzenesulfonamide (43)
Naphthalene-1-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (44)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3-methylbenzenesulfonami-
de (45) Thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-meth- ylene amide (46)
Quinoline-8-sulfonic acid amino-[(pyridin-2-yl-methyl)-am-
ino]-methylene amide (47)
5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (48)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulf-
onamide (49)
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-butylbenze-
nesulfonamide (50)
N-{amino[(pyrimidin-2-yl-methyl)-amino]-methylene}-4-te-
rt.-butylbenzenesulfonamide (51)
N-{amino[(furan-2-yl-methyl)-amino]-methy-
lene}-4-butylbenzenesulfonamide (52)
N-{amino[(furan-2-yl-methyl)-amino]-m-
ethylene}-4-methylbenzenesulfonamide (53)
N-{amino[(furan-2-yl-methyl)-ami-
no]-methylene}-4-isopropylbenzenesulfonamide (54)
N-{amino[(furan-2-yl-met-
hyl)-amino]-methylene}-4-propylbenzenesulfonamide (55)
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulfon-
amide (56)
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-butylbenzen-
esulfonamide (57)
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-prop-
ylbenzenesulfonamide (58)
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene-
}-4-isopropylbenzenesulfonamide (59)
N-{amino[(thiophen-2-yl-methyl)-amino-
]-methylene}-4-tert.-butylbenzenesulfonamide (60)
N-{amino[(thiophen-2-yl--
methyl)-amino]-methylene}-4-chlorobenzenesulfonamide (61)
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonam-
ide (62), and
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-chlorobenze-
nesulfonamide (63), optionally in the form of their racemates,
their pure stereoisomers, in particular enantiomers or
diastereomers, or in the form of mixtures of the stereoisomers, in
particular of the enantiomers or diastereomers, in an arbitrary
mixture ratio; in the represented form or in the form of their
acids or their bases; or in the form of their salts, in particular
the physiologically compatible salts, preferably the hydrochloride
or sodium salt; or in the form of their solvates, in particular the
hydrates; in both tautomeric forms according to formulas I and Ia,
exclusively in one of the tautomeric forms according to formulas I
or Ia or also in mixtures of both forms according to formulas I and
Ia.
17. A compound according to claim 16, wherein the sulfonylguanidine
compound is present entirely or substantially entirely in the
tautomeric form corresponding to formula I.
18. A compound according to claim 16, wherein the sulfonylguanidine
compound is present entirely or substantially entirely in the
tautomeric form corresponding to formula Ia.
19. A pharmaceutical composition comprising a pharmaceutically
active sulfonylguanidine compound according to claim 16, and at
least one pharmaceutical carrier, additive or auxiliary
substance.
20. A pharmaceutical composition according to claim 19, further
comprising a further pharmaceutically active compound.
21. A pharmaceutical composition according to claim 19, wherein the
sulfonylguanidine compound is present as a pure diastereomer, a
pure enantiomer, a non-equimolar mixture of the diastereomers or
enantiomers, or exclusively in one of the tautomeric forms
corresponding to formulas I and Ia.
22. A pharmaceutical composition according to claim 19, wherein the
sulfonylguanidine compound is present as a racemate or an equimolar
mixture of diastereomers or enantiomers, or in a mixture of the
tautomeric forms corresponding to formulas I and Ia.
23. A pharmaceutical composition according to claim 19, wherein the
sulfonylguanidine compound is present as pure diastereomer or
enantiomer, or as a non-equimolar mixture of diastereomers or
enantiomers.
24. A pharmaceutical composition according to claim 19, wherein the
sulfonylguanidine compound is present as as a racemate or as an
equimolar mixture of diastereomers or enantiomers.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of international patent
application no. PCT/EP01/11245, filed Oct. 1, 2001, designating the
United States of America, and published in German as WO 02/30881,
the entire disclosure of which is incorporated herein by reference.
Priority is claimed based on Federal Republic of Germany patent
application nos. DE 100 48 716.5 and DE 101 12 068.0, filed Sep.
30, 2000 and Mar. 12, 2001, respectively.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to sulfonylguanidine
compounds, processes for their production, pharmaceutical
compositions containing these compounds, and the use of
sulfonylguanidines for the production of medicaments and for
treating pain and other medical conditions.
[0003] The cyclic GABA analogue gabapentin is a clinically proven
antiepileptic. Gabapentin additionally exhibits further
interesting, medically relevant properties, in particular as an
analgesic. New classes of structures that have an affinity for the
gabapentin binding site are therefore of interest. In connection
with the aforementioned medical indications there is a further need
of substances that are similar in their properties to gabapentin,
for example as regards analgesic effect.
[0004] The treatment of chronic and non-chronic pain conditions is
very important in medicine. There is a wide need for highly
effective pain treatments. The urgent need for a patient-oriented
and targeted treatment of chronic and non-chronic pain conditions,
which is understood to be the successful and satisfactory treatment
of pain on the part of the patient, is documented in the large
number of scientific studies that have recently appeared in the
field of applied analgesia and in basic research relating to
nociception.
[0005] Conventional opioids such as morphine are highly effective
in treating severe to extremely severe pain. Their use is however
limited by the known side effects such as for example respiratory
depression, vomiting, sedation, constipation and development of
tolerance. Also, they are less effective in treating neuropathic or
incidental pain afflicting in particular tumor patients.
SUMMARY OF THE INVENTION
[0006] An object of the invention was accordingly to provide new
methods of treating pain and other medical conditions.
[0007] Another object of the invention was to provide new compounds
that have an affinity for the gabapentin binding site and/or
corresponding physiological activities, for example with regard to
analgesia, but also other GBP indications.
[0008] The present invention accordingly provides for the use of a
sulfonylguanidine according to the general tautomeric formulas I
and Ia, 1
[0009] wherein
[0010] R.sup.1 is selected from C.sub.1-10-alkyl that is branched
or unbranched, saturated or unsaturated, singly or multiply
substituted or unsubstituted; C.sub.3-8-cycloalkyl or bicyclic
alkylene, in each case saturated or unsaturated, singly or multiply
substituted or unsubstituted; aryl or heteroaryl, in each case
unsubstituted or singly or multiply substituted; or aryl,
C.sub.3-9-cycloalkyl or heteroaryl, bonded via saturated or
unsaturated C.sub.1-3-alkyl, in each case unsubstituted or singly
or multiply substituted;
[0011] R.sup.2 is selected from C.sub.1-10-alkyl that is branched
or unbranched, saturated or unsaturated, singly or multiply
substituted or unsubstituted; C.sub.3-8-cycloalkyl that is
saturated or unsaturated, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case unsubstituted or
singly or multiply substituted; or aryl, C.sub.3-9-cycloalkyl or
heteroaryl, bonded via saturated or unsaturated C.sub.1-3-alkyl,
S(O).sub.2 or NH, in each case unsubstituted or singly or multiply
substituted; or NR.sup.4R.sup.5,
[0012] where R.sup.4, R.sup.5 independently of one another are
selected from H; C.sub.1-8-alkyl that is branched or unbranched,
saturated or unsaturated, singly or multiply substituted or
unsubstituted; C.sub.3-8-cycloalkyl that is saturated or
unsaturated, singly or multiply substituted or unsubstituted; aryl
or heteroaryl, in each case unsubstituted or singly or multiply
substituted; or aryl, C.sub.3-9-cycloalkyl or heteroaryl, bonded
via saturated or unsaturated C.sub.1-3-alkyl, in each case
unsubstituted or singly or multiply substituted; or
SO.sub.2R.sup.6,
[0013] where R.sup.6 is selected from C.sub.1-18-alkyl that is
branched or unbranched, saturated or unsaturated, singly or
multiply substituted or unsubstituted; C.sub.3-8-cycloalkyl that is
saturated or unsaturated, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case unsubstituted or
singly or multiply substituted; or aryl, C.sub.3-9-cycloalkyl or
heteroaryl, bonded via saturated or unsaturated C.sub.1-3-alkyl, in
each case unsubstituted or singly or multiply substituted;
[0014] or R.sup.4 and R.sup.5 together form:
--CH.sub.2CH.sub.2OCH.sub.2CH- .sub.2--;
[0015] --CH.sub.2CH.sub.2N(R.sup.7)CH.sub.2CH.sub.2, where R.sup.7
is selected from C.sub.1-18-alkyl that is branched or unbranched,
saturated or unsaturated, singly or multiply substituted or
unsubstituted; C.sub.3-8-cycloalkyl that is saturated or
unsaturated, singly or multiply substituted or unsubstituted; aryl
or heteroaryl, in each case unsubstituted or singly or multiply
substituted; or aryl, C.sub.3-9-cycloalkyl or heteroaryl, bonded
via saturated or unsaturated C.sub.1-3-alkyl, in each case
unsubstituted or singly or multiply substituted;
[0016] R.sup.3 is selected from H, C.sub.1-10-alkyl that is
branched or unbranched, saturated or unsaturated, singly or
multiply substituted or unsubstituted; C.sub.3-8-cycloalkyl that is
saturated or unsaturated, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case unsubstituted or
singly or multiply substituted; or aryl, C.sub.3-9-cycloalkyl or
heteroaryl, bonded via saturated or unsaturated C.sub.1-3-alkyl, in
each case unsubstituted or singly or multiply substituted; or
[0017] R.sup.2 and R.sup.3 together form
--CH.sub.2(CH.sub.2).sub.nCH.sub.2-- n=2, 3
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2N(R.sup.8) CH.sub.2CH.sub.2--
[0018] where R.sup.8 is selected from C.sub.1-18-alkyl that is
branched or unbranched, saturated or unsaturated, singly or
multiply substituted or unsubstituted; C.sub.3-8-cycloalkyl or
bicyclic alkylene that is saturated or unsaturated, singly or
multiply substituted or unsubstituted; aryl or heteroaryl, in each
case unsubstituted or singly or multiply substituted; or aryl,
C.sub.3-9-cycloalkyl or heteroaryl, bonded via saturated or
unsaturated C.sub.1-3-alkyl, in each case unsubstituted or singly
or multiply substituted;
[0019] optionally in the form of their racemates, their pure
stereoisomers, in particular enantiomers or diastereomers, or in
the form of mixtures of the stereoisomers, in particular of the
enantiomers or diastereomers, in an arbitrary mixture ratio; in the
represented form or in the form of their acids or bases or in the
form of their salts, in particular of the physiologically
compatible salts, or in the form of their solvates, in particular
the hydrates; in both tautomeric forms according to formulas I and
Ia, exclusively in one of the tautomeric forms according to
formulas I or Ia or also in mixtures of both forms according to
formulas I and Ia, in which the preferred tautomeric form may vary
from compound to compound depending on the state of aggregation or
on the chosen solvent;
[0020] for the production of a medicament and for treating pain,
neuropathic, chronic or acute pain, epilepsy and/or migraine,
or
[0021] for the production of a medicament and for the treatment of
hyperalgesia and allodynia, in particular thermal hyperalgesia,
mechanical hyperalgesia and allodynia and cold-induced allodynia,
or inflammatory or post-operative pain, or
[0022] for the production of a medicament and for the treatment of
hot flashes, post-menopausal symptoms, amyotropic lateral sclerosis
(ALS), reflex sympathetic dystrophy (RSD), spastic paralysis,
restless leg syndrome, acquired nystagmus; psychiatric or
neuropathological disorders such as bipolar disorders, anxiety,
panic attacks, mood fluctuations, manic behavior, depression,
manic-depressive behavior; painful diabetic neuropathy, symptoms
and pain due to multiple sclerosis or Parkinson's disease,
neurodegenerative diseases such as Alzheimer's disease,
Huntington's disease, Parkinson's disease and epilepsy;
gastrointestinal lesions; erythromelalgic or post-poliomyelitic
pain, trigeminal or post-herpetic neuralgia; or as an
anticonvulsant, analgesic or anxiolytic.
[0023] In one embodiment of the invention the following applies as
regards the employed sulfonylguanidines according to the general
tautomeric formulas I and Ia: R.sup.1 is selected from
C.sub.11-oalkyl that is branched or unbranched, saturated or
unsaturated, singly or multiply substituted or unsubstituted;
C.sub.3-8-cycloalkyl or bicyclic alkylene, in each case saturated
or unsaturated, singly or multiply substituted or unsubstituted;
phenyl that is unsubstituted or singly or multiply substituted.
