U.S. patent application number 14/310690 was filed with the patent office on 2014-10-09 for spirocyclic cyclohexane compounds useful to treat substance dependency.
The applicant listed for this patent is GRUENENTHAL GmbH. Invention is credited to Elmar FRIDERICHS, Babette-Yvonne KOEGEL, Klaus LINZ.
Application Number | 20140303125 14/310690 |
Document ID | / |
Family ID | 36691523 |
Filed Date | 2014-10-09 |
United States Patent
Application |
20140303125 |
Kind Code |
A1 |
FRIDERICHS; Elmar ; et
al. |
October 9, 2014 |
Spirocyclic Cyclohexane Compounds Useful To Treat Substance
Dependency
Abstract
Spirocyclic cyclohexane compounds useful in pharmaceutical
compositions for use in the treatment of substance dependency.
Inventors: |
FRIDERICHS; Elmar;
(Stolberg, DE) ; KOEGEL; Babette-Yvonne;
(Langerwehe, DE) ; LINZ; Klaus; (Bonn,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUENENTHAL GmbH |
Aachen |
|
DE |
|
|
Family ID: |
36691523 |
Appl. No.: |
14/310690 |
Filed: |
June 20, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11870051 |
Oct 10, 2007 |
|
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14310690 |
|
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PCT/EP2006/003176 |
Apr 7, 2006 |
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11870051 |
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Current U.S.
Class: |
514/171 ;
514/409 |
Current CPC
Class: |
A61P 25/00 20180101;
A61K 31/438 20130101; A61K 31/485 20130101; A61K 31/485 20130101;
A61P 25/36 20180101; A61K 31/407 20130101; A61K 31/407 20130101;
A61K 31/137 20130101; A61K 45/06 20130101; A61K 31/137 20130101;
A61K 31/438 20130101; A61P 25/30 20180101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/171 ;
514/409 |
International
Class: |
A61K 31/407 20060101
A61K031/407; A61K 31/485 20060101 A61K031/485 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 11, 2005 |
DE |
10 2005 016 460.9 |
Claims
1-22. (canceled)
23. A method of treating opioid dependency in a patient, said
method comprising administering to said patient an effective amount
of
1,1-(3-dimethylamino-3-phenylpenta-methylene)-6-fluoro-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole in the form of a pure stereoisomer or a mixture
of stereoisomers in any mixing ratio, or a physiologically
acceptable salt thereof.
24. The method according to claim 23, wherein
1,1-(3-dimethylamino-3-phenylpenta-methylene)-6-fluoro-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole or the physiologically acceptable salt thereof
is in the form of a pure enantiomer or diastereomer.
25. The method according to claim 23, wherein the
1,1-(3-dimethylamino-3-phenylpenta-methylene)-6-fluoro-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole or the physiologically acceptable salt thereof
is in the form of a racemate.
26. The method according to claim 23, wherein the opioid dependency
is heroin, morphine or methadone dependency.
27. The method according to claim 23, wherein
1,1-(3-dimethylamino-3-phenylpenta-methylene)-6-fluoro-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole is used in combination with naloxone.
28. The method according to claim 23, wherein the
1,1-(3-dimethylamino-3-phenylpenta-methylene)-6-fluoro-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole is present in the form of its hydrochloride,
citrate, methane sulfonate or hemicitrate.
29. The method according to claim 23, wherein
1,1-(3-dimethylamino-3-phenylpenta-methylene)-6-fluoro-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole is used in the form of the free base.
30. The method according to claim 23, wherein
1,1-(3-dimethylamino-3-phenylpenta-methylene)-6-fluoro-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole is present in the form of the non-polar
diastereomer.
31. The method according to claim 23, wherein
1,1-(3-dimethylamino-3-phenylpenta-methylene)-6-fluoro-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole is present in the form of the non-polar
diastereomer of the free base.
32. The method according to claim 23, wherein
1,1-(3-dimethylamino-3-phenylpenta-methylene)-6-fluoro-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole is present in the form of the non-polar
diastereomer of the free base and the opioid dependency is heroin,
morphine or methadone dependency.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is continuation of U.S. application Ser.
No. 11/870,051, filed Oct. 10, 2007, which claims priority from
international patent application no. PCT/EP2006/003176, filed Apr.
7, 2006, designating the United States of America, and published in
German on Oct. 19, 2006 as WO 2006/108565, the entire disclosure of
which is incorporated herein by reference. Priority is claimed
based on Federal Republic of Germany Patent Application No. DE 10
2005 016 460.9, filed Apr. 11, 2005.
BACKGROUND OF THE INVENTION
[0002] Opiate dependency is a major medical and social problem,
which requires intensive medical care. A standard treatment is
opiate substitution by a specially suitable .mu.-opioid. Clinically
established substances for the substitution therapy of opiate
dependency are: [0003] methadone (racemate, in rare cases
levomethadone) [0004] LAAM (.alpha.-acetylmethadol) [0005]
buprenorphine All three substances are used to achieve the same
objectives: [0006] satisfaction of the opiate craving but without
any "kick" and with a significantly reduced euphoria [0007]
avoidance of bodily withdrawal symptoms [0008] re-socialisation of
the patient (controlled rehabilitation, ability to work, withdrawal
from the drug-related environment) [0009] long-term reduction in
the opiate dosage until complete abstinence is achieved. In order
that these effects can be achieved, the substitution therapeutic
agents must have the following properties: [0010] oral (possibly
also cutaneous) effect availability [0011] long effective duration
(1-3 days, possibly even longer) [0012] high potency [0013] low
euphorisation [0014] low "kick" [0015] low withdrawal symptoms
[0016] good long-term compatibility (only slight constipation, good
cardiovascular compatibility) The standard therapeutic agents used
up to now exhibit only some of these properties, with the result
that their therapeutic use is to some extent unsatisfactory. The
basic problems with the current standard therapeutic agents are the
following: methadone has a high potential for misuse. On account of
the only moderate action duration a daily administration is
necessary. In addition constipation is a side effect. LAAM has the
disadvantage of a high cardiotoxicity and can trigger Torsade de
Pointes arrhythmia. Buprenorphine has a high toxicity when combined
with benzodiazepines.
[0017] US 2006/004034 A1 (=WO 04/43967) and US 2005/192333 A1 (=WO
2005/066183) describe compounds that are particularly suitable for
the treatment of pain, but also inter alia for the treatment of
withdrawal symptoms as well as for reducing the potential for
opioid addiction. It has now been found that that selected
compounds from these patent applications are particularly suitable
for use as substitution therapeutic agents in treatment of
substance dependence.
SUMMARY OF THE INVENTION
[0018] The object of the present invention was to provide a new
method of treating substance dependence with substitution
therapeutic agents.
[0019] Another object of the invention is to provide a method of
treating opioid dependency which has advantages compared to the
standard therapies.
[0020] These and other objects have been achieved in accordance
with the present invention by providing spirocyclic cyclohexane
compounds corresponding to formula I
##STR00001##
wherein [0021] R.sup.1 and R.sup.2 independently of one another
denote H or CH.sub.3 or together denote (CH.sub.2).sub.4 or
(CH.sub.2).sub.5 and form a ring with the nitrogen to which they
are bound, wherein R.sup.1 and R.sup.2 do not simultaneously denote
H; [0022] R.sup.3 denotes phenyl, benzyl or heteroaryl in each case
unsubstituted or singly or multiply substituted with F, Cl, OH, CN
or OCH.sub.3; [0023] W denotes NR.sup.4, O or S, where [0024]
R.sup.4 denotes H; C.sub.1-5-alkyl, phenyl; phenyl, COR.sup.12
bound via a C.sub.1-3-alkyl group; [0025] SO.sub.2R.sup.12, where
[0026] R.sup.12 denotes H; C.sub.1-7-alkyl, branched or unbranched,
saturated or unsaturated, unsubstituted or singly or multiply
substituted with OH, F or COOC.sub.1-4-alkyl; C.sub.4-6-cycloalkyl;
aryl or heteroaryl, unsubstituted or singly or multiply substituted
with F, Cl, Br, CF.sub.3, OCH.sub.3, C.sub.1-4-alkyl, branched or
unbranched, substituted; or phenyl or heteroaryl bound via
saturated or unsaturated C.sub.1-3 alkyl, unsubstituted or singly
or multiply substituted with F, Cl, Br, CF.sub.3, OCH.sub.3,
C.sub.1-4-alkyl, branched or unbranched, substituted; or
C.sub.5-6-cycloalkyl bound via saturated or unsaturated
C.sub.1-3-alkyl; OR.sup.13; NR.sup.14R.sup.15; [0027] R.sup.5
denotes H; COOR.sup.13, CONR.sup.13, OR.sup.13; C.sub.1-5-alkyl,
saturated or unsaturated, branched or unbranched, unsubstituted or
singly or multiply substituted with OH, F, CF.sub.3 or CN; [0028]
R.sup.6 denotes H; or [0029] R.sup.5 and R.sup.6 together denote
(CH.sub.2).sub.n where n=2, 3, 4, 5 or 6, wherein individual
hydrogen atoms may also be replaced by F, Cl, NO.sub.2, CF.sub.3,
OR.sup.13, CN or C.sub.1-5-alkyl; [0030] R.sup.7, R.sup.8, R.sup.9
and R.sup.10 independently of one another denote H, F, Cl, Br,
NO.sub.2, CF.sub.3, OH, OCH.sub.3, CN, COOR.sup.13,
NR.sup.14R.sup.15; C.sub.1-5-alkyl, heteroaryl, unsubstituted or
singly or multiply substituted with benzyl, CH.sub.3, Cl, F,
OCH.sub.3 or OH; where [0031] R.sup.13 denotes H or
C.sub.1-5-alkyl; and [0032] R.sup.14 and R.sup.15 independently of
one another denote H or C.sub.1-5-alkyl; [0033] X denotes 0, S, SO,
SO.sub.2 or NR.sup.17; where [0034] R.sup.17 denotes H;
C.sub.1-5-alkyl, saturated or unsaturated, branched or unbranched;
COR.sup.12 or SO.sub.2R.sup.12, in the form of their pure
diastereomers, their racemates, their pure enantiomers, or in the
form of mixtures of the stereoisomers in an arbitrary mixture
ratio; as bases or in the form of their salts, in particular of the
physiologically compatible salts or salts of physiological
compatible acids or cations; or in the form of their solvates,
wherein the ratio of the ORL1 receptor affinity to the .mu.-opioid
receptor affinity is 0.3 or greater, for the treatment of substance
dependency.
