CA2383114C - Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceutical compositions - Google Patents
Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceutical compositions Download PDFInfo
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- C07D307/06—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
Abstract
The invention relates to substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3- benzazocines of the general formula (1), wherein the groups R1, R2, R3, R3', R4, R5, R6, X and A are defined as per the description and claims, to a method for their production and to the use thereof as medicaments.
Description
Case 1/1116-Ausland BOEHRINGER INGELHEIM PHARMA KG
Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceutical compositions The present invention relates to substituted 1,2,3,4,5,6-hexahydro-2,6-methano-benzazocines of general formula 1 R
9 ~ 1 2 wherein 1o Rl and R2 which may be identical or different denote hydrogen, Cl -C6-alkyl, CII-C6-alkyloxy, OH, F, Cl or Br;
R3 and R3' which may be identical or different denote hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which may optionally be substituted by a group selected from among F, Cl, Br, methyl, ethyl, OH, CF3 and methoxy;
R4, R5 and R6 which may be identical or different may denote hydrogen, methyl or ethyl, X may denote NH2, NH-(CI-C6-alkyl), N(Cj-C6-alkyl)2, the two CII-C6-alkyl groups of which may be identical or different, NH-COH, NH-CO(Cl-C6-alkyl) or F;
A may denote -(CH2)3-, -CH2-CH2-O-, -CH2-O-CH2-, -(CH2)4-, -CH(Cj-C6-alkyl)-O-CH2-, -(CH2)2-O-CH2-, -(CH2)3-0-, -(CH2)5-, -CH2-O-(CH2)3-, -(CH2)2-0-(CH2)2-, -(CH2)3-O-CH2-, -(CH2)4-0-, -CH2-O-CH2-CH2-O-, H/\
-C'0 H or iH' OIH~ iHI OIHI
=
Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceutical compositions The present invention relates to substituted 1,2,3,4,5,6-hexahydro-2,6-methano-benzazocines of general formula 1 R
9 ~ 1 2 wherein 1o Rl and R2 which may be identical or different denote hydrogen, Cl -C6-alkyl, CII-C6-alkyloxy, OH, F, Cl or Br;
R3 and R3' which may be identical or different denote hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which may optionally be substituted by a group selected from among F, Cl, Br, methyl, ethyl, OH, CF3 and methoxy;
R4, R5 and R6 which may be identical or different may denote hydrogen, methyl or ethyl, X may denote NH2, NH-(CI-C6-alkyl), N(Cj-C6-alkyl)2, the two CII-C6-alkyl groups of which may be identical or different, NH-COH, NH-CO(Cl-C6-alkyl) or F;
A may denote -(CH2)3-, -CH2-CH2-O-, -CH2-O-CH2-, -(CH2)4-, -CH(Cj-C6-alkyl)-O-CH2-, -(CH2)2-O-CH2-, -(CH2)3-0-, -(CH2)5-, -CH2-O-(CH2)3-, -(CH2)2-0-(CH2)2-, -(CH2)3-O-CH2-, -(CH2)4-0-, -CH2-O-CH2-CH2-O-, H/\
-C'0 H or iH' OIH~ iHI OIHI
=
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Preferred compounds are those of general formula 1 wherein Rl and R2 which may be identical or different denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, OH, F, Cl or Br;
R3 and RT which may be identical or different denote hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which is substituted by a group selected from among F, Cl, Br and preferably methyl;
R4, R5 and R6 which may be identical or different may denote hydrogen or methyl;
X may denote NH2, NH-(methyl), N(methyl)2, NH-(ethyl), N(ethyl)2, NH-COH, NH-COMe or F;
A may denote -CH2-CH2-O-, -CH2-O-CH2-, -CH(methyl)-O-CH2-, -CH(ethyl)-O-CH2-, -CH(isopropyl)-O-CH2-, -(CH2)2-O-CH2-, -(CH2)3-0-, -CH2-O-(CH2)3-, -(CH2)2-0-(CH2)2-, -(CH2)3-O-CH2-, -(CH2)4-0-, -CH2-O-CH2-CH2-O-, H,\ ~ n -C\O~H_ /H\O'H\ or /H\OIH\
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are compounds of general formula 1 wherein Rl and R2 which may be identical or different may denote hydrogen or F;
R3 and R3' which may be identical or different may denote hydrogen, F, Cl, Br, or methyl;
R4, R5 and R6 which may be identical or different may denote hydrogen or methyl;
X may denote NH2, NH-(methyl), N(methyl)2, NH-COH, NH-COMe or F;
Preferred compounds are those of general formula 1 wherein Rl and R2 which may be identical or different denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, OH, F, Cl or Br;
R3 and RT which may be identical or different denote hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which is substituted by a group selected from among F, Cl, Br and preferably methyl;
R4, R5 and R6 which may be identical or different may denote hydrogen or methyl;
X may denote NH2, NH-(methyl), N(methyl)2, NH-(ethyl), N(ethyl)2, NH-COH, NH-COMe or F;
A may denote -CH2-CH2-O-, -CH2-O-CH2-, -CH(methyl)-O-CH2-, -CH(ethyl)-O-CH2-, -CH(isopropyl)-O-CH2-, -(CH2)2-O-CH2-, -(CH2)3-0-, -CH2-O-(CH2)3-, -(CH2)2-0-(CH2)2-, -(CH2)3-O-CH2-, -(CH2)4-0-, -CH2-O-CH2-CH2-O-, H,\ ~ n -C\O~H_ /H\O'H\ or /H\OIH\
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are compounds of general formula 1 wherein Rl and R2 which may be identical or different may denote hydrogen or F;
R3 and R3' which may be identical or different may denote hydrogen, F, Cl, Br, or methyl;
R4, R5 and R6 which may be identical or different may denote hydrogen or methyl;
X may denote NH2, NH-(methyl), N(methyl)2, NH-COH, NH-COMe or F;
A may denote -CH(methyl)-O-CH2-, -CH2-O-CH2- or H
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Of particular importance according to the invention are compounds of general formula 1, wherein io Rl and R2 which may be identical or different may denote hydrogen or F;
R3 and RT which may be identical or different may denote hydrogen, F, CI, Br, or methyl;
R4, R5 and R6 which may be identical or different may denote hydrogen or methyl;
X may denote NH2, NH-(methyl) or NH-COH;
A may denote -CH(Methyl)-O-CH2-, -CH2-O-CH2- or ~I
"IIH,O'H--' optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Of comparable importance according to the invention are compounds of general formula 1 wherein Rl and R2 which may be identical or different may denote hydrogen or F;
R3 and RT may denote hydrogen;
R4, R5 and R6 which may be identical or different may denote hydrogen or methyl;
X may denote F;
A may denote -CH(methyl)-O-CH2-, optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
In the abovementioned compounds of general formula 1, Rl, if it is other than hydrogen, is preferably in the ortho or para position, most preferably in the ortho position in relation to the bridge A. In the abovementioned compounds of general formula 1, R2, if it is other than hydrogen, is preferably in the ortho position in relation to the bridge A.
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Of particular importance according to the invention are compounds of general formula 1, wherein io Rl and R2 which may be identical or different may denote hydrogen or F;
R3 and RT which may be identical or different may denote hydrogen, F, CI, Br, or methyl;
R4, R5 and R6 which may be identical or different may denote hydrogen or methyl;
X may denote NH2, NH-(methyl) or NH-COH;
A may denote -CH(Methyl)-O-CH2-, -CH2-O-CH2- or ~I
"IIH,O'H--' optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Of comparable importance according to the invention are compounds of general formula 1 wherein Rl and R2 which may be identical or different may denote hydrogen or F;
R3 and RT may denote hydrogen;
R4, R5 and R6 which may be identical or different may denote hydrogen or methyl;
X may denote F;
A may denote -CH(methyl)-O-CH2-, optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
In the abovementioned compounds of general formula 1, Rl, if it is other than hydrogen, is preferably in the ortho or para position, most preferably in the ortho position in relation to the bridge A. In the abovementioned compounds of general formula 1, R2, if it is other than hydrogen, is preferably in the ortho position in relation to the bridge A.
In the abovementioned compounds of general formula 1, R3, if it is other than hydrogen, is preferably in the 7-position, i.e. in the para position relative to the group X. In the abovementioned compounds of general formula 1, R3', if it is other than hydrogen, is preferably in the 9-position, i.e. in the ortho position relative to the group X.
Particularly preferred according to the invention are compounds of formula 1 wherein R3' denotes hydrogen.
1o Of particular interest are compounds of general formula 1 selected from the group comprising:
- (2R,6S,2S')-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2S')-10-amino-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,11 R,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 11 S, 2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine-d ihydrochloride;
- (2R,6S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S,5"S)-10-amino-3-[5"-phenyl-tetrahydrofuran-2"-yl)methyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S)-10-acetamino-3-[2(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride;
- (2R,6S,2"S)-10-acetamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride;
- (2R,6S,2"S)-10-formylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride;
- (2R,6S,2"S)-10-methylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S)-10-dimethylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S)-10-ethylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S)-10-amino-7-methyl-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
.
- (2R,6S,2"S)-10-amino-7-methyl-3-[2-(2,6-difluorophenyl-methoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-chloro-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-5 6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-chloro-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-bromo-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-bromo-3-[2(2,6-difiuorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S)-10-amino-7-fluoro-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-d ihyd rochloride;
- (2R,6S,2"S,5"S)-10-amino-7-methyl-3-[5"-phenyl-tetrahydrofuran-2"-yl)methyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-trifluoromethyl-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-(4-methylphenyl)-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihydrochloride;
C1-C6-alkyl denotes a branched or unbranched hydrocarbon group having 1 to 6 carbon atoms which may optionally also contain ring systems. The alkyl substituents may be identical or different and may optionally be substituted with one or more halogen atoms, preferably fluorine. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl. In some cases, common abbreviations are also used for the abovementioned alkyl groups, such as for example Me for methyl, Et for ethyl, prop for propyl etc.
C1-C6-alkyloxy denotes a branched or unbranched hydrocarbon group having 1 to carbon atoms which is linked via an oxygen atom. The alkyloxy substituents may be identical or different. Examples include methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, cyclopropylmethyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. If desired, the term alkoxy is used for the abovementioned alkyloxy groups. Thus, methoxy may be used instead of methyloxy, ethoxy instead of ethyloxy, propoxy instead of propyloxy, etc. In some cases, the abovementioned alkyloxy groups may be replaced by common abbreviations such as, for example, MeO for methyloxy, EtO for ethyloxy, PropO for propyloxy, etc.
According to the invention, the double-bonded groups representing group A may be linked to the adjacent groups in both possible orientations.
If desired, the compounds of general formula (1) may be converted into the salts thereof, particularly, for pharmaceutical use, into the pharmacologically acceptable io acid addition salts thereof with an inorganic or organic acid. Suitable acids for this purpose include, for example, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid or citric acid. Mixtures of the abovementioned acids may also be used.
The compounds according to the invention are blockers of the voltage-dependent sodium channel. They are compounds which competitively or non-competitively displace batrachotoxin (BTX) with a high affinity (Ki < 1000 nM) from the binding site on the sodium channel. Such substances exhibit "use-dependency" in blocking the sodium channels, i.e. in order for the substances to bind to the sodium channel the sodium channels first have to be activated. The maximum blockade of the sodium channels is only achieved after repeated stimulation of the sodium channels.
Consequently, the substances preferentially bind to sodium channels which are activated repeatedly.
As a result, the substances are capable of acting preferentially in those parts of the body which are pathologically overstimulated. This includes diseases such as arrhythmias, spasms, cardiac and cerebral ischaemia, pain and neurodegenerative diseases of various origins. The following may be mentioned, for example:
epilepsy, 3o hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.
Another aspect of the invention therefore relates to the use of compounds of general formula 1 as pharmaceutical compositions, particularly as pharmaceutical compositions in which the blockade of the voltage-dependent sodium channel may have a therapeutic value.
Particularly preferred according to the invention are compounds of formula 1 wherein R3' denotes hydrogen.
1o Of particular interest are compounds of general formula 1 selected from the group comprising:
- (2R,6S,2S')-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2S')-10-amino-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,11 R,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 11 S, 2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine-d ihydrochloride;
- (2R,6S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S,5"S)-10-amino-3-[5"-phenyl-tetrahydrofuran-2"-yl)methyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S)-10-acetamino-3-[2(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride;
- (2R,6S,2"S)-10-acetamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride;
- (2R,6S,2"S)-10-formylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride;
- (2R,6S,2"S)-10-methylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S)-10-dimethylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S)-10-ethylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S)-10-amino-7-methyl-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
.
- (2R,6S,2"S)-10-amino-7-methyl-3-[2-(2,6-difluorophenyl-methoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-chloro-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-5 6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-chloro-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-bromo-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-bromo-3-[2(2,6-difiuorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S,2"S)-10-amino-7-fluoro-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-d ihyd rochloride;
- (2R,6S,2"S,5"S)-10-amino-7-methyl-3-[5"-phenyl-tetrahydrofuran-2"-yl)methyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-trifluoromethyl-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihydrochloride;
- (2R,6S, 2"S)-10-amino-7-(4-methylphenyl)-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihydrochloride;
C1-C6-alkyl denotes a branched or unbranched hydrocarbon group having 1 to 6 carbon atoms which may optionally also contain ring systems. The alkyl substituents may be identical or different and may optionally be substituted with one or more halogen atoms, preferably fluorine. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl. In some cases, common abbreviations are also used for the abovementioned alkyl groups, such as for example Me for methyl, Et for ethyl, prop for propyl etc.
C1-C6-alkyloxy denotes a branched or unbranched hydrocarbon group having 1 to carbon atoms which is linked via an oxygen atom. The alkyloxy substituents may be identical or different. Examples include methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, cyclopropylmethyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. If desired, the term alkoxy is used for the abovementioned alkyloxy groups. Thus, methoxy may be used instead of methyloxy, ethoxy instead of ethyloxy, propoxy instead of propyloxy, etc. In some cases, the abovementioned alkyloxy groups may be replaced by common abbreviations such as, for example, MeO for methyloxy, EtO for ethyloxy, PropO for propyloxy, etc.
According to the invention, the double-bonded groups representing group A may be linked to the adjacent groups in both possible orientations.
If desired, the compounds of general formula (1) may be converted into the salts thereof, particularly, for pharmaceutical use, into the pharmacologically acceptable io acid addition salts thereof with an inorganic or organic acid. Suitable acids for this purpose include, for example, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid or citric acid. Mixtures of the abovementioned acids may also be used.
The compounds according to the invention are blockers of the voltage-dependent sodium channel. They are compounds which competitively or non-competitively displace batrachotoxin (BTX) with a high affinity (Ki < 1000 nM) from the binding site on the sodium channel. Such substances exhibit "use-dependency" in blocking the sodium channels, i.e. in order for the substances to bind to the sodium channel the sodium channels first have to be activated. The maximum blockade of the sodium channels is only achieved after repeated stimulation of the sodium channels.
Consequently, the substances preferentially bind to sodium channels which are activated repeatedly.
As a result, the substances are capable of acting preferentially in those parts of the body which are pathologically overstimulated. This includes diseases such as arrhythmias, spasms, cardiac and cerebral ischaemia, pain and neurodegenerative diseases of various origins. The following may be mentioned, for example:
epilepsy, 3o hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.
