U.S. patent application number 12/045830 was filed with the patent office on 2008-10-30 for use of 1-phenyl-3-dimethylamino-propane compounds for treating neuropathic pain.
This patent application is currently assigned to GRUENENTHAL GmbH. Invention is credited to Thomas Christoph, Elmar Friderichs, Babette-Yvonne Koegel.
Application Number | 20080269326 12/045830 |
Document ID | / |
Family ID | 39345501 |
Filed Date | 2008-10-30 |
United States Patent
Application |
20080269326 |
Kind Code |
A1 |
Christoph; Thomas ; et
al. |
October 30, 2008 |
Use of 1-Phenyl-3-Dimethylamino-propane Compounds for Treating
Neuropathic Pain
Abstract
Use of 1-phenyl-3-dimethylaminopropane compounds for the
production of medicaments for treating neuropathic pain, preferably
polyneuropathic pain, also preferably diabetic neuropathic pain,
more preferably diabetic peripheral neuropathic pain, and
furthermore preferably for treating diabetic peripheral
neuropathy.
Inventors: |
Christoph; Thomas; (Aachen,
DE) ; Friderichs; Elmar; (Stolberg, DE) ;
Koegel; Babette-Yvonne; (Langerwehe-Hamich, DE) |
Correspondence
Address: |
CROWELL & MORING LLP;INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON
DC
20044-4300
US
|
Assignee: |
GRUENENTHAL GmbH
Aachen
DE
|
Family ID: |
39345501 |
Appl. No.: |
12/045830 |
Filed: |
March 11, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60906220 |
Mar 12, 2007 |
|
|
|
Current U.S.
Class: |
514/529 ;
514/646 |
Current CPC
Class: |
A61K 31/137 20130101;
A61P 29/00 20180101; A61P 3/10 20180101; A61P 43/00 20180101; A61P
25/00 20180101; A61P 25/02 20180101; A61P 25/04 20180101 |
Class at
Publication: |
514/529 ;
514/646 |
International
Class: |
A61K 31/135 20060101
A61K031/135; A61K 31/215 20060101 A61K031/215; A61P 25/00 20060101
A61P025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 12, 2007 |
DE |
10 2007 012 165.4 |
Claims
1. A method of treating pain in a subject in need thereof, said
method comprising administering to the subject an effective pain
inhibiting amount of a 1-phenyl-3-dimethylamino-propane compound
corresponding to Formula I: ##STR00023## wherein X denotes OH, F,
Cl, OC(O)CH.sub.3 or H; R.sup.1 denotes saturated and
unsubstituted, branched or unbranched C.sub.1-4-alkyl; R.sup.2 and
R.sup.3 independently denote H or saturated and unsubstituted,
branched or unbranched C.sub.1-4-alkyl; or R.sup.2 and R.sup.3
together with the carbon atom to which they are attached form a
saturated or unsaturated, and unsubstituted, monosubstituted or
polysubstituted C.sub.5-6-cycloalkyl group; and at least 3 of
R.sup.9 to R.sup.13 denote H and the remainder are independently
selected from the group consisting of H, Cl, F, OH, CF.sub.2H,
CF.sub.3, saturated and unsubstituted, branched or unbranched
C.sub.1-4-alkyl, OR.sup.14 and SR.sup.14; wherein R.sup.14 denotes
saturated and unsubstituted, branched or unbranched
C.sub.1-3-alkyl,; or R.sup.12 and R.sup.11 together form a
3,4-OCH.dbd.CH ring; or a pharmaceutically acceptable salt
thereof.
2. A method according to claim 1, wherein in said compound of
Formula I: X denotes OH, F, OC(O)CH.sub.3 or H; R.sup.1 denotes
CH.sub.3, C.sub.2H.sub.5, C.sub.4H.sub.9 or t-butyl; R.sup.2 and
R.sup.3 independently denote H, CH.sub.3, C.sub.2H.sub.5, i-propyl
or t-butyl; or R.sup.2 and R.sup.3 together with the carbon atom to
which they are attached form a saturated and unsubstituted
C.sub.5-6-cycloalkyl group; and at least 3 of R.sup.9 to R.sup.13
denote H and the remainder are independently selected from the
group consisting of H, Cl, F, OH, CF.sub.2H, CF.sub.3, OCH.sub.3
and SCH.sub.3;
3. A method according to claim 1, wherein in said compound of
Formula I, R.sup.9, R.sup.11 and R.sup.13 denote H, one of R.sup.10
and R.sup.12 also denotes H, and the other is selected from the
group consisting of Cl, F, OH, CF.sub.2H, CF.sub.3, OR.sup.14 and
SR.sup.14.
4. A method according to claim 3, wherein the other of R.sup.10 and
R.sup.12 is selected from the group consisting of OH, CF.sub.2H,
OCH.sub.3 and SCH.sub.3.
5. A method according to claim 1, wherein in said compound of
Formula I, R.sup.9 and R.sup.13 each denote H; R.sup.11 denotes OH,
OCH.sub.3, Cl or F; and one of R.sup.10 and R.sup.12 denotes H,
while the other denotes OH, OCH.sub.3, Cl or F.
6. A method according to claim 5, wherein R.sup.11 and the other of
R.sup.10 and R.sup.12 each denote Cl.
7. A method according to claim 1, wherein in said compound of
Formula I, R.sup.9, R.sup.10 ,R.sup.12 and R.sup.13 each denote H;
and R.sup.11 denotes CF.sub.3, CF.sub.2H, Cl or F.
8. A method according to claim 1, wherein in said compound of
Formula I, R.sup.10, R.sup.11 and R.sup.12 each denote H; and one
of R.sup.9 and R.sup.13 denotes H, while the other denotes OH,
OC.sub.2H.sub.5 or OC.sub.3H.sub.7.
9. A method according to claim 1, wherein said compound of Formula
I is in the form of an isolated stereoisomer.
10. A method according to claim 1, wherein said compound of Formula
I is in the form of a mixture of stereoisomers.
11. A method according to claim 10, wherein said mixture is a
racemic mixture.
12. A method according to claim 1, wherein said pain is neuropathic
pain.
13. A method according to claim 12, wherein said neuropathic pain
is selected from the group consisting of mononeuropathic pain,
polyneuropathic pain, and diabetic peripheral neuropathic pain.
14. A method according to claim 1, wherein in said compound of
Formula I, R.sup.3 denotes H, and said compound is present in the
form of an isolated diastereomer having the stereochemical
configuration of Formula Ia ##STR00024## or a mixture of
diastereomers containing more than 50% of the diastereomer having
the stereochemical configuration of Formula Ia.
