Esters derived from substituted phennyl-cyclohexyl compounds

Details Esters derived from substituted phennyl-cyclohexyl compounds Esters derived from substituted phennyl-cyclohexyl compounds

2001-05-04

2002-09-24

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C560S032000, C560S037000, C560S056000, C560S057000, C560S105000, C514S544000

Reexamination Certificate

active

06455585

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new esters derived from substituted phenyl-cyclohexyl compounds, which are derived from Tramadol. The obtained compounds have a higher analgesic activity, a lower toxicity and a longer effective time period than Tramadol.
BACKGROUND OF THE INVENTION
The treatment of pain is of great importance in the field of medicine. The pharmacological agents presently used for the treatment of pain can be primarily classified into two large groups: opioid compounds and non-steroidal anti-inflammatories (NSAIs). The NSAIs are only useful in the case of light or moderate pain; severe pain has traditionally been treated with opiod compounds. However, these opioid compounds have several undesirable side effects, such as constipation, respiratory depression, tolerance and possibility of addiction.
U.S. Pat. No. 3,652,589 describes a type of analgesic compounds with a structure of substituted cycloalkanol phenol ethers having a basic amino group in the cycloalkyl ring. Among them the (1R, 2R or 1S, 2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol compound, generally known as Tramadol, is specially noted and specifically claimed in said patent.
A series of products derived from the above, in which the dehydration in the cycloalkanol ring has occurred together with the demethylation of the methoxyl in the 3 position of the phenyl ring, of structure:
have been described in the Dutch patent NL 6610022.
This patent also describes products derived from those of said US patent, in which the methoxyl group in the 3 position of the phenyl ring has been demethylated. That is, products of structure:
O-demethyltramadol is included among those products described in patent NL 6610022, said product having been described as one of the metabolization products of Tramadol (Von W. Lintz et al. Arzneim-Forsch (
Drug Res
) 31 (II); 1932-43 (1982). The analgesic activity of Tramadol is attributed to its (+) isomer (Lars Poulsen et al.
Clin. Pharmacol. Ther
(St. Louis) 1996, 60 (6), 636-644). However, there is no data as to the clinical use of the O-demethyltramadol metabolite.
More recently, in patent EP 753506, new derivatives of Tramadol have been described, which are O-demethylsubstituted, halogenated at position 1 and/or 3-cyclohexyl substituted.
Tramadol has an opioid agonist effect. However, the clinical experience with Tramadol shows that in spite of this, it does not present some of the side effects typical of the opioid agonists, such as respiratory depression (W. Vogel et al.
Arzneim. Forsch
(
Drug Res
) 28 (I), 183 (1978)), constipation (I. Arend et al.
Arzneim. Forsch
(
Drug Res
) 28 (I), 199 (1978), tolerance (L. Flohe et al.,
Arzneim. Forsch
(
Drug Res
) 28 (I), 213 (1978)) and possibility of abuse (T. Yenagita et al.,
Arzneim. Forsch
(
Drug Res
) 28 (I), 158 (1978)). Some side effects specific for Tramadol have been found, which are caused when it is injected intravenously (i.v.) and quickly, such as hot flushes and sweating.
Another of the disadvantages associated with Tramadol is its short effective time period (T. Matthiesen, T. Wohrmann, T. P. Coogan, H. Uragg, “The experimental toxicology of tramadol: an overview”,
Toxicology Letters
95, 63-71, (1998)).
U.S. Pat. No. 5,733,936 (hereinafter, “the '936 patent) discloses some esters of 6-dimethylaminomethyl-1-phenyl-cyclohexane in the general formula of the description section with analgesic activity and low toxicity.
The object of the '936 patent is to obtain esters, phosphates, ethers, phenols, carbonates, carbamates, etc of derivatives of 6-dimethylaminomethyl-1phenyl-cyclohexane, said derivatives can be substituted in the 5-position of ciclohexyl (according to the meaning of R
2
and R
3
of the claims) as well as of tehir dehydroxilated, chlorinated, phluorated analog compounds.