Another aspect of the invention therefore relates to the use of compounds of general formula 1 as pharmaceutical compositions, particularly as pharmaceutical compositions in which the blockade of the voltage-dependent sodium channel may have a therapeutic value.
The compounds of general formula 1 according to the invention are preferably used to prepare a pharmaceutical composition for the prevention or treatment of arrhythmias, spasms, cardiac and cerebral ischaemias, pain and neurodegenerative disorders.
The compounds of general formula 1 according to the invention are most preferably used as hereinbefore to prepare pharmaceutical compositions for the prevention or treatment of epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, io cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.
The test system used to detect the blocking effect on the sodium channel is the BTX
binding to the sodium channel [S.W. Postma & W.A. Catterall, Mol. Pharmacol 25, 219-227 (1984)] and patch-clamp experiments which can be used to show that the compounds according to the invention block the electrically stimulated sodium channel in a "use-dependent" manner [W.A. Catterall, Trends Pharmacol. Sci., 8, 57-2o 65 (1987)]. The effect of the substances on various subtypes of sodium channel can be investigated by suitable selection of the cell system (e.g. neuronal, cardiac, DRG
cells).
The sodium channel blocking property of the compounds according to the invention can be demonstrated by the blockade of the veratridine-induced glutamate release [S. Villanueva, P. Frenz, Y. Dragnic, F. Orrego, Brain Res. 461, 377-380 (1988)].
Veratridine is a toxin which permanently opens the sodium channel. As a result, there is an increased influx of sodium ions into the cell. By means of the cascade described above, this sodium influx in the neuronal tissue leads to an increased glutamate release. The compounds according to the invention will antagonise this glutamate release.
The anticonvulsant properties of the substances according to the invention have been demonstrated by their protective effect against convulsions induced by a maximum electric shock in mice [M. A. Rogawski & R.J. Porter, Pharmacol. Rev.
42, 223-286 (1990)].
Neuroprotective properties have been demonstrated by the protective effect in a rat-MCAO model [U. Pschorn & A. J. Carter, J. Stroke Cerebrovascular Diseases, 6, 99 (1996)], a malonate-induced lesion model [ M.F. Beal, Annals of Neurology, 38, 357-366 (1995) and J.B. Schulz, R.T. Matthews, D.R. Henshaw and M.F. Beal, Neuroscience, 71, 1043-1048 (1996)] and an MPTP-induced degeneration model [J.P. Steiner, et al. Proc. Nati. Acad. Sci. 94, 2019-2024 (1997)].
The analgesic effect was shown in a formalin-induced pain model [D. Dubuisson and S.G. Dennis, Pain, 4, 161-174 (1977)] and in a ligature model [G. J. Bennett &
Y.-K.
Xie, Pain 33, 87-107 (1988)].
1o It has also been shown that sodium channel blockers can be used to treat cyclophrenia (manic depressive disease) [J. R. Calabrese, C. Bowden, M.J.
Woyshville; in: Psychopharmacology: The Fourth Generation of Progress (Eds.:
D.
E. Bloom and D. J. Kupfer) 1099-1111. New York: Raven Press Ltd.].
The compounds according to the invention 1 may be prepared analogously to methods of synthesis known per se. One possible method of synthesis is shown in diagram 1.
Diagram 1:
~ CF3 S, ~
H N~A R2 0 NZA R2 Rs' R6 R5 R3 R6 R5 / 1 ~ R1 NHz AN /'~A \ R2 X 4N rA \ R2 R3' 55 1 (where X = amino) The key step is the conversion of the phenol 2 into the compound of formula 1 wherein X = NH2, which is done by means of a Buchwald reaction [J. P. Wolfe, J.
Ahman, J. P. Sadighi, R. A. Singer, S. L. Buchwald, THL 1997, 6367-6370].
The compounds of general formula 1 according to the invention are most preferably used as hereinbefore to prepare pharmaceutical compositions for the prevention or treatment of epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, io cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.
The test system used to detect the blocking effect on the sodium channel is the BTX
binding to the sodium channel [S.W. Postma & W.A. Catterall, Mol. Pharmacol 25, 219-227 (1984)] and patch-clamp experiments which can be used to show that the compounds according to the invention block the electrically stimulated sodium channel in a "use-dependent" manner [W.A. Catterall, Trends Pharmacol. Sci., 8, 57-2o 65 (1987)]. The effect of the substances on various subtypes of sodium channel can be investigated by suitable selection of the cell system (e.g. neuronal, cardiac, DRG
cells).
The sodium channel blocking property of the compounds according to the invention can be demonstrated by the blockade of the veratridine-induced glutamate release [S. Villanueva, P. Frenz, Y. Dragnic, F. Orrego, Brain Res. 461, 377-380 (1988)].
Veratridine is a toxin which permanently opens the sodium channel. As a result, there is an increased influx of sodium ions into the cell. By means of the cascade described above, this sodium influx in the neuronal tissue leads to an increased glutamate release. The compounds according to the invention will antagonise this glutamate release.
The anticonvulsant properties of the substances according to the invention have been demonstrated by their protective effect against convulsions induced by a maximum electric shock in mice [M. A. Rogawski & R.J. Porter, Pharmacol. Rev.
42, 223-286 (1990)].
Neuroprotective properties have been demonstrated by the protective effect in a rat-MCAO model [U. Pschorn & A. J. Carter, J. Stroke Cerebrovascular Diseases, 6, 99 (1996)], a malonate-induced lesion model [ M.F. Beal, Annals of Neurology, 38, 357-366 (1995) and J.B. Schulz, R.T. Matthews, D.R. Henshaw and M.F. Beal, Neuroscience, 71, 1043-1048 (1996)] and an MPTP-induced degeneration model [J.P. Steiner, et al. Proc. Nati. Acad. Sci. 94, 2019-2024 (1997)].
The analgesic effect was shown in a formalin-induced pain model [D. Dubuisson and S.G. Dennis, Pain, 4, 161-174 (1977)] and in a ligature model [G. J. Bennett &
Y.-K.
Xie, Pain 33, 87-107 (1988)].
1o It has also been shown that sodium channel blockers can be used to treat cyclophrenia (manic depressive disease) [J. R. Calabrese, C. Bowden, M.J.
Woyshville; in: Psychopharmacology: The Fourth Generation of Progress (Eds.:
D.
E. Bloom and D. J. Kupfer) 1099-1111. New York: Raven Press Ltd.].
The compounds according to the invention 1 may be prepared analogously to methods of synthesis known per se. One possible method of synthesis is shown in diagram 1.
Diagram 1:
~ CF3 S, ~
H N~A R2 0 NZA R2 Rs' R6 R5 R3 R6 R5 / 1 ~ R1 NHz AN /'~A \ R2 X 4N rA \ R2 R3' 55 1 (where X = amino) The key step is the conversion of the phenol 2 into the compound of formula 1 wherein X = NH2, which is done by means of a Buchwald reaction [J. P. Wolfe, J.
Ahman, J. P. Sadighi, R. A. Singer, S. L. Buchwald, THL 1997, 6367-6370].
The triflates 3 required for this reaction may be prepared from these compounds 2 with trifluoromethanesulphonic acid anhydride in the presence of an auxiliary base.
Suitable auxiliary bases according to the invention include organic amines such as, for example, dimethylaminopyridine, pyridine or tert. amines such as trimethylamine, triethylamine, diisopropylethylamine or DBU (diazabicycloundecene). Of the abovementioned amines, the tert. amines are preferably used, and triethylamine is most preferably used as the auxiliary base. The reaction is carried out in aprotic, organic solvents, preferably in solvents selected from among dimethyiformamide, dimethylacetamide, methylene chloride, toluene or tetrahydrofuran. Methylene 1o chloride should be mentioned as being particularly preferred. The reactions to form the triflates 3 are preferably carried out at temperatures below ambient temperature, more preferably at -50 C to 0 C, most preferably at between -30 C and -5 C.
After 0.5 to 4 h stirring is continued at ambient temperature until the reaction is complete (about 1-12 h). After working up, the crude products 3 thus obtained are reacted, without further purification, in an aromatic organic solvent, preferably selected from among toluene, benzene or xylene, most preferably toluene, with palladium as catalyst, preferably in the presence of a phosphine ligand, with a nitrogen source, preferably with ketimines, most preferably with benzophenonimine. Suitable palladium catalysts according to the invention include tris(dibenzylidene-acetone)-2o dipalladium, palladium(II)acetate or tetrakistriphenylphosphine-palladium, for example. Suitable phosphine ligands which may be used include, for example, ligands selected from among DPPF, BINAP, p-toIBINAP, PPh2-CHMe-P(tBu)2, phosphine-substituted ferrocenes or triphenylphosphine. Tris(dibenzylidene-acetone)-dipalladium/BINAP is preferably used as the catalyst system. The reaction is preferably carried out with the exclusion of moisture and oxygen and preferably at elevated temperature. The solvent used is preferably refluxed during the reaction.
The imine adduct obtained as an intermediate can be converted by acid hydrolysis, preferably with dilute inorganic acids, most preferably with dilute hydrochloric acid, into the compounds according to the invention 1 (where X=NH2). The products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g.
the hydrochlorides.
As can be seen from the above remarks, the triflates of general formula 3 are of central importance in the synthesis of the compounds of general formula 1 according to the invention.
Accordingly, another aspect of the present invention relates to the intermediate compounds of general formula 3 R' O'\ ,O ~
F3C~S~0 4N ~A ~ R2 R3 R4 wherein the groups R1, R2, R3, RT, R4, R5, R6 and A may be as hereinbefore defined.
5 In order to synthesise the compounds according to the invention of general formula 1 where X#NH2 the following process may be used.
Compounds of formula 1 wherein X = NHC1-C6-alkyl or N(C1-C6-alkyl)2 may be obtained by methods known per se by alkylation of 1 where X=NH2, by reductive io amination or by acylation, optionally in the presence of organic bases, with subsequent reduction.
For alkylation, the following method may be used. A compound of general formula 1 where X=NH2 is dissolved in a polar organic solvent such as dimethylformamide, dimethylacetamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide or methylene chloride. The resulting solution is mixed with a base and a corresponding alkylating agent. Suitable bases include alkali- and alkaline earth metal hydrides, preferably sodium hydride. Suitable alkylating agents include alkyl halides, such as alkyl chloride, alkyl bromide, particularly alkyl iodide and alkyl tosylates, mesylates, triflates, dialkylsulphates. After conventional working up the alkylated compounds of general formula 1 may be purified by chromatography on silica gel or by crystallisation, optionally in the form of the pharmacologically acceptable addition salts thereof, preferably as hydrochlorides.
In order to prepare the compounds of general formula 1 by reductive amination the amines 1 where X=NH2 are mixed with aldehydes or ketones in the presence of acids such as dilute hydrochloric acid, dilute acetic acid or dilute sulphuric acid, under otherwise conventional reaction conditions, with cooling, preferably at -50 C to ambient temperature, most preferably between -30 C and 0 C, and the Schiff bases or iminium salts thus formed as intermediates are then reduced. The reduction is carried out using metal hydrides such as sodium borohydride, LiAIH4, Li-alkoxyhydrides, NaBH4, NaBHCN3, NaBH(OAc)3 ; sodium borohydride is preferably used. After working up in the usual way, the alkylated compounds of general formula 1 may be purified by chromatography on silica gel or by crystallisation, optionally in the form of their pharmacologically acceptable acid addition salts thereof, preferably as hydrochlorides.
Compounds of formula 1 where X = NHCO(Cl-C6-alkyl) may be prepared by methods known perse by acylating 1 where X=NH2, preferably with acid chlorides or anhydrides. For this, the amino compound of formula 1 where X=NH2 is suspended in an organic solvent, combined with an organic base and the desired acid chloride or anhydride is added. The mixture is kept at ambient temperature for 40 to 60 minutes, preferably 25 to 45 minutes at ambient temperature. Suitable organic io solvents are dimethylformamide, dimethylacetamide, methylene chloride, toluene or tetrahydrofuran, methylene chloride being preferred. Suitable organic bases are dimethylaminopyridine, pyridine, tert. amines, e.g. trimethylamine, triethylamine, diisopropylethylamine, DBU (diazabicycloundecene). After working up, the products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g.
the hydrochlorides.
Starting from the compounds of formula 1 with X = NHCO(Cl-C6-alkyl) which may be obtained by the method described above, compounds of formula 1 with X =
2o NH(Cl-C6-alkyl), for example, may also be obtained by reduction with metal hydrides such as LiAIH4, Li-alkoxyhydrides, NaBH4, NaBHCN3, NaBH(OAc)3, preferably sodium borohydride. These reactions are preferably carried out in ethereal organic solvents, preferably in tetrahydrofuran or dioxan in the presence of Lewis acids, preferably boron trifluoride etherate, at elevated temperature, preferably above 50 C, most preferably at the reflux temperature of the solvent used.
After working up, the products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g. the hydrochlorides.
3o The formylated compounds of formula 1(X =NHCOH) may be obtained, for example, by reacting the compounds of formula 1 where X=NH2 with formic acid at elevated temperature, preferably at reflux temperature. After working up, the products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g.
the hydrochlorides.
The fluorine-substituted compounds 1( with X= F) may be obtained by methods known per se by diazotisation of 1 where X=NH2 and subsequent decoction with BF4 . Preferably, the reaction is carried out with NOBF4 as the diazotisation and fluorination reagent in ethereal solvents, preferably in tetrahydrofuran or dioxan at elevated temperature, preferably above 50 C, most preferably at the reflux temperature of the solvent used. After working up, the products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g. the hydrochlorides.
The 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols (2) designated as starting compounds in diagram 1 may be obtained using methods known from the prior art. In this context, reference is hereby made to European Patent Application 1o EP 521422 and the International Patent Applications WO 97/06146 and WO
99/14199.
Compounds of general formula 2 wherein R3 denotes hydrogen, are prepared starting from the compounds of general formula 4 analogously to the methods of synthesis described in W099/14199. In order to prepare compounds of general formula 1 wherein R3 does not denote hydrogen, the compounds of general formula 4 first have to be modified. This is done by analogously using methods of synthesis known in principle as described in the following reaction plans.
For example, a p-methyl substituent (R3 equals methyl) may be introduced using the method given in Diagram 2.
In order to prepare the brominated compound of formula 5 the compounds of formula 4 are dissolved in a suitable solvent, preferably in acetic acid or trifluoroacetic acid, most preferably in a mixture of acetic acid and trifluoroacetic acid and NBS (N-bromosuccinimide) is added batchwise at 0-23 C, preferably at 10 C.
The reaction is complete after about 1 to 5 hours. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 5.