15. A method according to claim 1, wherein said compound of Formula
I is selected from the group consisting of:
(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2methyl-pentan-3-ol,
(+)-(2R,
3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol,
(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol,
(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol,
(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol,
(2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2methyl-pentan-3-ol,
(2RS,3RS)-3-(3-difluoromethylphenyl)-1-dimethylamino-2methyl-pentan-3-ol,
(2RS,
3RS)-1-dimethylamino-2-methyl-3-(3-methylsulfanylphenyl)-pentan-3-o-
l,
(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-4,4-dimethylpentan-3-ol,
(2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol,
(1RS, 2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol,
(+)-(1R,
2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol, (1R,
2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,
(-)-(1S,
2S)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol, (1S,
2S)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol, (RS,
RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (-)-(1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (+)-(1S,
2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (1S,
2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (+)-(1R,
2R)-acetic
acid-3-dimethylamino-1-ethyl-1-(3-methoxy-phenyl)-2-methyl propyl
ester, (2RS,
3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-methylpentan-3-ol,
(+)-(2R,
3R)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol,
(2RS, 3RS)-4-dimethylamino-2-(3-methoxyphenyl)-3methylbutan-2-ol,
(+)-(2R,
3R)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-2-ol, and
pharmaceutically acceptable salts thereof.
16. A method according to claim 15, wherein said compound of
Formula I is selected from the group consisting of: (RS,
RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol, (-)-(1S,
2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (1S,
2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, and
pharmaceutically acceptable acid addition salts thereof.
17. A method according to claim 16, wherein said compound of
Formula I is (1RS,
2RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol or a
hydrochloride salt thereof.
18. A method according to claim 16, wherein said compound of
Formula I is
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a
hydrochloride salt thereof.
19. A method according to claim 1, wherein said pain is diabetic
neuropathic pain.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional
patent application No. 60/906,220, filed Mar. 12, 2007 and Federal
Republic of Germany patent application no. DE 10 2007 012 165.4,
filed Mar. 12, 2007, the entire disclosures of which are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to the use of
1-phenyl-3-dimethylaminopropane compounds for the production of
medicaments for treating neuropathic, preferably mononeuropathic
and/or polyneuropathic pain, particularly preferably
polyneuropathic pain, and also preferably diabetic neuropathic
pain, preferably diabetic peripheral neuropathic pain, and
furthermore preferably for treating diabetic peripheral
neuropathy.
[0003] The normal physiological pain sensation, which serves as a
protective function for the organism, is transmitted via nerve
fibres as a response to corresponding painful stimuli. This is
referred to as nociceptive pain. This nociceptive pain may be acute
or chronic, somatic or visceral, and may be present with or without
an inflammatory component. Appropriate stimuli may be mechanical
(e.g. pressure), thermal (e.g. heat) or chemical (e.g. acid). Also,
electrical stimuli may be perceived as painful.
[0004] In contrast to nociceptive pain--and also in most cases not
treatable with the same means--neuropathic pain (a non-nociceptive
pain; for a review see Hansson et al., 2001 Neuropathic Pain;
Pathophysiology and Treatment in Progress in Pain Research and
Management, Vol. 21 eds. Hansson et al. IASP Press, Seattle;
Bridges et al., 2001 Br J Anaesthesia 87:12-26) is characterized by
the occurrence of spontaneous pain and/or pain triggered by
abnormal stimuli. Spontaneously occurring pain results for example
from so-called ectopic activity of the pain-conducting nerve
fibres. In this case the nerve fibre sends a pain signal from the
periphery to the central nervous system even though there was no
appropriate stimulus. An example of pain that is triggered by an
abnormal stimulus is the phenomenon of allodynia. Allodynia is
defined as a painful sensation produced by a normally non-painful
stimulus. Allodynia is not restricted to neuropathic pain. Thus,
allodynia occurs for example in non-neuropathic conditions such as
sunburn or arthritis. The underlying mechanisms of allodynia differ
however in principle from one another and can be classified by a
detailed medical case history and investigation.
[0005] A further example of abnormal pain sensation is
hyperalgesia. In this case a normally painful stimulus is perceived
as producing a more severe pain than would be the case in a healthy
situation. This type of increased pain perception occurs not only
in neuropathic pain but also for example in inflammatory pain,
where however it has a different cause (inflammation) than in
neuropathic pain.
[0006] Various metabolic diseases may be the cause of neuropathic
changes and may subsequently be implicated in neuropathic pain. An
example of such a neuropathy is diabetic neuropathy, which occurs
in a large number of patients suffering from diabetes mellitus and
may be associated with a large number of clinical symptoms such as
a feeling of numbness, tingling sensation, or pain. The most common
form of diabetic neuropathy is distal symmetrical sensomotor
polyneuropathy.
[0007] Neuropathic pain occurs inter alia after damage to
peripheral or central nerves and can therefore be induced and
observed in animal experiments by targeted lesions of individual
nerves. Two possible animal models are the nerve lesion according
to Bennett (Bennett and Xie, 1988 Pain 33:87-107) as well as that
according to Chung (Kim and Chung, 1992 Pain 50:355-363). In the
Bennett model the sciatic nerve is bound unilaterally with loose
ligatures; in the Chung model two spinal nerves are bound
unilaterally. In both cases the development of symptoms of
neuropathic pain can be observed and quantified by means of thermal
or mechanical allodynia.
[0008] A known animal model for investigating diabetic neuropathy
is the induction of diabetes in rodents by administration of a
single dose of streptozotocin, an antibiotic extract from
Streptomyces acromogenes, which selectively damages the .beta.
cells of the pancreas. After some time the animals exhibit typical
symptoms of diabetic neuropathic pain, such as for example
mechanical, thermal or chemical hyperalgesia (Courteix et al., 1993
Pain 53:81-88).
[0009] To treat neuropathic pain, among other things, gabapentin is
used, which however is relatively ineffective, and then only at
significant dosages. On the other hand morphine is also often used,
the range of side effects of which are, as is known, not without
problems. Against the background of the prior art there was
therefore a need for compounds with a favorable ratio of
effectiveness to side effects, and to provide compounds for the
treatment of neuropathic pain.
SUMMARY OF THE INVENTION
[0010] An object of the present invention was accordingly to
discover compounds that are effective in treating neuropathic pain,
in particular polyneuropathic pain and especially diabetic
pain.
[0011] A further object of the invention was to provide a new
method of effectively treating neuropathic pain without excessive
side effects.
[0012] The achievement of these objects is complicated by the fact
that a large to overwhelming proportion of the substances effective
in treating nociceptive pain--such as acute pain--are not effective
at all, or are only slightly effective, in treating neuropathic
pain.
[0013] It has now surprisingly been found that the compounds
disclosed hereinbelow are highly effective in treating neuropathic
pain, and surprisingly particularly effective in treating
polyneuropathic and diabetic neuropathic pain.
