3-amino-2-benzyl-1-phenylpropane derivatives

Details 3-amino-2-benzyl-1-phenylpropane derivatives 3-amino-2-benzyl-1-phenylpropane derivatives

2002-01-16

2003-11-25

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S317000, C564S355000, C564S361000, C564S363000, C564S344000, C564S345000, C564S378000, C564S383000, C564S265000, C514S644000, C514S648000, C514S653000, C514S654000

Reexamination Certificate

active

06653508

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to substituted 3-amino-2-benzyl-1-phenylpropane derivatives, processes for their preparation, pharmaceutical products containing these compounds, as well as the use of these substances for producing pharmaceutical products.
Pain is one of the main symptoms present in clinical practice, and there is a universal need for effective treatments for pain. The urgent need to provide a patient-oriented and targeted treatment for chronic and non-chronic painful conditions, which is understood to include the successful and satisfactory treatment of pain for patients, is documented in the large number of scientific articles that have recently been published in the field of applied analgesics and in basic research on pain relief. Thus, 1-phenyl-3-dimethylaminopropane compounds having an analgesic effect are known for example from DE-A-44 26 245.
Conventional opioids such as, e.g. morphine are effective in the treatment of severe to extremely severe pain. However, their undesirable side effects include, inter alia, respiratory depression, vomiting, sedation, constipation, as well as tolerance development. Also, they are less effective in neuropathic or incidental painful conditions such as frequently occur, especially in patients with tumours.
Tramadol hydrochloride-(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol occupies a special position among analgesics acting on the central nervous system, since this active substance has a powerful pain-inhibiting effect without the side effects known in the case of opioids (J. Pharmacol. Exptl. Ther. 267, 33 (1993)).
2-Benzyl-3-dimethylamino-1-phenylpropane and the corresponding methyl iodide are described in J. Am. Chem. Soc., 1966, 88, 5518-5521 as an intermediate product of a &ggr;-elimination reaction. The analgesic effect of 1,3-diphenylpropanol derivatives and &bgr;-phenylpropiophenone derivatives is described in J. Med. Chem., 1964, 7, S 716-721 and Bull. Soc. Chim. Fr., 1963, 12, 2747-2748, though a detailed investigation has not been carried out however on account of undesirable side effects.
SUMMARY OF THE INVENTION
The object of the invention was accordingly to provide analgesically effective substances that are suitable for treating severe pain, in particular for treating chronic and neuropathic pain. Furthermore these active substances should exhibit as few as possible of the side effects of the opioid analgesics, such as for example nausea, vomiting, dependence, respiratory depression and constipation.
According to the invention this is achieved by substituted 3-amino-2-benzyl-1-phenylpropanes of the general formula I, these compounds having a pronounced analgesic effect.
The present invention accordingly provides substituted 3-amino-2-benzyl-1-phenylpropane derivatives of the general formula I,
wherein
R
0
denotes H, OH or a single bond,
R
1
denotes H, a C
1-10
-alkyl, an aryl or an aryl radical bound via a C
1-6
-alkylene group, preferably denotes H, a C
1-3
-alkyl or an aryl radical bound via a C
1-3
-alkylene group,
R
2
denotes H, a C
1-10
-alkyl, an aryl, or an aryl radical bound via a C
1-6
-alkylene group, preferably denotes H, a C
1-3
-alkyl or an aryl radical bound via a C
1-3
-alkylene group,
R
3
denotes H, OH, NH
2
, halogen, OR
7
, OHR
8
, CHR
9
, a C
1-10
-alkyl, a C
2-10
-alkenyl, an aryl or an aryl radical bound via a C
1-6
-alkylene group, and preferably denotes H, F, Cl, a C
1-3
-alkyl, a C
2-3
-alkenyl- or an aryl radical bound via a C
1-3
-alkylene group,
or together with R
0
denotes a group ═O, ═CHR
11
or ═N—OH, preferably ═O,
R
4
-radicals, which may be identical or different, denote H, OH, CN, OR
7
, SR
7
, halogen, a C
1-10