[0035] As used herein, the term salt is understood to denote 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
counter-ion (a cation or anion) and/or is present in solution. The
term is also understood to include complexes of the active
constituent with other molecules and ions, in particular complexes
which are complexed via ionic interactions. In particular the term
is understood to include (and this is also a preferred embodiment
of the present invention) physiologically compatible salts, in
particular physiologically compatible salts with cations or bases
and physiologically compatible salts with anions or acids or also a
salt formed with a physiologically compatible acid or with a
physiologically compatible cation.
[0036] The term salt formed with a physiologically compatible acid
is understood within the context of the present invention to denote
salts of the respective active constituent with inorganic or
organic acids, which are physiologically compatible--especially
when used in humans and/or mammals. The hydrochloride and citrate
are particularly preferred. Examples of physiologically compatible
acids are: hydrochloric acid, hydrobromic acid, sulphuric acid,
methanesulfonic acid, formic acid, acetic acid, oxalic acid,
succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic
acid, citric acid, glutanic acid,
1,1-dioxo-1,2-dihydro1.lamda..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, .alpha.-lipoic acid,
acetylglycine, hippuric acid and/or aspartic acid.
[0037] In the context of the present invention, the expressions
"C.sub.1-3-alkyl" "C.sub.1-5-alkyl", "C.sub.1-7-alkyl" and
"C.sub.1-4-alkyl" include acyclic saturated or unsaturated
hydrocarbon radicals, which may be branched or straight-chain, with
respectively 1, 2 or 3 C atoms, 1, 2, 3, 4 or 5 C atoms, 1, 2, 3,
4, 5, 6 or 7 C atoms or 1, 2, 3 or 4 C atoms. Unsaturated compounds
have at least one C--C double bond or at least one C--C triple
bond. From the above group alkyl is advantageously selected, which
includes methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl,
sec.-butyl, tert.-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl,
2-hexyl; ethylenyl (vinyl), ethinyl, propenyl
(--CH.sub.2CH.dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C(.dbd.CH.sub.2)--CH.sub.3), propinyl (--CH--C.ident.CH,
--C.ident.C--CH.sub.3), 1,1-dimethylethyl, 1,1-dimethylpropyl,
butenyl, butinyl, pentenyl and pentinyl.
[0038] For the purposes of the present invention, the expression
"C.sub.5-6-cycloalkyl" denotes cyclic hydrocarbons with 5 or 6
Carbon atoms, wherein the hydrocarbons may be saturated or
unsaturated (but not aromatic). From the above group
C.sub.5-6-cycloalkyl is advantageously selected, which includes
cyclopentyl and cyclohexyl.
[0039] The expression "heteroaryl" denotes a 5-, 6- or 7-membered
cyclic aromatic radical, which contains at least 1, but possibly
also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are
identical or different and the heterocycle may be unsubstituted or
singly or multiply substituted; in the case of substitution in the
heterocycle, the substituents may be identical or different and in
any arbitrary and possible position of the heteroaryl. Preferred
heteroatoms are nitrogen, oxygen and sulphur. It is preferred to
select the heteroaryl radical from the group comprising pyrrolyl,
furyl (furanyl), benzofuranyl, thienyl, pyrazolyl, imidazolyl,
thiazolyl, oxazolyl, isoxazolyl, pyridinyl, or carbazolyl, wherein
the bonding to the compounds of the general structure I can be
effected by any arbitrary and possible ring member of the
heteroaryl radical. Pyridyl and thienyl are particularly preferred.
Pyrazolyl and furyl are also particularly preferred.
[0040] Animal experiment investigations with substances from US
2006/004034 A1 and US 2005/192333 A1 have surprisingly shown that
the substances with a particularly high ORL1 affinity, which is not
more than one order of magnitude less than the .mu.-opioid receptor
affinity, are particularly suitable for an opiate substitution and
thus have the potential for a significant improvement in the
substitution therapy.
[0041] Among the spiro compounds described in US 2006/004034 A1 and
US 2005/066183 A1 are compounds with higher and lower ORL1
components. In naloxone-induced withdrawal symptoms in mice it was
shown that spirocyclic compounds with an ORL1 component which is
not weaker by a factor of more than 10 than the .mu.-component, can
suppress withdrawal symptoms. Compounds with a weaker ORL1
component on the other hand trigger withdrawal symptoms. In the
"withdrawal jumping" test mice are repeatedly treated over a
defined period with the test substance. In the case of a
.mu.-opioid a systemic dependency is induced within this period. At
the end of the treatment the effect of the opioid is cancelled
immediately by administering naloxone, a .mu.-antagonist. When the
mice become systemically dependent they exhibit characteristic
withdrawal symptoms, which are manifested in the form of jumping
movements (Saelens J K, Arch Int Pharmacodyn 190: 213-218,
1971).
[0042] The compounds according to the invention have on account of
the ORL1 active component additional properties which the standard
substances such as methadone, LAAM or buprenorphine do not possess
and which improve the treatment. In withdrawal jumping in mice it
was shown that in the case of mice that had been treated with
combined .mu.-/ORL1 agonists, as in Example 1, Example 3 or Example
4, no, or only a minimal, withdrawal behaviour is triggered by
naloxone. This confirms that the withdrawal symptoms are suppressed
by the ORL1 component. This results in a significant advantage if
these substances are used in the treatment of withdrawal symptoms,
since the occurrence of withdrawal symptoms is one of the most
important side effects of this treatment and often leads to
non-compliance. The ORL1/.mu.-affinity should be 0.3 or greater. It
is preferred if the ORL1/.mu.-affinity ratio is .gtoreq.1,
particularly preferably .gtoreq.1.7.
[0043] The result that the compounds according to the invention
with a stronger ORL1 component suppress the withdrawal jumping that
should be triggered by the .mu.-component, demonstrates the
efficacy of these compounds for use in substitution therapy. It is
therefore preferred if the substance dependency is opiate
dependency, for example dependency on alfentanil, buprenorphine,
butorphanol, codeine, dextromoramide, dextropropoxyphene, dezocin,
dihydrocodeine, diphenoxylate, ethylmorphine, hydrocodone,
hydromorphone, ketobemidone, LAAM, levorphanol, meptazinol,
oxycodon, oxymorphone, fentanyl, morphine, heroin, pethidine,
sufentanil or tilidin, preferably morphine, methadone or
heroin.
[0044] The spirocyclic cyclohexane derivatives according to the
invention can also be used in combination with an opioid receptor
antagonist, preferably with naloxone.
[0045] In the synthesis of the compounds according to the
invention, as described in US 2006/004034 A1 and US 2005/066183 A1,
two or more diastereomers can occur. In most cases the non-polar
diastereomers have compared to the polar diastereomers a higher
affinity for the two investigated opiate receptors. It is therefore
preferred if the substances according to the invention are present
in the form of the non-polar diastereomer.
[0046] Spirocyclic cyclohexane derivatives in which R.sup.3 denotes
heteroaryl are preferred in the context of the present invention.
Also preferred in the context of the present invention are
spirocyclic cyclohexane derivatives in which R.sup.3 denotes
phenyl, unsubstituted or singly or multiply substituted with F, OH,
Cl or OCH.sub.3, or denotes benzyl.
[0047] Also preferred are spirocyclic cyclohexane derivatives in
which R.sup.1 and R.sup.2 denote CH.sub.3 or H, in which case
R.sup.1 and R.sup.2 do not simultaneously denote H.
[0048] It is preferred to use spirocyclic cyclohexane derivatives
selected from the group: [0049] 1
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-
-b]indole; [0050] 2
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2-nitrobenzoyl)-1,3,4,9-t-
etrahydro-2,9-diazafluorene; [0051] 3
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydrop-
yrano[3,4-b]indole; [0052] 4
1,1-(3-dimethylamino-3-(2-thienyl)pentamethylene)-1,3,4,9-tetrahydropyran-
o[3,4-b]indole; [0053] 5
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydrop-
yrano[3,4-b]indole; [0054] 6
1,1-(3-dimethylamino-3-phenylpentamethylene)-3,6-dimethyl-1,3,4,9-tetrahy-
dropyrano[3,4-b]indole; [0055] 7
1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
-pyrano[3,4-b]indole; [0056] 8
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-hydroxymethyl-1,3,4,9-tetr-
ahydro-2,9-diazafluorene; [0057] 9
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2,3,4,5,6-pentafluoro-ben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0058] 10
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(methoxycarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0059] 11
1,1-(3-dimethylamino-3-phenylpentamethylene)-7-fluoro-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0060] 12
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-aza-9-o-
xafluorene; [0061] 13
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
-2,9-diazafluorene; [0062] 14
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-acetyl-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0063] 15
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole; [0064] 16
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-chloro-3-methyl-1,3,4,9-te-
trahydropyrano[3,4-b]indole; [0065] 17
1,1-(3-dimethylamino-3-(2-pyridyl)pentamethylene)-1,3,4,9-tetrahydro-2,9--
diazafluorene; [0066] 18
1,1-(3-dimethylamino-3-(3-thienyl)pentamethylene)-6-fluoro-1,3,4,9-tetrah-
ydropyrano[3,4-b]indole; [0067] 19
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-acetyl-7-fluoro-1,3,4,9-te-
trahydro-2,9-diazafluorene; [0068] 20
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2,9-diaza-
fluorene; [0069] 21
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetra-hydro-
pyrano[3,4-b]indole; [0070] 22
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9--
azafluorene; [0071] 23
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-6-nitro-1,3,4,9-tet-
rahydropyrano[3,4-b]indole; [0072] 24
1,1-(3-dimethylamino-3-(3-thienyl)pentamethylene)-1,3,4,9-tetrahydro-pyra-
no[3,4-b]indole; [0073] 25
1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
-2,9-diazafluorene; [0074] 26
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0075] 27
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-oxo-1,3,4,9-tetrahydro-2-t-
hia-9-azafluorene; [0076] 28
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9--
azafluorene; [0077] 29
1,1-(3-dimethylamino-3-(2-thienyl)pentamethylene)-6-fluoro-1,3,4,9-tetrah-
ydro-pyrano[3,4-b]indole; [0078] 30
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0079] 31
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-3-methyl-1,3,4,9-te-
trahydropyrano[3,4-b]indole; [0080] 32
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-hydroxy-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole; [0081] 33
1,1-(3-dimethylamino-3-(3-hydroxyphenyl)pentamethylene)-1,3,4,9-tetrahydr-
opyrano[3,4-b]indole; [0082] 34
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9--
azafluorene; [0083] 35
6,6-(3-dimethylamino-3-phenylpentamethylene)-1,2,3,4,4a,6,7,11c-octahydro-
-5-oxa-7-aza-benzo[c]fluorine; [0084] 36
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydrop-
yrano[3,4-b]indole; [0085] 37
1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-2-acetyl-1,3,4,9-t-
etrahydro-2,9-diazafluorene; [0086] 38
1,1-(3-dimethylamino-3-benzylpentamethylene)-1,3,4,9-tetrahydro-2,9-diaza-
fluorene; [0087] 39
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0088] 40
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0089] 41
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-bromo-3-methyl-1,3,4,9-tet-
rahydropyrano[3,4-b]indole; [0090] 42
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydrop-
yrano[3,4-b]indole; [0091] 43
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-bromo-1,3,4,9-tetrahydropy-
rano[3,4-b]indole; [0092] 44
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methoxy-1,3,4,9-tetra-hydr-
opyrano[3,4-b]indole; [0093] 45
1,1-(3-(1-Pyrrolidyl)-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,-
4-b]indole; [0094] 46
1,1-(3-dimethylamino-3-phenylpentamethylene)-7,8-dichloro-1,3,4,9-tetrahy-
dropyrano[3,4-b]indole; [0095] 47
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-(1-benzyl-pyrazol-4-yl)-1,-
3,4,9-tetrahydro-pyrano[3,4-b]indole; [0096] 48
1,1-(3-Methylamino-3-(2-thienyl)pentamethylene)-1,3,4,9-tetrahydro-pyrano-
[3,4-b]indole; [0097] 49
1,1-(3-methylamino-3-(2-thienyl)pentamethylene)-6-fluoro-1,3,4,9-tetrahyd-
ro-pyrano[3,4-b]indole; [0098] 50
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-cinnamoyl-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0099] 51
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,3-dimethylbut-
anoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0100] 52
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(cyclopentylcarb-
onyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0101] 53
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,3-dimethylbutanoyl)-1,3-
,4,9-tetrahydro-2,9-diazafluorene; [0102] 54
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(pentanoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0103] 55
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-furylcarbonyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0104] 56
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-furylcarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0105] 57
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-fluorobenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0106] 58
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0107] 59
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-methylbutanoyl)-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0108] 60
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(cyclohexylcarbo-
nyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0109] 61
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-benzoyl-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0110] 62
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(cyclohexylcarbonyl)-1,3,4-
,9-tetrahydro-2,9-diazafluorene; [0111] 63
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(phenylacetyl)-1-
,3,4,9-tetrahydro-2,9-diazafluorene; [0112] 64
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0113] 65
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(4-trifluoromethylbenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0114] 66
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(thien-2-ylacety-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0115] 67
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(phenylacetyl)-1-
,3,4,9-tetrahydro-2,9-diazafluorene; [0116] 68
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-butanoyl-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0117] 69
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(4-trifluoromethylbenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0118] 70
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(3-fluoro-5-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0119] 71
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,3-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0120] 72
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0121] 73
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-phenylpropanoyl)-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0122] 74
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,4-dichlorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0123] 75
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-cinnamoyl-1,3,4,9-tetrahyd-
ro-2,9-diazafluorene; [0124] 76
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,6-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0125] 77
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-methoxycarbonylpropanoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0126] 78
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-chlorobenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0127] 79
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-fluorobenzoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0128] 80
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2,6-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0129] 81
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,4-dichloroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0130] 82
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,3,4,5,6-pentafluorobenz-
oyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0131] 83
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-cyclohexylcarbonyl-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0132] 84
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-cyclopentylpropanoyl)-1-
,3,4,9-tetrahydro-2,9-diazafluorene; [0133] 85
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-fluoro-3-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0134] 86
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0135] 87
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,4,5-trimethox-
ybenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0136] 88
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-cyclobutylcarbonyl-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0137] 89
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,6-dichlorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0138] 90
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0139] 91
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-thienylcarbonyl)-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0140] 92
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-propanoyl-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0141] 93
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,4-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0142] 94
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,5-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0143] 95
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-tert.butylben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0144] 96
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(3-methoxycarbonylpropanoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0145] 97
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,4-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0146] 98
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-ethylhexanoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0147] 99
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0148] 100
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-phenylpropanoyl)-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0149] 101
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-fluoro-5-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0150]
102