Me. Me. Me. O ~-O NH O NH N \/
\ \ --~- \
Ra R R a -~ crR6R
Rs R Br Rs B4 5 ~ ~
OH N \/ Me.O N 1/ Me.O N
\ \ \
Ra 1*- Ra Ra Me R9 Me RR8 7 R
OH OH N ~A IRz NH
Ra Ra R R
Me R Me Rs 2 (where R3 = methyl) - (where R3' = hydrogen) Diagram 2:
The benzylation of the compounds 5 to form the compounds 6 is preferably carried out in an organic solvent, preferably in a solvent selected from among 5 dichloromethane, dimethylformamide and dimethylacetamide, particularly preferably in dimethylacetamide. For this, the compounds 5 are dissolved in the solvent and benzyl chloride is added in the presence of a base at a temperature of 0-50 C, particularly preferably at ambient temperature (about 23 C). Suitable bases are organic or inorganic bases. Suitable inorganic bases are the alkali metal- or alkaline io earth metal carbonates of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. Suitable organic bases are preferably organic amines, particularly preferably diisopropylethylamine, triethylamine, cyclic amines such as DBU, or pyridine. After the benzyl chloride has all been added the mixture is stirred for a further I to 6, preferably 2 to 4 hours at elevated temperature, preferably at about 50-120 C, particularly preferably at about 100 C, but at most at the boiling temperature of the solvent in question. The product is worked up in the usual way.
The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 6.
The compounds 7 are prepared from the compounds 6 by reacting with suitable formulating reagents. For this, the compounds 6 are dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent, preferably in an ethereal solvent selected from among diethylether, tetrahydrofuran and dioxan, preferably in diethylether, and butyllithium, preferably dissolved in n-hexane, is added at low temperature, preferably at below -20 C, particularly preferably at a temperature between -50 C and -78 C. After about 0.5 to 2 hours stirring in the temperature range mentioned above, the formulating reagent, preferably dimethylformamide, is 1o added and stirred for another 0.5 to 2 hours, optionally at slightly elevated temperature, preferably at -30 C to 0 C, particularly preferably at about -10 C. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 7.
Reduction of the compounds 7 leads to the methyl compounds 8. For this the compounds 7 are dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent, preferably in an ethereal solvent selected from among diethylether, tetrahydrofuran and dioxan, preferably in tetrahydrofuran, and a suitable reducing 2o agent, preferably a metal salt hydride, particularly preferably NaBH4 or NaCNBH3, preferably NaCNBH3, is added. It is also necessary to add boron trifluoride, or BF3-etherate. After the addition of the reducing agent the mixture is stirred for another 1 to 6 hours, preferably 2 to 4 hours at constant temperature, preferably at ambient temperature. After the addition of a protic solvent, particularly preferably a lower alcohol selected from among methanol, ethanol or isopropanol, particularly preferably methanol and hydrolysis with an aqueous acid, preferably with aqueous hydrochloric acid, the mixture is stirred for a further 0.5 to 4 hours, optionally at elevated temperature, preferably at a temperature above 50 C, particularly preferably at the reflux temperature of the solvent. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 8.
The cleaving of the methoxy group in 8 leads to the hydroxy compounds 9 and is carried out with the use of strong acids, such as HI and HBr, particularly preferably concentrated HBr at elevated temperature, preferably at more than 50 C, particularly preferably at reflux temperature. There is no need to use a solvent if HBr is used, for example. The reaction is complete after about 1 to 6, preferably 2 to 4 hours.
The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 9. The cleaving of the methoxy group in 8 to yield the hydroxy compounds 9 may alternatively be carried out using BBr3 analogously to the procedure described for reacting the compounds 17 to obtain the hydroxy compounds 18.
The compounds 10 may be obtained from the compounds 9 by hydrogenolytic cleaving of the benzyl group. This reduction is preferably carried out by catalytic TM
hydrogenation, preferably on palladium catalysts or on Raney nickel, particularly preferably on palladium catalysts in alcoholic solvents, preferably in methanol, at lo ambient temperature. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on their crystallisation tendencies.
The compounds of general formula 2 may be prepared starting from the compounds 15 of general formula 10 analogously to the methods of synthesis described in W099/14199.
A p-fluoro substituent is introduced by the method shown in diagram 3. To do this, a compound of formula 6 is dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent, preferably in an ethereal solvent selected from among diethylether, tetrahydrofuran and dioxan, preferably in diethylether, and buthyllithium, preferably dissolved in n-hexane, is added at low temperature, preferably at below -20 C, particularly preferably at a temperature between -50 C and -78 C. After about 0.5 to 2 hours stirring in the temperature range specified above, a suitable fluorinating agent, preferably N-fluorobenzenesulphonimide, dissolved in one of the solvents mentioned above, is slowly added and stirring is continued for another 0.5 to 2 hours at constant temperature. The product is worked up in the usual way.
The products are purified either by crystallisation or by chromatography depending on their crystallisation tendencies.
- - ~
Me, O N Me. O N OH N
~
\ \ \
Ra --~ ~/ Ra -~ I Ra Br R6 F R6 F R6 R 12 ~
R
OH ~A Iz N R OH NH
R( / Ra qF \
R ~6R
(where R3 = fluorine) 13 (where R3' = hydrogen) Diagram 3:
The compounds 11 are converted into the hydroxy compounds 12 as described for the reaction of the compounds 8 to form the compounds 9. The conversion of the compounds 12 into the debenzylated compounds 13 is carried out as described for the reaction of the compounds 9 to form the compounds 10.
The compounds of general formula 2 may be prepared starting from the compounds of general formula 13 analogously to the methods of synthesis described in lo W099/14199.
A p-CF3 substituent is introduced according to the method of synthesis shown in diagram 4.
In a first step, a compound of formula 4 is converted into an iodide of formula 14.
This reaction is carried out analogously to the procedure described for reacting 4 to 5 using NIS (N-iodosuccinimide).
From the compounds 14 it is possible to obtain the N-protected compounds 15 wherein PG denotes an amino protecting group. The protecting group used may be 2o any of the groups commonly used to protect the amino function. Examples include the benzyl group, the benzyloxycarbonyl and tert.-butyloxycarbonyl group, the latter being preferred. The following method is used to introduce the tert.-butyloxycarbonyl group. The reaction is preferably carried out in an organic solvent, preferably in a solvent selected from among dichloromethane, dimethylformamide and dimethylacetamide, particularly preferably in dichloromethane. For this, the compounds 14 are dissolved in the solvent and in the presence of a base at a temperature of -50 C to 10 C, preferably at -20 C to 0 C, and an inorganic base is added. The inorganic base may be, for example, an alkali metal- or alkaline earth metal hydroxide of lithium, sodium, potassium, calcium such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide and preferably potassium hydroxide, optionally in aqueous solution. Then di-t-butyldicarbonate, optionally dissolved in one of the abovementioned organic solvents, is added. After it has all been added, the mixture is stirred for another 0.5 to 6, preferably 1 to 3 hours, optionally at fairly elevated temperature, preferably at ambient temperature.
The product is worked up in the usual way. The products are purified either by io crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 15.
Me, Me, O NH O NH Me.O IPG
N
a R 30 Ra ~ a R6 Rs Rs R
I ~
R' OH N/' A Rz OR' NH Me.O PG
N
a aE
R ER ~ R ( Ra Rs s CF3 R6 CF3 R6 CF Re R
2(where R3 = CF3 17 (R' =Me) 16 (where R3' = hydrogen) 18 (R' =H) Diagram 4:
The trifluoromethyl compounds 16 may be prepared from the compounds 15. For this, a compound 15 is dissolved in a suitable organic solvent, preferably in a polar organic solvent selected from among dimethylacetamide, dimethylsulphoxide or dimethylformamide, particularly preferably dimethylformamide, and methyl fluorosulphonyl-difluoroacetate and Cul, preferably anhydrous Cul, are added.
Then the reaction mixture is heated to a temperature in the range from 50-90 C, particularly preferably to 70 C. It is stirred at constant temperature for between 1 day and 4 days, preferably about 2 days. Depending on the progress of the reaction it may be necessary to add more methyl fluorosulphonyl-difluoroacetate and Cul.
The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 16.
The cleaving of the amino protecting group starting from the compounds 16 yields the compounds 17. The processes for cleaving the protecting groups used are known from the prior art. At this point, we should mention a possible alternative method of cleaving the tert.-butyloxycarbonyl protecting group, solely by way of example. This is done by reacting 16 with trifluoroacetic acid in a suitable organic solvent, preferably in dichloromethane at ambient temperature within a period of 1 to 3 hours. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies 1o of the compounds 17.
The cleaving of the methoxy group starting from the compounds 17 yields the compounds 18 and is carried out by reacting with BBr3 solution in the presence of trifluoroacetic acid in a suitable organic solvent, preferably in dichloromethane at low temperature, preferably at below -50 C, particularly preferably between -75 C
and -60 C. After the reactants have all been added at the temperature specified above the reaction is completed by stirring at a temperature in the range from -20 C
to C, preferably at about 0 C, over a period of 4 to 12 hours. The product is worked up in the usual way. The products are purified either by crystallisation or by 20 chromatography depending on the crystallisation tendencies of the compounds 18.
Alternatively to the method described above, the cleaving of the methoxy group in 17 to form the hydroxy compounds 18 may also be carried out using strong acids.
On this subject we refer the reader to the corresponding remarks regarding the reaction of the compounds 8 to form the hydroxy compounds 9.
The compounds of general formula 2 may be prepared starting from the compounds of general formula 18 analogously to the methods of synthesis described in W099/14199.
3o A p-phenyl substituent may also be introduced as illustrated in diagram 5.
Me. 0 Me.O N Pd-cat. N
Ra OH
Ra R&%H R5 R R
Br R B
R ~
Ri OH NH
J:>' OH ~A
N
R
Ra Rs I i 2 (where R3 = substituted phenyl) 20 R (where R3' = hydrogen) Dia rq am 5:
Starting from the compounds 6 the compounds 19 are obtained by reacting with suitably substituted borates and subsequent transmetallisation with palladium(0) compounds. Phenylboric acids substituted with the group R are used as the borates.
For the reaction, 6 is dissolved in a suitable organic solvent, preferably in an anhydrous, oxygen-free organic solvent, preferably in an ethereal solvent selected from among diethylether, tetrahydrofuran and dioxan, preferably in dioxan, and the abovementioned boric acid derivative, potassium phosphate and a suitable io palladium(O) catalyst are added successively. The Pd(0) catalyst according to the invention may be tris(dibenzylidene-acetone)-dipalladium, palladium(II)acetate or tetrakistriphenylphosphine palladium, for example, preferably tris(dibenzylidene-acetone)-palladium(0). Phosphines or phosphites also have to be added. The phosphine ligands may be, for example, ligands selected from among DPPF, BINAP, p-toIBINAP, PPh2-CHMe-P(tBu)2, phosphine-substituted ferrocenes, triphenylphosphine or trimethylphosphite, preferably trimethylphosphite. After all the reaction components have been added, the mixture is stirred at elevated temperature, preferably at a temperature above 50 C, particularly preferably at the reflux temperature of the solvent, for 0.5 to 2 hours. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 19.
The compounds 19 are converted into the hydroxy compounds 20 as described for the reaction of the compounds 8 into the compounds 10 (via 9).
The compounds of general formula 2 may be prepared starting from the compounds of general formula 20 analogously to the methods of synthesis described in W099/14199.
5 Halogen-substituted derivatives may be obtained, for example, by reacting the compounds 1 according to the invention wherein X denotes NH2 and R3 denotes hydrogen, with NIS, NBS or NCS (Diagram 6). As a rule, mixtures of the para-, ortho-and para-/ortho-disubstituted compounds are obtained, which can be separated by chromatography.
R
/
NH2 N~A \ R2 NHaIS
R4 where Ha CI, Br s Rs R
1 (where X = NH2;
(R3 and R3 = hydrogen);
/ R
a R' R' ~
NH2 N~A R2 NHZ ~A R2 NHZ ~ 2 A R
Hal -N Hal ~ N
Ra + Ra + / R4 Hal RB Hal R6 Rs 1 (where X NH2; 1(where X NH2; 1(where X= NHz;
R3 = Hal and R3 and R3= Hal); R3' = Hal and 10 R3' = hydrogen); R3 = hydrogen);
Dia rg am 6:
The compounds of general formula 2 wherein R3 denotes hydrogen may be prepared starting from the compounds of general formula 4 analogously to the methods of synthesis described in W099/14199. In order to prepare the compounds 15 2 wherein R3 denotes hydrogen, the compounds of formula 21 are used as starting material (diagram 7). These may be obtained from the compounds 4. The compounds 21 are disclosed in W099/14199.
Me. 0 NH OH NH OH N/"-A R2 HBr -~- -~-( R4 R4 Ra Rs RS Rs R5 R 6 R5 4 21 2(where R3 and R3' Diagram 7: = hydrogen) The Examples that follow serve to illustrate the invention, without restricting it to the 20 compounds and processes disclosed by way of example.
1. Synthesis of the precursors 4 to 20:
The compounds of formula Me H Me H Me N Me N H
I\ H H H H
Me Me Me = Me Me 4a~ Me 4b ~ Me 4c and Me 4d are known, for example, from W099/14199.
Compounds of formula 5:
(2R,6S)-7-bromo-l0-methoxy-1,2,3,4,5,6-hexahydro-6.11,11-trimethyl-2 6-methano-1o 3-benzazocine-hydrochloride 5a:
24.7 g (0.1 mol) ) (2R,6S)-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 4a) are dissolved in 220 mL of acetic acid and 22 mL of trifluoroacetic acid, cooled to 10 C, and 19.6 g of NBS (N-bromosuccinimide) is added batchwise. The mixture is stirred for 3 h at 10 C, the solvent is eliminated in 15 vacuo and the residue is combined with ice-cooled ammonia solution. Then it is extracted twice with 200 mL of ethyl acetate, the combined organic phase is dried and the solvent is eliminated in vacuo. The residue is dissolved in acetone and the hydrochloride is precipitated with ethereal HCI.
Yield: 32,6 g (91%), melting point: 203 C.
Compounds of formula 6:
(2R,6S)-3-Benzyl-7-bromo-10-methoxy-1,2,3,4,5.6-hexahydro-6.11 11-trimethvl-2 methano-3-benzazocine 6a:
32.6 g (91 mmol) of (2R,6S)-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride 5a are dissolved in 160 mL
of dimethylacetamide, combined with 28 g of K2CO3 and 18.9 g of benzyl chloride and stirred for 3h at 100 C. Then the solvent is eliminated in vacuo, the residue is combined with water and twice with 200 mL aliquots of ethyl acetate. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo. Yield: 24.5 g (73%); oil.
Compounds of formula 7:
(2R,6S)-3-Benzyl-7-formyl-10-methoxy-1,2,3,4,5,6-hexahyd ro-6 11 11 -trimethyl-methano-3-benzazocine 7a:
24.5 g (59 mmol) of (2R,6S)-3-benzyl-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 6a are dissolved in 250 mL of abs.
ether, cooled to - 70 C and 40.7 mL of BuLi (1.6 M in hexane) are added dropwise.
Then the mixture is stirred for 1 h at -60 C, 10 mL of DMF are added dropwise thereto and after another hour the resulting mixture is allowed to come up slowly to -10 C. It is then added to 500 mL of water and extracted twice with 300 mL
aliquots To of ether. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo. Yield: 18.3 g (85%); oil.
Compounds of formula 8:
(2R,6S)-3-Benzyl-7-methyl-10-methoxy-1.2,3,4,5,6-hexahvdro-6 11 11-trimethyl-2 methano-3-benzazocine 8a:
8 g (22mmol) of (2R,6S)-3-benzyl-7-formyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 7a are dissolved in 80 mL of THF, mixed with 4 g of NaCNBH3 and 20 mL of BF3-etherate and stirred for 3 h at RT.