-alkyl, a PO(OR
10
)
3
, an aryl, a heterocyclyl, an aryl or heterocyclyl radical bound via a C
1-6
alkylene group, and preferably denote H, F, Cl, a C
1-6
-alkyl, an aryl or heterocyclyl radical bound via a C
1-3
-alkylene group,
R
5
-radicals, which may be identical or different, denote H, OH, CN, OR
7
, SR
7
, halogen, a C
1-10
-alkyl, a PO(OR
10
)
3
, an aryl, a heterocyclyl, or an aryl or heterocyclyl radical bound via a C
1-6
alkylene group, and preferably denote H, F, Cl, a C
1-6
-alkyl or an aryl or heterocyclyl radical bound via a C
1-3
-alkylene group,
R
6
-radicals, which may be identical or different, denote H, OH, CN, OR
7
, SR
7
, halogen, a C
1-10
-alkyl, a PO(OR
10
)
3
, an aryl, a heterocyclyl, or an aryl or heterocyclyl radical bound via a C
1-6
alkylene group, and preferably denote H, F, Cl, a C
1-6
-alkyl or an aryl or heterocyclyl radical bound via a C
1-3
-alkylene group,
R
7
-radicals, which may be identical or different, denote a C
1-10
-alkyl, an aryl or an aryl radical bound via a C
1-6
alkylene group, and preferably denote C
1-3
-alkyl or an aryl radical bound via a C
1-3
-alkylene group,
R
8
denotes a C
1-10
-alkyl, an aryl or an aryl radical bound via a C
1-6
-alkylene group, and preferably denotes a C
1-3
-alkyl or an aryl radical bound via a C
1-3
-alkylene group,
R
9
denotes OH, halogen, OR
10
, SR
10
or a C
1-10
-alkyl radical, and preferably denotes F, Cl or a C
1-3
-alkyl radical,
R
10
denotes a C
1-10
-alkyl or a C
4-8
-cycloalkyl radical, preferably a C
1-3
-alkyl radical,
R
11
denotes a C
1-10
-alkyl radical, preferably a C
1-3
-alkyl radical,
R
12
-radicals, which may be identical or different, denote H, a C
1-10
-alkyl, a C
4-8
-cycloalkyl, an aryl or an aryl radical bound via a C
1-6
-alkylene group, preferably a C
1-3
-alkyl radical,
and/or their enantiomers, diastereomers, bases or salts of physiologically compatible acids,
the compounds of the general formula I′ being excluded
wherein the radicals are R
0
to R
6
and the radicals R
4′
to R
6′
denote H and also the radicals R
12
in each case denote CH
3
, as well as the corresponding methyliodide,
wherein the radicals R
0
and R
3
together denote the group ═O and R
1
, R
2
, R
4
to R
6
and R
4
to R
6′
denote H and also the radicals R
12
in each case denote CH
3
, as well as the corresponding hydrochloride,
wherein R
0
and R
3
together denote the group ═O, R
6
denotes the group OCH
3
and R
1
, R
2
, R
4
, R
5
and R
4′
to R
6′
denote H, and also the radicals R
12
in each case denote CH
3
, as hydrochloride,
wherein R
0
and R
3
together denote the group ═O, R
6′
denotes the group OCH
3
and R
1
, R
2
, R
4
to R
6
, R
4′
and R
5′
denote H, and also the radicals R
12
in each case denote CH
3
, as well as the corresponding hydrochloride,
wherein R
0
and R
3
together denote the group ═O, R
6′
denotes Cl and R
1
, R
2
, R
4
to R
6
, R
4′
and R
5′
denote H, and also the radicals R
12
in each case denote CH
3
,
wherein R
0
and R
3
together denote the group ═O, R
5′
and R
6′
in each case denote the group OCH
3
, and R
1
, R
2
, R
4
to R
6
and R
4′
denote H, and also the radicals R
12
in each case denote CH
3
, as hydrochloride,
wherein R
0
and R
3
together denote the group ═O, R
4
, R
6
and R
6′
in each case denote the group OCH
3
, and R
1
, R
2
, R
5
, R
4′
and R
5′
denote H, and also the radicals R
12
in each case denote CH
3
, as hydrochloride,
wherein R
0
denotes OH, R
3
denotes H, CH
3
, unbranched C
3
H
7
, unbranched C
5
H
11
, cyclohexyl, phenyl or benzyl, and R
1
, R
2
, R
4
to R
6
and R
4′
to R
6′
denote H, and also the radicals R
12
in each case denote CH
3
, as well as the corresponding hydrochlorides,
wherein R
0
denotes OH, R
3
denotes C
2
H
5
and R
1
, R
2
, R
4
to R
6
and R
4′
to R
6′
denote H and also the radicals R
12
n each case denote CH
3
, as well as the corresponding hydrochloride and the corresponding methyliodide,
wherein R
0
denotes OH, R
3
denotes phenyl, R
6
denotes Cl, R
1
, R
2
, R
4
, R
5
and R
4′
to R
6′
denote H, and also the radicals R
12
in each case denote CH
3
, as well as the corresponding hydrochloride,
wherein

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