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(4-fluoro-3-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0151] 103
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-nitrobenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0152] 104
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,5-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0153] 105
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2-trifluoromethylbenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0154] 106
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,4-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0155] 107
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(4-chlorobenzoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0156] 108
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0157] 109
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,3,4,5-tetrafl-
uorobenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0158] 110
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,6-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0159] 111
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-furylcarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0160] 112
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,4-dichloroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0161] 113
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-methoxycarbon-
ylpropanoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0162] 114
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-chlorobenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0163] 115
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-fluoro-5-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0164]
116
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-fluoro-4-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0165]
117
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2-thienylacetyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0166] 118
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,6-dichlorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0167] 119
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,4-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0168] 120
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(3-methylbenzoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0169] 121
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-methoxycarbonylpropanoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0170] 122
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-fluoro-6-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0171]
123
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-methylbenzoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0172] 124
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,5-dichlorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0173] 125
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2-furylcarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0174] 126
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(pentanoyl)-1,3,4,9-tetrah-
ydro-2,9-diazafluorene; [0175] 127
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(6-fluoro-2-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0176] 128
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0177] 129
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(4-tert.butylbenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0178] 130
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(phenylacetyl)-1,3,4,9-tet-
rahydro-2,9-diazafluorene;
[0179] 131
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,5-dichloroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0180] 132
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,3,4,5,6-pentafluoro-ben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0181] 133
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(3-nitrobenzoyl)-1,3,4,9-t-
etrahydro-2,9-diazafluorene; [0182] 134
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-nitrobenzoyl)-1,3,4,9-t-
etrahydro-2,9-diazafluorene; [0183] 135
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,3,4,5-tetrafluorobenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0184] 136
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-thienylacetyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0185] 137
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-fluoro-4-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0186] 138
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-fluorobenzoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0187] 139
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(cyclobutylcarbonyl)-1,3,4-
,9-tetrahydro-2,9-diazafluorene; [0188] 140
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-methoxybenzoyl)-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0189] 141
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2,5-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0190] 142
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-bromobenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0191] 143
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-fluoro-5-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0192] 144
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-fluoro-5-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0193] 145
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2,3-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene, and physiologically compatible
salts thereof
[0194] It has been found that spirocyclic cyclohexane derivatives
in which W denotes NR.sup.4 and X denotes NR.sup.17 are
particularly advantageous. Accordingly it is preferred to use
compounds in which R denotes NR.sup.4 and X denotes NR.sup.17. It
is particularly preferred to use compounds selected from the group
consisting of: [0195] 2
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2-nitrobenzoyl)-1,3,4,9-t-
etrahydro-2,9-diazafluorene; [0196] 8
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-hydroxymethyl-1,3,4,9-tetr-
ahydro-2,9-diazafluorene; [0197] 9
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2,3,4,5,6-pentafluoro-ben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0198] 10
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(methoxycarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0199] 11
1,1-(3-dimethylamino-3-phenylpentamethylene)-7-fluoro-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0200] 13
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
-2,9-diazafluorene; [0201] 14
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-acetyl-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0202] 17
1,1-(3-dimethylamino-3-(2-pyridyl)pentamethylene)-1,3,4,9-tetrahydro-2,9--
diazafluorene; [0203] 19
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-acetyl-7-fluoro-1,3,4,9-te-
trahydro-2,9-diazafluorene; [0204] 20
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2,9-diaza-
fluorene; [0205] 25
1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
-2,9-diazafluorene; [0206] 26
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0207] 30
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0208] 37
1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-2-acetyl-1,3,4,9-t-
etrahydro-2,9-diazafluorene; [0209] 38
1,1-(3-dimethylamino-3-benzylpentamethylene)-1,3,4,9-tetrahydro-2,9-diaza-
fluorene; [0210] 39
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0211] 40
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0212] 50
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-cinnamoyl-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0213] 51
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,3-dimethylbut-
anoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0214] 52
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(cyclopentylcarb-
onyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0215] 53
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,3-dimethylbutanoyl)-1,3-
,4,9-tetrahydro-2,9-diazafluorene; [0216] 54
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(pentanoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0217] 55
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-furylcarbonyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0218] 56
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-furylcarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0219] 57
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-fluorobenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0220] 58
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0221] 59
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-methylbutanoyl)-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0222] 60
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(cyclohexylcarbo-
nyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0223] 61
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-benzoyl-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0224] 62
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(cyclohexylcarbonyl)-1,3,4-
,9-tetrahydro-2,9-diazafluorene; [0225] 63
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(phenylacetyl)-1-
,3,4,9-tetrahydro-2,9-diazafluorene; [0226] 64
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0227] 65
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(4-trifluoromethylbenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0228] 66
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(thien-2-ylacety-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0229] 67
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(phenylacetyl)-1-
,3,4,9-tetrahydro-2,9-diazafluorene; [0230] 68
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-butanoyl-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0231] 69
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(4-trifluoromethylbenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0232] 70
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(3-fluoro-5-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0233] 71
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,3-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0234] 72
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0235] 73
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-phenylpropanoyl)-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0236] 74
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,4-dichlorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0237] 75
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-cinnamoyl-1,3,4,9-tetrahyd-
ro-2,9-diazafluorene; [0238] 76
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,6-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0239] 77
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-methoxycarbonylpropanoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0240] 78
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-chlorobenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0241] 79
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-fluorobenzoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0242] 80
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2,6-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0243] 81
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,4-dichloroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0244] 82
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,3,4,5,6-pentafluorobenz-
oyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0245] 83
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-cyclohexylcarbonyl-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0246] 84
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-cyclopentylpropanoyl)-1-
,3,4,9-tetrahydro-2,9-diazafluorene; [0247] 85
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-fluoro-3-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0248] 86
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0249] 87
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,4,5-trimethox-
ybenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0250] 88
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-cyclobutylcarbonyl-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0251] 89
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,6-dichlorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0252] 90
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0253] 91
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-thienylcarbonyl)-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0254] 92
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-propanoyl-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0255] 93
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,4-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0256] 94
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,5-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0257] 95
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-tert.butylben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0258] 96
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(3-methoxycarbonylpropanoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0259] 97
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,4-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0260] 98
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-ethylhexanoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0261] 99
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0262] 100
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-phenylpropanoyl)-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0263] 101
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-fluoro-5-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0264]
102
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(4-fluoro-3-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0265] 103
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-nitrobenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0266] 104
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,5-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0267] 105
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2-trifluoromethylbenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0268] 106
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,4-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0269] 107
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(4-chlorobenzoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0270] 108
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0271] 109
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,3,4,5-tetrafl-
uorobenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0272] 110
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,6-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0273] 111
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-furylcarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0274] 112
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,4-dichloroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0275] 113
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-methoxycarbon-
ylpropanoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0276] 114
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-chlorobenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0277] 115
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-fluoro-5-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0278]
116
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-fluoro-4-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0279]
117
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2-thienylacetyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0280] 118
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,6-dichlorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0281] 119
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,4-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0282] 120
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(3-methylbenzoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0283] 121
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-methoxycarbonylpropanoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0284] 122
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-fluoro-6-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0285]
123
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-methylbenzoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0286] 124
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,5-dichlorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0287] 125
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2-furylcarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0288] 126
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(pentanoyl)-1,3,4,9-tetrah-
ydro-2,9-diazafluorene; [0289] 127
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(6-fluoro-2-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0290] 128
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0291] 129
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(4-tert.butylbenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0292] 130
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(phenylacetyl)-1,3,4,9-tet-
rahydro-2,9-diazafluorene; [0293] 131
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,5-dichloroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0294] 132
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,3,4,5,6-pentafluorobenz-
oyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0295] 133
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(3-nitrobenzoyl)-1,3,4,9-t-
etrahydro-2,9-diazafluorene; [0296] 134
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-nitrobenzoyl)-1,3,4,9-t-
etrahydro-2,9-diazafluorene; [0297] 135
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,3,4,5-tetrafluorobenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0298] 136
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-thienylacetyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0299] 137
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-fluoro-4-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0300] 138
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-fluorobenzoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0301] 139
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(cyclobutylcarbonyl)-1,3,4-
,9-tetrahydro-2,9-diazafluorene; [0302] 140
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-methoxybenzoyl)-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0303] 141
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2,5-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0304] 142
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-bromobenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0305] 143
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-fluoro-5-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0306] 144
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-fluoro-5-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0307] 145
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2,3-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene, and physiologically compatible
salts thereof.