[0024] In a further embodiment of the invention the following
applies as regards the employed sulfonylguanidines according to the
general tautomeric formulas I and Ia:
[0025] R.sup.2 is selected from C.sub.1-10-alkyl that is branched
or unbranched, saturated or unsaturated, singly or multiply
substituted or unsubstituted; C.sub.3-8-cycloalkyl that is
saturated or unsaturated, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case unsubstituted or
singly or multiply substituted; or aryl, C.sub.3-9-cycloalkyl or
heteroaryl, bonded via saturated or unsaturated C.sub.1-3-alkyl, in
each case unsubstituted or singly or multiply substituted.
[0026] In another embodiment of the invention the following applies
as regards the employed sulfonylguanidines according to the general
tautomeric formulas I and Ia, R.sup.3 is selected from H or
CH.sub.3.
[0027] In yet a further embodiment of the invention the following
applies as regards the employed sulfonylguanidines according to the
general tautomeric formulas I and Ia:
[0028] R.sup.2 and R.sup.3 together form
--CH.sub.2(CH.sub.2) CH.sub.2--, where n=2 or 3,
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2N(R.sup.8) CH.sub.2CH.sub.2--.
[0029] In a particularly preferred embodiment of the invention the
following applies as regards the employed sulfonylguanidines
according to the general tautomeric formulas I and Ia:
[0030] R.sup.1 is selected from C.sub.3-8-cycloalkyl or bicyclic
alkylene, in each case saturated or unsaturated, singly or multiply
substituted or unsubstituted; aryl or heteroaryl, in each case
unsubstituted or singly or multiply substituted; or aryl,
C.sub.3-8-cycloalkyl or heteroaryl, bonded via saturated or
unsaturated C.sub.1-4-alkyl, in each case unsubstituted or singly
or multiply substituted;
[0031] R.sup.2 is selected from C.sub.1-10-alkyl that is branched
or unbranched, saturated or unsaturated, singly or multiply
substituted or unsubstituted; C.sub.3-8-cycloalkyl that is
saturated or unsaturated, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case unsubstituted or
singly or multiply substituted; or aryl, C.sub.3-9-cycloalkyl or
heteroaryl, bonded via saturated or unsaturated C.sub.1-3-alkyl, in
each case unsubstituted or singly or multiply substituted; and
[0032] R.sup.3 is selected from H, C.sub.1-10-alkyl that is
branched or unbranched, saturated or unsaturated, singly or
multiply substituted or unsubstituted.
[0033] These substances bind to the gabapentin binding site and
exhibit a pronounced analgesic action.
[0034] Within the context of the present invention, alkyl radicals
and cycloalkyl radicals are understood to be saturated and
unsaturated (but not aromatic), branched, unbranched and cyclic
hydrocarbons that may be unsubstituted or singly or multiply
substituted. In this connection C.sub.1-2-alkyl denotes C1- or
C2-alkyl, C.sub.1-3-alkyl denotes C1-, C2- or C3-alkyl,
C.sub.1-4-alkyl denotes Cl-, C2-, C3- or C4-alkyl, C.sub.1-5-alkyl
denotes C1-, C2-, C3-, C4 or C5-alkyl, C.sub.1-6-alkyl denotes C1-,
C2-, C3-, C4-, C5- or C6-alkyl, C.sub.1-7-alkyl denotes C1-, C2-,
C3-, C4-, C5-, C6- or C7-alkyl, C.sub.1-8-alkyl denotes C1-, C2-,
C3-, C4-, C5-, C6-, C7 or C8-alkyl, C.sub.1-10-alkyl denotes C1-,
C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and
C.sub.1-18-alkyl denotes C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-.
C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl.
In addition C.sub.3-4-cycloalkyl denotes C3- or C4-cycloalkyl,
C.sub.3-5-cycloalkyl denotes C3-, C4- or C5-cycloalkyl,
C.sub.3-6-cycloalkyl denotes C3-, C4-, C5- or C6-cycloalkyl,
C.sub.3,7-cycloalkyl denotes C3-, C4-, C5-, C6- or C7-cycloalkyl,
C.sub.3-8-cycloalkyl denotes C3-, C4-, C5-, C6-, C7- or
C8-cycloalkyl, C.sub.4-5-cycloalkyl denotes C4- or C5-cycloalkyl,
C.sub.4-6-cycloalkyl denotes C4-, C5- or C6-cycloalkyl,
C.sub.4-7-cycloalkyl denotes C4-, C5-, C6- or C7-cycloalkyl,
C.sub.5-6-cycloalkyl denotes C5- or C6-cycloalkyl and
C.sub.5-7-cycloalkyl denotes C5-, C6- or C7-cycloalkyl. With regard
to cycloalkyl, the term also includes saturated cycloalkyls in
which 1 or 2 carbon atoms are replaced by a heteroatom, i.e. S, N
or O. The term cycloalkyl however also includes in particular
singly or multiply, preferably singly, unsaturated cycloalkyls
without a heteroatom in the ring as long as the cycloalkyl does not
form an aromatic system. The alkyl or cycloalkyl radicals are
preferably methyl, ethyl, vinyl (ethenyl), propyl,
allyl(2-propenyl), 1-propinyl, methylethyl, butyl, 1-methylpropyl,
2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl,
1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl,
cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl,
cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl,
cyclooctyl, but also adamantyl, CHF.sub.2, CF.sub.3 or CH.sub.2OH
as well as pyrazolinone, oxopyrazolinone, [1,4]dioxane or
dioxolane.
[0035] In connection with alkyl and cycloalkyl, the term
"substituted" within the context of the present invention
denotes--unless expressly defined otherwise--the substitution of at
least one (optionally also several) hydrogen atom(s) by F, Cl, Br,
I, NH.sub.2, SH or OH, wherein the terms "multiply substituted" and
"substituted" in the case of multiple substitution denote that the
substitution takes place on different as well as on the same atoms
multiply with the same or different substituents, for example
triple substitution on the same C atom as in the case of CF.sub.3,
or at different positions as in the case of
--CH(OH)--CH.dbd.CH--CHCl.sub.2. Particularly preferred
substituents in this connection are F, Cl and OH. With regard to
cycloalkyl, the hydrogen atom may also be replaced by
OC.sub.1-3-alkyl or C.sub.1-3-alkyl (in each case singly or
multiply substituted or unsubstituted), in particular methyl,
ethyl, n-propyl, i-propyl, CF.sub.3, methoxy or ethoxy.
[0036] The term (CH.sub.2).sub.3-6 is understood to denote
--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.- 2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, and
the term (CH.sub.2).sub.1-4 is understood to denote --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, and the term
(CH.sub.2).sub.4-5 is understood to denote
--CH.sub.2--CH.sub.2--CH.sub.2- --CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, etc.
[0037] The term "aryl radical" is understood to mean ring systems
with at least one aromatic ring but without heteroatoms in even
only one of the rings. Examples are phenyl, naphthyl,
fluoranthenyl, fluorenyl, tetralinyl or indenyl, in particular
9H-fluorenyl or anthracenyl radicals, which may be unsubstituted or
singly or multiply substituted.
[0038] The term heteroaryl radical is understood to mean
heterocyclic ring systems with at least one unsaturated ring that
may contain one or more heteroatoms from the group comprising
nitrogen, oxygen and/or sulfur, and which may also be singly or
multiply substituted. Examples of the group of heteroaryls that may
be mentioned include furan, benzofuran, thiophene, benzothiophene,
pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline,
phthalazine, benzo[1,2,5]thiadiazole, benzothiazole, indole,
benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and
quinazoline.
[0039] In connection with aryl and heteroaryl, the term substituted
is understood to mean the substitution of the aryl or heteroaryl
group by R.sup.23, OR.sup.23, a halogen, preferably F and/or Cl, a
CF.sub.3, a CN, an NO.sub.2, an NR.sup.24R.sup.25, a
C.sub.1-6-alkyl (saturated), a C.sub.1-6-alkoxy, a
C.sub.3-8-cycloalkoxy, a C.sub.3-8-cycloalkyl or a
C.sub.2-6-alkylene.
[0040] In this connection the radical R.sup.23 denotes H, a
C.sub.1-10-alkyl, preferably a C.sub.1-6-alkyl, an aryl or
heteroaryl radical, or an aryl or heteroaryl radical bonded via
C.sub.1-3-alkyl that is saturated or unsaturated, or a
C.sub.1-3-alkylene group, wherein these aryl and heteroaryl
radicals may not themselves be substituted by aryl or heteroaryl
radicals; the radicals R.sup.24 and R.sup.25, which may be
identical or different, denote H, a C.sub.1-10-alkyl, preferably a
C.sub.1-6-alkyl, an aryl, a heteroaryl radical, or an aryl or
heteroaryl radical bonded via a C.sub.1-3-alkyl that is saturated
or unsaturated, or a C.sub.1-3-alkylene group, wherein these aryl
and heteroaryl radicals may not themselves be substituted by aryl
or heteroaryl radicals, or the radicals R.sup.24 and R.sup.25
together denote --CH.sub.2CH.sub.2OCH.sub.- 2CH.sub.2,
--CH.sub.2CH.sub.2NR.sub.26CH.sub.2CH.sub.2 or (CH.sub.2) 3-6 and
the radical R.sup.26 denotes H, a C.sub.1-10-alkyl, preferably a
C.sub.1-6-alkyl, an aryl or heteroaryl radical, or an aryl or
heteroaryl radical bonded via a C.sub.1-3-alkyl that is saturated
or unsaturated, or a C.sub.1-3-alkylene group, wherein these aryl
and heteroaryl radicals may not themselves be substituted by aryl
or heteroaryl radicals.
[0041] The term salt is understood to mean any form of the active
constituent according to the invention in which this adopts an
ionic form or is charged and is coupled to a counterion (a cation
or anion), and is present in solution. The term is also understood
to include complexes of the active constituent with other molecules
and ions, in particular complexes that are complexed via ionic
interactions. In particular the term is understood to mean
physiologically compatible salts with cations or bases and
physiologically compatible salts with anions or acids.
[0042] The term physiologically compatible salts with cations or
bases is understood within the context of the present invention to
mean salts of at least one of the compounds according to the
invention--generally of a (deprotonated) acid--as an anion with at
least one, preferably inorganic cation, that are physiological
compatible, especially when used in humans and/or mammals.
Particularly preferred are the salts of alkali and alkaline earth
metals, but also with NH.sub.4.sup.+, and in particular (mono) or
(di)sodium, (mono) or (di)potassium, magnesium or calcium
salts.
[0043] The term physiologically compatible salt with anions or
acids is understood within the context of the present invention to
mean salts of at least one of the compounds according to the
invention--generally protonated, for example on the nitrogen
atom--as a cation with at least one anion, that are physiologically
compatible, especially when used in humans and/or mammals. In the
context of the present invention the term is particularly
understood to denote the salt formed with a physiologically
compatible acid, namely salts of the respective active constituent
with inorganic or organic acids, that are physiologically
compatible, especially when used in humans and/or mammals. Examples
of physiologically compatible salts of specific acids are salts of:
hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic
acid, formic acid, acetic acid, oxalic acid, succinic acid,
tartaric acid, mandelic acid, fumaric acid, lactic acid, citric
acid, glutamic acid, 1,1-dioxo-1,2-dihydro
16-benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic
acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3-
or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, .alpha.-lipoic
acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or
aspartic acid. The hydrochloride salt is particularly
preferred.
[0044] All the substances listed hereinbefore and specified for use
displace gabapentin from its binding site, which has also not yet
been experimentally determined. This implies however that the
substances according to the invention bind at the same binding site
or receptor and act physiologically via the same receptor,
presumably with the same activity profile as gabapentin. This
assumption that the same activity is also exerted at the same
binding site is demonstrated by the analgesic effect.