[0014] Accordingly, the present invention provides for the use of a
1-phenyl-3-dimethylaminopropane compound corresponding to formula
I
##STR00001##
wherein [0015] X is OH, F, Cl, OC(O)CH.sub.3 or H, preferably OH,
F, OC(O)CH.sub.3 or H; [0016] R.sup.1 is saturated and
unsubstituted, branched or unbranched C.sub.1-4-alkyl, preferably
CH.sub.3, C.sub.2H.sub.5, C.sub.4H.sub.9 or t-butyl, in particular
CH.sub.3 or C.sub.2H.sub.5; [0017] R.sup.2 and R.sup.3 are
independently selected from the group consisting of H and saturated
and unsubstituted, branched or unbranched C.sub.1-4-alkyl;
preferably H, CH.sub.3, C.sub.2H.sub.5, i-propyl or t-butyl, in
particular H or CH.sub.3, especially preferably R.sup.3.dbd.H;
[0018] and [0019] three or four of R.sup.9 to R.sup.13 correspond
to H, and the remainder of R.sup.9 to R.sup.13 are independently
selected from the group consisting of H, Cl, F, OH, CF.sub.2H,
CF.sub.3, saturated and unsubstituted, branched or unbranched
C.sub.1-4-alkyl; OR.sup.14 and SR.sup.14, wherein R.sup.14 is
saturated and unsubstituted, branched or unbranched
C.sub.1-3-alkyl; preferably the remainder of R.sup.9 to R.sup.13
are independently H, Cl, F, OH, CF.sub.2H, CF.sub.3, OCH.sub.3 or
SCH.sub.3; [0020] or R.sup.12 and R.sup.11 form a 3,4-OCH.dbd.CH
ring, or a pharmaceutically acceptable salt thereof for the
treatment of neuropathic pain.
[0021] In particular [0022] if R.sup.9, R.sup.11 and R.sup.13
correspond to H, one of R.sup.10 and R.sup.12 also corresponds to
H, while the other is selected from the group consisting of Cl, F,
OH, CF.sub.2H, CF.sub.3, OR.sup.14 or SR.sup.14, preferably OH,
CF.sub.2H, OCH.sub.3 or SCH.sub.3; or [0023] if R.sup.9 and
R.sup.13 correspond to H and R.sup.11 corresponds to OH, OCH.sub.3,
Cl or F, preferably to Cl, then one of R.sup.10 and R.sup.12 also
corresponds to H, while the other corresponds to OH, OCH.sub.3, Cl
or F, preferably Cl; or [0024] if R.sup.9, R.sup.10, R.sup.12 and
R.sup.13 correspond to H, R.sup.11 is selected from CF.sub.3,
CF.sub.2H, Cl or F, preferably F; or [0025] if R.sup.10, R.sup.11
and R.sup.12 correspond to H, one of R.sup.9 and R.sup.13 also
corresponds to H, while the other is selected from OH,
OC.sub.2H.sub.5 or OC.sub.3H.sub.7.
[0026] The compounds optionally may be used in the form of their
racemates, their pure stereoisomers, in particular enantiomers or
diastereomers, or in the form of mixtures of the stereoisomers, in
particular of the enantiomers or diastereomers, in an arbitrary
mixture ratio; in the prepared form or in the form of their acids
or their bases or in the form of their salts, in particular the
physiologically compatible salts, or in the form of their solvates,
in particular the hydrates.
[0027] The neuropathic pain to be treated may preferably be
mononeuropathic and/or polyneuropathic pain, particularly
preferably polyneuropathic pain, and furthermore preferably
diabetic neuropathic pain, especially preferably diabetic
peripheral neuropathic pain. The method of the invention may also
preferably be used for treating diabetic neuropathy, and most
preferably for treating diabetic peripheral neuropathy.
[0028] About 1% of the population suffers from neuropathic pain, in
particular polyneuropathic pain, which is one of the most difficult
types of pain to treat. There is therefore a need for effective
medication for treating in particular diabetic neuropathic pain,
especially in patients who are sensitive to the side effects of
NSAID analgesics and to .mu.-opioid agonists, antidepressants and
anticonvulsants available on the market, or whose pain cannot be
adequately treated with other non-opioid analgesics,
antidepressants and anticonvulsants.
[0029] Surprisingly it has been found that the aforementioned
substances are extremely effective in the two most important in
vivo models of neuropathic pain and, what is particularly
surprising and should be emphasised, especially in the in vivo
model for diabetic neuropathy. The particular selectivity as
regards polyneuropathic and diabetic neuropathic pain is shown in
further in vivo models (Example 6), and is confirmed by a marked
difference in the efficacy (by a factor of 3!). Furthermore,
gabapentin was significantly less effective than these
compounds.
[0030] In particular the present application provides for the use
of the substance (1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol, a centrally
active analgesic, which has a dual mode of action (.mu.-opioid
receptor agonist and an inhibitor of noradrenaline uptake) coupled
with low opioid-typical side effects, in contrast to opioids
currently used and available on the market, for the treatment of
polyneuropathic, preferably diabetic neuropathic and more
particularly diabetic peripheral neuropathic pain.
[0031] In the context of the present invention alkyl and cycloalkyl
radicals are understood to denote saturated and unsaturated (but
not aromatic), branched, unbranched and cyclic hydrocarbons, which
may be unsubstituted or monosubstituted or polysubstituted. In this
connection C.sub.1-2-alkyl denotes C1- or C2-alkyl, C.sub.1-3-alkyl
denotes C1-, C2- or C3-alkyl, C.sub.1-4-alkyl denotes C1-, C2-, C3-
or C4-alkyl, C.sub.1-5-alkyl denotes C1-, C2-, C3-, C4- or
C5-alkyl, C.sub.1-6-alkyl denotes C1-, C2-, C3-, C4-, C5- or
C6-alkyl, C.sub.1-7-alkyl denotes C1-, C2-, C3-, C4-, C5-, C6- or
C7-alkyl, C.sub.1-8-alkyl denotes C1-, C2-, C3-, C4-, C5-, C6-, C7-
or C8-alkyl, C.sub.1-10-alkyl denotes C1-, C2-, C3-, C4-, C5-, C6-,
C7-, C8-, C9- or C10-alkyl and C.sub.1-18-alkyl denotes C1-, C2-,
C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-,
C15-, C16-, C17- or C18-alkyl. In addition C.sub.3-4-cycloalkyl
denotes C3- or C4-cycloalkyl, C.sub.3-5-cycloalkyl denotes C3-, C4
or C5-cycloalkyl, C.sub.3-6-cycloalkyl denotes C3-, C4-, C5- or
C6-cycloalkyl, C.sub.3-7-cycloalkyl denotes C3-, C4-, C5-, C6- or
C7-cycloalkyl, C.sub.3-8-cycloalkyl denotes C3-, C4-, C5-, C6-, C7-
or C8-cycloalkyl, C.sub.4-5-cycloalkyl denotes C4- or
C5-cycloalkyl, C.sub.4-6-cycloalkyl denotes C4-, C5- or
C6-cycloalkyl, C.sub.4-7cycloalkyl denotes C4-, C5-, C6- or
C7-cycloalkyl, C.sub.5-6-cycloalkyl denotes C5- or C6-cycloalkyl
and C.sub.5-7-cycloalkyl denotes C5-, C6- or C7 -cycloalkyl. With
regard to cycloalkyl the term also includes saturated cycloalkyls
in which one or two carbon atoms are replaced by a heteroatom S, N
or O. The term cycloalkyl however in addition also includes in
particular monounsaturated or polyunsaturated, preferably
monounsaturated, cycloalkyls without a heteroatom in the ring,
provided that the cycloalkyl does not form an aromatic system. The
alky and cycloalkyl radicals are preferably methyl, ethyl, vinyl
(ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl,
butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,
1,1-di-methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl,
1-methylpentyl, cyclopropyl, 2-methylcyclopropyl,
cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl,
cyclohexyl, cycloheptyl, cyclooctyl, but also adamantyl, CHF.sub.2,
CF.sub.3 or CH.sub.2OH as well as pyrazolinone, oxopyrazolinone,
[1,4]dioxane or dixolane.