Moreover, although the '936 patent discloses some esters of 6-dimethylaminomethyl-1-phenyl-cyclohexane, none of the examples in the '936 patent refer to the ester of O-demethyltramadol. None of these examples includes compounds which have the tertiary OH characteristic of O-demethyltramadol. In particular, Example 13 which is the closest to the application discloses an ester of an analog of O-demethyltramadol with acetyl salicylic acid and not an ester of O-demethyltramadol. Therefore, the '936 patent does not disclose an ester of O-demethyltramadol with the characteristic hydroxyl group in the 1-position. The '936 patent discloses no working examples of an ester of O-demethyltramadol. The three other esters examplified (Examples 14, 15, 16) also lack the tertiary hydroxyl group.
Therefore, stability, activity and side effects data could not have been foreseen nor suggested. According to the present application a surprising effect is achieved with the compounds of formula I.
Based on the above background of the invention, the compounds with an analgesic activity similar to or higher than that of Tramadol and with a lower toxicity and with a higher effective time period are still of interest.
DESCRIPTION OF THE INVENTION
The present invention relates to new esters of O-demethyltramadol or its 1,2-dehydrated derivative.
The analgesic activity of these compounds has been found to be higher than that of Tramadol with a lower toxicity and a longer effective time period when administered orally (see FIG.
1
).
In particular, the present invention describes and claims those products of general formula (I), its salts and optical isomers, as well as the process for obtaining them.
The products of the present invention are represented by the following general formula (I):
Shows possibility of asynumetric carbons
where R
1
is:
R
2
is: OH;
R
3
is: H;
or R
2
and R
3
together form a double bond;
R
4
is: H or C
1
-C
2
alkyl;
R
5
is: H, NH
2
, NH—R
11
or O—R
11
;
R
6
is: H, CO—R
11
, O—R
11
or halogen;
R
7
is: H, C
1
-C
5
alkyl, C
2
-C
5
O-alkenyl, phenyl, or R
6
and R
7
are —Ch═CR
12
-CR
13
═CH—, forming an optionally substituted condensed aromatic ring;
R
8
is: OH, —O—CO—N (CH
3
)
2
or NH—R
11
;
R
9
and R
10
are: H or C
1
-C
4
alkyl, whether equal ordifferent, or form a —CH
2
—CH
2
— group;
R
11
is: phenyl; phenyl optionally substituted by 1 or more of the following substituents: halogen (Cl, Br, I), NO
2
, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, OH, or NH
2
;
R
12
and R
13
are: H, or C
1
-C
3
O-alkyl, whether equal or different.
When R
1
is A, preferably, R
4
is methyl or H, R
5
is NH
2
, 2,5-dichlorophenylamino or H, R
6
is substituted CO-phenyl or H, R
7
is isobutyl or H, or R
6
and R
7
form a substituted condensed aromatic ring.
More preferably, when R
1
is A, the products are:
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl 2-(4-isobutyl-phenyl)-propionate
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 2-(6-methoxy-naphthalen-2-yl)-propionate
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(4-isobutyl-phenyl)-propionate
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-(6-methoxy-naphthalen-2-yl)-propionate
When R
1
is B, preferably, R
8
is OH or —O—CO—N(CH
3
)
2
.
More preferably, when R
1
is B, the products are:
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl 2-hydroxybenzoate
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-hydroxybenzoate
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl 2-dimethylcarbamoyloxy-benzoate
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl 2-dimethylcarbamoyloxy-benzoate.
When R
1
is C, preferably, R
9
is methyl or H or forms a —CH
2
—CH
2
— group with R
10
. More preferably, when R
1
is C, the products are:
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.
DESCRIPTION OF THE METHODS
The compounds of general formula (I) of the present invention can be obtained by a general process which is characterised by reacting a compound of general formula (II) with the corresponding acid or acid derivative of general formula III.
Where R
1
, R
2
, R
3
have the above defined meaning, and L=OH, ha

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