[0045] Thus, the compounds according to the invention not only
displace gabapentin from its binding site but--like
gabapentin--also have a marked analgesic effect. Accordingly, the
invention provides for the use of the aforementioned and defined
sulfonylguanidines in the previously mentioned medical indications
in which gabapentin is active, i.e. in particular in the treatment
of pain, epilepsy or migraine, but specifically also in neuropathic
pain including hyperalgesia and allodynia, and other conditions for
which the use of gabapentin is indicated.
[0046] Gabapentin is a known antiepileptic having an anticonvulsive
action. In addition to this gabapentin is also used in various
other medical conditions, and inter alia is prescribed by
physicians for the treatment of migraine and bipolar disorders as
well as hot flashes (e.g. in the post menopause) (M. Schrope,
Modern Drug Discovery, September 2000, p. 11). Other medical
conditions in which gabapentin exhibits a therapeutic potential
have been identified in human studies and in clinical practice (J.
S. Bryans, D. J. Wustrow; "3-Substituted GABA Analogs with Central
Nervous System Activity: A Review" in Med. Res. Rev. (1999), pp.
149-177). The action of gabapentin is listed in detail in this
review article. For example, gabapentin is effective in the
treatment of chronic pain and behavioral disturbances. In
particular the following properties of gabapentin are listed:
anticonvulsive and antiepileptic actions, the use to treat chronic,
neuropathic pain, in particular thermal hyperalgesia, mechanical
allodynia, and cold-induced allodynia. In addition gabapentin is
effective against neuropathy triggered by nerve damage, and in
particular is also successful in treating neuropathic pain as well
as inflammatory and post-operative pain. Gabapentin is also useful
as an antipsychotic agent, in particular as an anxiolytic. Further
proven indications for use include: amyotrophic lateral sclerosis
(ALS), reflex sympathetic dystrophy (RSD), spastic palsy, restless
leg syndrome, treatment of symptoms and pain caused by multiple
sclerosis, acquired nystagmus, treatment of the symptoms of
Parkinson's disease, painful diabetic neuropathy and psychiatric
disorders, for example bipolar disorders, mood fluctuations, manic
behavior. Gabapentin has also been successfully used to treat
erythromelalgic pain, post-poliomyelitic pain, trigeminal neuralgia
and post-herpetic neuralgia (Bryans and Wustrow (1999), etc.). The
general efficacy of gabapentin in neurodegenerative conditions is
generally known and is also demonstrated by the examples given in
the aforementioned review article. Such neurodegenerative
conditions include for example Alzheimer's disease, Huntington's
disease, Parkinson's disease and epilepsy. The effectiveness of
gabapentin in gastrointestinal disorders is also known.
[0047] In a preferred embodiment of the invention the following
applies as regards the employed sulfonylguanidines according to the
general tautomeric formulas I and Ia:
[0048] R.sup.1 is selected from aryl or heteroaryl, in each case
unsubstituted or singly or multiply substituted; or aryl or
heteroaryl bonded via saturated or unsaturated C.sub.1-3-alkyl, in
each case unsubstituted or singly or multiply substituted;
[0049] preferably, R.sup.1 is selected from aryl or heteroaryl that
is unsubstituted or singly or multiply substituted, preferably with
NO.sub.2, NH.sub.2, F, Cl, Br, I, OH or SH; or
--NHC(O)--C.sub.1-4-alkyl, --C.sub.1-4-alkyl, --OC.sub.1-4-alkyl,
--N(C.sub.1-4-alkyl).sub.2,
[0050] where the C.sub.1-4-alkyl group is in each case branched or
unbranched, saturated or unsaturated, singly or multiply
substituted or unsubstituted;
[0051] in particular, R.sup.1 is selected from phenyl or naphthyl,
especially phenyl, that is unsubstituted or singly or multiply
substituted, preferably by F, Cl, Br, I, OH, NO.sub.2, NH.sub.2;
C.sub.1-4-alkyl, O--C.sub.1-4-alkyl, in particular CH.sub.3,
C.sub.2H.sub.5, tert.-butyl, i-propyl, methoxy, OCF.sub.3 or
ethoxy, in each case branched or unbranched, saturated or
unsaturated, singly or multiply substituted or unsubstituted;
preferably substituted in the meta or para position and in
particular in the para position.
[0052] In another preferred embodiment of the invention the
following applies as regards the employed sulfonylguanidines
according to the general tautomeric formulas I and Ia:
[0053] R.sup.2 is selected from aryl or heteroaryl bonded via
saturated or unsaturated C.sub.1-3-alkyl, in particular CH.sub.2,
in each case unsubstituted or singly or multiply substituted;
[0054] preferably, R.sup.2 is selected from heteroaryl bonded via
saturated or unsaturated C.sub.1-3-alkyl, in particular
--CH.sub.2--, in each case unsubstituted or singly or multiply
substituted;
[0055] in particular, R.sup.2 is selected from pyridinyl,
thiophenyl, furanyl or pyrimidinyl, preferably pyridinyl, bonded
via saturated or unsaturated C.sub.1-3-alkyl, in particular
--CH.sub.2--, in each case unsubstituted or singly or multiply,
preferably singly substituted, in particular by F, Cl, Br, I, OH,
NO.sub.2, SH, NH.sub.2, C.sub.1-4-alkyl, O--C.sub.1-4-alkyl,
preferably substituted in the para position.
[0056] In another preferred embodiment of the invention the
following applies as regards the employed sulfonylguanidines
according to the general tautomeric formulas I and Ia:
[0057] R.sup.3 is selected from H or C.sub.1-4-alkyl, preferably H
or CH.sub.3, in particular H.
[0058] In a preferred embodiment of the invention, the
sulfonylguanidines employed are selected from the group consisting
of:
[0059]
N-{amino-[pyridin-2-yl-methyl)-amino]-methylene}-4-methylbenzenesul-
fonamide (1)
[0060] N-[amino-(benzylaminomethylene)]-4-methylbenzene-sulfonamide
(2)
[0061]
N-(aminomorpholin-4-yl-methylene)-4-methylbenzene-sulfonamide
(3)
[0062]
N-(aminocyclohexylaminomethylene)-4-methylbenzene-sulfonamide
(4)
[0063] N-(aminophenylaminomethylene)-4-methylbenzene-sulfonamide
(5)
[0064]
N-[(amino-4-methoxybenzylamino)-methylene]-4-methylbenzene-sulfonam-
ide (6)
[0065]
N-[amino-(naphthalin-2-yl-amino)-methylene]-4-methylbenzenesulfonam-
ide (7)
[0066]
N-[amino-(4-methylpiperazin-1-yl-amino)-methylene]-4-methylbenzenes-
ulfonamide (8)
[0067]
N-[amino-(N'-pyridin-2-yl-hydrazino)-methylene]-4-methylbenzenesulf-
onamide (9)
[0068] N-[aminopropylaminomethylene]-4-methylbenzene-sulfonamide
(10)
[0069] N-(aminobutylaminomethylene)-4-methylbenzene-sulfonamide
(11)
[0070] N-[aminobutylaminomethylene]-4-methylbenzene-sulfonamide
(12)
[0071] N-[aminobutylaminomethylene]-4-methylbenzene-sulfonamide
(13)
[0072] N-[aminophenethylaminomethylene]-4-methylbenzene-sulfonamide
(14)
[0073]
N-[amino-sec-butylaminomethylene]-4-methylbenzene-sulfonamide
(15)
[0074]
N-[amino-(N'-tosyl-2-yl-hydrazino)-4-methylbenzene-sulfonamide
(16)
[0075]
N-[amino-(2H-pyrazol-3-yl-amino)-methylene]-4-methylbenzenesulfonam-
ide (17)
[0076]
N-(aminopyrrolidin-1-yl-methylene)-4-methylbenzene-sulfonamide
(18)
[0077]
N-[amino-(naphthalin-1-yl-amino)-methylene]-4-methyl-benzenesulfona-
mide (19)
[0078]
N-[amino-(morpholin-4-yl-amino)-methylene]-4-methyl-benzenesulfonam-
ide (20)
[0079]
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide (21)
[0080]
N-{amino-[(pyridin-4-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (22)
[0081]
N-{amino-[(pyridin-3-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (23)
[0082]
N-[amino-(pyridin-3-yl-amino)-methylene]-4-methyl-benzenesulfonamid-
e (24)
[0083]
N-(aminopyrrolidin-1-yl-methylene)-4-chlorobenzene-sulfonamide
(25)
[0084] N-(aminopyrrolidin-1-yl-methylene)-benzenesulfonamide
(26)
[0085]
N-(aminopyrrolidin-1-yl-methylene)-2-nitrobenzene-sulfonamide
(27)
[0086]
N-[amino-(morpholin-4-yl-amino)-methylene]-4-chlorobenzenesulfonami-
de (28)
[0087]
N-[amino-(morpholin-4-yl-amino)-methylene]-benzenesulfonamide
(29)
[0088] Naphthalene-1-sulfonic acid
amino-(morpholin-4-yl-amino)-methylene amide (30)
[0089]
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-C-phenylmethanesu-
lfonamide (31)
[0090]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-bromobenzenesulf-
onamide (32)
[0091]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3,4-dichlorobenzen-
esulfonamide (33)
[0092]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-isopropylbenzene-
sulfonamide (34)
[0093]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-iodobenzenesulfo-
namide (35)
[0094]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-benzenesulfonamide
(36)
[0095] Naphthalene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene amide (37)
[0096] 1-methyl-1H-imidazole-4-sulfonic acid
amino-[(pyridin-2-yl-methyl)-- amino]-methylene amide (38)
[0097]
N-[4-({amino-[(pyridin-2-yl-methyl)-amino]-methylene}-sulfamoyl)-ph-
enyl]-acetamide (39)
[0098]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-fluorobenzenesul-
fonamide (40)
[0099]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-2,4,6-trimethylben-
zenesulfonamide (41)
[0100]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-propylbenzenesul-
fonamide (42)
[0101]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-methoxybenzenesu-
lfonamide (43)
[0102] Naphthalene-1-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene amide (44)
[0103]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3-methylbenzenesul-
fonamide (45)
[0104] Thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene amide (46)
[0105] Quinoline-8-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene amide (47)
[0106] 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (48)
[0107]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenze-
nesulfonamide (49)
[0108]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulf-
onamide (50)
[0109]
N-{amino[(pyrimidin-2-yl-methyl)-amino]-methylene}-4-tert.-butylben-
zenesulfonamide (51)
[0110]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfon-
amide (52)
[0111]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfo-
namide (53)
[0112]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesu-
lfonamide (54)
[0113]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfo-
namide (55)
[0114]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzene-
sulfonamide (56)
[0115]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-butylbenzenesul-
fonamide (57)
[0116]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-propylbenzenesu-
lfonamide (58)
[0117]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-isopropylbenzen-
esulfonamide (59)
[0118]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenz-
enesulfonamide (60)
[0119]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide (61)
[0120]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (62), and
[0121]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfo-
namide (63)
[0122] optionally in the form of their racemates, their pure
stereoisomers, in particular enantiomers or diastereomers, or in
the form of mixtures of the stereoisomers, in particular of the
enantiomers or diastereomers, in an arbitrary mixture ratio; in the
represented form or in the form of their acids or their bases; or
in the form of their salts, in particular the physiologically
compatible salts, preferably the hydrochloride or sodium salt; or
in the form of their solvates, in particular the hydrates; in both
tautomeric forms according to formulas I and Ia, exclusively in one
of the tautomeric forms according to formulas I or Ia or also in
mixtures of both forms according to formulas I and Ia wherein the
preferred tautomeric form may vary from compound to compound
depending for example on the state of aggregation or on the chosen
solvent.
