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HK1051845B - Substituted 1 and 2 naphthol mannich bases - Google Patents

Substituted 1 and 2 naphthol mannich bases Download PDF

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Publication number
HK1051845B
HK1051845B HK03102524.8A HK03102524A HK1051845B HK 1051845 B HK1051845 B HK 1051845B HK 03102524 A HK03102524 A HK 03102524A HK 1051845 B HK1051845 B HK 1051845B
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Hong Kong
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radical
phenyl
radicals
aryl
alkyl
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HK03102524.8A
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German (de)
French (fr)
Chinese (zh)
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HK1051845A1 (en
Inventor
Gerlach Matthias
Maul Corinna
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Grunenthal Gmbh
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Priority claimed from DE19963179A external-priority patent/DE19963179B4/en
Application filed by Grunenthal Gmbh filed Critical Grunenthal Gmbh
Publication of HK1051845A1 publication Critical patent/HK1051845A1/en
Publication of HK1051845B publication Critical patent/HK1051845B/en

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Description

The invention relates to substituted 1- and 2-naphthol-mannitic bases, methods for their manufacture, medicinal products containing these compounds and the use of these compounds in the manufacture of medicinal products.
Pain is one of the basic symptoms in the clinic. There is a worldwide need for effective pain therapies. The urgent need for patient-centred and targeted treatment of chronic and non-chronic pain conditions, including successful and satisfactory pain management for the patient, is documented in the large number of scientific papers that have recently appeared in the field of applied analgesics or basic research on nociception.
Traditional opioids, such as morphine, are effective in treating severe to very severe pain, but have side effects such as respiratory depression, vomiting, sedation, constipation and development of tolerance.
Tramadol hydrochloride - (1 RS, 2 RS) - 2-[dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol - has a special place among the centrally acting analgesics because this active substance produces a strong analgesic without the side effects known for opioids.
The present invention was therefore intended to provide new compounds which are particularly suitable as active substances in medicinal products.
These active substances are intended in particular for the treatment of pain and inflammatory and allergic reactions, drug and/or alcohol abuse, diarrhoea, gastritis, ulcers, cardiovascular diseases, urinary incontinence, depression, shock, migraine, narcolepsy, obesity, asthma, glaucoma and/or hyperkinetic syndrome, and according to the invention, this task is solved by the provision of substituted 1- and 2-naphthol mannich bases of the following general formula I, which have a pronounced analgesic effect and are also suitable for the treatment of inflammatory and allergic reactions, drug and/or alcohol abuse, hyperkinetic shock, gastritis, cardiovascular diseases, asthma, shock, asthma, asthma, asthma/migraine, shock, asthma, asthma, asthma, asthma, asthma and/or migraine.
The invention is therefore based on substituted 1- and 2-naphthal-mannitic bases of general formula I, In which R1 = CH(R9)N(R10)(R11) and R2 = OR12 means or R1 = OR12 and R2 = CH(R9)N(R10) ((R11) means that and each the residues R3 to R8, whether or not equal to or different from = H, F, Cl, Br, CF3, CN, NO2, SO2NH2, SO2NHR13, NHR13, SR15, OR16, CO(OR20), CH2CO(OR21), CO(R22), a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably = H, F, Cl, Br, SO2NH2, NHR13, CO(R22), OR16, CO(OR20), means a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group, preferably HOR13, NHR13, CO(R22), OR16, CO(20), R9 an aryl residue, a heteroaryl residue or an alkyl residue without acidic proton in the α position,'preferably an unsubstituted phenyl residue or a phenyl residue at least simply substituted with C1-4 alkyl, C1-3 alkoxy, halogen, CF3, CN, O-phenyl or OH dimethyl dimethyl, dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dimethyl dim R10, R11, whether or not identical, a branched, unbranched, saturated, unsaturated, unsubstituted or at least simply substituted C1-6 alkyl residue or an unsubstituted or at least simply substituted phenyl, benzyl or phenethyl residue,preferably a saturated, unsubstituted or at least simply substituted C1-6 alkyl residue, preferably a CH3 residue, or R10 and R11 together (CH2) n with n = an integer from 3 to 6 or (CH2) 2O ((CH2) 2), preferably (CH2) n with n = 4 or 5, means R12 = H, COR22 means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably = H, a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group, R13 = H, COR14, a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably = H, a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group,particularly preferred = H, means R14 = H, means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group, R15 = H, means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably a C1-6 alkyl or an aryl residue bound by a C1-2 alkyl group, R16 = H, CO(R17), a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably H, a C1-6 alkyl, an aryl residue bound by a C1-2 alkyl group, or CO(R17), preferably H or CO(R17), means: R17 = H, a C1-10 alkyl,means an aryl, a heteroaryl or an aryl or heteroaryl residue bound by an alkyl group C1-6, preferably a C1-6, an aryl residue bound by an alkyl group C1-2 or a phenyl residue substituted with F, Cl, Br, C1-4-alkyl, C1-3-alkoxy, or, if applicable, a phenyl residue substituted with F, Cl, Br, C1-4-alkyl, C1-3-alkoxy, R18 = H, a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably a C1-6 alkyl, an aryl residue bound by a C1-2 alkyl group or a phenyl or naphthyl residue substituted, where appropriate, by F, Cl, Br, C1-4 alkyl or C1-3 alkoxy, preferably a phenyl or naphthyl residue, where appropriate, by F, Cl, Br, Br, C1-4 alkyl, C1-3, alkoxy substituted phenyl residue means: R20 = H,C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably H, a C1-6 alkyl, an aryl residue bound by a C1-2 alkyl group or a phenyl residue, if any, substituted with F, Cl, Br, C1-4 alkyl or C1-3 alkoxy residue, preferably H or a phenyl residue, if any, substituted with F, Cl, Br, C1-4 alkyl, C1-3 alkoxy residue, means: R21 = H, an aryl- or heteroaryl residue bound to an alkyl group, preferably = H, C1-6 alkyl or an aryl residue bound to a C1-2 alkyl group means R22 = H, NHNH2, NHR18, a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group, preferably H,'C1-6 alkyl' means an aryl residue, NHNH2, NHR'8, bound by a C1-2 alkyl group, or a phenyl residue, where appropriate, substituted with F, Cl, Br, C1-4 alkyl or C1-3 alkoxy, preferably NHNH2, NHR18 or a phenyl residue, where appropriate, substituted with F, Cl, Br, C1-4 alkyl or C1-3 alkoxy, preferably NHNH2 or NHR18, and/or their racemates, enantiomers, diastereomers and/or corresponding bases and/or corresponding salts of physiologically compatible acids, wherein the racemate of compounds in which the residues R1 = CH(R9)N(R10) ((R11) and R2 = OR12 and, respectively, the residues R3 to R8 and R12 = H, the residues R9 = phenyl, 2-chlorophenyl, 4-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 2-fluorophenyl, 2-bromophenyl, benzo-1,3-dioxol, 4-CH3OCO-phenyl or 2-methoxyphenyl and the residues R10 and R11 together = (CH2) 5 or the residues R3 to R8 and R12 = H,the residue R9 = phenyl, 4-methoxyphenyl, 4-dimethylaminophenyl, 4-hydroxy-2,3-di-tert butylphenyl, 2,3-dihydrobenzodioxane, 4-nitrophenyl or benzo-1,3-dioxol and the residues R10 and R11 together = (CH2) 2O ((CH2) 2) or the residues R3 to R8 and R12 = H, the residue R9 = 4-methoxyphenyl and the residues R10 and R11 together = (CH2) 4 or the residue R3 = CO(OR20), the residues R4 to R8 and R12 = H, the residue R9 = phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-nitrophenyl, p-benzaldehyde, the residues R10 and R11 together = (CH2) 5 and the residue R20 = CH3 or the residues R3 to R8 and R12 = H, the residue R9 = phenyl and both residues R10 and R11 = CH3, respectively,C2H5 or n-C3H7 means or the residues R3 to R8 and R12 = H, the residues R9 = 4-methoxyphenyl or benzo-1,3-dioxol and the residues R10 and R11 = CH3 respectively or the residues R3 to R5, R7, R8, R12 = H, the residues R6 = Br, the residues R9 = phenyl and the residues R10 and R11 together = (CH2) 5 or the residues R3 to R5, R7, R8, R12 = H, the residue R6 = Br, the residue R9 = 4-hydroxy-3,5-di-tert-butylphenyl and the residues R10 and R11 together = (CH2) 2O ((CH2) 2) or The residues R3 to R8 and R12 = H, R9 = phenyl and R10 and R11 = CH3 respectively, are to be classified as hydrochloride or the residues R3 to R8 and R12 = H,The residue R9 = phenyl or 4-methoxyphenyl and the residues R10 and R11 together = (CH2) 5 means as hydrochloride or The remainder R3 = CO(OR20), the remainder R4 to R8 and R12 = H, the remainder R9 = phenyl, the remainder R10 and R11 together = (CH2) 5 and the remainder R20 = CH3 are to be classified as hydrochloride or the residues R3 to R8 and R12 = H, the residues R9 = thiophen and the residues R10 and R11 together = (CH2) 2O ((CH2) 2) or the residues R3 to R8 = H, the residue R12 = CH3, the residue R9 = thiophen, 4-methoxyphenyl or 3,4-dimethoxyphenyl and the residues R10 and R11 together = (CH2) 2O ((CH2) 2) and the enantiomers of the compound of general formula I,where R1 = CH(R9)N(R10)(R11) and R2 = OR12 and the residues R3 to R8, R12 = H, R9 = phenyl, R10 and R11 together = (CH2) 5 (+) 1-α-N,N-dimethylaminobenzyl) 2-naphthol and the corresponding tartrate, (-) 1-α-N,N-dimethylaminobenzyl) 2-naphthol and the corresponding tartrate, and Other, of a kind used in the textile, paper or paperboard industry and the racemate of compounds in which the residues R1 = OR12 and R2 = CH(R9)N(R10)(R11) are, and each the residues R3 to R8 and R12 = H, the remainder R9 = phenyl, 2-bromphenyle, 3-bromphenyle or 4-bromphenyle and the remainders R10 and R11 together = (CH2) 5 or R3 to R8 and R12 = H, the remainder R9 = phenyl or 2-nitrophenyl and the remainders R10 and R11 together = (CH2) 2O ((CH2) 2) or R3R4, R6, R8 and R12 = H, where R5, R7 = CH3, R9 = phenyl or 4-methoxyphenyl and R10 and R11 together = (CH2) 5 or R3 to R6, R8, R12 = H, the remainder R7 = CH3, the remainder R9 = 4-methoxyphenyl or phenyl and the remainders R10, R11 together = (CH2) 5 or R3 to R8 and R12 = H, the remainder R9 = phenyl, the remainder R10 = CH3 and the remainder R11 = C6H11 or the remainders R10 and R11 respectively = CH3 or R3 to R6, R8, R12 = H, the remainder R7 = CH3,The residue R9 = phenyl or 4-methoxyphenyl and the residues R10 and R11 together = (CH2) 2O ((CH2) 2) or R3, R4, R6, R8, R12 = H, where R5 and R7 = CH3, R9 = 4-methoxyphenyl and R10 and R11 together = (CH2) 2O (CH2) 2 or R3 to R8, R12 = H, the remainder R9 = phenyl and the remainders R10 and R11 together = (CH2) 2O (CH2) 2 means hydrochloride The Commission has not yet adopted a decision.
