Substituted 1 and 2 naphthol mannich bases

Details Substituted 1 and 2 naphthol mannich bases Substituted 1 and 2 naphthol mannich bases

2002-06-27

2004-08-10

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S428000, C546S206000, C548S570000

Reexamination Certificate

active

06774136

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to substituted 1- and 2-naphthol Mannich bases, processes for their preparation, medicaments comprising these compounds and the use of these compounds for the preparation of medicaments.
2. Description of the Background
Pain is one of the basic clinical symptoms. There is a worldwide need for effective pain treatments. The urgent need for 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, is documented 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 e.g. morphine, are effective in the treatment of severe to very severe pain. However, they have as undesirable concomitant symptoms, inter alia, respiratory depression, vomiting, sedation, constipation and development of tolerance.
Tramadol hydrochloride-(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol—occupies a special position among analgesics having an action on the central nervous system, since this active compound brings about potent inhibition of pain without the side effects known of opioids (J. Pharmacol. Exptl. Ther. 267, 33 (1993)). Research is being conducted worldwide into further pain-inhibiting agents.
The object of the present invention was therefore to provide new compounds which are suitable in particular as active compounds in medicaments.
These active compounds should be suitable in particular for pain treatment and for treatment of inflammatory and allergic reactions, drug and/or alcohol abuse, diarrhoea, gastritis, ulcers, cardiovascular diseases, urinary incontinence, depression, states of shock, migraines, narcolepsy, excess weight, asthma, glaucoma and/or hyperkinetic syndrome.
SUMMARY OF THE INVENTION
This object is achieved according to the invention by providing substituted 1- and 2-naphthol Mannich bases of the following general formula I which have a pronounced analgesic action and which moreover are suitable for treatment of/combating inflammatory and allergic reactions, drug and/or alcohol abuse, diarrhoea, gastritis, ulcers, cardiovascular diseases, urinary incontinence, depression, states of shock, migraines, narcolepsy, excess weight, asthma, glaucoma and/or hyperkinetic syndrome.
The invention therefore provides substituted 1- and 2-naphthol Mannich bases of the general formula I
wherein
R
1
=CH(R
9
)N(R
10
)(R
11
) and R
2
=OR
12
or
R
1
=OR
12
and R
2
=CH(R
9
)N(R
10
)(R
11
),
and in each case the radicals
R
3
to R
8
are identical or different and=H, F, Cl, Br, CF
3
, CN, NO
2
, SO
2
NH
2
, SO
2
NHR
13
, NHR
13
, SR
15
, OR
16
, CO(OR
20
), CH
2
CO(OR
21
), CO(R
22
), a C
1-10
-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C
1-6
-alkylene group, preferably=H, F, Cl, Br, SO
2
NH
2
, NHR
13
, CO(R
22
), OR
16
, CO(OR
20
), a C
1-6
-alkyl radical or an aryl radical bonded via a C
1-2
-alkylene group, particularly preferably H, NHR
13
, CO(R
22
), OR
16
or CO(OR
20
),
R
9
denotes an aryl radical, a heteroaryl radical or an alkyl radical without an acid proton in the &agr;-position, preferably an unsubstituted phenyl radical or a phenyl radical which is at least monosubstituted by C
1-4
-alkyl, C
1-3
-alkoxy, halogen, CF
3
, CN, O-phenyl or OH, particularly preferably an unsubstituted phenyl radical or a 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2-tert-butyl-phenyl, 3-tert-butyl-phenyl, 4-tert-butyl-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2-bromo-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 5-bromo-2-fluoro-phenyl, 2-chloro-4-fluoro-phenyl, 2-chloro-5-fluoro-phenyl, 2-chloro-6-fluoro-phenyl, 4-bromo-2-fluoro-phenyl, 3-bromo-4-fluoro-phenyl, 3-bromo-2-fluoro-phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichlorophenyl, 3,4-dichloro-phenyl, 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl, 2,5-dimethylphenyl, 2,3-dimethoxy-phenyl, 2,4-dimethoxy-phenyl, 2,5-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,4,5-trimethoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl or 4-trifluoromethyl-phenyl radical, very particularly preferably an unsubstituted phenyl radical,
R
10
, R
11
are identical or different and denote a branched or unbranched, saturated or unsaturated, unsubstituted or at least monosubstituted C
1-6
-alkyl radical or an unsubstituted or at least monosubstituted phenyl, benzyl or phenethyl radical, preferably a saturated, unsubstituted or at least monosubstituted C
1-6
-alkyl radical, particularly preferably a CH
3
radical,
or R
10
and R
11
together denote (CH
2
)
n
, where n=an integer from 3 to 6, or (CH
2
)
2
O(CH
2
)
2
, preferably (CH
2
)
n
, where n=4 or 5,
R
12
=H, COR
22
, a C
1-10
-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C
1-6
-alkylene group, preferably=H, a C
1-6
-alkyl radical or an aryl radical bonded via a C
1-2
-alkylene group,
R
13
=H, COR
14
, a C
1-10
-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C
1-6
-alkylene group, preferably=H, a C
1-6
-alkyl radical or an aryl radical bonded via a C
1-2
-alkylene group, particularly preferably=H,
R
14
=H, a C
1-10
-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C
1-6
-alkylene group, preferably a C
1-6
-alkyl radical or an aryl radical bonded via a C
1-2
-alkylene group,
R
15
=H, a C
1-10
-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C
1-6
-alkylene group, preferably a C
1-6
-alkyl radical or an aryl radical bonded via a C
1-2
-alkylene group,
R
16
=H, CO(R
17
), a C
1-10
-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C
1-6
-alkylene group, preferably H, a C
1-6
-alkyl radical, an aryl radical bonded via a C
1-2
-alkylene group or CO(R
17
), particularly preferably H or CO(R
17
),
R
17
=H, a C
1-10
-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C
1-6
-alkylene group, preferably a C
1-6
-alkyl radical, an aryl radical bonded via a C
1-2
-alkylene group or a phenyl radical which is optionally substituted by F, Cl, Br, C
1-4
-alkyl or C
1-3
-alkoxy, particularly preferably a phenyl radical which is optionally substituted by F, Cl, Br, C
1-4
-alkyl or C
1-3
-alkoxy,
R
18
=H, a C
1-10
-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C
1-6
-alkylene group, preferably a C
1-6
-alkyl radical, an aryl radical bonded via a C
1-2
-alkylene group or a phenyl or naphthyl radical which is optionally substituted by F, Cl, Br, C
1-4
-alkyl or C
1-3
-alkoxy, particularly preferably a phenyl radical which is optionally substituted by F, Cl, Br, C
1-4
-alkyl or C
1-3
-alkoxy,
R
20
=H, a C
1-10
-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C
1-6
-alkylene group, preferably H, a C
1-6
-alkyl radical, an aryl radical bonded via a C
1-2
-alkylene group or a phenyl radical which is optionally substituted by F, Cl, Br, C
1-4
-alkyl or C
1-3
-alkoxy, particularly preferably H or a phenyl radical which is optionally substituted by F, Cl, Br, C
1-4
-alkyl or C
1-3
-alkoxy,
R
21
=H, a C
1-10
-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C
1-6
-alkylene group, preferably=H, a C
1-6
-alkyl radical or an aryl radical bonded via a C
1-2
-alkylene group,
R
22
=H, NHNH
2
, NHR
18
, a C
1-10
-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C
1-6
-alkylene group, preferably H, a C
1-6
-alkyl radical, an aryl radical bonded via a C
1-2
-alkylene group, NHNH
2
, NHR
18
or a p

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