Substituted aminomethyl-phenyl-cyclohexane derivatives

Details Substituted aminomethyl-phenyl-cyclohexane derivatives Substituted aminomethyl-phenyl-cyclohexane derivatives

2002-07-05

2004-01-06

Raymond, Richard L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S331000, C514S539000, C514S568000, C514S620000, C514S646000, C544S106000, C544S158000, C544S162000, C544S170000, C546S192000, C546S234000, C546S236000, C560S042000, C562S451000, C564S164000, C564S165000, C564S442000, C564S443000, C564S305000

Reexamination Certificate

active

06673794

ABSTRACT:

BACKGROUND AND SUMMARY OF THE INVENTION
The present invention relates to substituted aminomethyl-phenyl-cyclohexane derivatives and processes for their preparation, their use for the preparation of medicaments and medicaments comprising these compounds.
Treatment of chronic and non-chronic states of pain is of great importance in medicine. There is a worldwide need for pain treatments with a good action for target-orientated treatment of chronic and non-chronic states of pain appropriate for the patient, by which is to be understood successful and satisfactory pain treatment for the patient. This manifests itself in the large number of scientific works which have been published in the field of applied analgesia and basic research in nociception in recent years.
Conventional opioids, such as morphine, have a good action in the treatment of severe to very severe pain. However, their use is limited by their known side effects, e.g. respiratory depression, vomiting, sedation, constipation, addiction, dependency and development of tolerance. They can therefore be administered over a relatively long period of time or in relatively high dosages only if particular safety precautions are taken, such as specific prescription instructions (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York 1990). They furthermore show a lower activity with some states of pain, in particular neuropathic pain.
Tramadol hydrochloride—(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride—is another known therapeutic for treatment of severe pain. It occupies a special position among analgesics having an action on the central nervous system, inasmuch as this active compound brings about potent inhibition of pain without the side effects known of opioids (J. Pharmacol. Exptl. Ther. 267, 33 (1993)), both the enantiomers of tramadol and the enantiomers of tramadol metabolites participating in the analgesic action (J. Pharmacol. Exp. Ther. 260, 275 (1992)). Needless to say, tramadol is also not without side effects.
There is thus a need to provide substances which have an analgesic action and are suitable for treatment of pain. These substances should furthermore have as few side effects as possible, such as nausea, dependency, respiratory depression or constipation.
DETAILED DESCRIPTION OF THE INVENTION
This object is achieved by the substituted aminomethyl-phenyl-cyclohexane derivatives according to the invention. The invention therefore provides substituted aminomethyl-phenyl-cyclohexane derivatives of the general formula I and Ia, also in the form of their diastereomers or enantiomers and of their free bases or of a salt formed with a physiologically tolerated acid, in particular the hydrochloride salt.
wherein
R
1
and R
1
′ independently of one another are
H, C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl or C
2
-C
10
-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; F; Cl; Br; I; NR
6
R
6
′; NO
2
; CN; OR
6
; SR
6
; OC(O)R
6
; C(O)OR
6
; C(O)R
6
or C(O)NR
6
R
6
, wherein R
6
and R
6
′ are
H; C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl or C
2
-C
10
-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C
3
-C
7
-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by N, S or O; alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or
R
1
and R
1
together form —CH═CH—CH═CH— resulting in a naphthyl system which can be mono- or polysubstituted,
X is
H, F, Cl, Br, I, CF
3
, OS(O
2
)C
6
H
4
-pCH
3
, OR
7
or OC(O)R
7
, wherein R
7
is
H; C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl or C
2
-C
10
-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C
3
-C
7
-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by N, S or O; alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or
if the compound contains no X, according to formula Ia a double bond is formed between C atom A and C atom B or C atom B and C atom C,
R
4
, R
5
independently of one another are
H; C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl or C
2
-C
10
-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C
3
-C
7
-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by N, S or O; alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or
R
4
and R
5
together form a C
3
-C
7
-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR
8
, wherein R
8
is H; or C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl or C
2
-C
10
-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted;
and
R
2
, R
3
independently of one another are
R
9
or YR
9
, wherein Y is C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl or C
2
-C
10
-alkinyl, branched or unbranched and mono- or polysubstituted or unsubstituted, wherein R
9
is
H; F; Cl; Br; I; CN; NO
2
; C
1
-C
18
-alkyl, C
2
-C
18
-alkenyl or C
2
-C
18
-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; or C
3
-C
7
-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR
10
, where R
10
is
H; or C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl or C
2
-C
10
-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted;
OR
11
, OC(O)R
11
, OC(O)OR
11
, OC(S)R
11
, C(O)R
11
, C(O)OR
11
, C(S)R
11
, C(S)OR
11
, SR
11
, S(O)R
11
or S(O
2
)R
11
, wherein R
11
is
H; C
1
-C
18
-alkyl, C
2
-C
18
-alkenyl or C
2
-C
18
-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C
3
-C
7
-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR
12
, where R
12
is chosen from
H, C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl or C
2
-C
10
-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted;
alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted;
NR
13
R
14
, NR
13
C(O)R
14
, C(O)NR
13
R
14
or S(O
2
)NR
13
R
14
, wherein R
13
and R
14
independently of one another are
H; O; C
1
-C
18
-alkyl, C
2
-C
18
-alkenyl or C
2
-C
18
-alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted; C
3
-C
7
-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR
15
, where R
15
is
H, C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl or C
2
-C
10
—alkinyl, in each case branched or unbranched and mono- or polysubstituted or unsubstituted;
alkylaryl, saturated or unsaturated and mono- or polysubstituted or unsubstituted; or aryl or heteroaryl, in each case mono- or polysubstituted or unsubstituted; or
R
13
and R
14
together form a C
3
-C
7
-cycloalkyl, saturated or unsaturated and mono- or polysubstituted or unsubstituted, or a corresponding heterocyclic radical, in which one C atom in the ring is replaced by S, O or NR
16
, where R
16
is
H; or C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl or C
2
-C
10
-alkinyl, in ea

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