Alkyl residues are preferably at least simple with halogen, CN, CF3 and/or OH- and especially preferably with F, Cl, Br or OH- substituted hydrocarbon residues. If these contain more than one substituent, these substituents may be the same or different. The alkyl residues may be branched, unbranched or cyclic.
An aryl residue is preferably a phenyl or naphthyl residue substituted with at least one OH, one halogen, preferably F, Br or Cl, one CF3, one CN, one C1-6-alkyl, one C1-6-alkoxy or one phenyl residue. The unsubstituted or substituted phenyl residues may also be condensed with further rings. In particular, the aryl residues are preferably 2-, 3-, 4-bromophenyl, 4-bromophenyl-2-fluorophenyl, 5-bromophenyl-2-fluorophenyl, 3-bromophenyl-4-fluorophenyl, 4-tryphobutyl-phenyl, 2-ceto-4-methoxy-fluorophenyl, 2-ceto-6-fluorophenyl, 4-dimethyl, 2-diphenyl, 2,3-diphenyl, 2,3-diphenyl, 2,4-diphenyl, 2,3-diphenyl, 2,4-diphenyl, 2,4-diphenyl, 2,4-diphenyl, 2,3-diphenyl, 2,4-diphenyl, 2,4-diphenyl, 2,4-diphenyl, 2,4-diphenyl, 2,4-diphenyl, 2,4-diphenyl, 2,4-diphenyl, 2,4-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-diphenyl, 2-
A heteroaryl residue is an aromatic compound containing at least one heteroatom, preferably nitrogen and/or oxygen and/or sulphur, preferably nitrogen and/or oxygen, which may preferably be substituted with a halogen, CN, CF3 or OH residue.
The following substituted 1- and 2-naphthal-mannitic bases are particularly preferred: The term 'methyl methacrylate' means a compound containing a compound with a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, and a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, containing a high content of methacrylate, and a high content of methacrylate, and a high content of methacrylate, and a high content of methacrylate, and a high content of methacrylate, and a high content of methacrylate, and a high content of methacrylate, and a high content of methacrylate, and a high content of methacrylate, and a content of methacrylate, and a content
The invention also relates to methods for the preparation of substituted 1- and 2-naphthal-mannitic bases of general formula I, in which the residue R12 is H and the residues R1 to R11, R13 to R18 and R20 to R22 have the meanings given by general formula I, characterized by the following: aromatic aldehyde compounds, heteroaromatic aldehyde compounds and/or aliphatic aldehyde compounds of general formula II, in which R9 has the meaning according to the general formula I, in solution, preferably in an organic solvent, preferably in toluene, in the presence of a base, preferably potassium carbonate or boric anhydride, preferably at a temperature of - 10 °C to + 110 °C with secondary amines of general formula III,Other where R10 and R11 are the values given by the general formula I, converted into amines of general formula IV and these amines of general formula IV, without further purification, into amines of general formula V by an acid chloride, preferably acetyl chloride, in absolute solvent, preferably diethyl ether and these iminium salts of general formula V are incorporated without further purification into a solution, preferably in acetonitrile with substituted and/or unsubstituted naphthal compounds of general formula VI, where R1 = H and R2 = OH or R1 = OH and R2 = H and the residues R3 to R8, R13 to R18 and R20 to R22 have the meanings given in general formula I,The resulting 1- and 2-naphthol compounds of general formula I, where the residue R12 is H and the residues R1 to R11, R13 to R18 and R20 to R22 have the meanings given in general formula I, are extracted and isolated by the usual methods.
The present invention also relates to methods for the preparation of substituted 1- and 2-naphthol-mannitic bases of general formula I, where the residue R12 = COR22, means a C1-10 alkyl, an aryl, a heteroaryl or an aryl or heteroaryl residue bound by a C1-6 alkyl group and the residues R1 to R11, R13 to R18 and R20 to R22 have the meaning according to general formula I, characterized by the fact that aromatic aldehyde compounds, heteroaromatic aldehyde compounds and/or aliphatic aldehyde compounds of general formula II, in which R9 has the value according to the general formula I, in solution, preferably in an organic solvent, preferably in toluene,in the presence of a base, preferably potassium carbonate or boric anhydride, preferably at a temperature of - 10 to +110 °C with secondary amines of general formula III, where R10 and R11 are the values given by the general formula I, to amine compounds of general formula IV and these amine compounds of general formula IV, without further purification, are converted into amino salts of general formula V by an acid chloride, preferably acetyl chloride, in an absolute solvent, preferably diethyl ether and these iminium salts of general formula V are incorporated without further purification into a solution, preferably in acetonitrile with substituted and/or unsubstituted naphthal compounds of general formula VI, where R1 = H and R2 = OH or R1 = OH and R2 = H and the residues R3 to R8 respectively,R13 to R18 and R20 to R22 have the meanings given by the general formula I and the compounds thus obtained are those of general formula VI, where R1 = CH(R9)N(R10)(R11) and R2 = OH or R1 = OH and R2 = CH(R9)N(R10)(R11) and the residues R3 to R11, R13 to R18 and R20 to R22 have the meanings given by the general formula I, in solution, preferably in dimethylformamide, with compounds of general formula XR12', where X = Cl, Br or I, preferably and R12' for COR22, a C1-10 alkyl, an aryl, a heteroaryl or a hetero-aryl group with a cyclic group of C1-6 or an aryl-aryl-aryl group,preferably in the presence of a base, preferably triethylamine or potassium tert-butylate, preferably at a temperature of 10 to 150 °C, and the resulting 1- and 2-naphtholamnickel bases of general formula I, in which the residue R12 is given for COR22, a C1-10-alkyl, an aryl, an aryl or heteroaryl or for an aryl or heteroaryl residue bound by a C1-6-alkyl group, preferably in the presence of a C1-6-alkyl or a C1-2-alkyl group, and the residue R11 to R18 is given by the general formula R11 to R20 and the residue R13 to R20 and the residue R20 to R20 are given by the general formula R11 to R20 and the residue R20 to R20 are given by the general formula R20 and the residue R20 to R20 and the residue R20 to R20 are given by the general formula R20 to R20 and the residue R20 to R20 and the residue R20 to R20 are given by the general formula R20 to R20 and the residue R20 to R20 and the residue R20 to R20 and the residue R20 to R20 are given by the general formula R20 to R20 and the general formula R20 to R20 and the residue R20 to R20 and the residue R20 to R20 and the residue R20 to R20 are given by the general formula R20 and the general formula R20 to R20 and the R20 to R20 to R20 and the R20 to R20 and the R20 to R20 to R20 respectively to R20 and the R20 to R20 and the R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 to R20 toThe following substances are to be used in the preparation of the product:
Preferably, the synthesis of the substituted 1- and 2-naphthal-mannitic bases of the invention is carried out on an automatic Zymark plant as described in Figures 1 and 2 below.
The 1- and 2-naphthal-mannaric bases of general formula I substituted in accordance with the invention can be transferred to their salts in a manner known to the professional with physiologically compatible acids, preferably hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, formic acid, acetic acid, oxalic acid, benzoic acid, tartaric acid, almond acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. The salination is preferably carried out in a solvent, preferably diethyl ether, diisopropyl ketone, acetic acid, acetic acid, 2-ethyl ester or trimethanethyl ether, and preferably in the form of methylenes.
The 1- and 2-naphthal-mannitic bases of the generic formula I substituted according to the invention are toxicologically safe and therefore suitable pharmaceutical active substances.
The invention also relates to medicinal products containing as an active substance at least one substituted 1- and/or 2-naphthal-mannitic base of general formula I and, where appropriate, other active substances and/or excipients. Preferably, the medicinal product may also contain a mixture of enantiomers containing at least one substituted 1-naphthol-mannitic base and/or 2-naphthol-mannitic base of general formula I, preferably not containing the enantiomers in equimolar amounts.