[0308] Particularly preferred compounds are selected from the group
consisting of: [0309] 8
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-hydroxymethyl-1,3,4,9-tetr-
ahydro-2,9-diazafluorene; [0310] 10
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(methoxycarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0311] 11
1,1-(3-dimethylamino-3-phenylpentamethylene)-7-fluoro-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0312] 13
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
-2,9-diazafluorene; [0313] 14
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-acetyl-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0314] 17
1,1-(3-dimethylamino-3-(2-pyridyl)pentamethylene)-1,3,4,9-tetrahydro-2,9--
diazafluorene; [0315] 19
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-acetyl-7-fluoro-1,3,4,9-te-
trahydro-2,9-diazafluorene; [0316] 20
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2,9-diaza-
fluorene; [0317] 25
1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
-2,9-diazafluorene; [0318] 50
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-cinnamoyl-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0319] 51
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,3-dimethylbut-
anoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0320] 52
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(cyclopentylcarb-
onyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0321] 53
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,3-dimethylbutanoyl)-1,3-
,4,9-tetrahydro-2,9-diazafluorene; [0322] 54
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(pentanoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0323] 55
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-furylcarbonyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0324] 56
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-furylcarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0325] 57
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-fluorobenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0326] 58
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0327] 59
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-methylbutanoyl)-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0328] 60
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(cyclohexylcarbo-
nyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0329] 61
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-benzoyl-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0330] 62
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(cyclohexylcarbonyl)-1,3,4-
,9-tetrahydro-2,9-diazafluorene; [0331] 63
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(phenylacetyl)-1-
,3,4,9-tetrahydro-2,9-diazafluorene; [0332] 64
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0333] 65
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(4-trifluoromethylbenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0334] 66
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(thien-2-ylacety-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0335] 67
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(phenylacetyl)-1-
,3,4,9-tetrahydro-2,9-diazafluorene; [0336] 68
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-butanoyl-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0337] 69
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(4-trifluoromethylbenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0338] 70
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(3-fluoro-5-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0339] 71
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,3-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0340] 72
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0341] 73
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-phenylpropanoyl)-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0342] 74
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,4-dichlorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0343] 75
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-cinnamoyl-1,3,4,9-tetrahyd-
ro-2,9-diazafluorene; [0344] 76
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,6-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0345] 77
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-methoxycarbonylpropanoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0346] 78
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-chlorobenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0347] 79
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-fluorobenzoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0348] 80
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2,6-difluorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0349] 81
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,4-dichloroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0350] 82
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,3,4,5,6-pentafluorobenz-
oyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0351] 83
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-cyclohexylcarbonyl-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0352] 84
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-cyclopentylpropanoyl)-1-
,3,4,9-tetrahydro-2,9-diazafluorene; [0353] 85
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-fluoro-3-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0354] 86
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0355] 87
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,4,5-trimethox-
ybenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0356] 88
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-cyclobutylcarbonyl-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0357] 89
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(2,6-dichlorobenzoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0358] 90
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0359] 91
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-thienylcarbonyl)-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0360] 92
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-propanoyl-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0361] 93
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,4-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0362] 94
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,5-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0363] 95
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-tert.butylben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0364] 96
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(3-methoxycarbonylpropanoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0365] 97
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,4-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0366] 98
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-ethylhexanoyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0367] 99
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0368] 100
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-phenylpropanoyl)-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0369] 101
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3-fluoro-5-trif-
luoromethylbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0370]
102
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(4-fluoro-3-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; and physiologically
compatible salts thereof.
[0371] Particularly preferred are compounds selected from the group
consisting of: [0372] 8
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-hydroxymethyl-1,3,4,9-tetr-
ahydro-2,9-diazafluorene; [0373] 10
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(methoxycarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0374] 11
1,1-(3-dimethylamino-3-phenylpentamethylene)-7-fluoro-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0375] 13
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
-2,9-diazafluorene; [0376] 14
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-acetyl-1,3,4,9-tetrahydro--
2,9-diazafluorene; [0377] 17
1,1-(3-dimethylamino-3-(2-pyridyl)pentamethylene)-1,3,4,9-tetrahydro-2,9--
diazafluorene; [0378] 50
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-cinnamoyl-1,3,4,-
9-tetrahydro-2,9-diazafluorene; [0379] 51
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(3,3-dimethylbut-
anoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0380] 52
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(cyclopentylcarb-
onyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0381] 53
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3,3-dimethylbutanoyl)-1,3-
,4,9-tetrahydro-2,9-diazafluorene; [0382] 54
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(pentanoyl)-1,3,-
4,9-tetrahydro-2,9-diazafluorene; [0383] 55
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-furylcarbonyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0384] 56
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(2-furylcarbonyl)-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0385] 57
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-fluorobenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0386] 58
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0387] 59
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(3-methylbutanoyl)-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0388] 60
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(cyclohexylcarbo-
nyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0389] 61
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-benzoyl-1,3,4,9--
tetrahydro-2,9-diazafluorene; [0390] 62
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(cyclohexylcarbonyl)-1,3,4-
,9-tetrahydro-2,9-diazafluorene; [0391] 63
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(phenylacetyl)-1-
,3,4,9-tetrahydro-2,9-diazafluorene; [0392] 64
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-methoxybenzoy-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0393] 65
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-(4-trifluoromethylbenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0394] 66
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(thien-2-ylacety-
l)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0395] 67
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(phenylacetyl)-1-
,3,4,9-tetrahydro-2,9-diazafluorene; [0396] 68
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-butanoyl-1,3,4,9-
-tetrahydro-2,9-diazafluorene; [0397] 69
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(4-trifluoromethylbenzoyl)-
-1,3,4,9-tetrahydro-2,9-diazafluorene; [0398] 70
1,1-(3-dimethylamino-3-benzylpentamethylene)-2-(3-fluoro-5-trifluoromethy-
lbenzoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0399] 71
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(2,3-difluoroben-
zoyl)-1,3,4,9-tetrahydro-2,9-diazafluorene; [0400] 72
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-2-(4-methylbenzoyl-
)-1,3,4,9-tetrahydro-2,9-diazafluorene, and physiologically
acceptable salts thereof
[0401] Furthermore, is has been shown that spirocyclic cyclohexane
derivatives in which W denotes NR.sup.4 and X denotes O are
likewise particularly preferred. Accordingly, in the context of the
present invention spirocyclic cyclohexane derivatives in which W
denotes NR.sup.4 and X denotes O are preferred. It is particularly
preferred to use compounds selected from the group consisting of:
[0402] 1
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-pyrano[3,-
4-b]indole; [0403] 3
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydro--
pyrano[3,4-b]indole; [0404] 4
1,1-(3-dimethylamino-3-(2-thienyl)pentamethylene)-1,3,4,9-tetrahydropyran-
o[3,4-b]indole; [0405] 5
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydrop-
yrano[3,4-b]indole; [0406] 6
1,1-(3-dimethylamino-3-phenylpentamethylene)-3,6-dimethyl-1,3,4,9-tetrahy-
dropyrano[3,4-b]indole; [0407] 7
1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
-pyrano[3,4-b]indole; [0408] 12
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-aza-9-o-
xafluorene; [0409] 15
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole; [0410] 16
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-chloro-3-methyl-1,3,4,9-te-
trahydropyrano[3,4-b]indole; [0411] 18
1,1-(3-dimethylamino-3-(3-thienyl)pentamethylene)-6-fluoro-1,3,4,9-tetrah-
ydropyrano[3,4-b]indole; [0412] 21
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetra-hydro-
pyrano[3,4-b]indole; [0413] 23
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-6-nitro-1,3,4,9-tet-
rahydropyrano[3,4-b]indole; [0414] 24
1,1-(3-dimethylamino-3-(3-thienyl)pentamethylene)-1,3,4,9-tetrahydro-pyra-
no[3,4-b]indole; [0415] 29
1,1-(3-dimethylamino-3-(2-thienyl)pentamethylene)-6-fluoro-1,3,4,9-tetrah-
ydro-pyrano[3,4-b]indole; [0416] 31
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-3-methyl-1,3,4,9-te-
trahydropyrano[3,4-b]indole; [0417] 32
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-hydroxy-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole; [0418] 33
1,1-(3-dimethylamino-3-(3-hydroxyphenyl)pentamethylene)-1,3,4,9-tetrahydr-
opyrano[3,4-b]indole; [0419] 35
6,6-(3-dimethylamino-3-phenylpentamethylene)-1,2,3,4,4a,6,7,11c-octahydro-
-5-oxa-7-aza-benzo[c]fluorine; [0420] 36
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydrop-
yrano[3,4-b]indole; [0421] 41
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-bromo-3-methyl-1,3,4,9-tet-
rahydropyrano[3,4-b]indole; [0422] 42
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydrop-
yrano[3,4-b]indole; [0423] 43
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-bromo-1,3,4,9-tetrahydropy-
rano[3,4-b]indole; [0424] 44
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methoxy-1,3,4,9-tetra-hydr-
opyrano[3,4-b]indole; [0425] 45
1,1-(3-(1-Pyrrolidyl)-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,-
4-b]indole; [0426] 46
1,1-(3-dimethylamino-3-phenylpentamethylene)-7,8-dichloro-1,3,4,9-tetrahy-
dropyrano[3,4-b]indole; [0427] 47
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-(1-benzyl-pyrazol-4-yl)-1,-
3,4,9-tetrahydro-pyrano[3,4-b]indole; [0428] 48
1,1-(3-Methylamino-3-(2-thienyl)pentamethylene)-1,3,4,9-tetrahydro-pyrano-
[3,4-b]indole; [0429] 49
1,1-(3-Methylamino-3-(2-thienyl)pentamethylene)-6-fluoro-1,3,4,9-tetrahyd-
ro-pyrano[3,4-b]indole, and physiologically acceptable salts
thereof.