[0123] Preferred compounds according to the invention are selected
from the group consisting of:
[0124]
N-{amino-[pyridin-2-yl-methyl)-amino]-methylene}-4-methylbenzenesul-
fonamide (1)
[0125] N-[amino-(benzylaminomethylene)]-4-methylbenzene-sulfonamide
(2)
[0126]
N-(aminomorpholin-4-yl-methylene)-4-methylbenzene-sulfonamide
(3)
[0127]
N-(aminocyclohexylaminomethylene)-4-methylbenzene-sulfonamide
(4)
[0128] N-(aminophenylaminomethylene)-4-methylbenzene-sulfonamide
(5)
[0129]
N-[(amino-4-methoxybenzylamino)-methylene]-4-methylbenzene-sulfonam-
ide (6)
[0130]
N-[amino-(naphthalin-2-yl-amino)-methylene]-4-methylbenzenesulfonam-
ide (7)
[0131]
N-[amino-(4-methylpiperazin-1-yl-amino)-methylene]-4-methylbenzenes-
ulfonamide (8)
[0132]
N-[amino-(N'-pyridin-2-yl-hydrazino)-methylene]-4-methylbenzenesulf-
onamide (9)
[0133] N-[aminopropylaminomethylene]-4-methylbenzene-sulfonamide
(10)
[0134] N-(aminobutylaminomethylene)-4-methylbenzene-sulfonamide
(11)
[0135] N-[aminobutylaminomethylene]-4-methylbenzene-sulfonamide
(12)
[0136] N-[aminobutylaminomethylene]-4-methylbenzene-sulfonamide
(13)
[0137] N-[aminophenethylaminomethylene]-4-methylbenzene-sulfonamide
(14)
[0138]
N-[amino-sec-butylaminomethylene]-4-methylbenzene-sulfonamide
(15)
[0139]
N-[amino-(N'-tosyl-2-yl-hydrazino)-4-methylbenzene-sulfonamide
(16)
[0140]
N-[amino-(2H-pyrazol-3-yl-amino)-methylene]-4-methylbenzenesulfonam-
ide (17)
[0141]
N-(aminopyrrolidin-1-yl-methylene)-4-methylbenzene-sulfonamide
(18)
[0142]
N-[amino-(naphthalin-1-yl-amino)-methylene]-4-methyl-benzenesulfona-
mide (19)
[0143]
N-[amino-(morpholin-4-yl-amino)-methylene]-4-methyl-benzenesulfonam-
ide (20)
[0144]
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide (21)
[0145]
N-{amino-[(pyridin-4-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (22)
[0146]
N-{amino-[(pyridin-3-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (23)
[0147]
N-[amino-(pyridin-3-yl-amino)-methylene]-4-methyl-benzenesulfonamid-
e (24)
[0148]
N-(aminopyrrolidin-1-yl-methylene)-4-chlorobenzene-sulfonamide
(25)
[0149] N-(aminopyrrolidin-1-yl-methylene)-benzenesulfonamide
(26)
[0150]
N-(aminopyrrolidin-1-yl-methylene)-2-nitrobenzene-sulfonamide
(27)
[0151]
N-[amino-(morpholin-4-yl-amino)-methylene]-4-chlorobenzenesulfonami-
de (28)
[0152]
N-[amino-(morpholin-4-yl-amino)-methylene]-benzenesulfonamide
(29)
[0153] Naphthalene-1-sulfonic acid
amino-(morpholin-4-yl-amino)-methylene amide (30)
[0154]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-bromobenzenesulf-
onamide (32)
[0155]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3,4-dichlorobenzen-
esulfonamide (33)
[0156]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-isopropylbenzene-
sulfonamide (34)
[0157]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-iodobenzenesulfo-
namide (35)
[0158]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-benzenesulfonamide
(36)
[0159] Naphthalene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene amide (37)
[0160]
N-[4-({amino-[(pyridin-2-yl-methyl)-amino]-methylene}-sulfamoyl)-ph-
enyl]-acetamide (39)
[0161]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-fluorobenzenesul-
fonamide (40)
[0162]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-2,4,6-trimethylben-
zenesulfonamide (41)
[0163]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-propylbenzenesul-
fonamide (42)
[0164]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-methoxybenzenesu-
lfonamide (43)
[0165] Naphthalene-1-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene amide (44)
[0166]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3-methylbenzenesul-
fonamide (45)
[0167] Thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene amide (46)
[0168] Quinoline-8-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene amide (47)
[0169] 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (48)
[0170]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenze-
nesulfonamide (49)
[0171]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulf-
onamide (50)
[0172]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfon-
amide (52)
[0173]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfo-
namide (53)
[0174]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesu-
lfonamide (54)
[0175]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfo-
namide (55)
[0176]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzene-
sulfonamide (56)
[0177]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-butylbenzenesul-
fonamide (57)
[0178]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-propylbenzenesu-
lfonamide (58)
[0179]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-isopropylbenzen-
esulfonamide (59)
[0180]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenz-
enesulfonamide (60)
[0181]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide (61)
[0182]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (62), and
[0183]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfo-
namide (63),
[0184] especially
[0185]
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide (21)
[0186]
N-{amino-[(pyridin-4-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (22)
[0187]
N-{amino-[(pyridin-3-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (23)
[0188]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-bromobenzenesulf-
onamide (32)
[0189]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3,4-dichlorobenzen-
esulfonamide (33)
[0190]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-isopropylbenzene-
sulfonamide (34)
[0191]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-iodobenzenesulfo-
namide (35)
[0192]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-benzenesulfonamide
(36)
[0193] Naphthalene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene amide (37)
[0194]
N-[4-({amino-[(pyridin-2-yl-methyl)-amino]-methylene}-sulfamoyl)-ph-
enyl]-acetamide (39)
[0195]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-fluorobenzenesul-
fonamide (40)
[0196]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-2,4,6-trimethylben-
zenesulfonamide (41)
[0197]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-propylbenzenesul-
fonamide (42)
[0198]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-methoxybenzenesu-
lfonamide (43)
[0199] Naphthalene-1-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene amide (44)
[0200]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3-methylbenzenesul-
fonamide (45)
[0201] Thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene amide (46)
[0202] Quinoline-8-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene amide (47)
[0203] 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (48)
[0204]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenze-
nesulfonamide (49)
[0205]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulf-
onamide (50)
[0206]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfon-
amide (52)
[0207]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfo-
namide (53)
[0208]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesu-
lfonamide (54)
[0209]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfo-
namide (55)
[0210]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzene-
sulfonamide (56)
[0211]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-butylbenzenesul-
fonamide (57)
[0212]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-propylbenzenesu-
lfonamide (58)
[0213]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-isopropylbenzen-
esulfonamide (59)
[0214]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenz-
enesulfonamide (60)
[0215]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide (61)
[0216]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (62), and
[0217]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfo-
namide (63),
[0218] optionally in the form of their racemates, their pure
stereoisomers, in particular enantiomers or diastereomers, or in
the form of mixtures of the stereoisomers, in particular of the
enantiomers or diastereomers, in an arbitrary mixture ratio; in the
represented form or in the form of their acids or their bases; or
in the form of their salts, in particular the physiologically
compatible salts, preferably the hydrochloride or sodium salt; or
in the form of their solvates, in particular the hydrates; in both
tautomeric forms according to formulas I and Ia, exclusively in one
of the tautomeric forms according to formulas I or Ia or also in
mixtures of both forms according to formulas I and Ia wherein the
preferred tautomeric form may vary from compound to compound
depending for example on the state of aggregation or on the chosen
solvent.
[0219] Further compounds from which are selected compounds that are
preferably used according to the invention, optionally in the form
or their racemates, their pure stereoisomers, in particular
enantiomers or diastereomers, or in the form of mixtures of the
stereoisomers, in particular of the enantiomers or diastereomers,
in an arbitrary mixture ratio; in the represented form or in the
form of their acids or bases or in the form of their salts, in
particular of the physiologically compatible salts, preferably the
hydrochloride or sodium salt; or in the form of their solvates, in
particular the hydrates; in both tautomeric forms according to
formulas I and Ia, exclusively in one of the tautomeric forms
according to formulas I or Ia or also in mixtures of both forms
according to formulas I and Ia, in which the preferred tautomeric
form may vary from compound to compound for example depending on
the state of aggregation or on the chosen solvent, are shown as
structural formulas of FIGS. 1-40.
[0220] In this connection it is furthermore preferred if the
sulfonylguanidine used according to the invention is present
entirely or substantially entirely in the tautomeric form according
to formula I.
[0221] The present invention preferably also provides
sulfonylguanidines used according to the invention that are present
entirely or substantially entirely in the tautomeric form according
to formula Ia.
[0222] The invention moreover provides the sulfonylguanidines
according to the general tautomeric formulas I and Ia, 2
[0223] wherein
[0224] R.sup.1 is selected from C.sub.1-10-alkyl that is branched
or unbranched, saturated or unsaturated, singly or multiply
substituted or unsubstituted; C.sub.3-8-cycloalkyl or bicyclic
alkylene, in each case saturated or unsaturated, singly or multiply
substituted or unsubstituted; aryl or heteroaryl, in each case
unsubstituted or singly or multiply substituted; or aryl,
C.sub.3-9-cycloalkyl or heteroaryl, bonded via saturated or
unsaturated C.sub.1-4-alkyl, in particular C.sub.1-3-alkyl, in each
case unsubstituted or singly or multiply substituted;
[0225] R.sup.2 is selected from C.sub.1-10-alkyl that is branched
or unbranched, saturated or unsaturated, singly or multiply
substituted or unsubstituted; C.sub.3-8-cycloalkyl that is
saturated or unsaturated, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case unsubstituted or
singly or multiply substituted; or aryl, C.sub.3-9-cycloalkyl or
heteroaryl, bonded via saturated or unsaturated C.sub.1-3-alkyl,
S(O).sub.2 or NH, in each case unsubstituted or singly or multiply
substituted; or NR.sup.4R.sup.5,
[0226] where R.sup.4, R.sup.5 independently of one another are
selected from H; C.sub.1-18-alkyl that is branched or unbranched,
saturated or unsaturated, singly or multiply substituted or
unsubstituted; C.sub.3-8-cycloalkyl that is saturated or
unsaturated, singly or multiply substituted or unsubstituted;
[0227] aryl or heteroaryl, in each case unsubstituted or singly or
multiply substituted; or aryl, C.sub.3-9-cycloalkyl or heteroaryl,
bonded via saturated or unsaturated C.sub.1-3-alkyl, in each case
unsubstituted or singly or multiply substituted; or
SO.sub.2R.sup.6,
[0228] where R.sup.6 is selected from C.sub.1-18-alkyl that is
branched or unbranched, saturated or unsaturated, singly or
multiply substituted or unsubstituted; C.sub.3-8-cycloalkyl that is
saturated or unsaturated, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case unsubstituted or
singly or multiply substituted; or aryl, C.sub.3-9-cycloalkyl or
heteroaryl, bonded via saturated or unsaturated C.sub.1-3-alkyl, in
each case unsubstituted or singly or multiply substituted;
[0229] or R.sup.4 and R.sup.5 together form
--CH.sub.2CH.sub.2OCH.sub.2CH.- sub.2--;
[0230] --CH.sub.2CH.sub.2N(R.sup.7)CH.sub.2CH.sub.2, where R.sup.7
is selected from C.sub.1-18-alkyl that is branched or unbranched,
saturated or unsaturated, singly or multiply substituted or
unsubstituted; C.sub.3-8-cycloalkyl that is saturated or
unsaturated, singly or multiply substituted or unsubstituted; aryl
or heteroaryl, in each case unsubstituted or singly or multiply
substituted; or aryl, C.sub.3-9-cycloalkyl or heteroaryl, bonded
via saturated or unsaturated C.sub.1-3-alkyl, in each case
unsubstituted or singly or multiply substituted;
[0231] R.sup.3 is selected from H, C.sub.1-10-alkyl that is
branched or unbranched, saturated or unsaturated, singly or
multiply substituted or unsubstituted; C.sub.3-8-cycloalkyl that is
saturated or unsaturated, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case unsubstituted or
singly or multiply substituted; or aryl, C.sub.3-9-cycloalkyl or
heteroaryl, bonded via saturated or unsaturated C.sub.1-3-alkyl, in
each case unsubstituted or singly or multiply substituted;
[0232] or R.sup.2 and R.sup.3 together form
--CH.sub.2(CH.sub.2).sub.nCH.sub.2--, where n=2 or 3,
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2N(R.sup.8)CH.sub.2CH.sub.2
[0233] where R.sup.8 is selected from C.sub.1-18-alkyl that is
branched or unbranched, saturated or unsaturated, singly or
multiply substituted or unsubstituted; C.sub.3-8-cycloalkyl or
bicyclic alkylene that is saturated or
[0234] unsaturated, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case unsubstituted or
singly or multiply substituted; or aryl, C.sub.3-9-cycloalkyl or
heteroaryl, bonded via saturated or unsaturated C.sub.1-3-alkyl, in
each case unsubstituted or singly or multiply substituted;
[0235] optionally in the form of their racemates, their pure
stereoisomers, in particular enantiomers or diastereomers, or in
the form of mixtures of the stereoisomers, in particular of the
enantiomers or diastereomers, in an arbitrary mixture ratio; in the
represented form or in the form of their acids or bases or in the
form of their salts, in particular of the physiologically
compatible salts, or in the form of their solvates, in particular
the hydrates; in both tautomeric forms according to formulas I and
Ia, exclusively in one of the tautomeric forms according to
formulas I or Ia or also in mixtures of both forms according to
formulas I and Ia, in which the preferred tautomeric form may vary
from compound to compound depending on the state of aggregation or
on the chosen solvent.