Preferably, the medicinal products are used to treat/ control pain and/ or inflammatory and/ or allergic reactions and/ or drug and/ or alcohol abuse and/ or diarrhoea and/ or gastritis and/ or ulceration and/ or cardiovascular disease and/ or urinary incontinence and/ or depression and/ or shock and/ or migraine and/ or narcolepsy and/ or overweight and/ or asthma and/ or glaucoma and/ or hyperkinetic syndrome.
The use of at least one substituted 1- and/or 2-naphthal-mannitic base of generic formula I in accordance with the invention to manufacture a medicinal product for the treatment/control of pain and/or inflammatory and/or allergic reactions and/or drug abuse and/or alcohol abuse and/or diarrhoea and/or gastritis and/or ulceration and/or cardiovascular disease and/or urinary incontinence and/or depression and/or shock and/or migraine and/or narcolepsy and/or obesity and/or asthma and/or glaucoma and/or hyperkinetic syndrome is also the subject of the present invention.
For the preparation of appropriate pharmaceutical formulations, carrier materials, fillers, solvents, diluents, colours and/ or binders are used in addition to at least one substituted 1- and/ or 2-naphthol-mannitic base of generic formula I. The choice of excipients depends on whether the product is to be applied orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically, for example to infections of the skin, mucous membranes and eyes. For oral application, the preparations are in the form of tablets, drops, capsules, granules, drops, syrups, syrups, toothpastes, inhalation solutions and easily reconstituted suspensions, and in the form of syrups, syrups and syrups for parenteral application.
The 1- or 2-naphthal-mannitic bases of generic formula I substituted according to the invention in a solvent or patch, where appropriate with the addition of skin-penetrating agents, are suitable percutaneous application preparations.
The dose to be given to the patient will vary depending on the patient' s weight, the type of application, the indication and the severity of the disease.
Pharmacological tests: In vitro tests
The broad efficacy testing of the 1- and 2-naphthol-mannitic bases of the invention was performed using the standard high throughput screening methods described in John P. Devlin, High Throughput Screening, 1997, Marcel Dekker Inc. These are hereby introduced as a reference.
The action of the 1- and 2-naphthol-mannitic bases of the invention is determined in particular by affinity for the N-Methyl-D-aspartate (NMDA) receptor family, α-adrenergic receptors and opioid receptors.
2) Analgesia test in the mouse writhing test
The enhanced analgesic study was performed in the mouse with phenylquinone-induced writhing (modified from I.C. Hendershot, J. Forsaith, J. Pharmacol. Exp. Ther. 125, 237-240 (1959)), using male NMRI mice weighing 25-30 g. Groups of 10 animals were given 0.3 ml/mouse of 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, Fa. Sigma, Deisenhofen; preparation of solution with 5 minutes of additional ethanol and storage in water at 45°C) 10 minutes after intravenous administration of the test substances. The number of animals was individually monitored by an intracellular coagulation system.
The substances were tested at the standard dose of 10 mg/kg. The inhibition of the wrist-wringing reactions by one substance was calculated according to the following formula:
The following examples are intended to illustrate the invention.
Examples: General synthesis rules for the preparation of aminal compounds of general formula IV: General rule of synthesis 1:
The solution was then stirred for another 30 minutes at 80°C, then cooled to room temperature and mixed with 0.57 equivalent potassium carbonate, forming two separate phases, the aqueous phase being extracted three times with 100 ml ester each. The combined organic phases were dried using potassium carbonate and released from the solvent. The resulting compounds of the general IV were then added to the subsequent foraging reactions without further foraging.
General rule of synthesis 2:
A solution of 1.0 equivalent of the respective aromatic, heteroaromatic or aliphatic aldehyde compound of general formula II was added to 80 ml of absolute toluene, followed by 1.6 equivalent of boric anhydride. A solution of 2.4 equivalent of a secondary amine of general formula III was added to 85 ml of absolute toluene, stirred vigorously. The reaction was initiated by a significant increase in temperature. The reaction solution was then stirred for a further two hours at 45 to 50 °C. After cooling to room temperature, the excess boric anhydride was separated and the filtrat was removed from the solvent. The resulting compounds of further general formula IV were then incorporated into the subsequent forridine reactions without further forridine.
General synthesis rule for the synthesis of iminium salts of general formula V: General rule of synthesis 3:
A solution of 1.0 acetyl chloride equivalent in absolute diethyl ether was slowly dripped to 1.0 equivalent of an ice-cold solution or suspension of the amine compound of general formula IV produced according to the general synthesis rule 1 or 2. The reaction mixture was then stirred overnight at about 20 °C. This produced precipitation which was sucked under nitrogen and then dried in the oil pump. The resulting iminium salts of general formula V were used in the following reactions without further purification.
General synthesis rule for the synthesis of 1- and 2-naphthal-mannitic bases of general formula I: General synthesis rule 4:
The synthesis of the naphthalol-mannitic bases of the invention was carried out on an automatic Zymark plant as shown in Figure 1 and Figure 2 respectively:
Figure 1 comprises a capper station (point 1) for closing the reaction tubes, a robot 1 (point 2) and a robot 2 (point 3) where robot 1 moves the reaction tubes or racks and robot 2 pipettes the reagents into the reaction tubes, a tempered reactor block (point 4), R-block (point 5) and a filtration station (point 6) where the reaction solution is filtered.
Figure 2 also includes a robot 1 (point 1) and a robot 2 (point 2) which both move the glass tubes with the synthesis products to the various stations, namely a pre-exposure unit (point 3) for mixing the samples and for dosing solutions or solvents, a spin reactor (point 4) for mixing samples, a phase separation unit (point 5) for detecting the phase boundary and phase separation and a station (point 6) for drying the synthesis products by salting.
For the synthesis, a round glass tube (diameter 16 mm, length 125 mm) with threads was manually stirred and sealed with a screw cap with septum at the capper station (point 1) as shown in Figure 1. The tube was placed by robot 1 (point 2) into the reactor block (point 4) which had been heated to 25°C. Robot 2 (point 3) pipetted the following reagents in succession: 1.) 1 ml of a 0.1 M solution of 1- or 2-naphthol or a substituted 1- or 2-naphthol compound of general formula VI and 14 μl of triethylamine in acetonitrile2.) 1.2 ml of a 0.1 M solution of an iminium salt of general formula V in acetonitrile.
The iminium salts were prepared as shown in the following examples. The reaction mixture was then stirred at 90°C in one of the stirring blocks (Figure 5) for 960 min. The reaction solution was then filtered at the filtration station (Figure 6). The tube was rinsed twice with 1 ml of dichloromethane and 200 μl of water. The rack containing the tubes was then manually placed on an automatic treatment plant as shown in Figure 2.
The mixture was then mixed thoroughly for 10 minutes in the spin reactor (fig. 4) and a clear phase boundary was formed by the slow decrease in rotation. This phase boundary was optically detected at the phase detection station (fig. 5) and the aqueous phase was pipetted. The aqueous phase was then stirred with 2 ml of acetic acid and set to a pH of 11 with 1 ml of saturated sodium hydrocarbonate solution. The organic phase was thoroughly dried again for 10 minutes in the spin reactor (fig. 4) and then desiccated. The next step was to distil the desiccated phase into 1.5 ml of concentrated organic solution (pg.
General synthesis rule for the synthesis of alkylated 1- and 2-naphthal-mannitic bases of general formula I: General synthesis rule 5:
A solution of 1.0 equivalent 1- and/ or 2-naphthol Mannich base of general formula I with R12 = H in absolute N,N-dimethylformamide was treated with 1.0 equivalent potassium butylate for 15 minutes, then mixed with 1.0 equivalent alkylation reagent (R12-Hal) and stirred for another 24 hours at about 20°C. This was followed by 3.0 equivalent 3- (< 3-mercaptophenyl) -panpanpan-naphthol-pramethylpolystyrrols, mixed for another three hours, filtered from the PS resin and concentrated the filtrate in a vacuum. The resulting residue was taken in a 1:1 dichlorometallic water-glycol solution for 30 minutes, with the phosphates, which were each mixed with 20 mL of magnesium sulphate, being drawn in three separate phases and then extracted in a vacuum.
General synthesis rule for the synthesis of acylated 1- and 2-naphthal-mannitic bases of general formula I: General rule of synthesis 6:
A solution of 1.0 equivalent 1- and/ or 2-naphthol Mannich base of the general formula I with R12 = H in absolute N,N-dimethylformamide was treated with 1.0 equivalent potassium butylate for 15 minutes, then mixed with 1.0 equivalent aclarification reagent (R12-Hal) and stirred for another 24 hours at about 20°C. This was followed by the addition of 3.0 polymer-bound trisodium 2-aminoethyl, followed by another three hours of inter-action, filtration of PS resin and concentration of the filtrate in a vacuum. The resulting residue was taken in a 1:1 dichloromethane/water-dry solution, stirred for 30 minutes, separated three times, each phase being treated with 20 mL of magnesium chloride, and then extracted by means of a solvent.
Synthesis of 1- and 2-naphthal-mannitic bases of general formula I: Example 1:
The following substances are to be classified in the same heading as the active substance: Stage 1 Benzylides and their salts
The implementation of 32.0 ml (0.213 mol) of dimethylamine solution and 8.0 ml (0.079 mol) of benzaldehyde according to the general synthesis rule 1 and the subsequent reaction with 4.7 ml (0.079 mol) of acetyl chloride according to the general synthesis rule 3 yielded 9.5 g (corresponding to 70.7% of the theoretically calculated yield) of benzylidene dimethyl ammonium chloride.