2o Then 100 mL of methanol are carefully added dropwise, 100 mL of 2 N HCI are added and the mixture is refluxed for 1 h. The solvent is eliminated in vacuo, ammonia is added to the residue and it is then extracted twice with 100 mL
aliquots of ethyl acetate. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo. Yield: 5.5 g (72%); oil.
Comaounds of formula 9:
(2R,6S)-3-Benzyl-7-methyl-10-hydroxy-1,2,3,4,5,6-hexahydro-6 11 1.11 -trimethyl6-methano-3-benzazocine 9a:
5.3 g (15 mmol) of (2R,6S)-3-benzyl-7-methyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 8a are dissolved in 54 mL of conc.
HBr and refluxed for 2 h. The mixture is evaporated down in vacuo, the residue is combined with ice and conc. ammonia and extracted twice with 50 mL of ethyl acetate. The combined organic phase is dried and the solvent is eliminated in vacuo.
The residue is dissolved in acetone and the hydrochloride is precipitated with ethereal HCI. Yield: 3.7 g (66%), Compounds of formula 10:
(2R,6S)-3-Benzyl-7-methvl-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11 1.11 -trimeI-2 methano-3-benzazocine 10a:
3.6 g (10 mmol) of (2R,6S)-3-benzyl-l0-hydroxy-7-methyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 9a are hydrogenated on 0.4 g of PdC
in 60 mL of methanol at 5 bar for 4 hours. The mixture is then filtered and the solvent is eliminated in vacuo. Yield 2.6 g (92%); oil.
Compounds of formula 11:
1o (2R,6S)-3-Benzyl-7-fluoro-10-methoxy-1,2,3,4,5,6-hexahydro-6.11,11-trimethyl-2 6-methano-3-benzazocine 11 a:
8 g (20mmol) of (2R,6S)-3-benzyl-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 6a are dissolved in 100 mL of ether, cooled to -65 C and under nitrogen 15 mL of BuLi (1.6 M in hexane) are added dropwise. After I h, 8 g of N-fluorobenzenesulphonimide in 100 mL of THF are added dropwise and the mixture is stirred for 1 h at -60 C. It is then heated to RT, any insoluble matter is removed by suction filtering and the solvent is eliminated in vacuo. The residue is taken up in 100 mL of water, combined with 10 mL of conc.
ammonia and extracted twice with 150 mL of ether. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo. Yield: 3.4 g (48%); oil.
Compounds of formula 12:
(2R,6S)-3-Benzyl-7-fluoro-10-hydroxy-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2 methano-3-benzazocine 12a:
Prepared analogously to the preparation of compound 9 starting from 11;oil;
Compounds of formula 13:
(2R,6S)-7-Fluor-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2 6-methano-3o benzazocine 13a:
Prepared analogously to the preparation of compound 10 starting from 12;oil;
Compounds of formula 14:
(2R,6S)-7-iodo-10-hvdroxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2 6-methano-benzazocine 14a:
32.5 g (0.13 moI) of (2R,6S)-1 0-methoxy-1,2,3,4,5,6-hexahydro-6,1 1,11 -trimethyl-2,6-methano-3-benzazocine 4a are dissolved in 330 mL of acetic acid and 110 mL
of trifluoroacetic acid, cooled to 5 C and 32.9 g of NIS is added batchwise. The mixture is stirred for 3 h at 10 C, the solvent is eliminated in vacuo and the residue is combined with ice-cooled ammonia solution. It is then extracted twice with mL aliquots of ethyl acetate, the combined organic phase is dried and the solvent is eliminated in vacuo. The residue is dissolved in ethyl acetate and the hydrochloride is precipitated with ethereal HCI. Yield: 31.7 g (59%), melting point: 231 C.
Compounds of formula 15:
(2R,6S)-3-t-Butyloxycarbonyl-7-iodo-10-methoxy-1,2,3,4,5,6-hexahyd ro-6 11 11-trimethyl-2,6-methano-3-benzazocine 15a:
31.6 g (78 mmol) of (2R,6S)-7-iodo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-io trimethyl-2,6-methano-3-benzazocine-hydrochloride 14a are suspended in 350 mL of dichloromethane, cooled to -5 C, combined with 9 g of KOH in 18 mL of water and 17.7 g of di-t-butyldicarbonate in 50 mL of dichloromethane are added dropwise. The mixture is then allowed to come slowly up to RT, is stirred for 2 h at room temperature and 200 mL of water are added. The organic phase is separated off, dried, and the solvent is eliminated in vacuo. Yield: 36.7 g (100%) of viscous oil.
Compounds of formula 16:
(2R,6S)-3-t-Butyloxycarbonyl-7-trifluoromethyl-10-methoxy-1,2 3 4 5 6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine 16a:
15.8 g (34 mmol) of (2R,6S)-3-t-butyloxycarbonyl-7-iodo-1 0-methoxy-1,2,3,4,5,6-hexahydro-6,1 1,11 -trimethyl-2,6-methano-3-benzazocine 15a is dissolved in 120 mL
of DMF, 10 g of methyl fluorosulphonyl-difluoroacetate and 2.3 g of Cul are added and the mixture is heated to 70 C. After 24 h another 3 g of methyl fluorosulphonyl-difluoroacetate and 0.7 g of Cul are added and stirring is continued for another 18 h at 70 C. The mixture is cooled, combined with 500 mL of ether and suction filtered to remove any insoluble matter. The filtrate was washed twice with dilute ammonia solution and with water. The organic phase was dried and the solvent eliminated in vacuo. Yield:13.6 g (98%); orange resin.
Compounds of formula 97:
(2R,6S)-7-Trifluoromethvl-10-methoxy-1,2,3,4,5,6-hexahydro-6 11 1.11 -trimethyl6-methano-3-benzazocine 17a:
13.6 g (33 mmol) of (2R,6S)-3-t-butyloxycarbonyl-7-trifluoromethyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 16a are dissolved in 250 mL of dichloromethane, 25 mL of trifluoroacetic acid are added dropwise and the mixture is stirred for 2 h at RT. It is then added to ice water and ammonia solution, the organic phase is separated off, dried and the solvent is eliminated in vacuo. Yield: 10.7 g (100%) orange resin.
Compounds of formula 18:
(2R,6S)-7-trifluoromethyl-10-hydroxy-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2 methano-3-benzazocine 18a:
1.0 g (3.2 mmol) of (2R,6S)-7-trifluoromethyl-10-methoxy-1,2,3,4,5,6-hexahydro-5 6,11,11-trimethyl-2,6-methano-3-benzazocine 17a are dissolved in 10 mL of dichloromethane, cooled to-65 C and 7 mL of BBr3 solution (1 M in dichloromethane) are added dropwise. The mixture is then allowed to come up to 0 C and stirred for 8 h at this temperature. 10 mL of MeOH are added, while cooling with ice, and the solvent is eliminated in vacuo. Yield: 1.2 g (100%), brown resin.
Compounds of formula 19:
(2R,6S)-3-Benzyl-7-(4-methyl)phenyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11 11-trimethyl-2,6-methano-3-benzazocine 19a:
4.1 g (10 mmol) of (2R,6S)-3-Benzyl-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 6a are dissolved in 100 mL of degassed dioxan under N2, combined with 12.6 g of K2P04, 2.9 g of 4-methylphenylboric acid, 0.92 g of tris(dibenzylideneacetone)-palladium(0) and 0.25 g of trimethylphosphite and refluxed for 1 h. Then the mixture is cooled, the salts are removed by suction filtering and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo.
Yield: 3.8 g (89%); oil.
Compounds of formula 20:
(2R,6S)- 10-Hydroxy-7-(4-methyl)ghenyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-methano-3-benzazocine-hydrobromide 20a;
Prepared from 19a analogously to the preparation of 10a;
melting point: >250 C.
Compounds of formula 21:
(2R,6S)-10-Hvdroxy-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2.6-methano-3-benzazocine-hydrobromide 21 a:
Prepared from 4a analogously to the preparation of 9a;
(2R,6S, 11 R)-10-Hydroxy-1,2,3,4,5,6-hexahydro-6,11-dimethvl-2.6-methano-3-benzazocine-hydrobromide 21 b:
Prepared from 4b analogously to the preparation of 9a;
(2R,6S, 11 S)-10-Hydroxy-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine-hydrobromide 21 c:
Prepared from 4c analogously to the preparation of 9a;
(2R,6S)-10-Hydroxy-1,2,3,4,5,6-hexahvdro-6-methvl-2,6-methano-3-benzazocine-hydrochloride 21d:
Prepared from 4d analogously to the preparation of 9c;
II. Synthesis of the compounds of formula 2:
lo (2R,6S,2"S)-10-Hydroxy-3-f2-(benzyloxy)propyll-1,2,3,4,5,6-hexahvdro-6 11 trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2a:
1.6 g (6.9 mmol) of (2R,6S)-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrobromide 21a are suspended in 30 mL of dichloromethane and 6 mL of N-methylmorpholine is added. After 30 min. the mixture is cooled to -5 C and a solution of 2.3 g (11.6 mmol) of (-)-S-2-bBenzyloxy-propionic acid chloride in 20 mL of dichloromethane is slowly added dropwise thereto. The mixture is stirred for a further 30 min. at -5 C, 40 mL of 2 N
hydrochloric acid are added and the organic phase is separated off. The organic phase is dried over MgSO4, the solvent is eliminated in vacuo and the residue is taken up in 80 mL of THF. To this solution are added 1.0 g (26 mmol) of LiAIH4 whereupon the temperature rises to 35 C. The solution is left to react for 30 min, 0.8 mL of water and 0.4 mL of 5 N sodium hydroxide solution are added and the inorganic precipitate is separated off. The precipitate is washed with 100 mL
of THF
and the combined organic phases are evaporated down in vacuo. The residue is taken up in 200 mL of ether, dried over MgSO4 and the hydrochloride is precipitated with ethereal hydrochloric acid. The crystals are separated off and washed with acetone.
Yield: 2.1 g (73%), melting point: 254 C, [a]p25 =(-) 20.7 (C=1 in methanol);
3o The following compounds 2 were also obtained using the corresponding carboxylic acids:
(2R,6S,2S')-10-Hydroxy-3-[2(2,6-difluorophenyl-methoxy)-propyll-1 2 3 4 5 6-hexahydro-6,11,11-trimethvl-2,6-methano-3-benzazocine-dihydrochloride 2b Prepared from 21 a analogously to the preparation of 2a;
(2R ,6S,11 R,2S')-10-Hvdroxy-3-f2(2,6-difluorophenyl-methoxv)-propyll-1 2 3 4 hexahydro-6,11-dimethvl-2,6-methano-3-benzazocine-dihvdrochloride 2c Prepared from 21 b analogously to the preparation of 2a;
(2R,6S, 11 S,2S')-10-Hydroxy-3-f2(benzyloxy)-propyll-1,2,3,4,5,6-hexahydro-6 dimethyl-2,6-methano-3-benzazocine-dihydrochloride 2d Prepared from 21 c analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-3-f2(benzyloxy)-propyll-1,2,3,4,5,6-hexahydro-6-methvl-methano-3-benzazocine-dihydrochioride 2e Prepared from 21d analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f2(2,6-difluorophenyl-methoxy)-ethyll-1,2,3,4,5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2f Prepared from 21 a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-3-f2(2,6-difluorophenyl-methoxY -isopentyll-1 2 3 4 5 6-hexahydro-6,11,11-trimethvl-2,6-methano-3-benzazocine-dihydrochloride 2q Prepared from 21a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f2(benzyloxy)-ethyll-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride 2h Prepared from 21 a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f2(2-fluorophenyl-methoxy)-ethyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2i Prepared from 21a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f2(2,4-difluorophenyl-methoxy)-ethyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2.6-methano-3-benzazocine-dihydrochloride 2i Prepared from 21 a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f2(2,6-dimethylphenyl-methoxy)-ethyll-1,2,3,4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2k Prepared from 21 a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hvdroxv-3-(2(benzvloxv)-butyll-1,2,3,4,5,6-hexahvdro-6 11 1.11 -trimethyl-2,6-methano-3-benzazocine-dihvdrochloride 21 Prepared from 21 a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-3-f2(2,6-difluorophenyl-methoxy)-butyll-1,2,3 4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2m Prepared from 21 a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-3-f2(2,6-difluorophenyl-methoxy)-propvll-1,2 3 4 5 6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihydrochloride 2n Prepared from 21d analogously to the preparation of 2a;
(2R,6S,2"R,5"S)-10-Hydroxy-3-f5"-phenyl-tetrahydrofuran-2"-yl)methyl]-1 2 3 4 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2o:
Prepared from 21a analogously to the preparation of 2a;
To (2R,6S,2"S,5"S)-10-Hydroxy-3-f5"-phenyl-tetrahydrofuran-2"-yl)methvll-1 2 3 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride 2p:
Prepared from 21 a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f3(2,6-difluorophenyloxy)-propyll-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2g Prepared from 21 a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f4(2,6-difluorophenyl)-butyll-1,2,3,4,5,6-hexahvdro-6,11 trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2r Prepared from 21 a analogously to the preparation of 2a;
(2Rs6S,2S')-10-Hydroxy-7-methyl-3-f2(2,6-difluorophenyl-methoxy)- ropyl]_ 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride 2s Prepared from 10a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hvdroxy-7-methyl-3-f2(benzyloxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2t Prepared from 10a analogously to the preparation of 2a;
(2R,6S, 2"S, 5"S)-10-Hyd roxy-7-methyl-3-f 5"-phenyl-tetrahyd rofuran-2"-yl)methyll-1,2,3,4,5,6-hexahvd ro-6,11,11-trimethvl-2,6-methano-3-benzazocine-dihvdrochloride 2u: Prepared from 10a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-7-fluoro-3-[2(benzyloxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2v Prepared from 13a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hvdroxy-7-trifluoromethyl-3-(2(benzyloxy)-propyll-1 2 3 4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2w Prepared from 18a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-7-(4-methylphenyl)-3-(2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihyd rochloride 2x Prepared from 20a analogously to the preparation of 2a;
1o (2R,6S)-10-Hydroxy-7-methyl-3-f2(2,6-difluorophenyl-methoxy)-ethyll-1,2 3 4 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2y Prepared from 10a analogously to the preparation of 2a;
III. Synthesis of the compounds of formula 1 according to the invention:
Example 1: (2R,6S,2S')-10-Amino-3-f2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride NHZ ~F ~.
N~ F
.,,,l H Me Me Me Me 13.5 g ( 0.03 moI) of (2R,6S,2"S)- 3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-1 0-ol 2d are dissolved in 135 mL of dichloromethane, combined with 30 mL of triethylamine and a spatula tip of 4-dimethylaminopyridine and cooled to-10 C. Then 6.8 mL of trifluoromethanesulphonic acid anhydride are added dropwise, the mixture is stirred for 1 h at -10 C and for a further 2 h at room temperature. The reaction mixture is poured onto ice, combined with 50 mL of ammonia, the organic phase is separated off and washed once with 50 mL of water. The organic phase is dried, the solvent is eliminated in vacuo, the residue is taken up in 350 mL of toluene, and 21.6 g of CsCO3 and 10.8 g of benzophenone-imine are added. Then nitrogen is bubbled through the suspension for 30 min., 1.2 g of BINAP and 0.6 g of tris(dibenzylidene-3o acetone)-dipalladium are added and the mixture is refluxed for 6 h. After cooling, it is washed with 200 mL of water, the organic phase is dried and the solvent is eliminated in vacuo. The residue is taken up in ethanol and the hydrochloride is precipitated with ethereal HCI. Yield: 13.7 g (88%), melting point: 266 C, [a]p2o =(-) 37.0 (c=1 in MeOH).
