O-substituted 6-methyltramadol derivatives

Details O-substituted 6-methyltramadol derivatives O-substituted 6-methyltramadol derivatives

2003-03-31

2004-12-07

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S646000, C549S074000, C564S445000

Reexamination Certificate

active

06828345

ABSTRACT:

BACKGROUND AND SUMMARY OF THE INVENTION
The present invention relates to O-substituted 6-methyltramadol derivatives, processes for their production, medicaments containing these compounds, and the use of O-substituted 6-methyltramadol derivatives for the production of medicaments for treating pain, and methods for treating pain using the medicaments.
The treatment of chronic and non-chronic pain conditions is very important in medicine. There is therefore a universal need for highly effective pain treatments. The urgent need for a patient-oriented and targeted treatment of chronic and non-chronic pain conditions, which is understood to include the successful and satisfactory treatment of pain on the part of the patient, is documented in the large number of scientific studies that have recently appeared in the field of applied analgesia and in basic research relating to nociception.
Conventional opioids such as morphine are highly effective in treating severe to extremely severe pain. Their use is however limited by the known side effects such as respiratory depression, vomiting, sedation, constipation and development of tolerance. Also, they are less effective in treating neuropathic or incidental pain afflicting in particular tumor patients.
DESCRIPTION OF THE INVENTION
An object on which the present invention is based was accordingly to provide new analgesically effective substances that are suitable for treating pain, in particular acute but also chronic and neuropathic pain.
The present invention accordingly provides O-substituted 6-methyltramadol derivatives of the general formula I
wherein
R is
H; C
1-3
-alkyl that is saturated or unsaturated, branched or unbranched, unsubstituted or substituted; CH
3
—C
4-6
-cycloalkyl, C
4-6
-cycloalkyl or thiophenyl;
optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular of the enantiomers or diastereomers, in an arbitrary mixture ratio; in the prepared form or in the form of their acids or bases or in the form of their salts, in particular physiologically compatible salts, or in the form of their solvates, in particular the hydrates.
The substances according to the invention exhibit a pronounced analgesic action.
Within the context of the present invention alkyl radicals and cycloalkyl radicals are understood to be saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons that may be unsubstituted or singly or multiply substituted. In this connection C
1-2
-alkyl denotes C
1
- or C
2
-alkyl, C
1-3
-alkyl denotes C
1
-, C
2
- or C
3
-alkyl, C
1-4
-alkyl denotes C
1
-, C
2
-, C
3
- or C
4
-alkyl, C
1-5
-alkyl denotes C
1
-, C
2
-, C
3
-, C
4
or C
5
-alkyl C
1-6
-alkyl denotes C
1
-, C
2
-, C
3
-, C
4
-, C
5
- or C
6
-alkyl, C
1-7
-alkyl denotes C
1
-, C
2
-, C
3
-, C
4
-, C
5
-, C
6
- or C
7
-alkyl, C
1-8
-alkyl denotes C
1
-, C
2
-, C
3
-, C
4
-, C
5
-, C
6
-, C
7
or C
8
-alkyl, C
1-10
-alkyl, denotes C
1
-, C
2
-, C
3
-, C
4
-, C
5
-, C
6
-, C
7
-, C
8
-. C
9
- or C
10
-alkyl and C
1-8
-alkyl denotes C
1
-, C
2
-, C
3
-, C
4
-, C
5
-, C
6
-, C
7
-, C
8
-. C
9
-, C
10
-, C
11
-, C
12
-, C
13
-, C
14
-, C
15
-, C
16
-, C
17
- or C
18
-alkyl. In addition C
3-4
-cycloalkyl denotes C
3
- or C
4
-cycloalkyl, C
3-5
-cycloalkyl denotes C
3
-, C
4
- or C
5
-cycloalkyl, C
3-6
-cycloalkyl denotes C
3
-, C
4
-, C
5
- or C
6
-cycloalkyl, C
3-7
-cycloalkyl denotes C
3
-, C
4
-, C
5
-, C
6
- or C
7
-cycloalkyl, C
3-8
-cycloalkyl denotes C
3
-, C
4
-, C
5
-, C
6
-, C
7
- or C
8
-cycloalkyl, C
4-5
-cycloalkyl denotes C
4
- or C
5
-cycloalkyl, C
4-6
-cycloalkyl denotes C
4
-, C
5
- or C
6
-cycloalkyl, C
4-7
-cycloalkyl denotes C
4
-, C
5
-, C
6
- or C
7
-cycloalkyl, C
5-6
-cycloalkyl denotes C
5
- or C
6
-cycloalkyl and C
5-7
-cycloalkyl denotes C
5
-, C
6
- or C
7
-cycloalkyl. The term cycloalkyl also includes singly or multiply, preferably singly, unsaturated cycloalkyls, as long as the cycloalkyl does not form an aromatic system. The alkyl or cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl(2-propenyl), 1-propinyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, but also CHF
2
, CF
3
, CH
2
OCH
3
or CH
2
OH.
In connection with alkyl and cycloalkyl the term “substituted” within the context of the present invention denotes—unless expressly defined otherwise—the substitution of at least one (optionally also several) hydrogen atom(s) by F, Cl, Br, I, NH
2
, SH or OH, and the terms “multiply substituted” and “substituted” in the case of multiple substitution denote that the substitution takes place on different as well as on the same atoms multiply with the same or different substituents, for example triple substitution on the same C atom as in the case of CF
3
, or at different positions as in the case of —CH(OH)—CH═CH—CHCl
2
. Particularly preferred constituents in this connection are F, Cl and OH. With regard to cycloalkyl, the hydrogen atom may also be replaced by OC
1-3
-alkyl or C
1-3
-alkyl (in each case singly or multiply substituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF
3
or ethoxy.
The term (CH
2
)
3-6
is understood to denote —CH
2
—CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—CH
2
—CH
2
— and —CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—, and the term (CH
2
)
1-4
is understood to denote —CH
2
—, —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
— and —CH
2
—CH
2
—CH
2
—CH
2
—etc.
The term “aryl radical” is understood to mean ring systems with at least one aromatic ring but without any heteroatom in any of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which may be unsubstituted or singly or multiply substituted.
The term “heteroaryl radical” is understood to mean heterocyclic ring systems with at least one unsaturated ring that may contain one or more heteroatoms, such as nitrogen, oxygen and/or sulfur, and which may also be singly or multiply substituted. Examples of the group of heteroaryls that may be mentioned include furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and quinazoline.
In connection with aryl and heteroaryl, the term “substituted”—unless expressly stated otherwise—denotes the substitution of the aryl or heteroaryl by OH, F, Cl, Br, I, NH
2
SH, CF
3
, CH
2
F, CHF
2
, CN, NO
2
, C
1-6
-alkyl (saturated), C
1-6
-alkoxy or C
2-6
-alkylene.
The term salt is understood to mean any form of the active constituent according to the invention which adopts an ionic form or is charged and is coupled to a counterion (a cation or an anion), and may be present in solution. The term is also understood to include complexes of the active constituent with other molecules and ions, in particular complexes that are complexed via ionic interactions. In particular the term is understood to mean physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids.
The term physiologically compatible salts with cations or bases is understood within the context of the present invention to mean salts of at least one of the compounds according to the invention—such as when deprotonated acid—as an anion, with at least one cation, preferably an inorganic cation, that are physiological compatible, especially when used in humans and/or other mammals. Particularly preferred are the salts of alkali and alkaline earth metals, but also with NH
4
+
, and in particular mono- or di-sodium, mono- or di-potassium, magnesium or calcium salts.
The term physiologically co

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