Stage two. The following substances are to be classified in the same heading as the active substance:
It was produced according to the general synthesis rule 4 from 5-hydroxy-1-naphthalene insulin sulfonamide and benzylidene dimethyl ammonium chloride.
The structure was determined by ESI-MS: calculated mass 356.45 g/mol, found mass M+H = 357.3 g/mol.
Example 2:
4-Amino-2- ((dimethylaminophenylmethyl) -naphthalene-1-ol) and its salts
The product was produced according to the general synthesis rule 4 from 1-amino-4-naphthal and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 292.38 g/mol, found mass M+H = 293.8.
Example 3:
4-dimethylaminophenylmethyl) 3-hydroxynaphthalene-2-carboxylic acid hydrazide
The product was produced according to the general synthesis rule 4 from 2-hydroxy-3-naphthose hydrazide and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 335.41 g/mol, found mass M+H = 336.3.
Example 4:
4-dimethylaminophenylmethyl) 3-hydroxynaphthalene-2-carboxylic acid methyl ester
The manufacture was carried out according to the general synthesis rule 4 from methyl-3-hydroxy-2-naphthoate and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 335.41 g/mol, found mass M+H = 336.5.
Example 5:
4-dimethylaminophenylmethyl) 3-hydroxynaphthalene-2-carbonic acid
The product was produced according to the general synthesis rule 4 from 2-hydroxy-3-naphthose acid and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 321.38 g/mol, found mass M+H = 322.2.
Example 6:
4-dimethylaminophenylmethyl) 3-hydroxynaphthalene-2-carbonic acid phenylester
The product was produced according to the general synthesis rule 4 from 2-hydroxy-3-naphthose phenylester and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 397.48 g/mol, found mass M+H = 398.2.
Example 7:
The following substances are to be classified in the same category as the active substance:
The product was produced according to the general synthesis rule 4 from 6-benzoyl-2-naphthal and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 381.48 g/mol, found mass M+H = 382.2.
Example 8:
3-Amino-1- ((dimethylaminophenylmethyl) -naphthalene-2-ol) and its salts
The product was produced according to the general synthesis rule 4 from 3-amino-2-naphthal and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 292.38 g/mol, found mass M+H = 293.3; M+H-NMe2 = 249.3.
Example 9:
The following shall be added to the list of active substances:
The manufacture was carried out according to the general synthesis rule 4 from 3-hydroxy-N- ((2-methoxyphenyl) -naphthalene carboxamide and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 426.52 g/mol, found mass M+H = 427.0.
Example 10:
4-dimethylaminophenylmethyl) 3-hydroxynaphthalene-2-carbonate o-tolylamide
The product was produced according to the general synthesis rule 4 from 3-hydroxy-N- ((o-tolyl) -naphthalene carboxamide and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS, mass calculated 410.52 g/mol, mass found M+H = 412.0.
Example 11:
4-dimethylaminophenylmethyl) 3-hydroxynaphthalene-2-carboxylic acid naphthalene-1-ylamide
The product was produced according to the general synthesis rule 4 from 3-hydroxy-N- ((naphthyl) -naphthalin-carboxamide and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 446.55 g/mol, found mass M+H = 447.8.
Example 12:
4-dimethylaminophenylmethyl) 3-hydroxy-7-methoxynaphthalene-2-carbonic acid
The manufacture was carried out according to the general synthesis rule 4 from 3-hydroxy-7-methoxy-2-naphthose acid and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS, mass 351.41 g/mol, mass M+H = 352.3.
Example 13:
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]
The product was produced according to the general synthesis rule 4 from 6-hydroxy-2-naphthose acid and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 321.38 g/mol, found mass M+H = 322.1.
Example 14:
The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 7-Methoxy-2-naphthal and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 307.36 g/mol, found mass M+H = 308.4.
Example 15:
The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 6-methoxy-2-naphthal and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 307.4 g/mol, found mass M+H = 308.3.
Example 16:
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]
The product was produced according to the general synthesis rule 4 from 6-hydroxy-1-naphthose acid and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 321.38 g/mol, found mass M+H = 322.2.
Example 17:
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C4.]
The product was produced according to the general synthesis rule 4 from the sodium salt of 3-hydroxy-7-methoxy-2-naphthose acid and benzylidene dimethyl ammonium chloride, which was produced according to example 1.
The structure was determined by ESI-MS: calculated mass 373.39 g/mol, found mass M+H-Na = 352.0.
Example 18:
The following substances are to be classified in the same heading as the active substance: Stage one 4- (β-methylbenzylides) -morpholine 4-ium chloride
The implementation of 8.5 g (0.100 mol) morpholine and 7.0 g (0.050 mol) 2-methoxybenzaldehyde according to the general synthesis rule 2 and the subsequent reaction with 3.9 g (0.050 mol) acetyl chloride according to the general synthesis rule 3 yielded 7.1 g (corresponding to 58 % of the theoretically calculated yield) of 4-methylbenzylides) morpholine-4-ium chloride.
Level 2 The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 4-chloro-1-naphthal and 4- ((2-methylbenzylides) morpholine-4-ium chloride.
The structure was determined by ESI-MS: calculated mass 367.88 g/mol, found mass M+H = 368.1.
Example 19:
The following substances are to be classified in the same heading as the active substance: Stage one The following substances are to be classified in the same heading as the product:
The implementation of 9.5 ml (0.096 mol) piperidine and 4.7 ml (0.040 mol) 2-methylbenzaldehyde according to the general synthesis rule 2 and the subsequent reaction with 2.4 ml (0.040 mol) acetyl chloride according to the general synthesis rule 3 yielded 5.8 g (corresponding to 65% of the theoretically calculated yield) of 1- (b) 2-methylbenzylides) piperidinium chloride.
Stage two. The following substances are to be classified in the same heading as the active substance:
It was produced according to the general synthesis rule 4 from 1- (-2-methyl benzylides) piperidinium chloride and 4-chloro-1-naphthal.
The structure was determined by ESI-MS: calculated mass 365.91 g/mol, found mass M+H = 366.2.
Example 20:
The following substances are to be classified in the same heading as the active substance: Stage one The following substances are to be classified in the same heading as the product:
The implementation of 8,5 g (0.100 mol) piperidine and 7,0 g (0.050 mol) 2-chlorobenzaldehyde according to the general synthesis rule 2 and the subsequent reaction with 3,9 g (0.050 mol) acetyl chloride according to the general synthesis rule 3 yielded 7,1 g (corresponding to 58% of the theoretically calculated yield) of 1-methylbenzylidene piperidinium chloride.
Stage two. The following substances are to be classified in the same heading as the active substance:
It was produced according to the general synthesis rule 4 from 1- (-2-chlorobenzyl) piperidinium chloride and 4-chlorobenzyl naphthole.
The structure was determined by ESI-MS: calculated mass 386.32 g/mol, found mass M+H = 386.1.
Example 21:
The following substances are to be classified in the same heading as the active substance: Stage one 4- (2,3-dimethoxybenzylides) morpholine 4-ium chloride
The conversion of 7.3 ml (0.084 mol) of morpholine and 5.8 g (0.035 mol) of 2,3-dimethoxybenzaldehyde according to the general synthesis rule 2 and subsequent reaction with 2,1 ml (0.035 mol) of acetyl chloride according to the general synthesis rule 3 yielded 5,6 g (corresponding to 59% of the theoretically calculated yield) of 4-dimethoxybenzylid) morpholine-4-ium chloride.
Stage two. The following substances are to be classified in the same heading as the active substance:
It was produced according to the general synthesis rule 4 from 4- (2,3-dimethoxybenzylides) morpholine-4-ium chloride and 4-chlor-1-naphthal.
The structure was determined by ESI-MS: calculated mass 413.91 g/mol, found mass M+H = 414.0.
Example 22:
The following substances are to be classified in the same heading as the active substance:
The manufacture was carried out according to the general synthesis rule 4 from 5-amino-1-naphthal and 1- (-2-chloro-benzylides) piperidinium chloride, which was produced according to example 20.
The structure was determined by ESI-MS: calculated mass 366.89 g/mol, found mass M+H = 367.4.
Example 23:
The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 5-amino-1-naphthal and 4- (2,3-dimethoxybenzylides) morpholine-4-ium chloride, which was produced according to example 21.
The structure was determined by ESI-MS: calculated mass 394.47 g/mol, found mass M+H = 395.1.
Example 24:
3-Hydroxy-4- ((piperidin-1-yl-o-tolylmethyl) -naphthalene-2-carboxylic acid hydrazide) Stage one The following substances are to be classified in the same heading as the product:
The implementation of 9.5 ml (0.096 mol) piperidine and 4.7 ml (0.040 mol) 2-methylbenzaldehyde according to the general synthesis rule 2 and the subsequent reaction with 2.4 ml (0.040 mol) acetyl chloride according to the general synthesis rule 3 yielded 5.8 g (corresponding to 65% of the theoretically calculated yield) of 1- (b) 2-methylbenzylides) piperidinium chloride.
Stage two. 3-Hydroxy-4- ((piperidin-1-yl-o-tolylmethyl) -naphthalene-2-carboxylic acid hydrazide)
It was produced according to the general synthesis rule 4 from 1- (-2-methylbenzylides) piperidinium chloride and 2-hydroxy-3-naphtoic acid hydrazide.
The structure was determined by ESI-MS: calculated mass 389.5 g/mol, found mass M-H = 388.5.
Example 25:
The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 7-Methoxy-2-naphthol and 4- ((2-Methylbenzylides) morpholine-4-ium chloride, which was produced according to example 18.
The structure was determined by ESI-MS, mass 389.41 g/mol, mass M+H = 389.5.