The following compounds were also obtained, inter alia:
Example 2: (2R,6S,2"S)-10-Amino-3-f2-(benzyloxy)propyll-1,2,3,4,5,6-hexahvdro-5 6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
NH2 /~.~
MIH Me Me Me Me Prepared from compound 2a analogously to Example 1;
melting point: 257 C, [a]o20 = (-) 29,3 (c=1 in MeOH).
io Example 3: (2R,6S,11 R,2GS)-10-Amino-3-[2(2,6-difluorophenyl-methoxv)-progYl-1,2,3,4,5,6-hexahydro-6,11-d imethyl-2,6-methano-3-benzazocine-dihvdrochloride:
NHZ
N F
11H Me Me Me Prepared from compound 2c analogously to Example 1;
melting point: 232 C, [a]p 4.1 (c=1 in MeOH).
Example 4: (2R,6S, 11S, 2"S)-10-Amino-3-f2(2,6-difluoroahenyl-methoxy)-proQyll-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine-dihvdrochloride:
o p 5EMeF
Me Prepared from compound 2d analogously to Example 1;
melting point: 267 C, Ho20 =(-) 2.4 (c=1 in MeOH).
Example 5: (2R,6S, 2"S)-10-Amino-3-f2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihydrochloride:
O \ 1 NHZ / l N F
,,,H Me Me Prepared from compound 2n analogously to Example 1;
melting point: 187 C, [a]o20 = 19.7 (c=1 in MeOH).
Example 6: (2R,6S,2S')-10-Amino-3-f2(2,6-difluorophenyl-methoxy)-butyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride NHOLMe F Me Me Me lo Prepared from compound 2m analogously to Example 1;
melting point: 200 C.
Example 7: (2R,6S,2S')-10-Amino-3-f2(2,6-difluorophenyl-methoxy)-isopentLrll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride NHZ
N F
p Me Me Me Me Me Prepared from compound 2nc analogously to Example 1;
melting point: 274 C, [a]p20 =(-) 21.8 (c=1 in MeOH).
Example 8: (2R,6S)-10-Amino-3-f2(2,6-difluorophenyl-methoxv)-ethyll-1,2 3 4 5 hexahydro-6,11,11-trimethvl-2,6-methano-3-benzazocine-dihvdrochloride F p H
Me _ Me Me Prepared from compound 2f analogously to Example 1;
melting point: 270 C, [a]p =(-) 77.4 (c=1 in MeOH).
Example 9: (2R,6S,2S')-10-Amino-3-f2(benzyloxy)-butyll-1.2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride NHZ
N
H Me Me = Me Me 1o Prepared from compound 21 analogously to Example 1;
melting point: >190 C (decomposition);.
Example 10: (2R,6S)-10-Amino-3-[2(benzyloxy)-ethyll-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihyd rochloride Q
NHZ N/--, O
H
Me Me Me Prepared from compound 2h analogously to Example 1;
melting point: 220 C;.
. =
Example 11: (2R,6S)-10-Amino-3-f2(2-fluorophenyl-methoxv)-ethvll-1,2,3,4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride / ' ~
NH2 ~
N/O F
H
Me = Me Me Prepared from compound 2i analogously to Example 1;
melting point: 220 C;.
Example 12: (2R,6S)-10-Amino-3-f3(2,6-difluorophenyloxy)-propyll-1.2,3,4,5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride F / t ~
NH2 N/"~0 F
H
Me = Me Me io Prepared from compound 2q analogously to Example 1;
melting point: 250 C;.
Example 13: (2R,6S)-10-Amino-3-f4(2,6-difluorophenyl)-butyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride F
NHZ
N F
H
Me Me Me Prepared from compound 2r analogously to Example 1;
melting point: 250 C;.
Example 14: (2R,6S)-10-Amino-3-f2(2,4-difluorophenyl-methoxy)-ethyll-1,2 3 4 5 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride F
NHZ N~/O F
H
Me Me Me Prepared from compound ~ analogously to Example 1;
melting point: 220 C;.
Example 15: (2R,6S)-10-Amino-342(2,6-dimethylphenyl-methoxv)-ethyll-1,2 3 4 5 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride / y \
m NH2 ~
N/ Me H
Me = Me Me lo Prepared from compound 2k analogously to Example 1;
melting point: 245 C;.
Example 16: (2R,6S,2"S,5"S)-10-Amino-3-f5"-phenyl-tetrahydrofuran-2"-yl)methylL
1.2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
H
N H
,= M15 Me ft Prepared from compound 2p analogously to Example 1;
melting point: 253 C, [a]p20 =(-) 135.40 (c=1 in MeOH).
Example 17: (2R.6S,2"R,5"S)-10-Amino-3-f5"-phenyl-tetrahvdrofuran-2"-vl)methyll-1,2,3,4.5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride=
H_ NHZ
N
,,,, H O ,"'H
-Me ~ ~
- Me Me Prepared from compound 2o analogously to Example 1;
5 melting point: 255 C;.
Example 18: (2R,6S,2"S)-10-Acetamino-3-f2(2,6-benzyloxy)propyll-1 2 3 4 5 6-hexahYdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride:
HN Me I \ .~H
/ Me Me Me 1o 2 mL of acetic anhydride are added to 1.1 g (2.4 mmol) of (2R,6S,2"S)-10-amino-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride (Example 2) and 5 mL of triethylamine in 50 mL of dichloromethane and the mixture is stirred for 0.5 h at room temperature. It is then evaporated down in vacuo, combined with 100 mL of ether and washed twice with 15 mL of water. The organic phase is dried, the solvent is eliminated in vacuo, the residue is taken up in ether and the hydrochloride is precipitated with ethereal HCI.
Yield: 0.8 g (73%), melting point: >100 C, [a]p20 = (-) 56.5 (c=1 in MeOH).
Example 19: (2R,6S.2"S)-10-Acetamino-3-f2(2,6-difluorophenyl-methoxy)-propyll-20 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride=
F / , HN J~ Me N/~( O ~
F
\ ,H 1Me I / Me Me Me Prepared from Example 1 analogously to Example 18;
melting point: 125 C, [a]p20 =(-) 58,7 (c=1 in MeOH).
Example 20: (2R,6S,2"S)-10-Formylamino-3-f2(2,6-difluorophenyl-methoxv)-propyl]_ 1 ,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride=
F
l~H O N F
HN p õH Me Me = Me Me 0.5 g (1.2 mmol) of (2R,6S,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine (Example 1) are combined with 10 mL of 97% formic acid and refluxed for 1 h. The mixture is then evaporated down in vacuo, the residue is combined with ice and 50 mL of ammonia and extracted twice with 50 mL of ethyl acetate. The combined organic phase is washed with 30 mL of water, dried and the solvent is eliminated in vacuo. The lo residue is taken up in ether and the hydrochloride is precipitated with ethereal HCI.
Yield: 0.3 g (52%), melting point: amorphous, [a]D 20 = (-) 41.6 (c=1 in MeOH).
Example 21: (2R,6S,2"S)-10-methylamino-3-f2(2,6-difluorophenyl-methoxv)-propyll-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride=
HN'Me O 9 N F
H Me Me = Me Me 1.0 g (2.4 mmol) of (2R,6S,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine (Example 1) are dissolved in 10 mL of ethyl acetate, and 1 mL of triethylamine and 1 mL of trifluoroacetic acid anhydride is added. After 10 min the mixture is washed twice with 10 mL of water, the organic phase is dried and the solvent is eliminated in vacuo.
The residue is taken up in 10 mL of dimethylacetamide and 0.5 g of NaH is added.
After 15 min. 1 mL of methyliodide is added and the mixture is stirred for 1 h at 50 C.
Then the solvent is eliminated in vacuo, the residue is combined with 20 mL of methanol and 2 mL of 20% NaOH and stirred for 30 min. at 60 C. The solution is once more evaporated down in vacuo, the residue is combined with 50 mL of water and extracted twice with 100 mL of ether. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue is chromatographed on silica gel. The appropriate fractions are combined and the hydrochloride is precipitated with ethereal HCI. Yield: 0.4 g (35%), melting point: 243 C, [a]p20 =(-) 20.5 (c=1 in MeOH).
Example 22: (2R,6S,2"S)-10-dimethylamino-3-f2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
Me,, NMe OF P
N F
.,,1H Me Me = Me Me A suspension of 0.4 g (1 mmol) of (2R,6S,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-1o benzazocine (Example 1) and 0.3 g of NaBH4 in 7 mL of THF is added batchwise to a solution of 0.6 mL of 37% formalin and 1.2 mL of 3N H2SO4 cooled to -10 C.
After it has all been added, the mixture is left to react for 10 min, ammonia is added and the resulting mixture is extracted twice with 20 mL of ethyl acetate. The organic phase is dried, the solvent is eliminated in vacuo, the residue is taken up in ether and the hydrochloride is precipitated with ethereal HCI. Yield: 0.5 g (97%), melting point:
125 C, [a]o = (-) 20.0 (c=1 in MeOH).
Example 23: (2R,6S,2"S)-10-ethylamino-3-(2(2,6-difluorophenvl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
HN'Et OF P
N F
,,,1H Me Me = Me Me 1.1 g (2.4 mmol) of (2R,6S,2"S)-10-acetamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine (Example 1) are dissolved in 30 mL of THF, combined with 0.5 g of NaBH4 and 1.5 mL of BF3-etherate and refluxed for 6 h. The mixture is allowed to cool, 30 mL
of MeOH and 60 mL of 2 N HCI are added and the resulting mixture is refluxed for a further 30 min. Then the solvent is eliminated in vacuo, the residue is combined with conc. ammonia and extracted twice with 30 mL of ethyl acetate. The combined organic phase is washed once with 20 mL of water, dried and the solvent is eliminated in vacuo. The residue is taken up in acetone and the hydrochloride is precipitated with ethereal HCI. Yield: 0.95 g(89 l0), melting point: 242 C, [a]p20 =(-) 24.8 (c=1 in MeOH).
Example 24: (2R,6S,2"S)-10-Fluoro-3-[2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride:
F
N F
0 p -IH Me Me = Me Me 1.5 g (3.6 mmoi) of (2R,6S,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine (Example 1) are io placed in 30 mL of dioxan, combined with 3 g of NOBF4 in 30 mL of dioxan and stirred for 1 h at 90 C. Then the solvent is eliminated in vacuo, the residue is combined with 50 mL of ethyl acetate and washed once with 30 mL of dilute ammonia and once with 30 mL of water. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue is chromatographed on silica gel. The appropriate fractions are combined and the hydrochloride is precipitated with ethereal HCI. Yield: 0.5 g (33%), melting point: 190 C, [a]D 20 =(-) 27.3 (c=1 in MeOH).
Example 25: (2R,6S,2"S)-10-Amino-7-methyl-3-f2-(2,6-difluorophenyl-methoxy)-propyll-1.2,3,4,5,6-hexahydro-6,11.11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
NH2 0F p N~ F
H Me Me Me Me Me Prepared from 2s analogously to Example 1;
melting point: 236 C;.
Example 26: (2R,6S,2"S)-10-Amino-7-methyl-3-[2-(benzyloxy)propv4]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-d ihydrochloride:
~1 NH2 0 \
AMN Me Me e Me M
e Prepared from 2t analogously to Example 1;
melting point: 227 C, [a]o20 = (-) 31,8 (c=1 in MeOH).
Example 27: (2R,6S,2"S)-10-Formylamino-7-methyl-3-f2-(benzyloxy)propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride:
I HN H ~ o/ , ~
N
,,H Me Me = Me Me Me Prepared from Example 26 analogously to Example 20;
melting point: 141 C;.
Example 28: (2R,6S,2"S)-10-Formylamino-7-methvl-3-(2-(2,6-difluorophenyl-methoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
J~.
HN H OF P
N F
H Me Me Me Me Me Prepared from Example 28 analogously to Example 20;
melting point: >105 C C (decomposition), [a]D 20 = (-)42,2 (c=1 in MeOH);.
Example 29: (2R,6S,2"S)-10-methylamino-7-methyl-3-f2-(benzvloxy)propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihyd rochloride=
HN'Me ~O 0 N
'H Me Me - Me Me Me Prepared from Example 26 analogously to Example 21;
5 melting point: >100 C (decomposition);.
Example 30: (2R,6S,2"S)-10-methylamino-7-methvl-3-l2-(2,6-difluorophenvl-methoxy)propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethvl-2,6-methano-3-benzazocine-dihydrobromide:
HN'Me O
N~ F
õI~H Me Me Me 10 Me Me Prepared from Example 25 analogously to Example 21;
melting point: 221 C (decomposition), [a]p = (-)29,4 (c=1 in MeOH);.
Example 31: (2R,6S,2"S)-10-Amino-8-methyl-3-f2-(benzyloxy)propyll-1 2 3 4 5 6-T5 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride=
NH2 N~
\ õ11H Me MeI Me Me Me Prepared analogously to Example 1; melting point: 250 C;.
Example 32: (2R,6S. 2"S)-10-Amino-7-chloro-3-f2(benzyloxv)-nropyIj-1 2 3 4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride:
N
,, Me Me - Me CI Me 4.5 g (10 mmol) of (2R,6S,2"S)-10-amino-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride (Example 2) are dissolved in 90 mL of MeOH and 90 mL of glacial acetic acid, 1.45 g of NCS
(N-chloro-succinimide) are added and the mixture is stirred for 4 h at room temperature. Then the solvent is eliminated in vacuo, the residue is taken up in 100 mL of aqueous ammonia solution and extracted twice with 50 mL of ethyl acetate.
lo The combined organic phase is dried, the solvent is eliminated in vacuo and the residue is chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo and the hydrochloride is precipitated with ethereal HCI.
Yield: 1.3 g (27%); melting point: 222 C, [a]o =(-)17.4 (c=1 in MeOH);.
Example 33: (2R,6S, 2"S)-10-Amino-7,9-dichloro-3-f2(benzyloxy)-propyll-1 ,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
NH2 aN
CI
\Me Me Me C1 Me Prepared together with Example 32;
Separation by chromatography produces:
Yield: 0.6 g (12%); melting point: 197 C, [a]p20 = 11,0 (c=1 in MeOH);.
Example 34: (2R,6S, 2"S)-10-Amino-7-chloro-3-f2(2,6-difluorophenyl-methoxv)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
F /
~
NH2 ~ \
F
UNII'-~
I \ H H Me Me - Me CI Me Prepared from Example 1 analogously to Example 32;
melting point: 247 C;.