[0032] At the same time, in connection with alkyl and
cycloalkyl--unless expressly defined otherwise--the term
"substituted" within the meaning of the present invention denotes
the substitution of at least one (optionally also several) hydrogen
atom(s) by F, Cl, Br, I, NH.sub.2, SH or OH, in which
"polysubstituted" and "substituted" in the case of polysubstitution
is understood to mean that the substitution occurs multiply with
the same or different substituents on different as well as on the
same atoms, for example triple substitution on the same C atom as
in the case of CF.sub.3, or at different sites, as in the case of
--CH(OH)--CH.dbd.CH--CHCl.sub.2. Particularly preferred
substituents in this connection are F, Cl and OH. With regard to
cycloalkyl the hydrogen atom may also be replaced by
OC.sub.1-3-alkyl or C.sub.1-3-alkyl (in each case monosubstituted
or polysubstituted, or unsubstituted) in particular by methyl,
ethyl, n-propyl, i-propyl, CF.sub.3, methoxy or ethoxy.
[0033] The term (CH.sub.2).sub.3-6 is understood to denote
--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-, the
term (CH.sub.2).sub.1-4 is understood to denote --CH.sub.2,
--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, and similarly the term
(CH.sub.2).sub.4-5 is understood to denote
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- and
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--, etc.
[0034] An aryl radical is understood to denote ring systems with at
least one aromatic ring, but without heteroatoms in even only one
of the rings. Examples are phenyl, naphthyl, fluoranthenyl,
fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or
anthracenyl radicals, which may be unsubstituted or monosubstituted
or polysubstituted.
[0035] A heteroaryl radical is understood to denote heterocyclic
ring systems with at least one unsaturated ring, which may contain
one or more heteroatoms from the group nitrogen, oxygen and/or
sulphur and may also be monosubstituted or polysubstituted.
Examples of heteroaryl compounds that may be mentioned include
furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine,
pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine,
benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole,
benzodioxolane, benzodioxane, carbazole, indole and
quinazoline.
[0036] 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) 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 that are complexed via ionic
interactions. In particular the term is understood to denote (and
this is also a preferred embodiment of the 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 a physiologically compatible
cation.
[0037] The term physiologically compatible is understood to mean
that the substance, in particular the salt as such, is compatible
when used in humans or mammals, and therefore for example does not
act in a non-physiological manner (e.g. is not toxic).
[0038] The term physiologically compatible salt with anions or
acids is understood within the meaning of the present invention to
denote salts of at least one of the compounds according to the
invention--generally protonated, for example on the nitrogen
atom--as cation with at least one anion, which are physiologically
compatible, especially when used in humans and/or mammals. In
particular the term is understood within the meaning of the present
invention to denote the salt formed with a physiologically
compatible acid, namely salts of the respective active constituent
with inorganic or organic acids, which are physiologically
compatible, especially when used in humans and/or mammals. Examples
of physiologically compatible salts of specific acids are salts of
the following: hydrochloric acid, hydrobromic acid, sulphuric acid,
methanesulfonic acid, formic acid, acetic acid, oxalic acid,
succinic acid, malic acid, tartaric acid, mandelic acid, fumaric
acid, lactic acid, citric acid, glutamic acid,
1,1-dioxo-1,2-dihydro 1.lamda..sup.6-benzo[3]isothiazol-3-one
(saccharinic acid), monomethylsebacic acid, 5-oxo-proline,
hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic
acid, 2,4,6-trimethylbenzoic acid, .alpha.-lipoic acid,
acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic
acid. The hydrochloride salt is particularly preferred.
[0039] The term salt formed with a physiologically compatible acid
is understood within the meaning 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 is
particularly preferred. Examples of physiologically compatible
acids include the following: 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, glutamic acid,
1,1-dioxo-1,2-dihydro1.lamda..sup.6-benzo[3]isothiazol-3-one
(saccharinic acid), monomethylsebacic acid, 5-oxo-proline,
hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic
acid, 2,4,6-trimethylbenzoic acid, .alpha.-lipoic acid,
acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic
acid.
[0040] The term physiologically compatible salts with cations or
bases is understood within the meaning of the present invention to
denote salts of at least one of the compounds according to the
invention--generally a (deprotonated) acid--as anion with at least
one, preferably inorganic, cation, which are physiologically
compatible, especially when used in humans and/or mammals.
Particularly preferred are the salts of the alkali and alkaline
earth metals, but also salts with NH.sub.4.sub.+, in particular
however (mono) or (di) sodium, (mono) or (di)potassium, magnesium
or calcium salts.
[0041] The term salt formed with a physiologically compatible
cation is understood within the meaning of the present invention to
denote salts of at least one of the respective compounds as anion
with at least one inorganic cation, which are physiologically
compatible, especially when used in humans and/or mammals.
Particularly preferred are the salts of the alkali and alkaline
earth metals, but also NH.sub.4.sub.+, in particular however (mono)
or (di)sodium, (mono) or (di)potassium, magnesium or calcium
salts.
[0042] The compounds used according to the invention and their
preparation are in principle known from DE 44 26 245 A1 with regard
to the 1-phenyl-3-dimethylaminopropane compounds according to the
general Formula I. All compounds other than these specific
compounds can easily be prepared by the person skilled in the art
in a similar way to the synthesis pathways described there.
[0043] In a particularly preferred variant of this embodiment, with
regard to the 1-phenyl-3-dimethylaminopropane compounds of the
general Formula I used according to the invention where
R.sup.3.dbd.H, these are present in the form of the diastereomers
with the relative configuration Ia
##STR00002##
in particular in mixtures with a larger proportion of this
diastereomer compared to the other diastereomer, or are used as
pure diastereomer.