Example 26:
The following substances are to be classified in the same heading as the active substance:
The manufacture was carried out according to the general synthesis rule 4 from 7-Methoxy-2-naphthal and 1- (-2-Chlor-benzylides) piperidinium chloride, which was produced according to example 20.
The structure was determined by ESI-MS: calculated mass 381.91 g/mol, found mass M+H = 382.2.
Example 27:
The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 7-Methoxy-2-naphthol and 4- (2,3-Dimethoxy-benzylids) morpholine-4-ium chloride, which was produced according to example 21.
The structure was determined by ESI-MS: calculated mass 409.49 g/mol, found mass M+H = 409.9.
Example 28:
The following substances are to be classified in the same heading as the active substance: Stage one 4- (methylbenzylidene) -morpholine 4-ium chloride, whether or not chemically defined
The implementation of 18.8 ml (0.216 mol) morpholine and 12.4 g (0.09 mol) 2-methoxybenzaldehyde according to the general synthesis rule 2 and subsequent reaction with 5.3 ml (0.110 mol) acetyl chloride according to the general synthesis rule 3 yielded 7.61 g (corresponding to 38 % of the theoretically calculated yield) of 4-methoxybenzylides) morpholine-4-ium chloride.
Stage two. The following substances are to be classified in the same heading as the active substance:
It was produced according to the general synthesis rule 4 from 4- ((2-methoxybenzylides) morpholine-4-ium chloride and 6-bromo-2-naphthol.
The structure was determined by ESI-MS: calculated mass 428.33 g/mol, found mass M+H = 428.1/430.0.
Example 29:
It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]
The manufacture was carried out according to the general synthesis rule 4 from 6-hydroxy-1-naphthose acid and 4- ((2-methoxybenzylids) morpholine-4-ium chloride, which was produced according to example 28.
The structure was determined by ESI-MS: calculated mass 393.44 g/mol, found mass M+H = 394.1.
Example 30:
The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 7-Methoxy-2-naphthal and 4- ((2-Methoxy-benzylids) morpholine-4-ium chloride, which was produced according to example 28.
The structure was determined by ESI-MS: calculated mass 379.46 g/mol, found mass M+H = 380.2.
Example 31:
The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 6-Methoxy-2-naphthal and 4- ((2-Methoxy-benzylids) morpholine-4-ium chloride, which was produced according to example 28.
The structure was determined by ESI-MS: calculated mass 379.46 g/mol, found mass M+H = 380.1.
Example 32:
The following substances are to be classified in the same heading as the active substance: Stage one 1- (β-methoxybenzylides) piperidinium chloride, whether or not chemically defined
The implementation of 18.4 g (0.216 mol) piperidine and 25.9 g (0.090 mol) 2-methoxybenzaldehyde according to the general synthesis rule 2 and the subsequent reaction with 5.3 ml (0.11 mol) acetyl chloride according to the general synthesis rule 3 yielded 13.4 g (corresponding to 62% of the theoretically calculated yield) of 1-methybenzylidene) piperidinium chloride.
Stage two. The following substances are to be classified in the same heading as the active substance:
It was produced according to the general synthesis rule 4 from 1- (2-methoxybenzylides) piperidinium chloride and 4-chloro-1-naphthal.
The structure was determined by ESI-MS: calculated mass 381.91 g/mol, found mass M+H-piperidine = 297.2.
Example 33:
The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 6-bromo-2-naphthal and 1- (β-methoxybenzylides) piperidinium chloride, which was produced according to example 32.
The structure was determined by ESI-MS: calculated mass 426.36 g/mol, found mass M+H = 426.1/428.2.
Example 34:
The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 6-Methoxy-2-naphthal and 1- (2-Methoxy-benzylids) piperidinium chloride, which was produced according to example 32.
The structure was determined by ESI-MS: calculated mass 377.49 g/mol, found mass M+H = 378.2.
Example 35:
The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 7-Methoxy-2-naphthal and 1- (2-Methoxy-benzylids) piperidinium chloride, which was produced according to example 32.
The structure was determined by ESI-MS: calculated mass 377.49 g/mol, found mass M+H = 378.2.
Example 36:
The following substances are to be classified in the same heading as the active substance: Stage one Other, of a kind used for the manufacture of rubber or plastics
The implementation of 17,0 ml (0.135 mol) of dimethylamine solution and 6,8 ml (0.050 mol) of 2-methoxybenzaldehyde according to the general synthesis rule 1 and subsequent reaction with 3,0 ml (0.050 mol) of acetyl chloride according to the general synthesis rule 3 yielded 4,8 g (48% of the theoretically calculated yield) of (2-methoxybenzylides) dimethylammonium chloride.
Stage two. The following substances are to be classified in the same heading as the active substance:
It was produced according to the general synthesis rule 4 from (2-methoxybenzylides) dimethylammonium chloride and 5-chlor-1-naphthal.
The structure was determined by ESI-MS: calculated mass 341.84 g/mol, found mass M+H-NMe2 = 297.2.
Example 37:
The following shall be indicated in the column 'Natural gas' of the table:
It was produced from 1-naphthal and benzylid dimethyl ammonium chloride and 4-methoxybenzyl chloride in accordance with general synthesis rules 4 and 5.
The structure was determined by 13C-NMR: δ = 159.59; 151.92; 143.30; 134.03; 132.03; 129.22 (Cq); 129.76; 128.38; 128.07; 127.99; 126.87; 125.84, 125.74; 124.61, 122.40, 114.10 (Ct); 75.85 (Cs); 69.46; 55.38; 44.82 (Cp).
Example 38:
The following shall be indicated in the column 'Natural gas' of the table:
The product was produced according to general synthesis rules 4 and 5 from 2-naphthal, benzylidene dimethyl ammonium chloride and 4-methoxybenzyl chloride. The structure was determined by ESI-MS: calculated mass 397.52 g/mol, found mass M+H = 398.0.
Example 39:
4-Methoxybenzoic acid-1-dimethylaminophenylmethyl) -naphthalene-2-yl ester
It was produced from 2-naphthol, benzylidene dimethyl ammonium chloride and 4-methoxybenzoyl chloride according to general synthesis rules 4 and 6. The structure was determined by ESI-MS: calculated mass 411.51 g/mol, found mass M+H = 412.0.
Example 40:
The following substances are to be classified in the same heading as the product:
The product was produced according to general synthesis rules 4 and 6 from 2-naphthal, benzylidene dimethyl ammonium chloride and 2-chlorobenzoyl chloride.
The structure was determined by ESI-MS: calculated mass 415.92 g/mol, found mass M+H = 416.0.
Example 41:
The following substances are to be classified in the same heading as the active substance: Stage one 4-benzylide morpholine 4-ium chloride
The implementation of 17.9 ml (0.200 mol) morpholine and 10.1 ml (0.100 mol) benzaldehyde according to the general synthesis rule 2 and the subsequent reaction with 6.0 ml (0.100 mol) acetyl chloride according to the general synthesis rule 3 yielded 10.1 g (48% of the theoretically calculated yield) of 4-benzylidene morpholine-4-ium chloride.
Stage two. 1- (morpholine-4-yl-phenyl-methyl) -naphthalene-2-ol, whether or not chemically defined
It was produced according to the general synthesis rule 4 from 4-benzylidene morpholine-4-ium chloride and 2-naphthal.
The structure was determined by ESI-MS: calculated mass 319,41 g/mol, found mass M+H = 320,1 g/mol.
Example 42:
The following substances are to be classified in the same heading as the active substance: Stage one The following substances are to be classified in the same heading as the product:
The conversion of 19.8 ml (0.200 mol) of piperidine and 10.1 ml (0.100 mol) of benzaldehyde according to the general synthesis rule 2 and the subsequent reaction with 6.0 ml (0.100 mol) of acetyl chloride according to the general synthesis rule 3 yielded 11.7 g (corresponding to 56% of the theoretically calculated yield) of 1-benzylidene piperidinium chloride.
Stage two. The following substances are to be classified in the same heading as the active substance:
It was produced according to the general synthesis rule 4 from 1-benzylidene piperidinium chloride and 2-naphthal.
The structure was determined by ESI-MS: calculated mass 317.43 g/mol, found mass M+H = 318.3 g/mol.
Example 43: The following substances are to be classified in the same heading as the active substance:
The product was produced according to the general synthesis rule 4 from 1-naphthal and (4-fluorobenzyl) pyrrolidinium chloride, which was produced from 4-fluorobenzaldehyde and pyrrolidine according to example 41.
The structure was determined by ESI-MS: calculated mass 321.4 g/mol, found mass M+H = 322.1 g/mol, M-pyrrolidine 251.3 g/mol.
Pharmacological tests: In vitro tests
The efficacy of the 1- and 2-naphthal-mannitic bases of the invention was tested as described above.
2) Analgesia test in the mouse writhing test
The in-depth analgesic study was performed in the mouse in phenylquinone-induced writhing, as described above.
The compounds of the invention tested showed analgesic effects.