[0236] In one embodiment of the invention the following applies as
regards the sulfonylguanidines according to the invention of the
general tautomeric formulas I and Ia: R.sup.1 is selected from
C.sub.1-10-alkyl that is branched or unbranched, saturated or
unsaturated, singly or multiply substituted or unsubstituted;
C.sub.3-8-cycloalkyl or bicyclic alkylene, in each case saturated
or unsaturated, singly or multiply substituted or unsubstituted;
phenyl that is unsubstituted or singly or multiply substituted.
[0237] In another embodiment of the invention the following applies
as regards the sulfonylguanidines according to the invention of the
general tautomeric formulas I and Ia:
[0238] R.sup.2 is selectd from C.sub.1-10-alkyl that is branched or
unbranched, saturated or unsaturated, singly or multiply
substituted or unsubstituted; C.sub.3-8-cycloalkyl that is
saturated or unsaturated, singly or multiply substituted or
unsubstituted; aryl or heteroaryl, in each case unsubstituted or
singly or multiply substituted; or aryl, C.sub.3-9-cycloalkyl or
heteroaryl, bonded via saturated or unsaturated C.sub.1-3-alkyl, in
each case unsubstituted or singly or multiply substituted, In yet a
further embodiment of the invention the following applies as
regards the sulfonylguanidines according to the invention of the
general tautomeric formulas I and Ia:
[0239] R.sup.3 is selected from H or CH.sub.3.
[0240] In a further embodiment of the invention the following
applies as regards the sulfonylguanidines according to the
invention of the general tautomeric formulas I and Ia:
[0241] R.sup.2 and R.sup.3 together form
--CH.sub.2(CH.sub.2).sub.nCH.sub.2--, where n=2 or 3,
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2N(R.sup.8)CH.sub.2CH.sub.2--.
[0242] In a particularly preferred embodiment of the invention the
following applies as regards the sulfonylguanidines according to
the invention of the general tautomeric formulas I and Ia:
[0243] R.sup.1 is selected from aryl or heteroaryl, in each case
unsubstituted or singly or multiply substituted;
[0244] R.sup.2 is selected from aryl or heteroaryl, in each case
unsubstituted or singly or multiply substituted and bonded via
saturated or unsaturated C.sub.1-3-alkyl, and
[0245] R.sup.3 is hydrogen, with the exception of compounds in
which R.sup.2 denotes phenyl bonded via CH.sub.2 and R.sup.1
denotes phenyl substituted or
[0246] unsubstituted by methyl or NH.sub.2, also with a
condensed-on ring system.
[0247] In a preferred embodiment of the invention the following
applies as regards the sulfonylguanidines according to the
invention of the general tautomeric formulas I and Ia:
[0248] R.sup.1 is selected from aryl or heteroaryl that is
unsubstituted or singly or multiply substituted with NO.sub.2,
NH.sub.2, F, Cl, Br, I, OH or SH; or --NHC(O)--C.sub.1-4-alkyl,
--C.sub.1-4-alkyl, --OC.sub.1-4-alkyl, --N(C.sub.1-4-alkyl).sub.2,
where the C.sub.1-4-alkyl group is in each case branched or
unbranched, saturated or unsaturated, singly or multiply
substituted or unsubstituted;
[0249] in particular, R.sup.1 is selected from phenyl or naphthyl,
in particular phenyl, that is unsubstituted or singly or multiply
substituted by F, Cl, Br, I, OH, NO.sub.2, NH.sub.2;
C.sub.1-4-alkyl, O-C.sub.1-4-alkyl, in particular CH.sub.3,
C.sub.2H.sub.5, i-propyl, tert.-butyl, methoxy, OCF.sub.3 or
ethoxy, in each case branched or unbranched, saturated or
unsaturated, singly or multiply substituted or unsubstituted;
preferably substituted in the meta or para position and in
particular in the para position.
[0250] In a preferred embodiment of the invention the following
applies as regards the sulfonylguanidines according to the
invention of the general tautomeric formulas I and Ia:
[0251] R.sup.2 is selected from heteroaryl bonded via saturated or
unsaturated C.sub.1-3-alkyl, in particular --CH.sub.2--, in each
case unsubstituted or singly or multiply substituted;
[0252] in particular, R.sup.2 is selected from pyridinyl,
thiophenyl, furanyl or pyrimidinyl, preferably pyridinyl, bonded
via saturated or unsaturated C.sub.1-3-alkyl, in particular
--CH.sub.2--, in each case unsubstituted or singly or multiply,
preferably singly substituted, in particular by F, Cl, Br, I, OH,
NO.sub.2, SH, NH.sub.2, C.sub.1-4-alkyl, O--C.sub.1-4-alkyl,
preferably substituted in the para position.
[0253] In one embodiment of the invention the sulfonylguanidines
according to the invention are selected from the following
group:
[0254]
N-{amino-[pyridin-2-yl-methyl)-amino]-methylene}-4-methylbenzenesul-
fonamide (1)
[0255] N-[amino-(benzylaminomethylene)]-4-methylbenzene-sulfonamide
(2)
[0256]
N-(aminomorpholin-4-yl-methylene)-4-methylbenzene-sulfonamide
(3)
[0257]
N-(aminocyclohexylaminomethylene)-4-methylbenzene-sulfonamide
(4)
[0258] N-(aminophenylaminomethylene)-4-methylbenzene-sulfonamide
(5)
[0259]
N-[(amino-4-methoxybenzylamino)-methylene]-4-methylbenzene-sulfonam-
ide (6)
[0260]
N-[amino-(naphthalin-2-yl-amino)-methylene]-4-methylbenzenesulfonam-
ide (7)
[0261]
N-[amino-(4-methylpiperazin-1-yl-amino)-methylene]-4-methylbenzenes-
ulfonamide (8)
[0262]
N-[amino-(N'-pyridin-2-yl-hydrazino)-methylene]-4-methylbenzenesulf-
onamide (9)
[0263] N-[aminopropylaminomethylene]-4-methylbenzene-sulfonamide
(10)
[0264] N-(aminobutylaminomethylene)-4-methylbenzene-sulfonamide
(11)
[0265] N-[aminobutylaminomethylene]-4-methylbenzene-sulfonamide
(12)
[0266] N-[aminobutylaminomethylene]-4-methylbenzene-sulfonamide
(13)
[0267] N-[aminophenethylaminomethylene]-4-methylbenzene-sulfonamide
(14)
[0268]
N-[amino-sec-butylaminomethylene]-4-methylbenzene-sulfonamide
(15)
[0269]
N-[amino-(N'-tosyl-2-yl-hydrazino)-4-methylbenzene-sulfonamide
(16)
[0270]
N-[amino-(2H-pyrazol-3-yl-amino)-methylene]-4-methylbenzenesulfonam-
ide (17)
[0271]
N-(aminopyrrolidin-1-yl-methylene)-4-methylbenzene-sulfonamide
(18)
[0272]
N-[amino-(naphthalin-1-yl-amino)-methylene]-4-methyl-benzenesulfona-
mide (19)
[0273]
N-[amino-(morpholin-4-yl-amino)-methylene]-4-methyl-benzenesulfonam-
ide (20)
[0274]
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide (21)
[0275]
N-{amino-[(pyridin-4-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (22)
[0276]
N-{amino-[(pyridin-3-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (23)
[0277]
N-[amino-(pyridin-3-yl-amino)-methylene]-4-methyl-benzenesulfonamid-
e (24)
[0278]
N-(aminopyrrolidin-1-yl-methylene)-4-chlorobenzene-sulfonamide
(25)
[0279] N-(aminopyrrolidin-1-yl-methylene)-benzenesulfonamide
(26)
[0280]
N-(aminopyrrolidin-1-yl-methylene)-2-nitrobenzene-sulfonamide
(27)
[0281]
N-[amino-(morpholin-4-yl-amino)-methylene]-4-chlorobenzenesulfonami-
de (28)
[0282]
N-[amino-(morpholin-4-yl-amino)-methylene]-benzenesulfonamide
(29)
[0283] Naphthalene-1-sulfonic acid
amino-(morpholin-4-yl-amino)-methylene amide (30)
[0284]
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-C-phenylmethanesu-
lfonamide (31)
[0285]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-bromobenzenesulf-
onamide (32)
[0286]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3,4-dichlorobenzen-
esulfonamide (33)
[0287]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-isopropylbenzene-
sulfonamide (34)
[0288]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-iodobenzenesulfo-
namide (35)
[0289]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-benzenesulfonamide
(36)
[0290] Naphthalene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene amide (37)
[0291] 1-methyl-1H-imidazole-4-sulfonic acid
amino-[(pyridin-2-yl-methyl)-- amino]-methylene amide (38)
[0292]
N-[4-({amino-[(pyridin-2-yl-methyl)-amino]-methylene}-sulfamoyl)-ph-
enyl]-acetamide (39)
[0293]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-fluorobenzenesul-
fonamide (40)
[0294]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-2,4,6-trimethylben-
zenesulfonamide (41)
[0295]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-propylbenzenesul-
fonamide (42)
[0296]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-methoxybenzenesu-
lfonamide (43)
[0297] Naphthalene-1-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene amide (44)
[0298]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3-methylbenzenesul-
fonamide (45)
[0299] Thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene amide (46)
[0300] Quinoline-8-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene amide (47)
[0301] 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (48)
[0302]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenze-
nesulfonamide (49)
[0303]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulf-
onamide (50)
[0304]
N-{amino[(pyrimidin-2-yl-methyl)-amino]-methylene}-4-tert.-butylben-
zenesulfonamide (51)
[0305]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfon-
amide (52)
[0306]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfo-
namide (53)
[0307]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesu-
lfonamide (54)
[0308]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfo-
namide (55)
[0309]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzene-
sulfonamide (56)
[0310]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-butylbenzenesul-
fonamide (57)
[0311]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-propylbenzenesu-
lfonamide (58)
[0312]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-isopropylbenzen-
esulfonamide (59)
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-tert-
.-butylbenzenesulfonamide (60)
[0313]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide (61)
[0314]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (62)
[0315]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfo-
namide (63)
[0316] optionally in the form of their racemates, their pure
stereoisomers, in particular enantiomers or diastereomers, or in
the form of mixtures of the stereoisomers, in particular of the
enantiomers or diastereomers, in an arbitrary mixture ratio; in the
represented form or in the form of their acids or their bases; or
in the form of their salts, in particular the physiologically
compatible salts, preferably the hydrochloride or sodium salt; or
in the form of their solvates, in particular the hydrates; in both
tautomeric forms according to formulas I and Ia, exclusively in one
of the tautomeric forms according to formulas I or Ia or also in
mixtures of both forms according to formulas I and Ia, wherein the
preferred tautomeric form may vary from compound to compound
depending for example on the state of aggregation or on the chosen
solvent.