[0044] It is particularly preferred if the
1-phenyl-3-dimethylaminopropane compound of Formula I used
according to the invention is selected from the group consisting
of: [0045] (2RS,
3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2methyl-pentan-3-ol,
[0046] (+)-(2R,
3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol,
[0047] (2R,
3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, [0048]
(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3--
ol, [0049] (2S,
3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, [0050]
(2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2methyl-pentan-3-ol,
[0051]
(2RS,3RS)-3-(3-difluoromethylphenyl)-1-dimethylamino-2methyl-penta-
n-3-ol, [0052] (2RS,
3RS)-1-dimethylamino-2-methyl-3-(3-methylsulfanylphenyl)-pentan-3-ol,
[0053]
(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-4,4-dimethylpentan-3-ol,
[0054]
(2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phe-
nol, [0055] (1RS,
2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol,
[0056] (+)-(1R,
2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol, [0057]
(1R, 2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,
[0058] (-)-(1S,
2S)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol, [0059]
(1S, 2S)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,
[0060] (RS, RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,
[0061] (-)-(1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, [0062] (1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, [0063]
(+)-(1S, 2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,
[0064] (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,
[0065] (+)-(1R, 2R)-acetic
acid-3-dimethylamino-1-ethyl-1-(3-methoxy-phenyl)-2-methyl propyl
ester, [0066] (2RS,
3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-methylpentan-3-ol, [0067]
(+)-(2R,
3R)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol,
[0068] (2RS,
3RS)-4-dimethylamino-2-(3-methoxyphenyl)-3methylbutan-2-ol and
[0069] (+)-(2R,
3R)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-2-ol; and
physiologically compatible salts thereof. Hydrochloride salts are
preferred.
[0070] Particularly preferred substances include: [0071] (RS,
RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, [0072]
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,
[0073] (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol,
[0074] (-)-(1S,
2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, [0075] (1S,
2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, and
physiologically compatible salts thereof.
[0076] Especially preferred compounds are: [0077] (-)-(1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, [0078]
(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methylpropyl)phenol, or
physiologically compatible salts thereof.
[0079] The pharmaceutical compositions of the invention, which
comprise one or more of the aforementioned compounds according to
the invention, are useful for treating neuropathic pain, preferably
mono- and/or polyneuropathic pain, particularly preferably
polyneuropathic pain, furthermore preferably diabetic neuropathic
pain, more preferably diabetic peripheral neuropathic pain, and in
addition preferably for treating diabetic neuropathy, and
particularly preferably for treating diabetic peripheral
neuropathy. In accordance with the invention the compositions
contain at least one aforementioned active constituent used
according to the invention, as well as optionally suitable
additives and/or auxiliary substances.
[0080] Suitable additives and/or auxiliary substances within the
scope of the present invention include all substances known to
persons skilled in the art for producing galenical formulations.
The selection of these auxiliary substances as well as the amounts
to be used depend on whether the medicament is to be administered
orally, intravenously, intraperitonealy, intradermally,
intramuscularly, intranasally, buccally or topically. For oral
administration, suitable preparations may take the form of tablets,
chewable tablets, coated pills, capsules, granules, drops, juices
or syrups, while for parenteral, topical and inhalative
administration, suitable preparations may be formulated as
solutions, suspensions, readily reconstitutable dry preparations as
well as sprays. A further possible form is as suppositories for
rectal administration. Examples of percutaneous administration
forms include use in a depot in dissolved form, in a carrier film
or a plaster, optionally with the addition of agents promoting
penetration of the skin.
[0081] Examples of auxiliary substances and additives for oral
administration forms include disintegrants, lubricants, binders,
fillers, mold release agents, optionally solvents, taste enhancers,
sugars, in particular carriers, diluents, colorants, antioxidants,
etc. For suppositories there may be used inter alia waxes or fatty
acid esters, and for parenteral application agents there may be
used carriers, preservatives, suspension aids, etc. The compounds
according to the invention may be released in a delayed manner from
orally, rectally or percutaneously usable preparation forms. In the
medical indications for use according to the invention
corresponding Retard formulations, in particular in the form of a
"once daily" preparation, which need to be taken only once a day,
are especially preferred for use in treating many medical
indications for which the active substances of the invention are
suitable.
[0082] The amounts of active constituent to be administered to
patients vary depending on the patient's weight, type of
application, and the severity of the medical condition. Preferred
are medicaments that contain at least 0.05 to 90.0% of the active
constituent, in particular low active dosages, in order to avoid
side effects. Normally 0.1 to 5000 mg/kg, in particular 1 to 500
mg/kg and preferably 2 to 250 mg/kg of body weight of at least one
compound used according to the invention are administered. However,
the administration of 0.01-5 mg/kg, preferably 0.03 to 2 mg/kg and
especially 0.05 to 1 mg/kg of body weight is also preferred and
customary.
[0083] Examples of suitable auxiliary substances for inclusion in
the pharmaceutical compositions according to the invention include
water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene
glycol, polyethylene glycol, polypropylene glycol, glucose,
fructose, lactose, sucrose, dextrose, molasses, starch, modified
starch, gelatin, sorbitol, inositol, mannitol, microcrystalline
cellulose, methylcellulose, carboxymethylcellulose, cellulose
acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins,
waxes, natural and synthetic gums, acacia gum, alginates, dextran,
saturated and unsaturated fatty acids, stearic acid, magnesium
stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate,
edible oils, sesame oil, coconut oil, ground nut oil, soya bean
oil, lecithin, sodium lactate, polyoxyethylene and polyoxypropylene
fatty acid esters, sorbitan fatty acid esters, sorbic acid, benzoic
acid, citric acid, ascorbic acid, tannic acid, sodium chloride,
potassium chloride, magnesium chloride, calcium chloride, magnesium
oxide, zinc oxide, silicon dioxide, titanium oxide, titanium
dioxide, magnesium sulphate, zinc sulphate, calcium sulphate,
potassium carbonate, calcium phosphate, dicalcium phosphate,
potassium bromide, potassium iodide, talcum, kaolin, pectin,
crospovidone, agar and bentonite.
[0084] Medicaments and pharmaceutical compositions according to the
invention may be prepared using agents, equipment, methods and
processes known in the prior art for producing pharmaceutical
formulations, such as are described, for example, in "Remington's
Pharmaceutical Sciences", edited by A. R. Gennaro, 17th Ed., Mack
Publishing Company, Easton, Pa. (1985), in particular in Part 8,
Chapters 76 to 93.