The results of selected writhing studies are summarised in Table 1 below. Other Tabelle1:
Analgesieprüfung im Writhing-Test an der Maus
Beispiel Nr. Hemmung der Writhingreaktion in %
37 40
38 81
39 21
40 48
41 30
42 92

Claims (76)

  1. Substituted 1- and 2-naphthol Mannich bases of the general formula I wherein R1 = CH(R9)N(R10)(R11) and R2 = OR12 or R1 = OR12 and R2 = CH(R9)N(R10) (R11), and in each case the radicals R3 to R8 are identical or different and = H, F, Cl, Br, CF3, CN, NO2, SO2NH2, SO2NHR13, NHR13, SR15, OR16, CO(OR20), CH2CO (OR21), CO(R22), a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, R9 denotes an aryl radical, a heteroaryl radical or an alkyl radical without an acid proton in the α-position, R10, R11 are identical or different and denote a branched or unbranched, saturated or unsaturated, unsubstituted or at least monosubstituted C1-6-alkyl radical or an unsubstituted or at least monosubstituted phenyl, benzyl or phenethyl radical, or R10 and R11 together denote (CH2)2O(CH2)2 or (CH2)n, where n = an integer from 3 to 6 R12 = H, COR22, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, R13 = H, COR14, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, R14 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, R15 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, R16 = H, CO(R17), a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, R17 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, R18 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, R20 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, R21 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, R22 = H, NHNH2, NHR18, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, and/or their racemates, enantiomers, diastereomers and/or corresponding bases and/or corresponding salts of physiologically tolerated acids, excluding the racemates of the compounds in which the radical R1 = CH(R9)N(R10)(R11) and R2 = OR12 and in each case the radicals R3 to R8 and R12 = H, the radical R9 = phenyl, 2-chlorophenyl, 4-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 2-fluorophenyl, 2-bromophenyl, benzo-1,3-dioxole, 4-CH3OCO-phenyl or 2-methoxyphenyl and the radicals R10 and R11 together = (CH2)5 or the radicals R3 to R8 and R12 = H, the radical R9 = phenyl, 4-methoxyphenyl, 4-dimethylaminophenyl, 4-hydroxy-2,3-di-tert-butylphenyl, 2,3-dihydrobenzodioxane, 4-nitrophenyl or benzo-1,3-dioxole and the radicals R10 and R11 together = (CH2)2O(CH2)2 or the radicals R3 to R8 and R12 = H, the radical R9 = 4-methoxyphenyl and the radicals R10 and R11 together = (CH2)4 or the radical R3 = CO(OR20), the radicals R4 to R8 and R12 = H, the radical R9 = phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-nitrophenyl or p-benzaldehyde, the radicals R10 and R11 together = (CH2)5 and the radical R20 = CH3 or the radicals R3 to R8 and R12 = H, the radical R9 = phenyl and the two radicals R10 and R11 each = CH3, C2H5 or n-C3H7 or the radicals R3 to R8 each denote H, the radical R12 = CH3, the radical R9 = phenyl and the two radicals R10 and R11 each = CH3 or the radicals R3 to R8 and R12 = H, the radical R9 = 4-methoxyphenyl or benzo-1,3-dioxole and the radicals R10 and R11 each = CH3 or the radicals R3 to R5, R7, R8, R12 = H, the radical R6 = Br, the radical R9 = phenyl and the radicals R10 and R11 together = (CH2)5 or the radicals R3 to R5, R7, R8, R12 = H, the radical R6 = Br, the radical R9 = 4-hydroxy-3,5-di-tert-butylphenyl and the radicals R10 and R11 together = (CH2)2O(CH2)2 or the radicals R3 to R8 and R12 = H, the radical R9 = phenyl and the radicals R10 and R11 each = CH3 as the hydrochloride or the radicals R3 to R8 and R12 = H, the radical R9 = phenyl or 4-methoxyphenyl and the radicals R10 and R11 together = (CH2)5 as the hydrochloride or the radical R3 = CO(OR20), the radicals R4 to R8 and R12 = H, the radical R9 = phenyl, the radicals R10 and R11 together = (CH2)5 and the radical R20 = CH3 as the hydrochloride or the radicals R3 to R8 and R12 = H, the radical R9 = thiophene and the radicals R10 and R11 together = (CH2)2O(CH2)2 or the radicals R3 to R8 = H, the radical R12 = CH3, the radical R9 = thiophene, 4-methoxyphenyl or 3,4-dimethoxyphenyl and the radicals R10 and R11 together = (CH2)2O(CH2)2 and the enantiomers of the compound of the general formula I in which R1 = CH(R9)N(R10) (R11) and R2 = OR12 and the radicals R3 to R8, R12 = H, R9 = phenyl and R10 and R11 together = (CH2)5, (+)-1-(α-N,N-dimethylaminobenzyl)-2-naphthol and the corresponding tartrate, (-)-1-(α-N,N-dimethylaminobenzyl)-2-naphthol and the corresponding tartrate, and (-)-[(2-methoxynaphth-1-yl)benzyl]-dimethylamine and the racemates of the compounds in which the radicals R1 = OR12 and R2 = CH(R9)N(R10)(R11) and in each case the radicals R3 to R8 and R12 = H, the radical R9 = phenyl, 2-bromophenyl, 3-bromophenyl or 4-bromophenyl and the radicals R10 and R11 together = (CH2)5 or R3 to R8 and R12 = H, the radical R9 = phenyl or 2-nitrophenyl and the radicals R10 and R11 together = (CH2)2O(CH2)2 or R3, R4, R6, R8 and R12 = H, the radicals R5, R7 = CH3, the radical R9 = phenyl or 4-methoxyphenyl and the radicals R10 and R11 together = (CH2)5 or R3 to R6, R8, R12 = H, the radical R7 = CH3, the radical R9 = 4-methoxyphenyl or phenyl and the radicals R10, R11 together = (CH2)5 or R3 to R8 and R12 = H, the radical R9 = phenyl, the radical R10 = CH3 and the radical R11 = C6H11 or the radicals R10 and R11 each = CH3 or R3 to R6, R8, R12 = H, the radical R7 = CH3, the radical R9 = phenyl or 4-methoxyphenyl and the radicals R10 and R11 together = (CH2)2O(CH2)2 or R3, R4, R6, R8, R12 = H, the radicals R5 and R7 = CH3, the radical R9 = 4-methoxyphenyl and the radicals R10 and R11 together = (CH2)2O(CH2)2 or R3 to R8, R12 = H, the radical R9 = phenyl and the radicals R10 and R11 together = (CH2)2O(CH2)2 as the hydrochloride.
  2. Substituted 1- and 2-naphthol Mannich bases according to claim 1, characterized in that at least one of the radicals R3, R4, R5, R6, R7 or R8 represents H and the other radicals R3, R4, R5, R6 R7 or R8, R9 to R18 and R20 to R22 have the meaning according to claim 1.
  3. Substituted 1- and 2-naphthol Mannich bases according to claim 1, characterized in that at least one of the radicals R3, R4, R5, R6, R7 or R8 represents a C1-6-alkyl radical and the other radicals R3, R4, R5, R6, R7 or R8, R9 to R18 and R20 to R22 have the meaning according to claim 1.
  4. Substituted 1- and 2-naphthol Mannich bases according to claim 1, characterized in that at least one of the radicals R3, R4, R5, R6, R7 or R8 represents an aryl radical bonded via a C1-2-alkylene group and the other radicals R3, R4, R5, R6, R7 or R8, R9 to R18 and R20 to R22 have the meaning according to claim 1.
  5. Substituted 1- and 2-naphthol Mannich bases according to claim 1, characterized in that at least one of the radicals R3, R4, R5, R6, R7 or R8 represents F, Cl or Br and the other radicals R3, R4, R5, R6, R7 or R8, R9 to R18 and R20 to R22 have the meaning according to claim 1.
  6. Substituted 1- and 2-naphthol Mannich bases according to claim 1, characterized in that at least one of the radicals R3, R4, R5, R6, R7 or R8 represents SO2NH2 and the other radicals R3, R4, R5, R6, R7 or R8, R9 to R18 and R20 to R22 have the meaning according to claim 1.
  7. Substituted 1- and 2-naphthol Mannich bases according to claim 1, characterized in that at least one of the radicals R3, R4, R5, R6, R7 or R8 represents NHR13 and the other radicals R3, R4, R5, R6, R7 or R8, R9 to R18 and R20 to R22 have the meaning according to claim 1.
  8. Substituted 1- and 2-naphthol Mannich bases according to claim 1, characterized in that at least one of the radicals R3, R4, R5, R6, R7 or R8 represents CO(R22) and the other radicals R3, R4, R5, R6, R7 or R8, R9 to R18 and R20 to R22 have the meaning according to claim 1.
  9. Substituted 1- and 2-naphthol Mannich bases according to claim 1, characterized in that at least one of the radicals R3, R4, R5, R6, R7 or R8 represents OR16 and the other radicals R3, R9, R5, R6, R7 or R8, R9 to R18 and R20 to R22 have the meaning according to claim 1.
  10. Substituted 1- and 2-naphthol Mannich bases according to claim 1, characterized in that at least one of the radicals R3, R4, R5, R6, R7 or R8 represents CO(OR20) and the other radicals R3, R4, R5, R6, R7 or R8, R9 to R18 and R20 to R22 have the meaning according to claim 1.
  11. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 10, characterized in that the radical R9 denotes an unsubstituted phenyl radical or a phenyl radical which is at least monosubstituted by C1-4-alkyl, C1-3-alkoxy, halogen, CF3, CN, O-phenyl or OH, 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, particularly preferably an unsubstituted phenyl radical, and the radicals R10 to R18 and R20 to R22 have the meaning according to claim 1.
  12. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 11, characterized in that at least one of the radicals R10 or R11 represents a saturated, unsubstituted or at least monosubstituted C1-6-alkyl radical, preferably a CH3 radical, and the other particular radical R10 or R11 and the radicals R12 to R18 and R20 to R22 have the meaning according to claim 1.
  13. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 11, characterized in that the radicals R10 and R11 together denote (CH2)n, where n = 4 or 5, and the radicals R12 to R18 and R20 to R22 have the meaning according to claim 1.
  14. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 13, characterized in that the radical R12 represents H and the radicals R13 to R18 and R20 to R22 have the meaning according to claim 1.
  15. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 13, characterized in that the radical R12 represents a C1-6-alkyl radical and the radicals R13 to R18 and R20 to R22 have the meaning according to claim 1.