[0430] In particular, it is preferred to use compounds selected
from the group consisting of: [0431] 1
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-pyrano[3,-
4-b]indole [0432] 3
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydro--
pyrano[3,4-b]indole [0433] 4
1,1-(3-dimethylamino-3-(2-thienyl)pentamethylene)-1,3,4,9-tetrahydropyran-
o[3,4-b]indole [0434] 5
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydrop-
yrano[3,4-b]indole [0435] 6
1,1-(3-dimethylamino-3-phenylpentamethylene)-3,6-dimethyl-1,3,4,9-tetrahy-
dropyrano[3,4-b]indole [0436] 7
1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
-pyrano[3,4-b]indole [0437] 12
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-aza-9-o-
xafluorene [0438] 15
1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole [0439] 16
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-chloro-3-methyl-1,3,4,9-te-
trahydropyrano[3,4-b]indole [0440] 18
1,1-(3-dimethylamino-3-(3-thienyl)pentamethylene)-6-fluoro-1,3,4,9-tetrah-
ydropyrano[3,4-b]indole [0441] 21
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetra-hydro-
pyrano[3,4-b]indole [0442] 23
1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-6-nitro-1,3,4,9-tet-
rahydropyrano[3,4-b]indole [0443] 24
1,1-(3-dimethylamino-3-(3-thienyl)pentamethylene)-1,3,4,9-tetrahydro-pyra-
no[3,4-b]indole [0444] 47
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-(1-benzyl-pyrazol-4-yl)-1,-
3,4,9-tetrahydro-pyrano[3,4-b]indole [0445] 48
1,1-(3-Methylamino-3-(2-thienyl)pentamethylene)-1,3,4,9-tetrahydro-pyrano-
[3,4-b]indole, and physiologically acceptable salts thereof.
[0446] It is most particularly preferred to use compounds selected
from the group: [0447] 1
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-pyrano[3,-
4-b]indole; [0448] 3
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydrop-
yrano[3,4-b]indole; [0449] 4
1,1-(3-dimethylamino-3-(2-thienyl)pentamethylene)-1,3,4,9-tetrahydro-pyra-
no[3,4-b]indole, and physiologically acceptable salts thereof
[0450] Also preferred are compounds selected from the group
consisting of: [0451] 22
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-
-2-thia-9-azafluorene; [0452] 27
1,1-(3-dimethylamino-3-phenylpentamethylene)-2-oxo-1,3,4,9-tetrahydro-2-t-
hia-9-azafluorene; [0453] 28
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9--
azafluorene; [0454] 34
1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9--
azafluorene, and physiologically acceptable salts thereof.
[0455] The synthesis of the compounds is described in US
2006/004034 A1 and US 2005/066183 A1. The isolation of the
compounds according to the invention by column chromatography with
silica gel as stationary phase leads to a separation of the
different polar diastereomers. These were characterised on the
basis of their running time as "non-polar" diastereomer (shorter
running time) and "polar" diastereomer (longer running time).
Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt, was used.
The thin-layer chromatography investigations were carried out with
HPTLC precoated plates from E. Merck, Darmstadt. As solvent, for
example methanol/ethyl acetate was used in a ratio of 1:1, 2:1, 3:1
or 4:1, preferably 3:1, or methanol/conc. ammonia solution 99.5:0.5
or methanol/ethyl acetate/conc. ammonia solution in a ratio of
66:33:0.5.
[0456] The pharmaceutical compositions of the invention optionally
contain, besides at least one compound according to the invention,
suitable additives and/or auxiliary substances, including carrier
materials, fillers, solvents, diluents, coloring agents and/or
binders, and may be administered as liquid medicament forms in the
form of injection solutions, drops or ointments, as semi-solid
medicament forms in the form of granules, tablets, pellets,
patches, capsules, plasters/spray 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, buccaly, rectally or
topically for example to the skin, mucus membranes or to the eyes.
For oral application suitable preparations are in the form of
tablets, coated tablets, capsules, granules, drops, ointments and
syrups, while for parenteral, topical and inhalative application
suitable forms are solutions, suspensions, readily reconstitutable
dry preparations, as well as sprays. Spirocyclic cyclohexane
derivatives according to the invention in depot form, in dissolved
form or in a plaster form, optionally with the addition of agents
promoting penetration of the skin, are suitable percutaneous
application preparations. Orally or percutaneously usable
preparation forms can provide for the delayed release of the
compounds according to the invention. The compounds according to
the invention can also be employed in parenteral long-term depot
forms, such as for example implants or implanted pumps. In
principle other active constituents known to the person skilled in
the art can be added to the medicaments according to the
invention.
[0457] The amount of active constituent to be administered to the
patient varies depending on the patient's weight, form of
application, medical implications and the severity of the illness.
Normally 0.00005 to 1 mg/kg, preferably 0.0001 to 0.05 mg/kg of at
least one spirocyclic cyclohexane derivative according to the
invention is applied.
[0458] All the aforementioned forms of the medicaments according to
the invention also may contain, in addition to at least one
compound according to the invention, a further active constituent,
in particular an opioid antagonist, preferably naloxone.
Comparative Investigations
[0459] For comparison purposes the standard medication
levomethadone, which has no significant ORL1 component, was tested
in the withdrawal jumping test. Levomethadone, which is one of the
standard therapeutic agents used in substitution therapy, likewise
induced withdrawal jumping. Among the compounds described in US
2006/004034 A1 and US 2005/066183 A1 are a number of substances
with a slight ORL1 component. Two typical members with a slight
ORL1 component (compounds m and n) were likewise tested in the
withdrawal jumping test and induced withdrawal jumping. This shows
the importance of the ORL1 component as regards the suitability of
a substance for substitution therapy within the group of compounds
described in US 2006/004034 A1 and US 2005/066183 A1.
[0460] The properties that are desired in the standard therapeutic
agents and which are to some extent manifested include: [0461] 1.
High opioid potency [0462] 2. Full intrinsic activity [0463] 3.
Long action duration (active metabolites such as for example in the
case of LAAM are even desirable in this indication) [0464] 4.
Slower action on set, especially with oral administration (less
"kick") [0465] 5. Lower cardio toxicity Whereas with the known
standard substances some of these properties are missing or are
insufficiently manifested, with the compounds according to the
invention all the required properties were present.
[0466] The compounds according to the invention show significantly
reduced cardiovascular side effects compared to methadone and LAAM.
The cardiovascular side effects are attributed to a delayed cardiac
repolarisation (manifested as a QTc extension in the outside ECG),
which is caused by the blockade of a special potassium channel
(HERG) (Kornick et al. Pain 2003, 105, 499-506). Both methadone and
LAAM exhibit interactions with the HERG channel (Jiesheng et al.,
Eur. J. Pharmacol. 2003, 458, 25-29; Katchman et al., J. Pharmacol.
Exp. Ther. 2002, 303, 688-694). In connection with the order issued
by Orlaam (LAAM) the FDA gave a warning in 2001 about the
cardiovascular effects (JAMA 2001, 285, 2705). In the case of the
compounds according to the invention it was shown for example that
the cardiovascular side effects are significantly less compared to
methadone and LAAM.
EXAMPLES
[0467] Within the group of spiro compounds described in US
2006/004034 A1 and US 2005/192333 A1 there are compounds with a
higher and lower ORL1 component.
Measurement of the ORL1 Binding
[0468] The cyclohexane derivatives of the general formula I were
investigated in a receptor binding assay with
.sup.3H-nociceptin/orphanin FQ with membranes of recombinant
CHO-ORL1 cells. This test system was implemented according to the
method proposed by Ardati et al. (Mol. Pharmacol., 51, 1997, pp.
816-824). The concentration of 3H-nociceptin/orphanin FQ in these
tests was 0.5 nM. The binding assays were carried out with 20 .mu.g
of membrane protein per 200 .mu.l of batch in 50 mM Hepes, pH 7.4,
10 mM MgCl.sub.2 and 1 mM EDTA. The binding to the ORL1 receptor
was determined using in each case 1 mg WGA-SPA beads
(Amersham-Pharmacia, Freiburg), by incubating the batch for one
hour at room temperature followed by measurement in a Trilux
scintillation counter (Wallac, Finland). The affinity is given in
Table 1 as nanomolar Ki.sub.j value in or % inhibition at c=1
.mu.M.
Measurement of the .mu.-Binding
[0469] The receptor affinity for the human .mu.-opiate receptor was
determined in a homogeneous batch in mikrotiter plates. For this
purpose dilution series of the respective substituted
cyclohexyl-1,4-diamine derivatives to be tested were incubated with
a receptor membrane preparation (15-40 .mu.g protein per 250 .mu.l
incubation batch) of CHO--K1 cells which express the human
.mu.-opiate receptor (RB-HOM receptor membrane preparation obtained
from the NEN company, Zaventem, Belgium) in the presence of 1
nmol/1 of the radioactive ligand [3H]-naloxone (NET719, NEN
company, Zaventem, Belgium) as well as of 1 mg WGA-SPA beads (wheat
germ agglutinin SPA Beads from Amersham/Pharmacia, Freiburg,
Germany) in a total volume of 250 .mu.l for 90 minutes at room
temperature. 50 mmol/l tris-HCl supplemented by 0.05 wt. % of
sodium azide and 0.06 wt. % of bovine serum albumin were used as
incubation buffer. In order to determine the non-specific binding,
25 .mu.mol/l of naloxone were additionally added. After the end of
the 9-minute incubation period the microtiter plates were
centrifuged for 20 minutes at 1000 G and the radioactivity was
measured in a .beta.-counter (Microbeta-Trilux, PerkinElmer Wallac
Company, Freiburg, Germany). The percentage displacement of the
radioactive ligand from its binding to the human .mu.-opiate
receptor at a concentration of the test substances of 1 .mu.mol/l
was determined and given as the percentage inhibition (%
inhibition) of the specific binding. In some cases IC.sub.50
inhibition concentrations which effect a 50% displacement of the
radioactive ligand were calculated on the basis of the percentage
displacement by different concentration of the compounds of the
general formula I to be tested. Ki values for the test substances
were obtained by conversion using the Cheng-Prusoff
relationship.