Example 35: (2R,6S, 2"S)-10-Amino-7-bromo-3-f2(benzyloxv)-propyll-1,2,3 4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
N
U
õ~
'H Me *Me Br Me Prepared from Example 2 analogously to Example 32 using NBS;
melting point: 215 C, [aJo20 =(-)17.3 (c=1 in MeOH);.
Example 36: (2R,6S, 2"S)-10-Amino-7,9-dibromo-3-f2(benzyloxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochioride:
n'z'~
NH2 ~ ~
):* 1H
Br Me Me Br Me Prepared together with Example 35 analogously to Example 33;
melting point: 177 C, [a]o20 = 11.5 (c=1 in MeOH);.
Example 37: (2R,6S, 2"S)-10-Amino-7-bromo-3-f2(2,6-difluorophenyi-methoxv)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
N F
Me (LI-f(.IH
Me _ Me Br Me Prepared from Example 1 analogously to Example 32 using NBS;
melting point: 233 C, [a]p20 =(-)20.5 (c=1 in MeOH);.
Example 38: (2R,6S, 2"S)-10-Amino-7,9-dibromo-3-f2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-io dihydrochloride:
F / ' NH2 0\
N F
Br Me ,,,H
Me : Me Br Me Prepared together with Example 37 analogously to Example 36;
melting point: 236 C, [a]p20 = 5,9 (c=1 in MeOH);.
Example 39: (2R,6S, 2"S)-10-Amino-9-bromo-3-f2(2,6-difluorophenvl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
F
NH0 Br )JaN
Me F
Me = Me Me Prepared together with Example 37 analogously to Example 32;
melting point: 252 C, [a]D 20 =(-)14,6 (c=1 in MeOH);.
Example 40: (2R,6S,2"S)-10-Amino-7-fluoro-3-[2-(benzvloxy)propyl)-1 2 3 4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride=
o NHZ
H Me Me Me F Me Prepared from 2v analogously to Example 1;
melting point: 150 C;.
Example 41: (2R,6S,2"S,5"S)-10-Amino-7-methyl-3-f5"-phenyl-tetrahydrofuran-2"-Yl)methyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2 6-methano-3-benzazocine-dihydrochloride:
H
N H
aNNI
H p H
~ / -Me = Me Me Me Prepared from 2u analogously to Example 1;
melting point: 250 C;.
Example 42: (2R,6S,2"S,5"S)-10-methvlamino-7-methvl-3-f5"-phenvl-tetrahydrofuran-2"-vl)methvll-1,2,3,4,5,6-hexahydro-6 11 11-trimethyl-2 6-methano-3-benzazocine-dihvdrochloride:
HN" Me H
N
H p Me Me Me Me Prepared from Example 41 analogously to Example 21;
melting point: 250 C;.
Example 43: (2R,6S,2"S,5"S)-10-Formvlamino-7-methvl-3-f5"-phenvl-tetrahydrofuran-2"-yl)methyll-1,2,3,4,5,6-hexahvdro-6 11 11-trimethvl-2 6-methano-3-benzazocine-dihvdrochloride:
Prepared from Example 41 analogously to Example 20;
melting point: 250 C;.
Example 44: (2R,6S, 2"S)-10-Amino-7-trifluoromethyl-3-f2(benzyloxv)-propyl1 1,2,3,4,5,6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihvdrochloride=
NHZ
õ..H Me CF3 Me Prepared from 2w analogously to Example 1;
5 melting point: 165 C;.
Example 45: (2R,6S, 2"S)-10-Amino-7-(4-methylphenyl)-3-f2(2 6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihydrochioride:
N~ F
1,1H Me Me = Me Me 10 Me Prepared from 2x analogously to Example 1;
melting point: 219 C, [a]p20 =(-)19.5 (c=1 in MeOH).
15 The compounds according to the invention may be administered orally, transdermally, nasally, by inhalation or parenterally. The compounds according to the invention occur as active ingredients in conventional preparations, for example in compositions which consist essentially of an inert pharmaceutical carrier and an effective dose of the active substance, such as for example tablets, coated tablets, 20 capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal systems etc.. An effective dose of the compounds according to the invention is between 1 and 1000, preferably between 1 and 500, most preferably between 5-300 mg/dose for oral administration, and between 0.001 and 50, preferably between 0.1 and 10 mg/dose for intravenous, subcutaneous or 25 intramuscular administration. For inhalation, according to the invention, solutions containing 0.01 to 1.0, preferably 0.1 to 0.5 % active substance are suitable.
For administration by inhalation the use of powders is preferred. It is also possible to use the compounds according to the invention as a solution for infusion, preferably in a physiological saline or nutrient saline solution.
The compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances. Suitable preparations include for example tablets, capsules, suppositories, solutions, elixirs, emulsions or 1o dispersible powders.
Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers.
Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g of. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Solutions for injection are prepared in the usual way, e.g of. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.
Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
A therapeutically effective daily dose is between 1 and 1000 mg, preferably 10 mg per adult.
The Examples which follow illustrate the present invention without restricting its scope:
Examples of pharmaceutical formulations A) Tablets per tablet active substance 300 mg lactose 240 mg corn starch 340 mg polyvinylpyrrolidone 45 mg magnesium stearate 15 mg 940 mg The finely ground active substance, lactose and some of the com starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the 3o remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.
B) Tablets per tablet active substance 80 mg corn starch 190 mg lactose 55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodium-carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
C) Coated tablets per coated tablet Active substance 5 mg Corn starch 41.5 mg Lactose 30 mg Polyvinylpyrrolidone 3 mg Magnesium stearate 0.5 mg 80 mg The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45 C and the granules are then passed through the same screen. After the magnesium stearate has been mixed in, convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine. The tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc. The finished coated tablets are polished with wax.
D) Capsules per capsule Active substance 1 50 mg Corn starch 268.5 mg Magnesium stearate 1.5 mg 420 mg The substance and corn starch are mixed and moistened with water. The 1o moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The finished mixture is packed into size 1 hard gelatine capsules.
E) Ampoule solution active substance 50 mg sodium chloride 50 mg water for inj. 5 ml 2o The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain mg, 25 mg and 50 mg of active substance.
F) Suppositories Active substance 50 mg Solid fat 1650 mg 1700 mg The hard fat is melted. At 40 C the ground active substance is homogeneously dispersed. It is cooled to 38 C and poured into slightly chilled suppository moulds.
Suitable auxiliary bases according to the invention include organic amines such as, for example, dimethylaminopyridine, pyridine or tert. amines such as trimethylamine, triethylamine, diisopropylethylamine or DBU (diazabicycloundecene). Of the abovementioned amines, the tert. amines are preferably used, and triethylamine is most preferably used as the auxiliary base. The reaction is carried out in aprotic, organic solvents, preferably in solvents selected from among dimethyiformamide, dimethylacetamide, methylene chloride, toluene or tetrahydrofuran. Methylene 1o chloride should be mentioned as being particularly preferred. The reactions to form the triflates 3 are preferably carried out at temperatures below ambient temperature, more preferably at -50 C to 0 C, most preferably at between -30 C and -5 C.
After 0.5 to 4 h stirring is continued at ambient temperature until the reaction is complete (about 1-12 h). After working up, the crude products 3 thus obtained are reacted, without further purification, in an aromatic organic solvent, preferably selected from among toluene, benzene or xylene, most preferably toluene, with palladium as catalyst, preferably in the presence of a phosphine ligand, with a nitrogen source, preferably with ketimines, most preferably with benzophenonimine. Suitable palladium catalysts according to the invention include tris(dibenzylidene-acetone)-2o dipalladium, palladium(II)acetate or tetrakistriphenylphosphine-palladium, for example. Suitable phosphine ligands which may be used include, for example, ligands selected from among DPPF, BINAP, p-toIBINAP, PPh2-CHMe-P(tBu)2, phosphine-substituted ferrocenes or triphenylphosphine. Tris(dibenzylidene-acetone)-dipalladium/BINAP is preferably used as the catalyst system. The reaction is preferably carried out with the exclusion of moisture and oxygen and preferably at elevated temperature. The solvent used is preferably refluxed during the reaction.
The imine adduct obtained as an intermediate can be converted by acid hydrolysis, preferably with dilute inorganic acids, most preferably with dilute hydrochloric acid, into the compounds according to the invention 1 (where X=NH2). The products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g.
the hydrochlorides.
As can be seen from the above remarks, the triflates of general formula 3 are of central importance in the synthesis of the compounds of general formula 1 according to the invention.
Accordingly, another aspect of the present invention relates to the intermediate compounds of general formula 3 R' O'\ ,O ~
F3C~S~0 4N ~A ~ R2 R3 R4 wherein the groups R1, R2, R3, RT, R4, R5, R6 and A may be as hereinbefore defined.
5 In order to synthesise the compounds according to the invention of general formula 1 where X#NH2 the following process may be used.
Compounds of formula 1 wherein X = NHC1-C6-alkyl or N(C1-C6-alkyl)2 may be obtained by methods known per se by alkylation of 1 where X=NH2, by reductive io amination or by acylation, optionally in the presence of organic bases, with subsequent reduction.
For alkylation, the following method may be used. A compound of general formula 1 where X=NH2 is dissolved in a polar organic solvent such as dimethylformamide, dimethylacetamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide or methylene chloride. The resulting solution is mixed with a base and a corresponding alkylating agent. Suitable bases include alkali- and alkaline earth metal hydrides, preferably sodium hydride. Suitable alkylating agents include alkyl halides, such as alkyl chloride, alkyl bromide, particularly alkyl iodide and alkyl tosylates, mesylates, triflates, dialkylsulphates. After conventional working up the alkylated compounds of general formula 1 may be purified by chromatography on silica gel or by crystallisation, optionally in the form of the pharmacologically acceptable addition salts thereof, preferably as hydrochlorides.
In order to prepare the compounds of general formula 1 by reductive amination the amines 1 where X=NH2 are mixed with aldehydes or ketones in the presence of acids such as dilute hydrochloric acid, dilute acetic acid or dilute sulphuric acid, under otherwise conventional reaction conditions, with cooling, preferably at -50 C to ambient temperature, most preferably between -30 C and 0 C, and the Schiff bases or iminium salts thus formed as intermediates are then reduced. The reduction is carried out using metal hydrides such as sodium borohydride, LiAIH4, Li-alkoxyhydrides, NaBH4, NaBHCN3, NaBH(OAc)3 ; sodium borohydride is preferably used. After working up in the usual way, the alkylated compounds of general formula 1 may be purified by chromatography on silica gel or by crystallisation, optionally in the form of their pharmacologically acceptable acid addition salts thereof, preferably as hydrochlorides.
Compounds of formula 1 where X = NHCO(Cl-C6-alkyl) may be prepared by methods known perse by acylating 1 where X=NH2, preferably with acid chlorides or anhydrides. For this, the amino compound of formula 1 where X=NH2 is suspended in an organic solvent, combined with an organic base and the desired acid chloride or anhydride is added. The mixture is kept at ambient temperature for 40 to 60 minutes, preferably 25 to 45 minutes at ambient temperature. Suitable organic io solvents are dimethylformamide, dimethylacetamide, methylene chloride, toluene or tetrahydrofuran, methylene chloride being preferred. Suitable organic bases are dimethylaminopyridine, pyridine, tert. amines, e.g. trimethylamine, triethylamine, diisopropylethylamine, DBU (diazabicycloundecene). After working up, the products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g.
the hydrochlorides.
Starting from the compounds of formula 1 with X = NHCO(Cl-C6-alkyl) which may be obtained by the method described above, compounds of formula 1 with X =
2o NH(Cl-C6-alkyl), for example, may also be obtained by reduction with metal hydrides such as LiAIH4, Li-alkoxyhydrides, NaBH4, NaBHCN3, NaBH(OAc)3, preferably sodium borohydride. These reactions are preferably carried out in ethereal organic solvents, preferably in tetrahydrofuran or dioxan in the presence of Lewis acids, preferably boron trifluoride etherate, at elevated temperature, preferably above 50 C, most preferably at the reflux temperature of the solvent used.
After working up, the products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g. the hydrochlorides.
3o The formylated compounds of formula 1(X =NHCOH) may be obtained, for example, by reacting the compounds of formula 1 where X=NH2 with formic acid at elevated temperature, preferably at reflux temperature. After working up, the products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g.
the hydrochlorides.
The fluorine-substituted compounds 1( with X= F) may be obtained by methods known per se by diazotisation of 1 where X=NH2 and subsequent decoction with BF4 . Preferably, the reaction is carried out with NOBF4 as the diazotisation and fluorination reagent in ethereal solvents, preferably in tetrahydrofuran or dioxan at elevated temperature, preferably above 50 C, most preferably at the reflux temperature of the solvent used. After working up, the products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g. the hydrochlorides.
The 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols (2) designated as starting compounds in diagram 1 may be obtained using methods known from the prior art. In this context, reference is hereby made to European Patent Application 1o EP 521422 and the International Patent Applications WO 97/06146 and WO
99/14199.
Compounds of general formula 2 wherein R3 denotes hydrogen, are prepared starting from the compounds of general formula 4 analogously to the methods of synthesis described in W099/14199. In order to prepare compounds of general formula 1 wherein R3 does not denote hydrogen, the compounds of general formula 4 first have to be modified. This is done by analogously using methods of synthesis known in principle as described in the following reaction plans.
For example, a p-methyl substituent (R3 equals methyl) may be introduced using the method given in Diagram 2.
In order to prepare the brominated compound of formula 5 the compounds of formula 4 are dissolved in a suitable solvent, preferably in acetic acid or trifluoroacetic acid, most preferably in a mixture of acetic acid and trifluoroacetic acid and NBS (N-bromosuccinimide) is added batchwise at 0-23 C, preferably at 10 C.
The reaction is complete after about 1 to 5 hours. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 5.
Me. Me. Me. O ~-O NH O NH N \/
\ \ --~- \
Ra R R a -~ crR6R
Rs R Br Rs B4 5 ~ ~
OH N \/ Me.O N 1/ Me.O N
\ \ \
Ra 1*- Ra Ra Me R9 Me RR8 7 R
OH OH N ~A IRz NH
Ra Ra R R
Me R Me Rs 2 (where R3 = methyl) - (where R3' = hydrogen) Diagram 2:
The benzylation of the compounds 5 to form the compounds 6 is preferably carried out in an organic solvent, preferably in a solvent selected from among 5 dichloromethane, dimethylformamide and dimethylacetamide, particularly preferably in dimethylacetamide. For this, the compounds 5 are dissolved in the solvent and benzyl chloride is added in the presence of a base at a temperature of 0-50 C, particularly preferably at ambient temperature (about 23 C). Suitable bases are organic or inorganic bases. Suitable inorganic bases are the alkali metal- or alkaline io earth metal carbonates of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. Suitable organic bases are preferably organic amines, particularly preferably diisopropylethylamine, triethylamine, cyclic amines such as DBU, or pyridine. After the benzyl chloride has all been added the mixture is stirred for a further I to 6, preferably 2 to 4 hours at elevated temperature, preferably at about 50-120 C, particularly preferably at about 100 C, but at most at the boiling temperature of the solvent in question. The product is worked up in the usual way.
The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 6.