  16. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 13, characterized in that the radical R12 represents an aryl radical bonded via a C1-2-alkylene group and the radicals R13 to R18 and R20 to R22 have the meaning according to claim 1.
  17. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 16, characterized in that the radical R13 represents H and the radicals R14 to R18 and R20 to R22 have the meaning according to claim 1.
  18. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 16, characterized in that the radical R13 represents a C1-6-alkyl radical and the radicals R14 to R18 and R20 to R22 have the meaning according to claim 1.
  19. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 16, characterized in that the radical R13 represents an aryl radical bonded via a C1-2-alkylene group and the radicals R14 to R18 and R20 to R22 have the meaning according to claim 1.
  20. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 19, characterized in that the radical R14 represents a C1-6-alkyl radical and the radicals R15 to R18 and R20 to R22 have the meaning according to claim 1.
  21. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 19, characterized in that the radical R14 represents an aryl radical bonded via a C1-2-alkylene group and the radicals R15 to R18 and R20 to R22 have the meaning according to claim 1.
  22. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 21, characterized in that the radical R15 represents a C1-6-alkyl radical and the radicals R16 to R18 and R20 to R22 have the meaning according to claim 1.
  23. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 21, characterized in that the radical R15 represents an aryl radical bonded via a C1-2-alkylene group and the radicals R16 to R18 and R20 to R22 have the meaning according to claim 1.
  24. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 23, characterized in that the radical R16 represents a C1-6-alkyl radical and the radicals R17, R18 and R20 to R22 have the meaning according to claim 1.
  25. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 23, characterized in that the radical R16 represents an aryl radical bonded via a C1-2-alkylene group and the radicals R17, R18 and R20 to R22 have the meaning according to claim 1.
  26. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 23, characterized in that the radical R16 represents H and the radicals R17, R18 and R20 to R22 have the meaning according to claim 1.
  27. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 23, characterized in that the radical R16 represents CO(R17) and the radicals R17, R18 and R20 to R22 have the meaning according to claim 1.
  28. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 27, characterized in that the radical R17 represents a C1-6-alkyl radical and the radicals R18 and R20 to R22 have the meaning according to claim 1.
  29. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 27, characterized in that the radical R17 represents an aryl radical bonded via a C1-2-alkylene group and the radicals R18 and R20 to R22 have the meaning according to claim 1.
  30. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 27, characterized in that the radical R17 represents a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy and the radicals R18 and R20 to R22 have the meaning according to claim 1.
  31. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 30, characterized in that the radical R18 represents a C1-6-alkyl radical and the radicals R20 to R22 have the meaning according to claim 1.
  32. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 30, characterized in that the radical R18 represents an aryl radical bonded via a C1-2-alkylene group and the radicals R20 to R22 have the meaning according to claim 1.
  33. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 30, characterized in that the radical R18 represents a phenyl or naphthyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, preferably a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, and the radicals R20 to R22 have the meaning according to claim 1.
  34. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 33, characterized in that the radical R20 represents a C1-6-alkyl radical and the radicals R21 and R22 have the meaning according to claim 1.
  35. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 33, characterized in that the radical R20 represents an aryl radical bonded via a C1-2-alkylene group and the radicals R21 and R22 have the meaning according to claim 1.
  36. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 33, characterized in that the radical R20 represents H and the radicals R21 and R22 have the meaning according to claim 1.
  37. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 33, characterized in that the radical R20 represents a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy and the radicals R21 and R22 have the meaning according to claim 1.
  38. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 37, characterized in that the radical R21 represents H and the radical R22 has the meaning according to claim 1.
  39. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 37, characterized in that the radical R21 represents a C1-6-alkyl radical and the radical R22 has the meaning according to claim 1.
  40. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 37, characterized in that the radical R21 represents an aryl radical bonded via a C1-2-alkylene group and the radical R22 has the meaning according to claim 1.
  41. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 40, characterized in that the radical R22 represents H.
  42. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 40, characterized in that the radical R22 represents a C1-6-alkyl radical.
  43. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 40, characterized in that the radical R22 represents an aryl radical bonded via a C1-2-alkylene group.
  44. Substituted 1- and 2-naphthol Mannich bases according to one of claims 1 to 40, characterized in that the radical R22 represents NHNH2, NHR18 or a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, preferably NHNH2 or NHR18.
  45. Substituted 1- and 2-naphthol Mannich bases according to claim 1:
    6-(dimethylaminophenylmethyl)-5-hydroxy-naphthalene-1-sulfonic acid amide
    4-amino-2-(dimethylaminophenylmethyl)-naphthalen-1-ol
    4-(dimethylaminophenylmethyl)-3-hydroxy-naphthalene-2-carboxylic acid hydrazide
    4-(dimethylaminophenylmethyl)-3-hydroxy-naphthalene-2-carboxylic acid methyl ester
    4-(dimethylamino-phenyl-methyl)-3-hydroxy-naphthalene-2-carboxylic acid
    4-(dimethylaminophenylmethyl)-3-hydroxy-naphthalene-2-carboxylic acid phenyl ester
    [5-(dimethylaminophenylmethyl)-6-hydroxynaphthalen-2-yl]-phenylmethanone
    3-amino-1-(dimethylaminophenylmethyl)-naphthalen-2-ol
    4-(dimethylaminophenylmethyl)-3-hydroxynaphthalene-2-carboxylic acid (2-methoxy-phenyl)-amide
    4-(dimethylaminophenylmethyl)-3-hydroxy-naphthalene-2-carboxylic acid o-tolylamide
    4-(dimethylaminophenylmethyl)-3-hydroxynaphthalene-2-carboxylic acid naphthalen-1-ylamide
    4-(dimethylaminophenylmethyl)-3-hydroxy-7-methoxynaphthalene-2-carboxylic acid
    5-(dimethylaminophenylmethyl)-6-hydroxynaphthalene-2-carboxylic acid
    1-(dimethylaminophenylmethyl)-7-methoxynaphthalen-2-ol
    1-(dimethylaminophenylmethyl)-6-methoxynaphthalen-2-ol
    5-(dimethylaminophenylmethyl)-6-hydroxynaphthalene-1-carboxylic acid
    4-(dimethylaminophenylmethyl)-3-hydroxy-7-methoxynaphthalene-2-carboxylate sodium salt
    4-chloro-2-(morpholin-4-yl-o-tolylmethyl)-naphthalen-1-ol
    4-chloro-2-(piperidin-1-yl-o-tolylmethyl)-naphthalen-1-ol
    4-chloro-2-[(2-chlorophenyl)-piperidin-1-yl-methyl]-naphthalen-1-ol
    4-chloro-2-[(2,3-dimethoxyphenyl)-morpholin-4-yl-methyl]-naphthalen-1-ol
    5-amino-2-[(2-chlorophenyl)-piperidin-1-yl-methyl]-naphthalen-1-ol
    5-amino-2-[(2,3-dimethoxyphenyl)-morpholin-4-yl-methyl]-naphthalen-1-ol
    3-hydroxy-4-(piperidin-1-yl-o-tolylmethyl)-naphthalene-2-carboxylic acid hydrazide
    7-methoxy-1-(morpholin-4-yl-o-tolylmethyl)-naphthalen-2-ol
    1-[(2-chlorophenyl)-piperidin-1-yl-methyl]-7-methoxynaphthalen-2-ol
    1-[(2,3-dimethoxyphenyl)-morpholin-4-yl-methyl]-7-methoxynaphthalen-2-ol
    6-bromo-1-[(2-methoxyphenyl)-morpholin-4-yl-methyl]-naphthalen-2-ol
    6-hydroxy-5-[(2-methoxyphenyl)-morpholin-4-yl-methyl]-naphthalene-1-carboxylic acid
    7-methoxy-1-[(2-methoxyphenyl)-morpholin-4-yl-mehtyl]-naphthalen-2-ol
    6-methoxy-1-[(2-methoxyphenyl)-morpholin-4-yl-methyl]-naphthalen-2-ol
    4-chloro-2-[(2-methoxyphenyl)-piperidin-1-yl-methyl]-naphthalen-1-ol
    6-bromo-1-[(2-methoxyphenyl)-piperidin-1-yl-methyl]-naphthalen-1-ol
    6-methoxy-1-[(2-methoxyphenyl)-piperidin-1-yl-methyl]-naphthalen-2-ol
    7-methoxy-1-[(2-methoxyphenyl)-piperidin-1-yl-methyl]-naphthalen-2-ol
    5-chloro-2-[dimethylamino-(2-methoxyphenyl)-methyl]-naphthalen-1-ol
    {[1-(4-methoxybenzyloxy)-naphthalen-2-yl]-phenylmethyl}-dimethylamine
    {[2-(4-methoxybenzyloxy)-naphthalen-1-yl]-phenylmethyl}-dimethylamine
    4-methoxybenzoic acid 1-(dimethylaminophenylmethyl)-naphthalen-2-yl ester
    2-chlorobenzoic acid 1-(dimethylaminophenylmethyl)-naphthalen-2-yl ester
    1-(morpholin-4-yl-phenylmethyl)-naphthalen-2-ol
    1-(phenylpiperidin-1-yl-methyl)-naphthalen-2-ol
    2-[(4-fluoro-phenyl)-pyrrolidin-1-yl-methyl]-naphthalen-1-ol.