[0470] The following table lists by way of example some compounds
which, although they bind very well to the .mu.-opiate receptor,
nevertheless have a relatively low ORL1 component:
TABLE-US-00001 ORL1/.mu. ratio calculated as ORL-1 .mu.-opiate-
Ki(.mu.)/Ki(ORL1) [1 .mu.M], receptor (only for measured % [1
.mu.M], Compound Structure Ki values) inhibition % inhibition a
##STR00002## 1 83 b ##STR00003## Citrate 5 89 c ##STR00004##
Citrate 11 74 d ##STR00005## 13 83 e ##STR00006## Citrate 15 75 f
##STR00007## Citrate 27 92 g ##STR00008## 31 91 h ##STR00009## 32
97 I ##STR00010## 32 99 j ##STR00011## Citrate 33 78 k ##STR00012##
41 82 l ##STR00013## Citrate 43 100 m ##STR00014## Citrate 0.03 69
nM (K.sub.i) 2.4 nM (K.sub.i) n ##STR00015## Hemicitrate 0.1 14.3
nM (K.sub.i) 1.8 nM (K.sub.i)
[0471] As shown by way of example in the compounds m and n, these
compounds do not suppress withdrawal jumping.
[0472] Compared to the above, the following compounds have an
almost balanced ORL1/.mu. ratio. Ideally, they have a more strongly
pronounced ORL1 component. The ORL1:.mu. ratio is however at least
1:3:
TABLE-US-00002 ORL1/.mu. Ratio ORL1 calculated human .mu. as
Ki(.mu.)/ Ki Ki No. Compound Name Remarks Ki(ORL1) [.mu.M] [.mu.M]
1 ##STR00016## 1,1-(3-dimethylamino- 3-phenylpentamethyl-
ene)-1,3,4,9- tetrahydropyrano[3,4- b]indole Hemicitrate Non-polar
diastereomer 2 0.0034 0.0058 2 ##STR00017## 1,1-(3-dimethylamino-
3-benzylpentamethyl- ene)-2-(2-nitro- benzoyl)-1,3,4,9-
tetrahydro-2,9- diazafluorene 0.32 0.0038 0.0012 3 ##STR00018##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-6-fluoro-1,3,4,9-
tetrahydropyrano[3,4- b]indole Hemicitrate Non-polar diastereomer
2.45 0.0026 0.006 4 ##STR00019## 1,1-(3-dimethylamino-
3-(2-thienyl)penta- methylene)-1,3,4,9- tetrahydropyrano[3,4-
b]indole Hemicitrate Non-polar diastereomer 2.07 0.0003 0.0006 5
##STR00020## 1,1-(3-dimethylamino- 3-phenylpentamethyl-
ene)-3-methyl-1,3,4,9- tetrahydropyrano[3,4- b]indole Hemicitrate
Non-polar diastereomer 3.82 0.0012 0.0047 6 ##STR00021##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-3,6-dimethyl-
1,3,4,9-tetrahydro- pyrano[3,4-b]indole Hemicitrate One of two
diastereomers 3.18 0.0044 0.014 7 ##STR00022##
1,1-(3-dimethylamino- 3-(4-fluorophenyl)- pentamethylene)-
1,3,4,9-tetrahydro- pyrano[3,4-b]indole Hemicitrate One of two
diastereomers 3.00 0.0032 0.010 8 ##STR00023##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-3-hydroxymethyl-
1,3,4,9-tetrahydro-2,9- diazafluorene Dicitrate Diastereomer
mixture 2.70 0.0010 0.0027 9 ##STR00024## 1,1-(3-dimethylamino-
3-phenylpentamethyl- ene)-2-(2,3,4,5,6- pentafluorobenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 0.32 0.13 0.041 10
##STR00025## 1,1-(3-dimethylamino- 3-phenylpentamethyl-
ene)-2-(methoxy- carbonyl)-1,3,4,9- tetrahydro-2,9- diazafluorene
Citrate Diastereomer Mixture 2.67 0.0009 0.0023 11 ##STR00026##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-7-fluoro-1,3,4,9-
tetrahydro-2,9- diazafluorene Citrate Polar Diastereomer 2.46 0.007
0.02 12 ##STR00027## 1,1-(3-dimethylamino- 3-phenylpentamethyl-
ene)-1,3,4,9- tetrahydro-2-aza-9- oxafluorene Citrate Diastereomer
mixture 2.39 0.07 0.17 13 ##STR00028## 1,1-(3-dimethylamino-
3-(3-fluorophenyl)- pentamethylene)- 1,3,4,9-tetrahydro-2,9-
diazafluorene Diastereomer mixture 2.22 0.0036 0.008 14
##STR00029## 1,1-(3-dimethylamino- 3-phenylpentamethyl-
ene)-2-acetyl-1,3,4,9- tetrahydro-2,9- diazafluorene hydrochloride
Non-polar diastereomer 1.98 0.0029 0.006 15 ##STR00030##
1,1-(3-dimethylamino- 3-(3-fluorophenyl)- pentamethylene)-
1,3,4,9-tetrahydro- pyrano[3,4-b]indole Hemicitrate One of two
diastereomers 1.79 0.0012 0.0022 16 ##STR00031##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-6-chloro-3-
methyl-1,3,4,9- tetrahydropyrano- [3,4-b]indole Citrate Non-polar
diastereomer 1.77 0.06 0.11 17 ##STR00032## 1,1-(3-dimethylamino-
3-(2-pyridyl)penta- methylene)-1,3,4,9- tetrahydro-2,9-
diazafluorene Diastereomer mixture 1.75 0.0016 0.0028 18
##STR00033## 1,1-(3-dimethylamino- 3-(3-thienyl)penta-
methylene)-6-fluoro- 1,3,4,9-tetrahydro- pyrano[3,4-b]indole
Hemicitrate Non-polar Diastereomer 1.62 0.0003 0.0006 19
##STR00034## 1,1-(3-dimethylamino- 3-phenylpentamethyl-
ene)-2-acetyl-7-fluoro- 1,3,4,9-tetrahydro-2,9- diazafluorene
Citrate Diastereomer mixture 1.41 0.0011 0.0016 20 ##STR00035##
1,1-(3-dimethylamino- 3-phenylpentamethyl- en)-1,3,4,9-tetrahydro-
2,9-diazafluorene Di- hydrochloride Diastereomer mixture 1.38
0.0003 0.0004 21 ##STR00036## 1,1-(3-dimethylamino-
3-phenylpentamethyl- ene)-3-methyl-1,3,4,9- tetrahydropyrano[3,4-
b]indole Citrate Diastereomer mixture 1.38 0.04 0.06 22
##STR00037## 1,1-(3-dimethylamino- 3-phenylpentamethyl-
en)-1,3,4,9-tetrahydro- 2-thia-9-azafluorene Citrate Diastereomer
mixture 1.33 0.02 0.02 23 ##STR00038## 1,1-(3-dimethylamino-
3-phenylpentamethyl- ene)-3-methyl-6-nitro- 1,3,4,9-tetrahydro-
pyrano[3,4-b]indole Citrate Polar diastereomer 1.29 0.03 0.04 24
##STR00039## 1,1-(3-dimethylamino- 3-(3-thienyl)penta-
methylene)-1,3,4,9- tetrahydropyrano- [3,4-b]indole Hemicitrate
Non-polar diastereomer 1.19 0.0006 0.0007 25 ##STR00040##
1,1-(3-dimethylamino- 3-(4-fluorophenyl)- pentamethylene)-
1,3,4,9-tetrahydro-2,9- diazafluorene Diastereomer mixture 1.12
0.0026 0.0029 26 ##STR00041## 1,1-(3-dimethylamino-
3-phenylpentamethyl- ene)-3-methyl-1,3,4,9- tetrahydro-2,9-
iazafluorene Citrate One of two diastereomers 0.94 0.0005 0.0005 27
##STR00042## 1,1-(3-dimethylamino- 3-phenylpentamethyl-
ene)-2-oxo-1,3,4,9- tetrahydro-2-thia-9- azafluorene Citrate 0.94
0.06 0.06 28 ##STR00043## 1,1-(3-dimethylamino-
3-phenylpentamethyl- en)-1,3,4,9-tetrahydro- 2-thia-9-azafluorene
Hemicitrate Non-polar diastereomer 0.84 0.0037 0.0031 29
##STR00044## 1,1-(3-dimethylamino- 3-(2-thienyl)penta-
methylene)-6-fluoro- 1,3,4,9-tetrahydro- pyrano[3,4-b]indole
Hemicitrate Non-polar diastereomer 0.82 0.0007 0.0006 30
##STR00045## 1,1-(3-dimethylamino- 3-phenylpentamethyl-
ene)-3-methyl-1,3,4,9- tetrahydro-2,9- diazafluorene Dihydro-
chloride Diastereomer mixture 0.78 0.0006 0.0005 31 ##STR00046##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-6-fluoro-3-
methyl-1,3,4,9- tetrahydropyrano- [3,4-b]indole Hemicitrate One of
two diastereomers 0.73 0.08 0.06 32 ##STR00047##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-6-hydroxy-
1,3,4,9-tetrahydro- pyrano[3,4-b]indole Citrate One of two
diastereomers 0.7 0.0016 0.0011 33 ##STR00048##
1,1-(3-dimethylamino- 3-(3-hydroxyphenyl)- pentamethylene)-
1,3,4,9-tetrahydro- pyrano[3,4-b]indole Methyl- sulfonate One of
two diastereomers 0.66 0.014 0.009 34 ##STR00049##
1,1-(3-dimethylamino- 3-phenylpentamethyl- en)-1,3,4,9-tetrahydro-
2-thia-9-azafluorene Citrate Polar diastereomer 0.62 0.13 0.08 35
##STR00050## 6,6-(3-dimethylamino- 3-phenylpentamethyl-
en)-1,2,3,4,4a,6,7,11c- octahydro-5-oxa-7-aza- benzo[c]fluorine
Citrate Diastereomer mixture 0.62 0.11 0.07 36 ##STR00051##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-6-methyl-1,3,4,9-
tetrahydropyrano- [3,4-b]indole Hemicitrate One of two
diastereomers 0.60 0.0045 0.0027 37 ##STR00052##
1,1-(3-dimethylamino- 3-(4-fluorophenyl)- pentamethylene)-2-
acetyl-1,3,4,9- tetrahydro-2,9- diazafluorene Citrate Diastereomer
mixture 0.55 0.006 0.0033 38 ##STR00053## 1,1-(3-dimethylamino-
3-benzylpentamethyl- en)-1,3,4,9-tetrahydro- 2,9-diazafluorene One
of two diastereomers 0.54 0.0011 0.0006 39 ##STR00054##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-6-fluoro-1,3,4,9-
tetrahydro-2,9- diazafluorene Dihydro- chloride One of two
diastereomers 0.51 0.0014 0.0007 40 ##STR00055##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-6-methyl-1,3,4,9-
tetrahydro-2,9- diazafluorene Citrate Polar diastereomer 0.47 0.03
0.02 41 ##STR00056## 1,1-(3-dimethylamino- 3-phenylpentamethyl-
ene)-6-bromo-3- methyl-1,3,4,9- tetrahydropyrano- [3,4-b]indole
Hemicitrate One of two diastereomers 0.45 0.02 0.010 42
##STR00057## 1,1-(3-dimethylamino- 3-phenylpentamethyl-
ene)-6-fluoro-1,3,4,9- tetrahydropyrano- [3,4-b]indole Citrate
Polar diastereomer 0.42 0.02 0.009 43 ##STR00058##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-6-bromo-1,3,4,9-
tetrahydropyrano- [3,4-b]indole Hemicitrate One of two
diastereomers 0.37 0.05 0.02 44 ##STR00059## 1,1-(3-dimethylamino-
3-phenylpentamethyl- ene)-6-methoxy- 1,3,4,9-tetrahydro-
pyrano[3,4-b]indole hydrochloride Non-polar diastereomer 0.34 0.006
0.0020 45 ##STR00060## 1,1-(3-(1-Pyrrolidyl)- 3-phenylpentamethyl-
en)-1,3,4,9-tetrahydro- pyrano[3,4-b]indole Hemicitrate Non-polar
diastereomer 0.31 0.0035 0.0011 46 ##STR00061##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-7,8-dichloro-
1,3,4,9-tetrahydro- pyrano[3,4-b]indole Methane sulfonate One of
two diastereomers 0.31 0.0045 0.0014 47 ##STR00062##
1,1-(3-dimethylamino- 3-phenylpentamethyl- ene)-6-(1-benzyl-
pyrazol-4-yl)-1,3,4,9- tetrahydropyrano- [3,4-b]indole
hydrochloride Non-polar diastereomer 2.73 0.0044 0.012 48
##STR00063## 1,1-(3-Methylamino-3- (2-thienyl)pentameth-
ylene)-1,3,4,9-tetra- hydropyrano[3,4-b]- indole One of two
diastereomers 6.56 0.00032 0.0021 49 ##STR00064##
1,1-(3-Methylamino-3- (2-thienyl)pentameth- ylene)-6-fluoro-
1,3,4,9-tetrahydro- pyrano[3,4-b]indole Citrate One of two
diastereomers 0.7 0.0042 0.0028 ORL1, ORL1/.mu. Ki .mu., Ki No.
Compound Name ratio [.mu.M] [.mu.M] 50 ##STR00065##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-cinnamoyl-1,3,4,9- tetrahydro-2,9-diazafluorene 21.43 0.0014
0.030000 51 ##STR00066## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3,3-dimethylbutanoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 5.00 0.0026 0.013000 52
##STR00067## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(cyclopentylcarbonyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 4.78 0.0067 0.032 53