[0085] Thus, for example, for a solid formulation such as a tablet,
the active constituent of the medicament can be granulated with a
pharmaceutical carrier, for example conventional tablet
constituents such as maize starch, lactose, sucrose, sorbitol,
talcum, magnesium stearate, dicalcium phosphate or pharmaceutically
acceptable gums, and pharmaceutical diluents, such as for example
water, in order to form a solid composition that contains the
active constituent in homogeneous distribution. A homogeneous
distribution is understood here to mean that the active constituent
is distributed uniformly over the whole composition, so that the
latter can be subdivided without any problem into identically
active unit dose forms such as tablets, pills or capsules. The
solid composition is then subdivided into unit dose forms. The
tablets or pills of the medicament according to the invention or of
the compositions according to the invention can also be coated or
compounded in some other way so as to produce a dose form having
delayed release. Suitable coating agents are inter alia polymeric
acids and mixtures of polymeric acids with materials such as for
example schellac, cetyl alcohol and/or cellulose acetate.
[0086] Even if the medicaments prepared according to the invention
exhibit only slight side effects, it can for example be
advantageous, in order to avoid certain forms of dependence, to
employ apart from the aforementioned compound according to the
invention also morphine antagonists, in particular naloxone,
naltrexone and/or levallorphan. In tests it was found for example
for morphine and compound 10 (see Example 0 hereinafter) that the
substances are also effective with naloxone in treating neuropathic
pain.
[0087] The invention also relates to a method for treating
neuropathic pain, for treating neuropathic, preferably
mononeuropathic and/or polyneuropathic pain, particularly
preferably polyneuropathic pain, and in addition preferably for
treating diabetic neuropathic pain, preferably diabetic peripheral
neuropathic pain, and in addition preferably for treating diabetic
neuropathy, particularly preferably diabetic peripheral neuropathy,
in which at least one of the aforementioned compounds is used
according to the invention.
[0088] The following examples are intended to describe the
invention in more detail, without however restricting the
subject-matter of the invention.
EXAMPLES
Example 0
Tested Substances
[0089] The following compounds were tested and are hereinafter
correspondingly abbreviated as compound (or Comp.) 1, etc. in Table
1:
TABLE-US-00001 TABLE 1 Name: Compound
(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2- 1
methylpentan-3-ol: hydrochloride
(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2- 2 methylpentan-3-ol;
hydrochloride (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2- 3
methylpentan-3-ol; hydrochloride
(1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2- 5
dimethylpropyl)-phenol; hydrochloride
(1S,2S)-3-(3-dimethylamino-1-hydroxy-1,2- 6 dimethylpropyl)phenol;
hydrochloride (1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2- 7
dimethylpropyl)phenol; hydrochloride
(2RS,3RS)-3-(difluoromethylphenyl)-1-dimethylamino-2- 8
methylpentan-3-ol; hydrochloride
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)- 9 phenol;
hydrochloride (1S,2S)-3-(3-dimethylamino-1-ethyl-2- 10
methylpropyl)phenol; hydrochloride
3-(3-dimethylamino-1,2-dimethylpropenyl)-phenol; 14 hydrochloride
Additionally: Morphine Mor Gabapentin GBP
Example 1
Bennett
Neuropathic Pain in Rats
[0090] The effectiveness in treating neuropathic pain was
investigated in the Bennett model (chronic constriction injury;
Bennett and Xie, 1988, Pain 33: 87-107).
[0091] Sprague-Dawley rats weighing 140-160 g are provided with
four loose ligatures of the right sciatic nerve under nembutal
narcosis. The animals develop a hypersensitivity in the paw
innervated by the damaged nerve, which after a healing phase of one
week is quantified over about four weeks by means of a 4.degree. C.
cold metal plate (cold allodynia). The animals are observed for two
minutes on this plate and the number of retractive movements of the
damaged paw are measured. The effect of the substance is determined
with reference to the base value before application of the
substance, at four different times over a period of one hour(15,
30, 45 and 60 minutes after application) and the resultant area
under the curve (AUD) as well as the inhibition of cold allodynia
at the individual measurement points is expressed in percent effect
with reference to the vehicle control (AUD) and to the initial
value (individual measurement points). The cohort size is n=10.
[0092] The results are summarized together with those from Example
2 in the following Table 2.
Example 2
Chung
In Vivo Experiments According to Chung
[0093] Spinal nerve ligatures according to Kim & Chung (1992
Pain 50, 355-363) were applied to the left L5/L6 spinal nerves of
male Spraque-Dawley rats. Four to six days after the operation the
tactile threshold baseline (withdrawal threshold) was measured on
the ipsilateral and contralateral rear paw by an electronic von
Frey anaesthesiometer (IITC Life Science, USA). After the test and
measurement of the baseline, morphine, gabapentin and some of the
aforementioned compounds used according to the invention were
administered. The tactile withdrawal thresholds were measured 30
minutes after the administration. The results are expressed as ED50
and % maximal possible effect (% MPE) on the ipsilateral side, in
which the baseline is taken as 0% and the withdrawal threshold of a
control group is taken as 100% MPE.
[0094] The results together with those from Example 1 are
summarized in Table 2:
TABLE-US-00002 TABLE 2 Testing of the inhibition of neuropathic
pain in rats after intraperitoneal (i.p.) or per oral (p.o.)
administration Cold allodynia Tactile allodynia ED50 mg/kg i.p.
ED50 mg/kg i.p. (95% confidence region) (95% confidence region)
[band width of the [band width of the Compound measurement values]
measurement values] Morphine 7.1 4.6 [5.7-9.4] [3.8-5.7] Gabapentin
214 (p.o.) 92.6 1 11.1 10.1 [9.9-12.3] 2 26.0 -- 3 9.2 -- 5 15.0 --
6 32.6 4.65 7 11.1 -- 8 17.1 -- 9 13 8.15 [3.8-14.5] 10 1.2 1.5
[0.6-3.1] [0.74-12.54] 14 3.6 --
[0095] The compounds all show a marked and dose-dependent
inhibition of cold allodynia in Bennett animals and of tactile
allodynia in Chung animals. Moreover, in Chung animals in some
cases a surprisingly long action duration of up to 30 hours after
i.p. application is observed.
Example 3
In Vivo Experiments in Rats with Diabetic Neuropathy
[0096] Male Sprague-Dawley rats weighing 160-180 g received an
intra-peritoneal injection of streptozotocin (75 mg/kg body weight)
dissolved in pH 4.6 citrate buffer. One week later diabetic animals
were identified by measuring the blood glucose level, and those
with a blood glucose level of .gtoreq.17 mM were included in the
study. Three and four weeks after administration of streptozotocin
the mechanical reaction threshold was measured in diabetic animals
by the method of Randall and Sellito (1957 Arch. Int. Pharmacody.
61:409-419) before (pre-test) and at various times after
administration of the test substance or vehicle (post-test).
Diabetic animals exhibit a reduced mechanical reaction threshold
and thus a mechanical hyperalgesia compared to control animals that
had simultaneously received vehicle solution instead of
streptozotocin. The maximum pressure exerted on the rear paw was
250 g. The end point of the mechanical reaction threshold in grams
was determined based on the reaction of the animal (withdrawal of
the rear paw, vocalisation or evasive reaction). The size of the
cohort in the individual dose stages was n=10. The maximum possible
response in percent (% MPE=% of maximum possible effect) was
calculated according to the formula:
% MPE=(post-test-pre-test)/(250-pre-test).times.100.