[0317] In a particularly preferred embodiment of the invention the
sulfonylguanidines according to the invention are selected from the
following group:
[0318]
N-{amino-[pyridin-2-yl-methyl)-amino]-methylene}-4-methylbenzenesul-
fonamide (1)
[0319] N-[amino-(benzylaminomethylene)]-4-methylbenzene-sulfonamide
(2)
[0320]
N-[(amino-4-methoxybenzylamino)-methylene]-4-methylbenzene-sulfonam-
ide (6)
[0321] N-[aminophenethylaminomethylene]-4-methylbenzene-sulfonamide
(14)
[0322]
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide (21)
[0323]
N-{amino-[(pyridin-4-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (22)
[0324]
N-{amino-[(pyridin-3-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (23)
[0325]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-bromobenzenesulf-
onamide (32)
[0326]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3,4-dichlorobenzen-
esulfonamide (33)
[0327]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-isopropylbenzene-
sulfonamide (34)
[0328]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-iodobenzenesulfo-
namide (35)
[0329]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-benzenesulfonamide
(36)
[0330] Naphthalene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene amide (37)
[0331] 1-methyl-1H-imidazole-4-sulfonic acid
amino-[(pyridin-2-yl-methyl)-- amino]-methylene amide (38)
[0332]
N-[4-({amino-[(pyridin-2-yl-methyl)-amino]-methylene}-sulfamoyl)-ph-
enyl]-acetamide (39)
[0333]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-fluorobenzenesul-
fonamide (40)
[0334]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-2,4,6-trimethylben-
zenesulfonamide (41)
[0335]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-propylbenzenesul-
fonamide (42)
[0336]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-methoxybenzenesu-
lfonamide (43)
[0337] Naphthalene-1-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene amide (44)
[0338]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3-methylbenzenesul-
fonamide (45)
[0339] Thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene amide (46)
[0340] Quinoline-8-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene amide (47)
[0341] 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (48)
[0342]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenze-
nesulfonamide (49)
[0343]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulf-
onamide (50)
[0344]
N-{amino[(pyrimidin-2-yl-methyl)-amino]-methylene}-4-tert.-butylben-
zenesulfonamide (51)
[0345]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfon-
amide (52)
[0346]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfo-
namide (53)
[0347]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesu-
lfonamide (54)
[0348]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfo-
namide (55)
[0349]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzene-
sulfonamide (56)
[0350]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-butylbenzenesul-
fonamide (57)
[0351]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-propylbenzenesu-
lfonamide (58)
[0352]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-isopropylbenzen-
esulfonamide (59)
[0353]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenz-
enesulfonamide (60)
[0354]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide (61)
[0355]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (62), and
[0356]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfo-
namide (63)
[0357] optionally in the form of their racemates, their pure
stereoisomers, in particular enantiomers or diastereomers, or in
the form of mixtures of the stereoisomers, in particular of the
enantiomers or diastereomers, in an arbitrary mixture ratio; in the
represented form or in the form of their acids or their bases; or
in the form of their salts, in particular the physiologically
compatible salts, preferably the hydrochloride or sodium salt; or
in the form of their solvates, in particular the hydrates; in both
tautomeric forms according to formulas I and Ia, exclusively in one
of the tautomeric forms according to formulas I or Ia or also in
mixtures of both forms according to formulas I and Ia, wherein the
preferred tautomeric form may vary from compound to compound
depending for example on the state of aggregation or on the chosen
solvent.
[0358] Further compounds which are preferred according to the
invention are selected in the form of their racemates, enantiomers,
diastereomers, in particular mixtures of their enantiomers or
diastereomers or of an individual enantiomer or diastereomer,
optionally in the form of their racemates, their pure
stereoisomers, in particular enantiomers or diastereomers, or in
the form of mixtures of these stereoisomers, in particular the
enantiomers or diastereomers, in an arbitrary mixture ratio, in the
represented form or in the form of their acids or their bases, or
in the form of their salts, in particular in the form of the
physiologically compatible salts, preferably the hydrochloride or
sodium salt, or in the form of their solvates, in particular the
hydrates, in both tautomeric forms according to formulas I and Ia,
exclusively in one of the tautomeric forms according to formulas I
or Ia, or also in mixtures of both forms according to formulas I
and Ia, wherein the preferred tautomeric form may vary from
compound to compound depending for example on the state of
aggregation or the chosen solvent, from the group of compounds
shown as structural formulas in FIGS. 1-40.
[0359] In this connection, it is furthermore preferred if the
sulfonylguanidine according to the invention is present entirely or
substantially entirely in the tautomeric form according to formula
I.
[0360] The present invention similarly preferably provides
sulfonylguanidines according to the invention that are present
invention entirely or substantially entirely in the tautomeric form
according to formula Ia.
[0361] The sulfonylguanidines according to the invention are
toxicologically harmless, with the result that they are suitable as
a pharmaceutically active constituent in medicaments. The invention
accordingly also provides medicaments containing at least one
sulfonylguanidine according to the invention, as well as optionally
suitable additives and/or auxiliary substances and/or optionally
further active constituents.
[0362] The same applies to the sulfonylguanidines used according to
the invention in the aforementioned medical conditions, since also
the sulfonylguanidines used according to the invention are
naturally toxicologically harmless, with the result that they are
suitable for use as a pharmaceutical active constituent in
medicaments. The invention furthermore also provides medicaments
containing at least one of the sulfonylguanidines used according to
the invention, as well as optionally suitable additives and/or
auxiliary substances and/or optionally further active
constituents.
[0363] The pharmaceutical compositions according to the invention
contain in addition to at least one sulfonylguanidine according to
the invention or used according to the invention, optionally
suitable additives and/or auxiliary substances, i.e. also carrier
materials, fillers, solvents, diluents, colourants and/or binders,
and may be administered as liquid medicament forms in the form of
injection solutions, droplets or juices, or as semi-solid
medicament forms in the form of granules, tablets, pellets,
patches, capsules, plasters or aerosols. The choice of the
auxiliary substances, etc., as well as the amounts thereof to be
used depend on whether the medicament is to be administered orally,
perorally, parenterally, intravenously, intraperitoneally,
intradermally, intramuscularly, intranasally, buccally, rectally or
topically, for example to the skin, the mucous membranes or the
eyes. For oral administration, preparations in the form of tablets,
sugar-coated pills, capsules, granules, drops, juices and syrups
are suitable, while for parenteral, topical and inhalative
application, solutions, suspensions, readily reconstitutable dry
preparations as well as sprays are suitable. Sulfonylguanidines
according to the invention in a dept form, in dissolved form or in
a plaster, optionally with the addition of agents promoting skin
penetration, are suitable percutaneous application preparations.
Orally or percutaneously usable preparation forms may provide for a
delayed release of the sulfonylguanidines according to the
invention used according to the invention. In principle further
active constituents known to the person skilled in the art may be
added to the medicaments according to the invention.
[0364] The amount of active constituent to be administered to the
patient varies depending on the patient's weight, type of
application, medical indication and the severity of the condition.
Normally 0.005 to 1000 mg/kg, preferably 0.05 to 5 mg/kg of at
least one sulfonylguanidine according to the invention used
according to the invention are applied.
[0365] In a preferred form of the medicament, a contained
sulfonylguanidine according to the invention used according to the
invention is present as a pure diastereomer and/or enantiomer, as a
racemate, or as a non-equimolar or equimolar mixture of the
diastereomers and/or enantiomers and/or exclusively in one of the
tautomeric forms according to formulas I or Ia or also in mixtures
of both forms according to formulas I and Ia.
[0366] The invention moreover provides for the use of a
sulfonylguanidine according to the invention of the general
tautomeric formulas I and Ia for the production of a medicament for
treating pain, in particular neuropathic, chronic or acute pain,
epilepsy and/or migraine, or for the production of a medicament for
the treatment of hyperalgesia and allodynia, in particular thermal
hyperalgesia, mechanical hyperalgesia and allodynia and
cold-induced allodynia, or inflammatory or post-operative pain,
or
[0367] for the production of a medicament for the treatment of hot
flashes, post-menopausal symptoms, amyotropic lateral sclerosis
(ALS), reflex sympathetic dystrophy (RSD), spastic paralysis,
restless leg syndrome, acquired nystagmus; psychiatric or
neuropathological disorders such as bipolar disorders, anxiety,
panic attacks, mood fluctuations, manic behavior, depression,
manic-depressive behavior; painful diabetic neuropathy, symptoms
and pain due to multiple sclerosis or Parkinson's disease,
neurodegenerative diseases such as Alzheimer's disease,
Huntington's disease, Parkinson's disease and epilepsy;
gastrointestinal lesions; erythromelalgic or post-poliomyelitic
pain, trigeminal or post-herpetic neuralgia; or
[0368] as an anticonvulsant, analgesic or anxiolytic.
[0369] With each of the aforementioned compounds according to the
invention, it may be preferred if the sulfonylguanidine that is
used is present as a pure diastereomer and/or enantiomer, as a
racemate or as a non-equimolar or equimolar mixture of the
diastereomers and/or enantiomers and/or exclusively in one of the
tautomeric forms according to formulas I or Ia or also in mixtures
of both forms according to formulas I and Ia.
[0370] The invention additionally provides a process for treating a
person or non-human mammal that requires treatment of medically
relevant symptoms by administration of a therapeutically effective
dose of a sulfonylguanidine according to the invention or used
according to the invention, or of a medicament according to the
invention. The invention relates in particular to suitable
processes for treating pain, in particular neuropathic, chronic or
acute pain, including migraine, hyperalgesia and allodynia,
especially thermal hyperalgesia, mechanical hyperalgesia and
allodynia and cold-induced allodynia, or for treating inflammatory
or post-operative pain, epilepsy, hot flashes, post-menopausal
symptoms, amyotropic lateral sclerosis (ALS), reflex sympathetic
dystrophy (RSD), spastic paralysis, restless leg syndrome, acquired
nystagmus; psychiatric or neuropathological disorders such as
bipolar disorders, anxiety, panic attacks, mood fluctuations, manic
behavior, depression, manic-depressive behavior; painful diabetic
neuropathy, symptoms and pain due to multiple sclerosis or
Parkinson's disease, neurodegenerative diseases such as Alzheimer's
disease, Huntington's disease, Parkinson's disease and epilepsy;
erythromelalgic or post-poliomyelitic pain, trigeminal or
post-herpetic neuralgia.
[0371] The present invention moreover provides a process for the
preparation of a sulfonylguanidine according to the invention as
illustrated in the following description and examples.
[0372] Synthesis Procedure
[0373] The synthesis of the compounds according to the invention is
carried out by reacting pyrazolesulfonic acid amides of the general
formula II, which are synthesised by methods known in the
literature (Larock, 2.sup.nd Edition), with a wide range of various
primary or secondary amines in the presence of methanesulfonic
acid. R.sup.1 to R.sup.3 have in this connection the meanings given
above for compounds of the formula I. 3
[0374] The reactions are preferably carried out in acetonitrile at
a bath temperature of preferably 0.degree. C. to 110.degree. C., in
particular at a bath temperature of 100.degree. C. to 110.degree.
C. The compounds of the formula I may also be converted in a manner
known per se into their salts with physiologically compatible
acids, preferably hydrobromic acid, sulfuric acid, methanesulfonic
acid, formic acid, acetic acid, oxalic acid, succinic acid,
tartaric acid, mandelic acid, fumaric acid, lactic acid, citric
acid, glutamic acid and/or aspartic acid and in particular
hydrochloric acid. The salt formation is preferably carried out in
a solvent, preferably diethyl ether, diisopropyl ether, acetic acid
alkyl esters, acetone or 2-butanone, or a mixture of these
solvents. Alternatively, trimethylsilane in aqueous solution is
also suitable for the production of the hydrochlorides.
[0375] Salt Formation
[0376] The compounds of the formula I can be converted into their
salts in a known manner with physiologically compatible acids, for
example hydrochloric acid, hydrobromic acid, sulfuric acid,
methanesulfonic acid, formic acid, acetic acid, oxalic acid,
succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic
acid, citric acid, glutamic acid,
1,1-dioxo-1,2-dihydro1.lambda..sup.6-benzo[d]isothiazol-3-one
(saccharinic acid), monomethylsebacic acid, 5-oxoproline,
hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic
acid, 2,4,6-trimethylbenzoic acid, a-lipoic acid, acetylglycine,
acetylsalicylic acid, hippuric acid and/or aspartic acid. The salt
formation is preferably carried out in a solvent, for example
diethyl ether, diisopropyl ether, alkyl esters of acetic acid,
acetone and/or 2-butanone or also water. For the production of the
hydrochlorides, trimethylchlorosilane in aqueous solution is
moreover suitable.