##STR00068## 1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(3,3-
dimethylbutanoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 3.54 0.0048
0.017 54 ##STR00069## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(pentanoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 3.42 0.0038 0.013 55 ##STR00070##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(2-furylcarbonyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 3.14
0.022 0.069 56 ##STR00071## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(2- furylcarbonyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 2.90 0.01 0.029 57 ##STR00072##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(4-fluorobenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 2.83
0.0046 0.013 58 ##STR00073## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(2-methoxybenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 2.78 0.00097 0.0027 59 ##STR00074##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(3-
methylbutanoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 2.68 0.0041
0.011 60 ##STR00075## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(cyclohexylcarbonyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 2.60 0.025 0.065 61
##STR00076## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-benzoyl-1,3,4,9-tetrahydro-
2,9-diazafluorene 2.50 0.0034 0.0085 62 ##STR00077##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-
(cyclohexylcarbonyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 2.40
0.002 0.0048 63 ##STR00078## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(phenylacetyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 2.35 0.002 0.0047 64 ##STR00079##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(4-methoxybenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 2.29
0.038 0.087 65 ##STR00080## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(4- trifluoromethylbenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 2.18 0.0078 0.017 66
##STR00081## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(thien-2-ylacetyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 2.12 0.017 0.036 67 ##STR00082##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(phenylacetyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 2.07 0.0014
0.0029 68 ##STR00083## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-butanoyl-1,3,4,9-tetrahydro-
2,9-diazafluorene 2.00 0.0014 0.0028 69 ##STR00084##
1,1-(3-dimethylamino-3- benzylpentamethylene)-2-(4-
trifluoromethylbenzoyl)- 1,3,4,9-tetrahydro-2,9- diazafluorene 1.91
0.011 0.021 70 ##STR00085## 1,1-(3-dimethylamino-3-
benzylpentamethylene)-2-(3- fluoro-5-trifluoromethyl-
benzoyl)-1,3,4,9-tetrahydro- 2,9-diazafluorene 1.82 0.0077 0.014 71
##STR00086## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(2,3-difluorobenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 1.79 0.0014 0.0025 72
##STR00087## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(4-methylbenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 1.77 0.026 0.046 73 ##STR00088##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(3-
phenylpropanoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 1.64 0.028
0.046 74 ##STR00089## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(3,4- dichlorobenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 1.64 0.014 0.023 75 ##STR00090##
1,1-(3-dimethylamino-3- benzylpentamethylene)-2-
cinnamoyl-1,3,4,9-tetrahydro- 2,9-diazafluorene 1.54 0.024 0.037 76
##STR00091## 1,1-(3-dimethylamino-3- benzylpentamethylene)-2-(2,6-
difluorobenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 1.54 0.054
0.083 77 ##STR00092## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(3- methoxycarbonylpropanoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 1.50 0.01 0.015 78
##STR00093## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3-chlorobenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 1.50 0.018 0.027 79 ##STR00094##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(3-
fluorobenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 1.50 0.0028
0.0042 80 ##STR00095## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(2,6- difluorobenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 1.50 0.01 0.015 81 ##STR00096##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(3,4-dichlorobenzoyl)- 1,3,4,9-tetrahydro-2,9- diazafluorene 1.37
0.019 0.026 82 ##STR00097## 1,1-(3-dimethylamino-3-
benzylpentamethylene)-2- (2,3,4,5,6-pentafluoro-
benzoyl)-1,3,4,9-tetrahydro- 2,9-diazafluorene 1.35 0.06 0.081 83
##STR00098## 1,1-(3-dimethylamino-3- benzylpentamethylene)-2-
cyclohexylcarbonyl-1,3,4,9- tetrahydro-2,9-diazafluorene 1.31 0.013
0.017 84 ##STR00099## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(3- cyclopentylpropanoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 1.29 0.0093 0.012 85 ##STR00100##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(4-fluoro-3-trifluoromethyl- benzoyl)-1,3,4,9-tetrahydro-
2,9-diazafluorene 1.28 0.0071 0.0091 86 ##STR00101##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(4-methylbenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 1.24
0.0055 0.0068 87 ##STR00102## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3,4,5-trimethoxybenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 1.21 0.019 0.023 88
##STR00103## 1,1-(3-dimethylamino-3- benzylpentamethylene)-2-
cyclobutylcarbonyl-1,3,4,9- tetrahydro-2,9-diazafluorene 1.17 0.041
0.048 89 ##STR00104## 1,1-(3-dimethylamino-3-
benzylpentamethylene)-2-(2,6- dichlorobenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 1.14 0.029 0.033 90 ##STR00105##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(3-methoxybenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 1.12
0.098 0.11 91 ##STR00106## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(2- thienylcarbonyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 1.09 0.032 0.035 92 ##STR00107##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-propanoyl-1,3,4,9- tetrahydro-2,9-diazafluorene 1.07 0.057 0.061
93 ##STR00108## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(2,4-difluorobenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 1.06 0.016 0.017 94
##STR00109## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3,5-difluorobenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 1.06 0.0035 0.0037 95
##STR00110## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(4-tert.butylbenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 1.06 0.0090 0.0095 96
##STR00111## 1,1-(3-dimethylamino-3- benzylpentamethylene)-2-(3-
methoxycarbonylpropanoyl)- 1,3,4,9-tetrahydro-2,9- diazafluorene
1.05 0.066 0.069 97 ##STR00112## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3,4-difluorobenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 1.04 0.0023 0.0024 98
##STR00113## 1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(2-
ethylhexanoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 1.04 0.047
0.049 99 ##STR00114## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(2-methylbenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 1.02 0.0092 0.0094 100 ##STR00115##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(3-
phenylpropanoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 1.00 0.04
0.04 101 ##STR00116## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3-fluoro-5-trifluoro-
methylbenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 1.00 0.0033
0.0033 102 ##STR00117## 1,1-(3-dimethylamino-3-
phenyl-pentamethylene)-2-(4- fluoro-3- trifluoromethylbenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 1.00 0.036 0.036 103
##STR00118## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(4-nitrobenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.97 0.0064 0.0062 104 ##STR00119##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(3,5-
difluorobenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 0.95 0.002
0.0019 105 ##STR00120## 1,1-(3-dimethylamino-3-
benzylpentamethylene)-2-(2- trifluoromethylbenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 0.95 0.019 0.018 106
##STR00121## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3,4-difluorobenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 0.94 0.0035 0.0033 107
##STR00122## 1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(4-
chlorobenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 0.91 0.011
0.010 108 ##STR00123## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3-methylbenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.91 0.011 0.010 109 ##STR00124##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(2,3,4,5-tetrafluorobenzoyl)- 1,3,4,9-tetrahydro-2,9-
diazafluorene 0.90 0.002 0.0018 110 ##STR00125##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(2,6-difluorobenzoyl)- 1,3,4,9-tetrahydro-2,9- diazafluorene 0.88
0.0089 0.0078 111 ##STR00126## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(2- furylcarbonyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.87 0.039 0.034 112 ##STR00127##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(2,4-dichlorobenzoyl)- 1,3,4,9-tetrahydro-2,9- diazafluorene 0.86
0.022 0.019 113 ##STR00128## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3-methoxycarbonyl-
propanoyl)-1,3,4,9-tetrahydro- 2,9-diazafluorene 0.86 0.029 0.025
114 ##STR00129## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3-chlorobenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.83 0.0075 0.0062 115 ##STR00130##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(2-fluoro-5-trifluoromethyl- benzoyl)-1,3,4,9-tetrahydro-
2,9-diazafluorene 0.80 0.11 0.088 116 ##STR00131##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(2-fluoro-4-trifluoro- methylbenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.80 0.0044 0.0035 117 ##STR00132##