The compounds 7 are prepared from the compounds 6 by reacting with suitable formulating reagents. For this, the compounds 6 are dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent, preferably in an ethereal solvent selected from among diethylether, tetrahydrofuran and dioxan, preferably in diethylether, and butyllithium, preferably dissolved in n-hexane, is added at low temperature, preferably at below -20 C, particularly preferably at a temperature between -50 C and -78 C. After about 0.5 to 2 hours stirring in the temperature range mentioned above, the formulating reagent, preferably dimethylformamide, is 1o added and stirred for another 0.5 to 2 hours, optionally at slightly elevated temperature, preferably at -30 C to 0 C, particularly preferably at about -10 C. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 7.
Reduction of the compounds 7 leads to the methyl compounds 8. For this the compounds 7 are dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent, preferably in an ethereal solvent selected from among diethylether, tetrahydrofuran and dioxan, preferably in tetrahydrofuran, and a suitable reducing 2o agent, preferably a metal salt hydride, particularly preferably NaBH4 or NaCNBH3, preferably NaCNBH3, is added. It is also necessary to add boron trifluoride, or BF3-etherate. After the addition of the reducing agent the mixture is stirred for another 1 to 6 hours, preferably 2 to 4 hours at constant temperature, preferably at ambient temperature. After the addition of a protic solvent, particularly preferably a lower alcohol selected from among methanol, ethanol or isopropanol, particularly preferably methanol and hydrolysis with an aqueous acid, preferably with aqueous hydrochloric acid, the mixture is stirred for a further 0.5 to 4 hours, optionally at elevated temperature, preferably at a temperature above 50 C, particularly preferably at the reflux temperature of the solvent. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 8.
The cleaving of the methoxy group in 8 leads to the hydroxy compounds 9 and is carried out with the use of strong acids, such as HI and HBr, particularly preferably concentrated HBr at elevated temperature, preferably at more than 50 C, particularly preferably at reflux temperature. There is no need to use a solvent if HBr is used, for example. The reaction is complete after about 1 to 6, preferably 2 to 4 hours.
The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 9. The cleaving of the methoxy group in 8 to yield the hydroxy compounds 9 may alternatively be carried out using BBr3 analogously to the procedure described for reacting the compounds 17 to obtain the hydroxy compounds 18.
The compounds 10 may be obtained from the compounds 9 by hydrogenolytic cleaving of the benzyl group. This reduction is preferably carried out by catalytic TM
hydrogenation, preferably on palladium catalysts or on Raney nickel, particularly preferably on palladium catalysts in alcoholic solvents, preferably in methanol, at lo ambient temperature. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on their crystallisation tendencies.
The compounds of general formula 2 may be prepared starting from the compounds 15 of general formula 10 analogously to the methods of synthesis described in W099/14199.
A p-fluoro substituent is introduced by the method shown in diagram 3. To do this, a compound of formula 6 is dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent, preferably in an ethereal solvent selected from among diethylether, tetrahydrofuran and dioxan, preferably in diethylether, and buthyllithium, preferably dissolved in n-hexane, is added at low temperature, preferably at below -20 C, particularly preferably at a temperature between -50 C and -78 C. After about 0.5 to 2 hours stirring in the temperature range specified above, a suitable fluorinating agent, preferably N-fluorobenzenesulphonimide, dissolved in one of the solvents mentioned above, is slowly added and stirring is continued for another 0.5 to 2 hours at constant temperature. The product is worked up in the usual way.
The products are purified either by crystallisation or by chromatography depending on their crystallisation tendencies.
- - ~
Me, O N Me. O N OH N
~
\ \ \
Ra --~ ~/ Ra -~ I Ra Br R6 F R6 F R6 R 12 ~
R
OH ~A Iz N R OH NH
R( / Ra qF \
R ~6R
(where R3 = fluorine) 13 (where R3' = hydrogen) Diagram 3:
The compounds 11 are converted into the hydroxy compounds 12 as described for the reaction of the compounds 8 to form the compounds 9. The conversion of the compounds 12 into the debenzylated compounds 13 is carried out as described for the reaction of the compounds 9 to form the compounds 10.
The compounds of general formula 2 may be prepared starting from the compounds of general formula 13 analogously to the methods of synthesis described in lo W099/14199.
A p-CF3 substituent is introduced according to the method of synthesis shown in diagram 4.
In a first step, a compound of formula 4 is converted into an iodide of formula 14.
This reaction is carried out analogously to the procedure described for reacting 4 to 5 using NIS (N-iodosuccinimide).
From the compounds 14 it is possible to obtain the N-protected compounds 15 wherein PG denotes an amino protecting group. The protecting group used may be 2o any of the groups commonly used to protect the amino function. Examples include the benzyl group, the benzyloxycarbonyl and tert.-butyloxycarbonyl group, the latter being preferred. The following method is used to introduce the tert.-butyloxycarbonyl group. The reaction is preferably carried out in an organic solvent, preferably in a solvent selected from among dichloromethane, dimethylformamide and dimethylacetamide, particularly preferably in dichloromethane. For this, the compounds 14 are dissolved in the solvent and in the presence of a base at a temperature of -50 C to 10 C, preferably at -20 C to 0 C, and an inorganic base is added. The inorganic base may be, for example, an alkali metal- or alkaline earth metal hydroxide of lithium, sodium, potassium, calcium such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide and preferably potassium hydroxide, optionally in aqueous solution. Then di-t-butyldicarbonate, optionally dissolved in one of the abovementioned organic solvents, is added. After it has all been added, the mixture is stirred for another 0.5 to 6, preferably 1 to 3 hours, optionally at fairly elevated temperature, preferably at ambient temperature.
The product is worked up in the usual way. The products are purified either by io crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 15.
Me, Me, O NH O NH Me.O IPG
N
a R 30 Ra ~ a R6 Rs Rs R
I ~
R' OH N/' A Rz OR' NH Me.O PG
N
a aE
R ER ~ R ( Ra Rs s CF3 R6 CF3 R6 CF Re R
2(where R3 = CF3 17 (R' =Me) 16 (where R3' = hydrogen) 18 (R' =H) Diagram 4:
The trifluoromethyl compounds 16 may be prepared from the compounds 15. For this, a compound 15 is dissolved in a suitable organic solvent, preferably in a polar organic solvent selected from among dimethylacetamide, dimethylsulphoxide or dimethylformamide, particularly preferably dimethylformamide, and methyl fluorosulphonyl-difluoroacetate and Cul, preferably anhydrous Cul, are added.
Then the reaction mixture is heated to a temperature in the range from 50-90 C, particularly preferably to 70 C. It is stirred at constant temperature for between 1 day and 4 days, preferably about 2 days. Depending on the progress of the reaction it may be necessary to add more methyl fluorosulphonyl-difluoroacetate and Cul.
The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 16.
The cleaving of the amino protecting group starting from the compounds 16 yields the compounds 17. The processes for cleaving the protecting groups used are known from the prior art. At this point, we should mention a possible alternative method of cleaving the tert.-butyloxycarbonyl protecting group, solely by way of example. This is done by reacting 16 with trifluoroacetic acid in a suitable organic solvent, preferably in dichloromethane at ambient temperature within a period of 1 to 3 hours. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies 1o of the compounds 17.
The cleaving of the methoxy group starting from the compounds 17 yields the compounds 18 and is carried out by reacting with BBr3 solution in the presence of trifluoroacetic acid in a suitable organic solvent, preferably in dichloromethane at low temperature, preferably at below -50 C, particularly preferably between -75 C
and -60 C. After the reactants have all been added at the temperature specified above the reaction is completed by stirring at a temperature in the range from -20 C
to C, preferably at about 0 C, over a period of 4 to 12 hours. The product is worked up in the usual way. The products are purified either by crystallisation or by 20 chromatography depending on the crystallisation tendencies of the compounds 18.
Alternatively to the method described above, the cleaving of the methoxy group in 17 to form the hydroxy compounds 18 may also be carried out using strong acids.
On this subject we refer the reader to the corresponding remarks regarding the reaction of the compounds 8 to form the hydroxy compounds 9.
The compounds of general formula 2 may be prepared starting from the compounds of general formula 18 analogously to the methods of synthesis described in W099/14199.
3o A p-phenyl substituent may also be introduced as illustrated in diagram 5.
Me. 0 Me.O N Pd-cat. N
Ra OH
Ra R&%H R5 R R
Br R B
R ~
Ri OH NH
J:>' OH ~A
N
R
Ra Rs I i 2 (where R3 = substituted phenyl) 20 R (where R3' = hydrogen) Dia rq am 5:
Starting from the compounds 6 the compounds 19 are obtained by reacting with suitably substituted borates and subsequent transmetallisation with palladium(0) compounds. Phenylboric acids substituted with the group R are used as the borates.
For the reaction, 6 is dissolved in a suitable organic solvent, preferably in an anhydrous, oxygen-free organic solvent, preferably in an ethereal solvent selected from among diethylether, tetrahydrofuran and dioxan, preferably in dioxan, and the abovementioned boric acid derivative, potassium phosphate and a suitable io palladium(O) catalyst are added successively. The Pd(0) catalyst according to the invention may be tris(dibenzylidene-acetone)-dipalladium, palladium(II)acetate or tetrakistriphenylphosphine palladium, for example, preferably tris(dibenzylidene-acetone)-palladium(0). Phosphines or phosphites also have to be added. The phosphine ligands may be, for example, ligands selected from among DPPF, BINAP, p-toIBINAP, PPh2-CHMe-P(tBu)2, phosphine-substituted ferrocenes, triphenylphosphine or trimethylphosphite, preferably trimethylphosphite. After all the reaction components have been added, the mixture is stirred at elevated temperature, preferably at a temperature above 50 C, particularly preferably at the reflux temperature of the solvent, for 0.5 to 2 hours. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 19.
The compounds 19 are converted into the hydroxy compounds 20 as described for the reaction of the compounds 8 into the compounds 10 (via 9).
The compounds of general formula 2 may be prepared starting from the compounds of general formula 20 analogously to the methods of synthesis described in W099/14199.
5 Halogen-substituted derivatives may be obtained, for example, by reacting the compounds 1 according to the invention wherein X denotes NH2 and R3 denotes hydrogen, with NIS, NBS or NCS (Diagram 6). As a rule, mixtures of the para-, ortho-and para-/ortho-disubstituted compounds are obtained, which can be separated by chromatography.
R
/
NH2 N~A \ R2 NHaIS
R4 where Ha CI, Br s Rs R
1 (where X = NH2;
(R3 and R3 = hydrogen);
/ R
a R' R' ~
NH2 N~A R2 NHZ ~A R2 NHZ ~ 2 A R
Hal -N Hal ~ N
Ra + Ra + / R4 Hal RB Hal R6 Rs 1 (where X NH2; 1(where X NH2; 1(where X= NHz;
R3 = Hal and R3 and R3= Hal); R3' = Hal and 10 R3' = hydrogen); R3 = hydrogen);
Dia rg am 6:
The compounds of general formula 2 wherein R3 denotes hydrogen may be prepared starting from the compounds of general formula 4 analogously to the methods of synthesis described in W099/14199. In order to prepare the compounds 15 2 wherein R3 denotes hydrogen, the compounds of formula 21 are used as starting material (diagram 7). These may be obtained from the compounds 4. The compounds 21 are disclosed in W099/14199.
Me. 0 NH OH NH OH N/"-A R2 HBr -~- -~-( R4 R4 Ra Rs RS Rs R5 R 6 R5 4 21 2(where R3 and R3' Diagram 7: = hydrogen) The Examples that follow serve to illustrate the invention, without restricting it to the 20 compounds and processes disclosed by way of example.
1. Synthesis of the precursors 4 to 20:
The compounds of formula Me H Me H Me N Me N H
I\ H H H H
Me Me Me = Me Me 4a~ Me 4b ~ Me 4c and Me 4d are known, for example, from W099/14199.
Compounds of formula 5:
(2R,6S)-7-bromo-l0-methoxy-1,2,3,4,5,6-hexahydro-6.11,11-trimethyl-2 6-methano-1o 3-benzazocine-hydrochloride 5a:
24.7 g (0.1 mol) ) (2R,6S)-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 4a) are dissolved in 220 mL of acetic acid and 22 mL of trifluoroacetic acid, cooled to 10 C, and 19.6 g of NBS (N-bromosuccinimide) is added batchwise. The mixture is stirred for 3 h at 10 C, the solvent is eliminated in 15 vacuo and the residue is combined with ice-cooled ammonia solution. Then it is extracted twice with 200 mL of ethyl acetate, the combined organic phase is dried and the solvent is eliminated in vacuo. The residue is dissolved in acetone and the hydrochloride is precipitated with ethereal HCI.
Yield: 32,6 g (91%), melting point: 203 C.
Compounds of formula 6:
(2R,6S)-3-Benzyl-7-bromo-10-methoxy-1,2,3,4,5.6-hexahydro-6.11 11-trimethvl-2 methano-3-benzazocine 6a:
32.6 g (91 mmol) of (2R,6S)-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride 5a are dissolved in 160 mL
of dimethylacetamide, combined with 28 g of K2CO3 and 18.9 g of benzyl chloride and stirred for 3h at 100 C. Then the solvent is eliminated in vacuo, the residue is combined with water and twice with 200 mL aliquots of ethyl acetate. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo. Yield: 24.5 g (73%); oil.
Compounds of formula 7:
(2R,6S)-3-Benzyl-7-formyl-10-methoxy-1,2,3,4,5,6-hexahyd ro-6 11 11 -trimethyl-methano-3-benzazocine 7a:
24.5 g (59 mmol) of (2R,6S)-3-benzyl-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 6a are dissolved in 250 mL of abs.
ether, cooled to - 70 C and 40.7 mL of BuLi (1.6 M in hexane) are added dropwise.
Then the mixture is stirred for 1 h at -60 C, 10 mL of DMF are added dropwise thereto and after another hour the resulting mixture is allowed to come up slowly to -10 C. It is then added to 500 mL of water and extracted twice with 300 mL
aliquots To of ether. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo. Yield: 18.3 g (85%); oil.
Compounds of formula 8:
(2R,6S)-3-Benzyl-7-methyl-10-methoxy-1.2,3,4,5,6-hexahvdro-6 11 11-trimethyl-2 methano-3-benzazocine 8a:
8 g (22mmol) of (2R,6S)-3-benzyl-7-formyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 7a are dissolved in 80 mL of THF, mixed with 4 g of NaCNBH3 and 20 mL of BF3-etherate and stirred for 3 h at RT.
2o Then 100 mL of methanol are carefully added dropwise, 100 mL of 2 N HCI are added and the mixture is refluxed for 1 h. The solvent is eliminated in vacuo, ammonia is added to the residue and it is then extracted twice with 100 mL
aliquots of ethyl acetate. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo. Yield: 5.5 g (72%); oil.
Comaounds of formula 9:
(2R,6S)-3-Benzyl-7-methyl-10-hydroxy-1,2,3,4,5,6-hexahydro-6 11 1.11 -trimethyl6-methano-3-benzazocine 9a:
5.3 g (15 mmol) of (2R,6S)-3-benzyl-7-methyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 8a are dissolved in 54 mL of conc.
HBr and refluxed for 2 h. The mixture is evaporated down in vacuo, the residue is combined with ice and conc. ammonia and extracted twice with 50 mL of ethyl acetate. The combined organic phase is dried and the solvent is eliminated in vacuo.