[0377] The invention is described in further detail hereinafter
with reference to examples and figures, without however being
restricted thereto.
BRIEF DESCRIPTION OF THE DRAWINGS
[0378] FIGS. 1-40 show further compounds produced according to the
following processes, in particular according to the basic process
1, Example 0, which are shown as structural formulas in the
figures. In the examples the compounds are compounds according to
the invention and/or compounds that can be used according to the
invention on account of their action structure.
EXAMPLES
[0379] The following examples illustrate compounds according to the
invention as well as their preparation and investigations of the
efficacy of the said compounds. The compounds were generally chosen
in the tautomeric form according to formula I. However, it should
be understood that the compounds may be present in one or other of
the forms and accordingly this form of the compound does not or
should not represent any restriction on the one or other tautomeric
form.
[0380] The following details apply in general:
[0381] The chemicals and solvents used were commercially obtained
from customary suppliers (Acros, Avocado, Aldrich, Fluka,
Lancaster, Maybridge, Merck, Sigma, TCI etc.) or were
synthesised.
[0382] The analysis was carried out by ESI mass spectrometry or
HPLC.
[0383] An ESI-MS was recorded in each case for purposes of
characterisation.
[0384] The following examples illustrate compounds that may be
contained in substance databanks as well as the preparation
thereof, and efficacy investigations carried out with the said
compounds.
[0385] The following details apply in general:
[0386] The chemicals and solvents used were commercially obtained
from customary suppliers (Acros, Avocado, Aldrich, Fluka,
Lancaster, Maybridge, Merck, Sigma, TCI etc. or were
synthesised).
[0387] The analysis was carried out by ESI mass spectrometry and/or
.sup.1H-NMR (Examples 1-21). For the Examples 22-30 according to
the invention, only mass spectroscopy data are available.
Example 0
Basic Process 1
[0388] A small round-bottomed threaded glass tube (diameter 16 mm,
length 125 mm) was provided manually with a stirrer and sealed on
the Capper station (see block diagram) with a screw cap with
septum. The tube was placed by the robot 1 in the stirrer block
kept at 110.degree. C. The robot 2 pipetted in the following
reagents in succession:
[0389] 1.) 0.5 ml of a solution containing methanesulfonic acid and
pyrazolesulfonic acid amide, in each case 0.2 M, in
acetonitrile
[0390] 2.) 0.5 ml of a 1.0 M amine solution in acetonitrile.
[0391] The reaction mixture was stirred for 45 hours at 110.degree.
C. in one of the stirrer blocks. The reaction solution was then
filtered out at the filtration station. The test tube was then
rinsed twice, once with 1.5 ml of dichloromethane and once with 1.5
ml of water.
[0392] The rack with the samples was placed manually on the
working-up station. The reaction mixture was shaken for 30 minutes.
The reaction mixture was briefly centrifuged in a centrifuge to
form the phase boundary. The phase boundary was optically detected
and the organic phase was pipetted off. In the next stage a further
1.5 ml of dichloromethane was added to the aqueous phase, which was
shaken, centrifuged, and the organic phase was pipetted off. The
combined organic phases were dried over 2.4 g of MgSO.sub.4
(granulated). The solvent was removed in a vacuum centrifuge. Each
sample was analysed by ESI-MS and/or NMR.
[0393] The automated synthesis procedure ensures the identical
treatment of all samples as well as balanced constant reaction
conditions.
Example 1
[0394] 4
[0395]
N-{amino-[pyridin-2-yl-methyl)-amino]-methylene}-4-methylbenzenesul-
fonamide (1)
[0396] The compound of Example I was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
2-picolylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 304.37; found mol. wt.
(M+H) 305.2; 609.0 (Dimer)
Example 2
[0397] 5
[0398] N-[amino-(benzylaminomethylene)]-4-methylbenzene-sulfonamide
(2)
[0399] The compound of Example 2 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
2-benzylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 303.38; found mol. wt.
(M+H) 304.4; 607.9 (Dimer)
Example 3
[0400] 6
[0401]
N-(aminomorpholin-4-yl-methylene)-4-methylbenzene-sulfonamide
(3)
[0402] The compound of Example 3 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
morpholine solution (1.0 M, acetonitrile) and filed in a substance
databank. Calculated mol. wt. 283.35; found mol. wt. (M+H)
284.1
Example 4
[0403] 7
[0404]
N-(aminocyclohexylaminomethylene)-4-methylbenzene-sulfonamide
(4)
[0405] The compound of Example 4 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
cyclohexylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 295.40; found mol. wt.
(M+H) 296.1; 591.5 (Dimer)
Example 5
[0406] 8
[0407] N-(aminophenylaminomethylene)-4-methylbenzenesulfonamide
(5)
[0408] The compound of Example 5 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
aniline solution (1.0 M, acetonitrile) and filed in a substance
databank. Calculated mol. wt. 289.35; found mol. wt. (M+H) 290.2;
579.0 (Dimer)
Example 6
[0409] 9
[0410]
N-[(amino-4-methoxybenzylamino)-methylene]-4-methylbenzene-sulfonam-
ide (6)
[0411] The compound of Example 6 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
4-methoxybenzylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 333.41; found mol. wt.
(M+H) 334.2; 667.0 (Dimer)
Example 7
[0412] 10
[0413]
N-[amino-(naphthalin-2-yl-amino)-methylene]-4-methylbenzenesulfonam-
ide (7)
[0414] The compound of Example 7 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
2-naphthylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 339.41; found mol. wt.
(M+H) 340.3; 679.1 (Dimer)
Example 8
[0415] 11
[0416]
N-[amino-(4-methylpiperazin-1-yl-amino)-methylene]-4-methylbenzenes-
ulfonamide (8)
[0417] The compound of Example 8 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
N-amino-4-methylpiperazine solution (1.0 M, acetonitrile) and filed
in a substance databank. Calculated mol. wt. 311.40; found mol. wt.
(M+H) 312.2; 623.0 (Dimer)
Example 9
[0418] 12
[0419]
N-[amino-(N'-pyridin-2-yl-hydrazino)-methylene]-4-methylbenzenesulf-
onamide (9) The compound of Example 9 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
2-hydrazinopyridine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 305.36; found mol. wt.
(M+H) 306.1; 621.6 (Dimer)
Example 10
[0420] 13
[0421] N-[aminopropylaminomethylene]-4-methylbenzenesulfonamide
(10)
[0422] The compound of Example 10 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
n-propylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 255.34; found mol. wt.
(M+H) 256.2; 511.0 (Dimer)
Example 11
[0423] 14
[0424] N-(aminobutylaminomethylene)-4-methylbenzenesulfonamide
(11)
[0425] The compound of Example 11 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
n-butylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 269.36; found mol. wt.
(M+H) 270.3; 539.1 (Dimer)
Example 12
[0426] 15
[0427] N-[aminobutylaminomethylene]-4-methylbenzenesulfonamide
(12)
[0428] The compound of Example 12 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
piperidine solution (1.0 M, acetonitrile) and filed in a substance
databank. Calculated mol. wt. 281.37; found mol. wt. (M+H) 282.2;
562.9 (Dimer)
Example 13
[0429] 16
[0430] N-[aminobutylaminomethylene]-4-methylbenzenesulfonamide
(13)
[0431] The compound of Example 13 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
N-methylaniline solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 303.38; found mol. wt.
(M+H) 304.2
Example 14
[0432] 17
[0433] N-[aminophenethylaminomethylene]-4-methylbenzene-sulfonamide
(14)
[0434] The compound of Example 14 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
phenethylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 317.41; found mol. wt.
(M+H) 318.3; 635.1 (Dimer)
Example 15
[0435] 18
[0436]
N-[amino-sec-butylaminomethylene]-4-methylbenzene-sulfonamide
(15)
[0437] The compound of Example 15 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
s-butylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 269.36; found mol. wt.
(M+H) 270.2; 539.1 (Dimer)
Example 16
[0438] 19
[0439]
N-[amino-(1-tosyl-2-yl-hydrazino)-4-methylbenzene-sulfonamide
(16)
[0440] The compound of Example 16 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
tosylhydrazide solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 382.46; found mol. wt.
(M+H) 383.2; 764.9 (Dimer)
Example 17
[0441] 20
[0442]
N-[amino-(2H-pyrazol-3-yl-amino)-methylene]-4-methylbenzenesulfonam-
ide (17)
[0443] The compound of Example 17 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
2-aminopyrazole solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 279.32; found mol. wt.
(M+H) 280.3; 559.0 (Dimer)
Example 18
[0444] 21
[0445]
N-(aminopyrrolidin-1-yl-methylene)-4-methylbenzene-sulfonamide
(18)
[0446] The compound of Example 18 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
pyrrolidine solution (1.0 M, acetonitrile) and filed in a substance
databank. Calculated mol. wt. 267.35; found mol. wt. (M+H) 268.2;
534.9 (Dimer)
Example 19
[0447] 22
[0448]
N-[amino-(naphthalin-1-yl-amino)-methylene]-4-methyl-benzenesulfona-
mide (19)
[0449] The compound of Example 19 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
1-naphthylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 339.41; found mol. wt.
(M+H) 340.3; 679.1 (Dimer)
Example 20
[0450] 23
[0451]
N-[amino-(morpholin-4-yl-amino)-methylene]-4-methyl-benzenesulfonam-
ide (20)
[0452] The compound of Example 20 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
N-aminomorpholine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 298.11; found mol. wt.
(M+H) 299.3; 597.1 (Dimer)
Example 21
[0453] 24
[0454]
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide (21)
[0455] The compound of Example 21 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
2-picolylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 327.79; found mol. wt.
(M+H) 328.3; 655.6 (Dimer)
Example 22
[0456] 25
[0457]
N-{amino-[(pyridin-4-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (22)
[0458] The compound of Example 22 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
4-picolylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 304.37; found mol. wt.
(M+H) 305.2; 609.1 (Dimer)
Example 23
[0459] 26
[0460]
N-{amino-[(pyridin-3-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide (23)
[0461] The compound of Example 23 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
3-picolylamine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 304.37; found mol. wt.
(M+H) 305.3; 609.2 (Dimer)
Example 24
[0462] 27
[0463]
N-[amino-(pyridin-3-yl-amino)-methylene]-4-methyl-benzenesulfonamid-
e (24)
[0464] The compound of Example 24 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
3-aminopyridine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 290.34; found mol. wt.
(M+H) 291.1; 580.9 (Dimer)
Example 25
[0465] 28
[0466]
N-(aminopyrrolidin-1-yl-methylene)-4-chlorobenzene-sulfonamide
(25)
[0467] The compound of Example 25 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
pyrrolidine solution (1.0 M, acetonitrile) and filed in a substance
databank. Calculated mol. wt. 287.77; found mol. wt. (M+H) 288.3;
574.8 (Dimer)
Example 26
[0468] 29
[0469] N-(aminopyrrolidin-1-yl-methylene)-benzenesulfonamide
(26)
[0470] The compound of Example 26 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1- -yl)-iminomethyl]-benzenesulfonamide
solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid
and 0.5 ml of pyrrolidine solution (1.0 M, acetonitrile) and filed
in a substance databank. Calculated mol. wt. 253.32; found mol. wt.
(M+H) 254.3; 506.9 (Dimer)
Example 27
[0471] 30
[0472]
N-(aminopyrrolidin-1-yl-methylene)-2-nitrobenzene-sulfonamide
(27)
[0473] The compound of Example 27 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-2-nitrobenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
pyrrolidine solution (1.0 M, acetonitrile) and filed in a substance
databank. Calculated mol. wt. 298.32; found mol. wt. (M+H) 299.3;
596.8 (Dimer)
Example 28
[0474] 31
[0475]
N-[amino-(morpholin-4-yl-amino)-methylene]-4-chlorobenzenesulfonami-
de (28)
[0476] The compound of Example 28 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1-
-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M,
acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of
N-aminomorpholine solution (1.0 M, acetonitrile) and filed in a
substance databank. Calculated mol. wt. 318.78; found mol. wt.