ED50 values (dose at which 50% maximum inhibition occurred) were
determined by regression analysis from the % MPE values at the time
of the maximum effect.
TABLE-US-00003 TABLE 3 Investigation of the inhibition of diabetic
neuropathic pain in rats after intraperitoneal (i.p.) substance
administration Mechanical hyperalgesia Mechanical hyperalgesia ED50
mg/kg i.p. (95% Maximum effect in % MPE at Compound confidence
region) (dose mg/kg i.p.) Morphine 3.0 (1.8-4.0) 89% (10 mg/kg)
Gabapentin 225 (186-274) 80% (464 mg/kg) Tramadol 9.2 (7.0-11.8)
86% (21.5 mg/kg) Compound 9 8.9 (7.1-11.1) 100% (31.6 mg/kg)
Of the tested compounds, compound 9 achieved the highest maximum
effect.
Example 4
Tolerance to Morphine
[0097] The underlying question is the action of a test substance
having a presumably opioid action mechanism in patients who are
tolerant or treatment-resistant to morphine. In Bennett animals
(according to Example 1) that have developed a tolerance to
morphine, the tested compounds still exhibited a significant
anti-allodynic action. The action of test substances in naive
(non-morphine-tolerant) animals and morphine-tolerant animals is
compared in Table 4. Morphine (Mor) understandably no longer
exhibits any effect, whereas the other tested compounds produce a
marked inhibition of cold allodynia in these animals. Morphine [10
mg/kg i.p.], Compound 9 [10 and 21.5 mg/kg i.p.], Compound 10 [0.46
and 1 mg/kg i.p.], Compound 4 [21.5 mg/kg i.p.] and Compound 11
[21.5 mg/kg i.p.] were tested analogously to Example 1.
TABLE-US-00004 TABLE 4 Examination of the inhibition of neuropathic
pain in rats after intraperitoneal (i.p.) substance administration
to naive and morphine- tolerant animals in % AUD. Compound Cold
allodynia (% AUD) Cold allodynia (% AUD) [dose mg/kg i.p.]
Morphine-tolerant animals Naive animals Morphine [10] -22.0 78.6 9
[10] 37.3 49.3 9 [21.5] 36.7 53.4 10 [0.46] 22.9 29.0 10 [1] 39.9
42.7 10 [2.15] 13.0 59.2 4 [21.5] 75.2 65.5 11 [21.5] 42.6 69.2
Example 5
Parenteral Application Form
[0098] 20 g of Compound 9 are dissolved in 1 litre of water for
injection at room temperature and then adjusted by addition of NaCl
to isotonic conditions.
Example 6
Comparison of Mononeuropathic and Polyneuropathic Pain
Experimental Procedure
[0099] Male Sprague Dawley rats (140-180g, Janvier, France) are
kept under standard conditions (06.00-18.00 hours light,
18.00-06.00 hours darkness; 20.degree.-24.degree. C. room
temperature; 35-70% relative atmospheric humidity, tap water and
standard feed as desired) in groups of five animals in Macrolon
type 4 cages.
Mononeuropathy (Spinal Nerve Ligature, SNL)
[0100] Under pentobarbital narcosis (Narcoren, 60 mg/kg i.p.,
Merial GmbH, Germany) the spinal nerves L5 and L6 are tightly bound
unilaterally on the left side with a silk thread (NC silk black,
USP 5/0, metric 1, Braun Melsungen A G, Germany) (Kim and Chung,
Pain 1992; 50: 355-63). After the operation the animals were
allowed to recover for one week and within this time developed a
hypersensitivity on the ipsilateral (left) paw. The
hypersensitivity to a pressure stimulus can be measured using an
electronic von Frey filament (Somedic, Sweden). For this purpose
the animals are placed on a grating under a hood. After the animals
became accustomed to the surroundings the damaged (ipsilateral,
left) and undamaged (contralateral, right) rear paws are subjected
to increasing pressure on the underside of the paw until the animal
tries to retract the corresponding paw. The median value of five
tests defines the withdrawal threshold of a test time point. The
animals are tested on both rear paws before and at various times
after administration of the substance or vehicle. For each animal
the difference between the test value and pre-test for the
ipsilateral and contralateral side is determined, and the result is
expressed as the mean value (MW) and standard error of the mean
(SEM) for the groups consisting in each case of 10 animals. The
difference between the mean difference values of the ipsilateral
and contralateral side defines the hypersensitivity induced by
mononeuropathy. The statistical significance of the effect of a
substance is determined on the basis of the difference values
compared to the vehicle group for the ipsilateral and contralateral
side, by means of bifactorial variance analysis and post hoc
analysis according to Bonferroni.
Polyneuropathy (Streptozotocin-Induced Diabetic Neuropathy,
STZ)
[0101] Rats receive a single i.p. dose of Streptozotocin (STZ,
Sigma Aldrich Chemie, Germany) or vehicle (0.1 mM citrate buffer,
pH 4.6). After one week the blood sugar values are determined and
animals treated with STZ that have a blood sugar value of
.gtoreq.17 mM are classed as diabetic in the experiment. Diabetic
animals develop a hypersensitivity in the rear paws. The
hypersensitivity to a pressure stimulus can be measured using a
pressure pain instrument (algesiometer; Ugo Basile, Italy)
according to the method of Randall and Selitto (Arch. Int.
Pharmcodyn. 1957; 111: 409-19) in diabetic animals compared to
healthy control animals of the same weight, in the third week after
STZ treatment. After the animals had become accustomed to the
surroundings, the rear right paw of damaged (diabetic) and
undamaged (healthy) animals was subjected to increasing pressure on
the upper side of the paw until the corresponding paw is withdrawn
or the animal gives a vocal response. This value defines the
withdrawal threshold of a test time point. Diabetic and healthy
animals are tested before and at various times after administration
of the substance or vehicle. For each animal the difference between
the test value and pre-test is determined, and for the groups, each
consisting of ten animals, the result is expressed as the mean
value (MW) and standard error of the mean (SEM). The difference
between the mean difference values of the diabetic and healthy
animals defines the polyneuropathy-induced hypersensitivity. The
statistical significance of the effect of a substance is determined
on the basis of the difference values with respect to the vehicle
group for diabetic and healthy animals by means of bifactorial
variance analysis and post hoc analysis according to
Bonferroni.