1,1-(3-dimethylamino-3- benzylpentamethylene)-2-(2-
thienylacetyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 0.79 0.014
0.011 118 ##STR00133## 1,1-(3-dimethylamino-3-
benzylpentamethylene)-2-(2,6- dichlorobenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.78 0.093 0.073 119 ##STR00134##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(3,4-
difluorobenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 0.76 0.0025
0.0019 120 ##STR00135## 1,1-(3-dimethylamino-3-
benzylpentamethylene)-2-(3- methylbenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.75 0.016 0.012 121 ##STR00136##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(3-
methoxycarbonylpropanoyl)- 1,3,4,9-tetrahydro-2,9- diazafluorene
0.71 0.021 0.015 122 ##STR00137## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(2-fluoro-6-trifluoromethyl-
benzoyl)-1,3,4,9-tetrahydro- 2,9-diazafluorene 0.67 0.0054 0.0036
123 ##STR00138## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(2- methylbenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.65 0.031 0.020 124 ##STR00139##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(3,5-
dichlorobenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 0.64 0.0550
0.035 125 ##STR00140## 1,1-(3-dimethylamino-3-
benzylpentamethylene)-2-(2- furylcarbonyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.63 0.0054 0.0034 126 ##STR00141##
1,1-(3-dimethylamino-3- benzylpentamethylene)-2-
(pentanoyl)-1,3,4,9-tetrahydro- 2,9-diazafluorene 0.63 0.0043
0.0027 127 ##STR00142## 1,1-(3-dimethylamino-3-
benzylpentamethylene)-2-(6- fluoro-2-trifluoromethyl-
benzoyl)-1,3,4,9-tetrahydro- 2,9-diazafluorene 0.62 0.055 0.034 128
##STR00143## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3-methoxybenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.57 0.028 0.016
129 ##STR00144## 1,1-(3-dimethylamino-3-
benzylpentamethylene)-2-(4- tert.butylbenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.54 0.11 0.059 130 ##STR00145##
1,1-(3-dimethylamino-3- benzylpentamethylene)-2-
(phenylacetyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 0.54 0.0099
0.0053 131 ##STR00146## 1,1-(3-dimethylamino-3-(3-
fluorophenyl)pentamethylene)- 2-(3,5-dichlorobenzoyl)-
1,3,4,9-tetrahydro-2,9- diazafluorene 0.53 0.030 0.016 132
##STR00147## 1,1-(3-dimethylamino-3- benzylpentamethylene)-2-
(2,3,4,5,6-pentafluorobenzoyl)- 1,3,4,9-tetrahydro-2,9-
diazafluorene 0.52 0.075 0.039 133 ##STR00148##
1,1-(3-dimethylamino-3- benzylpentamethylene)-2-(3-
nitrobenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 0.52 0.017
0.0088 134 ##STR00149## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(3- nitrobenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.51 0.069 0.035 135 ##STR00150##
1,1-(3-dimethylamino-3- benzylpentamethylene)-2-
(2,3,4,5-tetrafluorobenzoyl)- 1,3,4,9-tetrahydro-2,9- diazafluorene
0.50 0.030 0.015 136 ##STR00151## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(2- thienylacetyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.48 0.0069 0.0033 137 ##STR00152##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(2-
fluoro-4-trifluoromethylbenzoyl)- 1,3,4,9-tetrahydro-2,9-
diazafluorene 0.48 0.065 0.031 138 ##STR00153##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(2-
fluorobenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 0.47 0.018
0.0084 139 ##STR00154## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2- (cyclobutylcarbonyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.45 0.075 0.034 140 ##STR00155##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(2-
methoxybenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 0.43 0.046
0.020 141 ##STR00156## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(2,5- difluorobenzoyl)-1,3,4,9-
tetrahydro-2,9-diazafluorene 0.42 0.0045 0.0019 142 ##STR00157##
1,1-(3-dimethylamino-3-(3- fluorophenyl)pentamethylene)-
2-(2-bromobenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 0.41 0.046
0.019 143 ##STR00158## 1,1-(3-dimethylamino-3-
phenylpentamethylene)-2-(3- fluoro-5-trifluoromethyl-
benzoyl)-1,3,4,9-tetrahydro- 2,9-diazafluorene 0.41 0.037 0.015 144
##STR00159## 1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(2-
fluoro-5-trifluoromethyl- benzoyl)-1,3,4,9-tetrahydro-
2,9-diazafluorene 0.39 0.049 0.019 145 ##STR00160##
1,1-(3-dimethylamino-3- phenylpentamethylene)-2-(2,3-
difluorobenzoyl)-1,3,4,9- tetrahydro-2,9-diazafluorene 0.33 0.029
0.0096 ##STR00161##
Jumping Test in Mice: Experiment to Determine the Systemic
Dependency (Saelens J K, Arch Int Pharmacodyn 190: 213-218,
1971)
[0473] The test substances were applied intraperitoneally a total
of seven times over two days. Five applications were made on the
first day at 9:00, 10:00, 11:00, 13:00 and 15:00 hours, and on the
second day at 9:00 and 11:00 hours. The first three applications
were made in increasing dosages (dosage scheme), the further
applications being at the dosage of the third application. The
withdrawal symptoms were triggered with 30 mg/kg naloxone (i.p.)
two hours after the last substance application. Immediately
following this the animals were placed individually in transparent
observation cages (height 40 cm, diameter 15 cm) and the jumping
reactions were counted over 15 minutes in 5-minute periods in each
case. Morphine was administered in a dosage as comparison/standard.
The withdrawal symptoms were quantified by counting the number of
jumps over 0 to 10 minutes after application of naloxone. The
number of animals per group exhibiting more than 10 jumps/10
minutes was determined and recorded as "% positive animals". The
average jumping frequency in the group was also calculated. Twelve
animals were used per group.
BRIEF DESCRIPTION OF THE DRAWINGS
[0474] Results of the jumping tests are shown in the accompanying
Figures in which:
[0475] FIG. 1 is a graph of the mice jumping test results for
levomethadone;
[0476] FIG. 2 is a graph of the jumping test results for compound
m;
[0477] FIG. 3 is a graph of the jumping test results for compound
n;
[0478] FIG. 4 is a graph of the jumping test results according to
Example 1;
[0479] FIG. 5 is a graph of the jumping test results according to
Example 3, and
[0480] FIG. 6 is a graph of the jumping test results according to
Example 4.
INVESTIGATIONS OF CARDIOVASCULAR EFFECTS
ECG Method Description, Conscious Dogs:
[0481] Effects of the substances on the heart rate and
electrocardiograph parameters were investigated on conscious Beagle
dogs. The electrocardiogram measurement was carried out as a
bipolar limb lead according to Einthoven (lead II). For this
purpose the Beagle dogs were placed in a special hammock-like
holder (Animal sling, Havard Instruments, ZAK, Marktheidenfeld,
Germany) and loosely secured. A measurement electrode was applied
to each of the left and right front limbs, and a reference
electrode was also applied to the rear limb. All electrodes were
plate electrodes, which were fixed to the shaved skin by rubber
collars. The plate electrodes were connected to a ECG pre-amplifier
and the signals were continuously digitised by means of a
computer-controlled data receiving and archiving system (PO-NE-MAH,
Gould-Instrument Systems, USA) (digitising frequency: 2 kHz). The
mean values of the following parameters were determined from 10
successive ECG intervals per measurement time: RR interval, PR
interval, QRS interval and QT interval. The frequency correction of
the QT interval was made according to the correction formula of Van
de Water et al. (1989).
[0482] Each of the test substances was administered as an i.v.
short infusion (15 minutes) via the V. cephalica antibrachii. To
quantify effects of substances, the changes in the ECG parameters
over a period of 60 minutes after administration of the substance
were recorded relative to the base value before administration of
the substance. The statistical evaluation was carried out by means
of variance analysis (ANOVA) compared to synchronous vehicle
control measurements. (Van de Water A, Verheyen J, Xhonneux R,
Reneman R S. An improved method to correct the QT interval of the
electrocardiogram for changes in heart rate. J Pharmacol Methods.
1989 November; 22(3):207-17).
Patch-Clamp, hERG Current
[0483] Method description in: Bischoff U, Schmidt C, Netzer R,
Pongs O. Effects of fluoroquinolones on HERG currents. Eur J
Pharmacol. 2000; 406(3):341-3.
Blood Pressure, Conscious Rats
[0484] Method description in: Weeks J R, Compton L D. The
cardiovascular pharmacology of prostacyclin (PGI2) in the rat.
Prostaglandins 1979; 17(4):501-13.
TABLE-US-00003 TABLE A Summary of the cardiovascular effects of
Example 1: Model Dose Observation Patch clamp, IC50 >> 10
.mu.M (10 .mu.M: 29 .+-. 7% hERG current inhibition) Blood
pressure, Up to 14.7 .mu.g/kg No effect heart rate, i.v.**
conscious rat ECG, 10 .mu.g/kg i.v. Significant Bradycardia (heart
rate: conscious dog -40%) Non-significant extension of the QTc [van
der Water] Slight (<10%) significant increase in the QRS time No
effect on the PRinterval **Tail flick, rat: EC.sub.50 = 1.44
.mu.g/kg i.v.
[0485] For comparison: the IC.sub.50 value for LAAM is 2 .mu.m
(interactions of LAAM/HERG channel, see Jiesheng et al., Eur. J.
Pharmacol. 2003, 458, 25-29), the IC.sub.50 value for methadone is
9.8 .mu.M (see Katchman et al., J. Pharmacol. Exp. Ther. 2002, 303,
688-694).
[0486] In conscious rats, no cardiovascular effects are observed
with an administration of up to 1 order of magnitude greater than
the EC.sub.50 value in the tail flick test in rats of Example
1.
[0487] 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 within the scope of the appended
claims and equivalents thereof.
* * * * *