  46. Process for the preparation of substituted 1- and 2-naphthol Mannich bases of the general formula I according to one of claims 1 to 45, in which the radical R12 represents H and the radicals R1 to R11, R13 to R18 and R20 to R22 have the meaning according to the general formula I, characterized in that aromatic aldehyde compounds and/or heteroaromatic aldehyde compounds and/or aliphatic aldehyde compounds of the general formula II in which R9 has the meaning according to the general formula I, are reacted in solution in the presence of a base, preferably at a temperature of -10°C to +110°C, with secondary amines of the general formula III in which R10 and R11 have the meaning according to the general formula I, to give aminal compounds of the general formula IV and these aminal compounds of the general formula IV are reacted, without further purification, with an acid chloride in an absolute solvent to give iminium salts of the general formula V and these iminium salts of the general formula V are reacted, without further purification and in solution, preferably in acetonitrile, with substituted and/or unsubstituted 1- and 2-naphthol compounds of the general formula VI wherein R1 = H and R2 = OH or R1 = OH and R2 = H and in each case the radicals R3 to R8, R13 to R18 and R20 to R22 have the meaning according to the general formula I, and the 1- and 2-naphthol Mannich bases of the general formula I obtained in this way in which the radical R12 represents H and the radicals R1 to R11, R13 to R18 and R20 to R22 have the meaning according to the general formula I are purified by extraction and are isolated by conventional methods.
  47. Process for the preparation of substituted 1- and 2-naphthol Mannich bases of the general formula I according to one of claims 1 to 45 in which the radical R12 = COR22, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group and the radicals R1 to R11, R23 to R18 and R20 to R22 have the meaning according to the general formula I, characterized in that aromatic aldehyde compounds and/or heteroaromatic aldehyde compounds and/or aliphatic aldehyde compounds of the general formula II in which R9 has the meaning according to the general formula I, are reacted in solution in the presence of a base, preferably at a temperature of 10 to +110°C, with secondary amines of the general formula III in which R10 and R11 have the meaning according to the general formula I, to give aminal compounds of the general formula IV and these aminal compounds of the general formula IV are reacted, without further purification, with an acid chloride in an absolute solvent to give iminium salts of the general formula V and these iminium salts of the general formula V are reacted, without further purification and in solution, preferably in acetonitrile, with substituted and/or unsubstituted 1- and 2-naphthol compounds of the general formula VI wherein R1 = H and R2 = OH or R1 = OH and R2 = H and in each case the other radicals R3 to R8, R13 to R18 and R20 to R22 in each case have the meaning according to the general formula I, and the compounds of the general formula VI obtained in this way, wherein R1 = CH(R9)N(R10) (R11) and R2 = OH or R1 = OH and R2 = CH(R9)N(R10) (R11) and the radicals R3 to R11, R13 to R18 and R20 to R22 have the meaning according to the general formula I, are reacted in solution with compounds of the general formula XR12', wherein X= Cl, Br or I and R12' COR22, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, in the presence of a base at a temperature of preferably 10 to 150°C and the 1- and 2-naphthol Mannich bases of the general formula I obtained in this way, in which the radical R12 represents COR22, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group and the radicals R1 to R11, R13 to R18 and R20 to R22 have the meaning according to the general formula I, are purified by filtration and are isolated by conventional methods.
  48. Process according to claim 47, characterized in that the reaction with the compounds of the general formula XR12' is carried out in dimethylformamide.
  49. Process according to claim 47 or 48, characterized in that X = Cl.
  50. Process according to one of claims 47 to 49, characterized in that the reaction with the compounds of the general formula XR12' is carried out in the presence of triethylamine or potassium tert-butylate as the base.
  51. Process according to one of claims 47 to 50, characterized in that the compounds of the general formula I in which R12 ≠ H, are purified by filtration over a scavenger resin, preferably by filtration over polymer-bonded tris(2-aminoethyl)amine and/or 3-(3-mercaptophenyl)propane-amidomethylpolystyrene.
  52. Process according to one of claims 46 to 51, characterized in that the aromatic aldehyde compounds and/or heteroaromatic aldehyde compounds and/or aliphatic aldehyde compounds of the general formula II are reacted in an organic solvent, preferably in toluene, with secondary amines of the general formula III.
  53. Process according to one of claims 46 to 52, characterized in that the aromatic aldehyde compounds and/or heteroaromatic aldehyde compounds and/or aliphatic aldehyde compounds of the general formula II are reacted in the presence of potassium carbonate or boric acid anhydride as the base.
  54. Process according to one of claims 46 to 53, characterized in that the aminal compounds of the general formula IV are reacted with acetyl chloride to give iminium salts of the general formula V.
  55. Process according to one of claims 46 to 54, characterized in that the aminal compounds of the general formula IV are reacted in absolute diethyl ether to give iminium salts of the general formula V.
  56. Medicaments comprising, as the active compound, at least one substituted 1- and/or 2-naphthol Mannich base of the general formula I wherein R1 = CH(R9)N(R10)(R11) and R2 = OR12 or R1 = OR12 and R2 = CH(R9)N(R10)(R11), and in each case the radicals R3 to R8 are identical or different and = H, F, Cl, Br, CF3, CN, NO2, SO2NH2, SO2NHR13, NHR13, SR15, OR16, CO(OR20), CH2CO(OR21), CO(R22), a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably = H, F, Cl, Br, SO2NH2, NHR13, CO(R22), OR16, CO(OR20), a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group, particularly preferably H, NHR13, CO(R22), OR16 or CO(OR20), R9 denotes an aryl radical, a heteroaryl radical or an alkyl radical without an acid proton in the α-position, preferably an unsubstituted phenyl radical or a phenyl radical which is at least monosubstituted by C1-4-alkyl, C1-3-alkoxy, halogen, CF3, 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-dichlorophenyl, 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, R10, R11 are identical or different and denote a branched or unbranched, saturated or unsaturated, unsubstituted or at least monosubstituted C1-6-alkyl radical or an unsubstituted or at least monosubstituted phenyl, benzyl or phenethyl radical, preferably a saturated, unsubstituted or at least monosubstituted C1-6-alkyl radical, particularly preferably a CH3 radical, or R10 and R11 together denote (CH2)n, where n = an integer from 3 to 6, or (CH2)2O(CH2)2, preferably (CH2)n, where n = 4 or 5, R12 = H, COR22, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably = H, a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group, R13 = H, COR14, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably = H, a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group, particularly preferably = H, R14 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group, R15 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group, R16 = H, CO(R17), a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably H, a C1-6-alkyl radical, an aryl radical bonded via a C1-2-alkylene group or CO(R17), particularly preferably H or CO(R17), R17 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably a C1-6-alkyl radical, an aryl radical bonded via a C1-2-alkylene group or a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, particularly preferably a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, R18 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably a C1-6-alkyl radical, an aryl radical bonded via a C1-2-alkylene group or a phenyl or naphthyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, particularly preferably a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, R20 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably H, a C1-6-alkyl radical, an aryl radical bonded via a C1-2-alkylene group or a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, particularly preferably H or a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, R21 = H, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably = H, a C1-6-alkyl radical or an aryl radical bonded via a C1-2-alkylene group, R22 = H, NHNH2, NHR18, a C1-10-alkyl, an aryl or a heteroaryl radical or an aryl or heteroaryl radical bonded via a C1-6-alkylene group, preferably H, a C1-6-alkyl radical, an aryl radical bonded via a C1-2-alkylene group, NHNH2, NHR18 or a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, particularly preferably NHNH2, NHR18 or a phenyl radical which is optionally substituted by F, Cl, Br, C1-4-alkyl or C1-3-alkoxy, very particularly preferably NHNH2 or NHR18, and/or their racemates, enantiomers, diastereomers and/or corresponding bases and/or corresponding salts of physiologically tolerated acids and optionally further active compounds and/or auxiliary substances.
  57. Medicament according to claim 56, characterized in that it comprises as the active compound a mixture of enantiomers of at least one substituted 1-naphthol Mannich base and/or 2-naphthol Mannich base of the general formula I, the mixture containing the enantiomers in non-equimolar amounts.
  58. Medicament according to claim 57, characterized in that the relative proportion of one of the enantiomers of the mixture is 5 to 45 mol%, preferably 10 to 40 mol%, based on the mixture of enantiomers.
  59. Medicament according to one of claims 56 to 58 for treatment of/combating pain and/or inflammatory reactions and/or allergic reactions and/or drug abuse and/or alcohol abuse and/or diarrhoea and/or gastritis and/or ulcers and/or cardiovascular diseases and/or urinary incontinence and/or depression and/or states of shock and/or migraines and/or narcolepsy and/or excess weight and/or asthma and/or glaucoma and/or hyperkinetic syndrome.
  60. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for combating pain.
  61. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of inflammatory reactions.
  62. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of allergic reactions.
  63. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of drug and/or alcohol abuse.
  64. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of diarrhoea.
  65. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of gastritis.
  66. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of ulcers.
  67. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of cardiovascular diseases.
  68. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of urinary incontinence.
  69. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of depression.
  70. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of states of shock.
  71. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of migraines.
  72. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of narcolepsy.
  73. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of excess weight.
  74. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of asthma.
  75. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment of glaucoma.
  76. Use of at least one compound of the general formula I according to claims 1 to 45 for the preparation of a medicament for treatment in cases of hyperkinetic syndrome.
HK03102524.8A 1999-12-27 2000-12-20 Substituted 1 and 2 naphthol mannich bases HK1051845B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19963179 1999-12-27
DE19963179A DE19963179B4 (en) 1999-12-27 1999-12-27 Substituted 1- and 2-naphthol Mannich bases
PCT/EP2000/012972 WO2001047866A1 (en) 1999-12-27 2000-12-20 Substituted 1 and 2 naphthol mannich bases

Publications (2)

Publication Number Publication Date
HK1051845A1 HK1051845A1 (en) 2003-08-22
HK1051845B true HK1051845B (en) 2006-01-13

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