Results
Mononeuropathic Pain
[0102] (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
hydrochloride 9 (0.1-10 mg/kg, i.v., Table 1) shows a
dose-dependent increase of the withdrawal threshold on the
ipsilateral rear paw. The statistically significant minimal
effective dose is 1 mg/kg. The mean difference value between the
ipsilateral withdrawal threshold of healthy control animals and the
ipsilateral withdrawal threshold of mononeuropathic animals in this
series of experiments is 36 g. Complete inhibition of the
mononeuropathically-induced withdrawal threshold reduction is thus
achieved at values (test value-pre-test value) of .gtoreq.36 g on
the ipsilateral side. Time points at which this value is reached or
exceeded are given in bold type in boxes in the table.
Contralateral measurement values are not included in this analysis.
In the highest dosage group of 10 mg/kg i.v. full inhibition of the
mononeuropathically-induced withdrawal threshold reduction is
reached after 30 minutes. The contralateral withdrawal threshold is
also raised in a dose-dependent manner. The statistically
significant minimal effective dose is 10 mg/kg.
TABLE-US-00005 TABLE 1 (1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)- phenol
hydrochloride (9) mononeuropathy Dose (mg/kg, i.v.) Side 30 min 60
min 180 min Vehicle Ipsi MW 0.70 0.06 -1.33 SEM 1.16 1.31 1.09
Significance n.s. n.s. n.s. Contra MW -4.06 0.83 -3.79 SEM 2.63
3.77 2.90 Significance n.s. n.s. n.s. 0.1 Ipsi MW 1.74 -0.59 -2.24
SEM 1.55 1.44 1.15 Significance n.s. n.s. n.s. Contra MW 0.06 -3.13
-4.30 SEM 4.52 4.12 3.01 Significance n.s. n.s. n.s. 0.316 Ipsi MW
5.78 2.21 1.68 SEM 2.34 2.93 1.41 Significance n.s. n.s. n.s.
Contra MW 0.39 ta -6.20 2.21 SEM 4.71 3.03 3.81 Significance n.s.
n.s. n.s. 1 Ipsi MW 12.86 7.09 2.01 SEM 2.42 0.80 0.64 Significance
##STR00003## n.s. n.s. Contra MW 2.90 2.45 -6.65 SEM 3.32 3.92 2.45
Significance n.s. n.s. n.s. 3.16 Ipsi MW 18.43 20.32 11.06 SEM 2.90
2.39 1.45 Significance ##STR00004## ##STR00005## ##STR00006##
Contra MW 8.02 2.85 -0.34 SEM 4.13 3.09 3.81 Significance n.s. n.s.
n.s. 10 Ipsi MW ##STR00007## 19.47 13.65 SEM 3.50 1.52 1.40
Significance ##STR00008## ##STR00009## ##STR00010## Contra MW 31.85
10.62 4.51 SEM 3.23 4.92 4.17 Significance ##STR00011## n.s n.s.
(test value - pre-test value (g); * p < 0.05 with respect to
vehicle; n.s. = not significant with respect to vehicle)
Polyneuropathic Pain
[0103] (1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)hydrochloride 9
(0.1-1 mg/kg, i.v., Table 2) shows a dose-dependent increase of the
withdrawal threshold in the rear paw of diabetic rats. The
statistically significant minimal effective dose is 0.3 mg/kg. The
mean difference value between the withdrawal threshold of naive
control animals and the withdrawal threshold of polyneuropathic
animals is in this series of experiments 43 g . Complete inhibition
of the polyneuropathically-induced withdrawal threshold reduction
is thus achieved at values (test value-pre-test value) of
.gtoreq.43 g in diabetic animals. Time points at which this value
is reached or exceeded are shown in grey in the table. Measurement
values of naive animals are not included in this analysis. In the
highest dosage group of 1 mg/kg i.v. complete inhibition of the
polyneuropathically-induced withdrawal threshold reduction is
reached after 15 minutes and 30 minutes. The withdrawal threshold
of healthy control animals is also raised in a dose-dependent
manner. The statistically significant minimal effective dose is 1
mg/kg.
TABLE-US-00006 TABLE 2 (1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl) hydrochloride (9)
polyneuropathy Dose (mg/kg, i.v.) Group 15 min 30 min 45 min 60 min
0.1 Diabetes MW 1.0 -2.0 6.0 -2.0 SEM 6.4 5.5 3.4 5.5 Vehicle MW
3.0 2.0 -11.0 0.0 SEM 4.2 3.6 3.5 3.7 Significance n.s. n.s. n.s.
n.s. 0.1 Naive MW 4.0 -12.0 -2.0 -5.0 SEM 4.8 7.7 5.3 6.2 Vehicle
MW -9.0 -2.0 -5.0 -3.0 SEM 4.8 5.1 4.5 2.1 Significance n.s. n.s.
n.s. n.s. 0.316 Diabetes MW 35.0 30.0 24.0 16.0 SEM 9.2 6.3 6.9 4.8
Vehicle MW -6.0 -5.0 0.0 1.0 SEM 3.7 6.7 6.0 3.5 Significance
##STR00012## ##STR00013## ##STR00014## n.s. 0.316 Naive MW 17.0
-5.0 -5.0 2.0 SEM 3.3 7.3 4.5 2.5 Vehicle MW -6.0 -5.0 -14.0 2.0
SEM 6.7 5.8 6.7 4.4 Significance n.s. n.s. n.s. n.s. 1 Diabetes MW
##STR00015## ##STR00016## 34.0 27.0 SEM 10.8 8.7 6.5 6.2 Vehicle MW
1.0 -10.0 4.0 4.0 SEM 5.9 3.3 6.4 3.4 Significance ##STR00017##
##STR00018## ##STR00019## ##STR00020## 1 Naive MW 42.0 28.0 -2.0
7.0 SEM 7.6 7.4 6.3 4.5 Vehicle MW -4.0 -5.0 -15.0 -2.0 SEM 5.6 8.7
3.1 3.6 Significance ##STR00021## ##STR00022## n.s. n.s. (test
value - pre-test value (g); * p < 0.05 with respect to vehicle;
n.s. not significant with respect to vehicle)
[0104] 1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
hydrochloride 9 produces a dose-dependent increase of the
pressure-mediated withdrawal threshold in mononeuropathic and
polyneuropathic pain. In both pain models (1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol produces a
selective inhibition of the pathologically induced pain response,
without at the same time influencing the normal pain response. A
clear difference is found in the level of effectiveness of (1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol in both
models. Whereas in the polyneuropathic pain model a significant
inhibition is already detectable at 0.316 mg/kg i.v., a significant
inhibition in the mononeuropathic pain model occurs only at 1 mg/kg
i.v., i.e. at a three times higher dosage. A similar behavior is
observed at the dosage at which the maximum effect is achieved. In
the polyneuropathic pain model complete inhibition is reached at 1
mg/kg i.v., whereas in the mononeuropathic pain model complete
inhibition is reached only at 10 mg/kg i.v., i.e. at a ten times
higher dosage. These data show that 1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol is
particularly suitable for the treatment of polyneuropathic pain
states.
[0105] 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.
* * * * *