(M+H) 319.3; 637.0 (Dimer)
Example 29
[0477] 32
[0478]
N-[amino-(morpholin-4-yl-amino)-methylene]-benzene-sulfonamide
(29)
[0479] The compound of Example 29 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1- -yl)-iminomethyl]-benzenesulfonamide
solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid
and 0.5 ml of N-aminomorpholine solution (1.0 M, acetonitrile) and
filed in a substance databank. Calculated mol. wt. 284.34; found
mol. wt. (M+H) 285.3; 569.1 (Dimer)
Example 30
[0480] 33
[0481] Naphthalene-1-sulfonic Acid
amino-(morpholin-4-yl-amino)-methylene Amide (30)
[0482] The compound of Example 30 was prepared according to the
accompanying synthesis procedure from 0.5 ml of
N-[(3,5-dimethylpyrazol-1- -yl)-iminomethyl]-naphthol-1-sulfonamide
solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid
and 0.5 ml of N-aminomorpholine solution (1.0 M, acetonitrile) and
filed in a substance databank. Calculated mol. wt. 334.39; found
mol. wt. (M+H) 335.3; 669.1 (Dimer)
Examples 31 to 63
[0483] The compounds of Examples 31 to 63 were prepared according
to variants of the synthesis processes already described in the
foregoing general process and examples.
Example 31
[0484] 34
Example 31
[0485]
N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-phenylmethanesulf-
onamide; Hydrochloride (31)
Example 32
[0486] 35
[0487]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-bromobenzenesulf-
onamide; Hydrochloride (32)
Example 33
[0488] 36
[0489]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3,4-dichlorobenzen-
esulfonamide; Hydrochloride (33) Example 34 37
[0490]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-isopropylbenzene-
sulfonamide; Hydrochloride (34)
Example 35
[0491] 38
[0492]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-iodobenzenesulfo-
namide; Hydrochloride (35)
Example 36
[0493] 39
[0494]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-benzenesulfonamide-
; Hydrochloride (36)
Example 37
[0495] 40
[0496] Naphthalene-2-sulfonic Acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene Amide;
Hydrochloride (37)
Example 38
[0497] 41
[0498] 1-methyl-1H-imidazole-4-sulfonic Acid
amino-[(pyridin-2-yl-methyl)-- amino]-methylene Amide;
Hydrochloride (38)
Example 39
[0499] 42
[0500]
N-[4-({amino-[(pyridin-2-yl-methyl)-amino]-methylene}-sulfamoyl)-ph-
enyl]-acetamide; Hydrochloride (39)
Example 40
[0501] 43
[0502]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-fluorobenzenesul-
fonamide; Hydrochloride (40)
Example 41
[0503] 44
[0504]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-2,4,6-trimethylben-
zenesulfonamide; Hydrochloride (41)
Example 42
[0505] 45
[0506]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-propylbenzenesul-
fonamide; Hydrochloride (42)
Example 43
[0507] 46
[0508]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-methoxybenzenesu-
lfonamide; Hydrochloride (43)
Example 44
[0509] 47
[0510] Naphthalene-1-sulfonic Acid
amino-[(pyridin-2-yl-methyl)-amino]-met- hylene Amide;
Hydrochloride (44)
Example 45
[0511] 48
[0512]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3-methylbenzenesul-
fonamide (45)
Example 46
[0513] 49
[0514] Thiophene-2-sulfonic Acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene Amide (46)
Example 47
[0515] 50
[0516] Quinoline-8-sulfonic Acid
amino-[(pyridin-2-yl-methyl)-amino]-methy- lene Amide (47)
Example 48
[0517] 51
[0518] 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid
amino-[(pyridin-2-yl-methyl)-amino]-methylene Amide (48)
Example 49
[0519] 52
[0520]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenze-
nesulfonamide; Hydrochloride (49)
Example 50
[0521] 53
[0522]
N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulf-
onamide; Hydrochloride (50)
Example 51
[0523] 54
[0524]
N-{amino[(pyrimidin-2-yl-methyl)-amino]-methylene}-4-tert.-butylben-
zenesulfonamide; Hydrochloride (51)
Example 52
[0525] 55
[0526]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfon-
amide; Hydrochloride (52)
Example 53
[0527] 56
[0528]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfo-
namide; Hydrochloride (53)
Example 54
[0529] 57
Example 54
[0530]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesu-
lfonamide; Hydrochloride (54)
Example 55
[0531] 58
[0532]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfo-
namide; Hydrochloride (55) Example 56 59
[0533]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzene-
sulfonamide; Hydrochloride (56)
Example 57
[0534] 60
[0535]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-butylbenzenesul-
fonamide; Hydrochloride (57)
Example 58
[0536] 61
[0537]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-propylbenzenesu-
lfonamide; Hydrochloride (58)
Example 59
[0538] 62
[0539]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-isbpropylbenzen-
esulfonamide; Hydrochloride (59)
Example 60
[0540] 63
[0541]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenz-
enesulfonamide; Hydrochloride (60)
Example 61
[0542] 64
[0543]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesu-
lfonamide; Hydrochloride (61)
Example 62
[0544] 65
[0545]
N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-methylbenzenesu-
lfonamide; Hydrochloride (62)
Example 63
[0546] 66
[0547]
N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfo-
namide; Hydrochloride (63)
[0548] A considerable number of further compounds were synthesised
according to the aforementioned processes, in particular according
to the basic process 1, which are represented as structural
formulas in the accompanying FIGS. 1 to 40. The compounds in these
examples are compounds according to the invention and/or compounds
that can be used according to the invention because of their
activity profile.
[0549] Pharmacological Investigations
Example 64
Binding Assay
[0550] Gabapentin was used in a binding assay in order to check the
binding and affinities of the selected compounds. The affinity of
the compounds according to the invention was measured via the
displacement of gabapentin from its binding site. If the selected
compounds replace gabapentin from its binding site, then it may be
expected that they will exhibit pharmacological properties
comparable to those of gabapentin, for example as an agent to
control pain or epilepsy. The compounds according to the invention
exhibit a good inhibition/displacement of gabapentin in this assay.
Furthermore, the investigated compounds exhibited in this
biochemical assay an affinity for the hitherto unknown gabapentin
binding site.
1TABLE 1 Example Inhibition 10.sup.-5 .mu.M] IC.sub.50 [nM] 1 82%
421 2 69.7% 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 20 21 75% 779
22 23 24 25 26 27 28 29 30 31 n.a. 32 218 33 1100 34 33 35 50 36
17% 37 122 38 n.a. 39 27% 40 21% 41 438 42 27 43 634 44 5300 45 35%
46 36% 47 2800 48 136 49 90 50 170 51 5% 52 47% 53 26% 54 3510 55
3200 56 49% 57 41% 58 1820 59 970 60 5690 61 24% 62 29% 63 23.5%
n.a. denotes an insufficient measurement signal.
Example 65
In Vivo Experiments According to Chung
[0551] In male Sprague-Dawley rats spinal nerve ligatures were
applied according to Kim and Chung (1992) to the left L5/L6 spinal
nerves. At the same time spinal catheters were implanted according
to Pogatzki et al..sup.6 (2000). 4 to 6 days after the operation
the tactile threshold baseline (withdrawal thresholds) was measured
on the ipsilateral and contra lateral rear paw by an electronic
vonFrey anaesthesiometer (IITC Life Science, USA). The correct
position of the spinal catheters was confirmed by administering
lidocaine (10 .mu.1,2%), which resulted in a brief paralysis of the
bilateral rear member. After the test and baseline measurement,
gabapentin and substances according to the invention were
administered. The tactile withdrawal thresholds were measured 30
minutes after administration. The results are expressed as
ED.sub.50 and % maximal possible effect (% MPE; % of the maximal
possible effect) on the ipsilateral side, in which the baseline is
taken as 0% and the withdrawal threshold of a control group is
taken as 100% MPE.
[0552] The substance according to Example 1 showed a 50% effect at
a dose of 25 mg/kg, roughly corresponding to the ED.sub.50, and
gabapentin exhibited an ED.sub.50 of 92.6 mg/kg. Both substances
acted for at least 30 hours. Accordingly, the substance according
to Example 1 is superior to gabapentin in this model by a factor of
4.
[0553] Also in a further investigation, the substances according to
Example 1 and according to Example 21 show an effect in the Chung
test. Both substances act for at least 30 hours and are superior in
their effect to gabapentin (ED.sub.50=92.6 mg/kg).
2TABLE 2 Analgesia testing in rats according to Chung: Example No.
Formalin Test on Mice - ED.sub.50 21 13.3 mg/kg 1 10-20 mg/kg
[0554] Literature:
[0555] Kim, S. H.; Chung, J. M. (1992) An experimental model for
peripheral mononeuropathy produced by segmental spinal nerve
ligation in the rat. Pain 50, 355-363.
[0556] Pogatzki, E. M.; Zahn, P. K.; Brennan, T. J. (2000) Lumbar
catheterization of the subarachnoid space with a 32-gauge
polyurethane catheter in the rat. Eur. J. Pain 4, 111-113.
Example 66
Formalin Test on Mice
[0557] The investigations to determine the antinociceptive action
of the compounds according to the invention were carried out by the
formalin test on male albino mice (NMRI, 25-35 g, Iffa Credo,
Belgium).
[0558] In the formalin test the first (early) phase (0-15 minutes
after the formalin injection) and the second (late) phase (15-60
minutes after the formalin injection) differ (D. Dubuisson et al.,
Pain, Vol. 4, pp. 161-174 (1977)). The early phase, being a direct
reaction to the formalin injection, constitutes a model for acute
pain, whereas the late phase is regarded as a model for persistent
(chronic) pain (T. J. Coderre et al., Pain, Vol. 52, pp. 259-285
(1993)).
[0559] The compounds according to the invention were investigated
in the second phase of the formalin test in order to obtain
information on the effects of substances in chronic/inflammatory
pain. By means of a single subcutaneous formalin injection (20
.mu.1,1% aqueous solution) into the dorsal side of the right-hand
rear paw, a nociceptive reaction was induced in unconstrained
experimental animals, manifested in a noticeable licking and biting
of the affected paw.
[0560] The nociceptive behavior for the test period in the second
(late) phase of the formalin test was continuously monitored by
observing the animals. The pain reaction was quantified by
totalling the time in seconds during which the animals continued to
lick and bite the affected paw during the investigation period.
After injecting substances that have an antinociceptive effect in
the formalin test, the aforedescribed behavior pattern of the
animals is reduced or possibly even cancelled.
[0561] Corresponding to the substance tests, in which the animals
had been injected with the test substance before formalin, the
control animals were injected with a vehicle, i.e. solvent (e.g.
0.9% NaCl solution) before the formalin injection. The behavior of
the animals after administration of the substance (n=10 per
substance dose) was compared with a control group (n=10).
[0562] Based on the quantification of the pain reaction, the effect
of the substance in the formalin test was determined as the change
in the control in percentage terms. The ED.sub.50 calculations were
carried out by means of regression analysis. The application time
before the formalin injection (intraperitoneally: 15 minutes,
intravenously: 5 minutes) was chosen depending on the type of
application of the compounds according to the invention.
[0563] The compound of Example 21 according to the invention
exhibited an inhibition of the formalin-induced nociception. The
corresponding results in the formalin test on mice are shown in the
following Table 2. Gabapentin has an ED.sub.50 value of 79 mg/kg
(i.v.).
3TABLE 2 Analgesia investigation in the formalin test on mice
Example No. Formalin Test on Mice - ED.sub.50 21 97 mg/kg
[0564] The foregoing description and examples have been set forth
merely to illustrate the invention and are not intended to be
limiting. Since modifications of the described embodiments
incorporating the spirit and substance of the invention may occur
to persons skilled in the art, the invention should be construed
broadly to include all variations falling within the scope of the
appended claims and equivalents thereof.
* * * * *