The residue is dissolved in acetone and the hydrochloride is precipitated with ethereal HCI. Yield: 3.7 g (66%), Compounds of formula 10:
(2R,6S)-3-Benzyl-7-methvl-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11 1.11 -trimeI-2 methano-3-benzazocine 10a:
3.6 g (10 mmol) of (2R,6S)-3-benzyl-l0-hydroxy-7-methyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 9a are hydrogenated on 0.4 g of PdC
in 60 mL of methanol at 5 bar for 4 hours. The mixture is then filtered and the solvent is eliminated in vacuo. Yield 2.6 g (92%); oil.
Compounds of formula 11:
1o (2R,6S)-3-Benzyl-7-fluoro-10-methoxy-1,2,3,4,5,6-hexahydro-6.11,11-trimethyl-2 6-methano-3-benzazocine 11 a:
8 g (20mmol) of (2R,6S)-3-benzyl-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 6a are dissolved in 100 mL of ether, cooled to -65 C and under nitrogen 15 mL of BuLi (1.6 M in hexane) are added dropwise. After I h, 8 g of N-fluorobenzenesulphonimide in 100 mL of THF are added dropwise and the mixture is stirred for 1 h at -60 C. It is then heated to RT, any insoluble matter is removed by suction filtering and the solvent is eliminated in vacuo. The residue is taken up in 100 mL of water, combined with 10 mL of conc.
ammonia and extracted twice with 150 mL of ether. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo. Yield: 3.4 g (48%); oil.
Compounds of formula 12:
(2R,6S)-3-Benzyl-7-fluoro-10-hydroxy-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2 methano-3-benzazocine 12a:
Prepared analogously to the preparation of compound 9 starting from 11;oil;
Compounds of formula 13:
(2R,6S)-7-Fluor-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2 6-methano-3o benzazocine 13a:
Prepared analogously to the preparation of compound 10 starting from 12;oil;
Compounds of formula 14:
(2R,6S)-7-iodo-10-hvdroxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2 6-methano-benzazocine 14a:
32.5 g (0.13 moI) of (2R,6S)-1 0-methoxy-1,2,3,4,5,6-hexahydro-6,1 1,11 -trimethyl-2,6-methano-3-benzazocine 4a are dissolved in 330 mL of acetic acid and 110 mL
of trifluoroacetic acid, cooled to 5 C and 32.9 g of NIS is added batchwise. The mixture is stirred for 3 h at 10 C, the solvent is eliminated in vacuo and the residue is combined with ice-cooled ammonia solution. It is then extracted twice with mL aliquots of ethyl acetate, the combined organic phase is dried and the solvent is eliminated in vacuo. The residue is dissolved in ethyl acetate and the hydrochloride is precipitated with ethereal HCI. Yield: 31.7 g (59%), melting point: 231 C.
Compounds of formula 15:
(2R,6S)-3-t-Butyloxycarbonyl-7-iodo-10-methoxy-1,2,3,4,5,6-hexahyd ro-6 11 11-trimethyl-2,6-methano-3-benzazocine 15a:
31.6 g (78 mmol) of (2R,6S)-7-iodo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-io trimethyl-2,6-methano-3-benzazocine-hydrochloride 14a are suspended in 350 mL of dichloromethane, cooled to -5 C, combined with 9 g of KOH in 18 mL of water and 17.7 g of di-t-butyldicarbonate in 50 mL of dichloromethane are added dropwise. The mixture is then allowed to come slowly up to RT, is stirred for 2 h at room temperature and 200 mL of water are added. The organic phase is separated off, dried, and the solvent is eliminated in vacuo. Yield: 36.7 g (100%) of viscous oil.
Compounds of formula 16:
(2R,6S)-3-t-Butyloxycarbonyl-7-trifluoromethyl-10-methoxy-1,2 3 4 5 6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine 16a:
15.8 g (34 mmol) of (2R,6S)-3-t-butyloxycarbonyl-7-iodo-1 0-methoxy-1,2,3,4,5,6-hexahydro-6,1 1,11 -trimethyl-2,6-methano-3-benzazocine 15a is dissolved in 120 mL
of DMF, 10 g of methyl fluorosulphonyl-difluoroacetate and 2.3 g of Cul are added and the mixture is heated to 70 C. After 24 h another 3 g of methyl fluorosulphonyl-difluoroacetate and 0.7 g of Cul are added and stirring is continued for another 18 h at 70 C. The mixture is cooled, combined with 500 mL of ether and suction filtered to remove any insoluble matter. The filtrate was washed twice with dilute ammonia solution and with water. The organic phase was dried and the solvent eliminated in vacuo. Yield:13.6 g (98%); orange resin.
Compounds of formula 97:
(2R,6S)-7-Trifluoromethvl-10-methoxy-1,2,3,4,5,6-hexahydro-6 11 1.11 -trimethyl6-methano-3-benzazocine 17a:
13.6 g (33 mmol) of (2R,6S)-3-t-butyloxycarbonyl-7-trifluoromethyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 16a are dissolved in 250 mL of dichloromethane, 25 mL of trifluoroacetic acid are added dropwise and the mixture is stirred for 2 h at RT. It is then added to ice water and ammonia solution, the organic phase is separated off, dried and the solvent is eliminated in vacuo. Yield: 10.7 g (100%) orange resin.
Compounds of formula 18:
(2R,6S)-7-trifluoromethyl-10-hydroxy-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2 methano-3-benzazocine 18a:
1.0 g (3.2 mmol) of (2R,6S)-7-trifluoromethyl-10-methoxy-1,2,3,4,5,6-hexahydro-5 6,11,11-trimethyl-2,6-methano-3-benzazocine 17a are dissolved in 10 mL of dichloromethane, cooled to-65 C and 7 mL of BBr3 solution (1 M in dichloromethane) are added dropwise. The mixture is then allowed to come up to 0 C and stirred for 8 h at this temperature. 10 mL of MeOH are added, while cooling with ice, and the solvent is eliminated in vacuo. Yield: 1.2 g (100%), brown resin.
Compounds of formula 19:
(2R,6S)-3-Benzyl-7-(4-methyl)phenyl-10-methoxy-1,2,3,4,5,6-hexahydro-6,11 11-trimethyl-2,6-methano-3-benzazocine 19a:
4.1 g (10 mmol) of (2R,6S)-3-Benzyl-7-bromo-10-methoxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine 6a are dissolved in 100 mL of degassed dioxan under N2, combined with 12.6 g of K2P04, 2.9 g of 4-methylphenylboric acid, 0.92 g of tris(dibenzylideneacetone)-palladium(0) and 0.25 g of trimethylphosphite and refluxed for 1 h. Then the mixture is cooled, the salts are removed by suction filtering and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo.
Yield: 3.8 g (89%); oil.
Compounds of formula 20:
(2R,6S)- 10-Hydroxy-7-(4-methyl)ghenyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-methano-3-benzazocine-hydrobromide 20a;
Prepared from 19a analogously to the preparation of 10a;
melting point: >250 C.
Compounds of formula 21:
(2R,6S)-10-Hvdroxy-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2.6-methano-3-benzazocine-hydrobromide 21 a:
Prepared from 4a analogously to the preparation of 9a;
(2R,6S, 11 R)-10-Hydroxy-1,2,3,4,5,6-hexahydro-6,11-dimethvl-2.6-methano-3-benzazocine-hydrobromide 21 b:
Prepared from 4b analogously to the preparation of 9a;
(2R,6S, 11 S)-10-Hydroxy-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine-hydrobromide 21 c:
Prepared from 4c analogously to the preparation of 9a;
(2R,6S)-10-Hydroxy-1,2,3,4,5,6-hexahvdro-6-methvl-2,6-methano-3-benzazocine-hydrochloride 21d:
Prepared from 4d analogously to the preparation of 9c;
II. Synthesis of the compounds of formula 2:
lo (2R,6S,2"S)-10-Hydroxy-3-f2-(benzyloxy)propyll-1,2,3,4,5,6-hexahvdro-6 11 trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2a:
1.6 g (6.9 mmol) of (2R,6S)-10-hydroxy-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrobromide 21a are suspended in 30 mL of dichloromethane and 6 mL of N-methylmorpholine is added. After 30 min. the mixture is cooled to -5 C and a solution of 2.3 g (11.6 mmol) of (-)-S-2-bBenzyloxy-propionic acid chloride in 20 mL of dichloromethane is slowly added dropwise thereto. The mixture is stirred for a further 30 min. at -5 C, 40 mL of 2 N
hydrochloric acid are added and the organic phase is separated off. The organic phase is dried over MgSO4, the solvent is eliminated in vacuo and the residue is taken up in 80 mL of THF. To this solution are added 1.0 g (26 mmol) of LiAIH4 whereupon the temperature rises to 35 C. The solution is left to react for 30 min, 0.8 mL of water and 0.4 mL of 5 N sodium hydroxide solution are added and the inorganic precipitate is separated off. The precipitate is washed with 100 mL
of THF
and the combined organic phases are evaporated down in vacuo. The residue is taken up in 200 mL of ether, dried over MgSO4 and the hydrochloride is precipitated with ethereal hydrochloric acid. The crystals are separated off and washed with acetone.
Yield: 2.1 g (73%), melting point: 254 C, [a]p25 =(-) 20.7 (C=1 in methanol);
3o The following compounds 2 were also obtained using the corresponding carboxylic acids:
(2R,6S,2S')-10-Hydroxy-3-[2(2,6-difluorophenyl-methoxy)-propyll-1 2 3 4 5 6-hexahydro-6,11,11-trimethvl-2,6-methano-3-benzazocine-dihydrochloride 2b Prepared from 21 a analogously to the preparation of 2a;
(2R ,6S,11 R,2S')-10-Hvdroxy-3-f2(2,6-difluorophenyl-methoxv)-propyll-1 2 3 4 hexahydro-6,11-dimethvl-2,6-methano-3-benzazocine-dihvdrochloride 2c Prepared from 21 b analogously to the preparation of 2a;
(2R,6S, 11 S,2S')-10-Hydroxy-3-f2(benzyloxy)-propyll-1,2,3,4,5,6-hexahydro-6 dimethyl-2,6-methano-3-benzazocine-dihydrochloride 2d Prepared from 21 c analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-3-f2(benzyloxy)-propyll-1,2,3,4,5,6-hexahydro-6-methvl-methano-3-benzazocine-dihydrochioride 2e Prepared from 21d analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f2(2,6-difluorophenyl-methoxy)-ethyll-1,2,3,4,5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2f Prepared from 21 a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-3-f2(2,6-difluorophenyl-methoxY -isopentyll-1 2 3 4 5 6-hexahydro-6,11,11-trimethvl-2,6-methano-3-benzazocine-dihydrochloride 2q Prepared from 21a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f2(benzyloxy)-ethyll-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride 2h Prepared from 21 a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f2(2-fluorophenyl-methoxy)-ethyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2i Prepared from 21a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f2(2,4-difluorophenyl-methoxy)-ethyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2.6-methano-3-benzazocine-dihydrochloride 2i Prepared from 21 a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f2(2,6-dimethylphenyl-methoxy)-ethyll-1,2,3,4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2k Prepared from 21 a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hvdroxv-3-(2(benzvloxv)-butyll-1,2,3,4,5,6-hexahvdro-6 11 1.11 -trimethyl-2,6-methano-3-benzazocine-dihvdrochloride 21 Prepared from 21 a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-3-f2(2,6-difluorophenyl-methoxy)-butyll-1,2,3 4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2m Prepared from 21 a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-3-f2(2,6-difluorophenyl-methoxy)-propvll-1,2 3 4 5 6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihydrochloride 2n Prepared from 21d analogously to the preparation of 2a;
(2R,6S,2"R,5"S)-10-Hydroxy-3-f5"-phenyl-tetrahydrofuran-2"-yl)methyl]-1 2 3 4 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2o:
Prepared from 21a analogously to the preparation of 2a;
To (2R,6S,2"S,5"S)-10-Hydroxy-3-f5"-phenyl-tetrahydrofuran-2"-yl)methvll-1 2 3 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride 2p:
Prepared from 21 a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f3(2,6-difluorophenyloxy)-propyll-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2g Prepared from 21 a analogously to the preparation of 2a;
(2R,6S)-10-Hydroxy-3-f4(2,6-difluorophenyl)-butyll-1,2,3,4,5,6-hexahvdro-6,11 trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2r Prepared from 21 a analogously to the preparation of 2a;
(2Rs6S,2S')-10-Hydroxy-7-methyl-3-f2(2,6-difluorophenyl-methoxy)- ropyl]_ 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride 2s Prepared from 10a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hvdroxy-7-methyl-3-f2(benzyloxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2t Prepared from 10a analogously to the preparation of 2a;
(2R,6S, 2"S, 5"S)-10-Hyd roxy-7-methyl-3-f 5"-phenyl-tetrahyd rofuran-2"-yl)methyll-1,2,3,4,5,6-hexahvd ro-6,11,11-trimethvl-2,6-methano-3-benzazocine-dihvdrochloride 2u: Prepared from 10a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-7-fluoro-3-[2(benzyloxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2v Prepared from 13a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hvdroxy-7-trifluoromethyl-3-(2(benzyloxy)-propyll-1 2 3 4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2w Prepared from 18a analogously to the preparation of 2a;
(2R,6S,2S')-10-Hydroxy-7-(4-methylphenyl)-3-(2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihyd rochloride 2x Prepared from 20a analogously to the preparation of 2a;
1o (2R,6S)-10-Hydroxy-7-methyl-3-f2(2,6-difluorophenyl-methoxy)-ethyll-1,2 3 4 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride 2y Prepared from 10a analogously to the preparation of 2a;
III. Synthesis of the compounds of formula 1 according to the invention:
Example 1: (2R,6S,2S')-10-Amino-3-f2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride NHZ ~F ~.
N~ F
.,,,l H Me Me Me Me 13.5 g ( 0.03 moI) of (2R,6S,2"S)- 3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-1 0-ol 2d are dissolved in 135 mL of dichloromethane, combined with 30 mL of triethylamine and a spatula tip of 4-dimethylaminopyridine and cooled to-10 C. Then 6.8 mL of trifluoromethanesulphonic acid anhydride are added dropwise, the mixture is stirred for 1 h at -10 C and for a further 2 h at room temperature. The reaction mixture is poured onto ice, combined with 50 mL of ammonia, the organic phase is separated off and washed once with 50 mL of water. The organic phase is dried, the solvent is eliminated in vacuo, the residue is taken up in 350 mL of toluene, and 21.6 g of CsCO3 and 10.8 g of benzophenone-imine are added. Then nitrogen is bubbled through the suspension for 30 min., 1.2 g of BINAP and 0.6 g of tris(dibenzylidene-3o acetone)-dipalladium are added and the mixture is refluxed for 6 h. After cooling, it is washed with 200 mL of water, the organic phase is dried and the solvent is eliminated in vacuo. The residue is taken up in ethanol and the hydrochloride is precipitated with ethereal HCI. Yield: 13.7 g (88%), melting point: 266 C, [a]p2o =(-) 37.0 (c=1 in MeOH).
The following compounds were also obtained, inter alia:
Example 2: (2R,6S,2"S)-10-Amino-3-f2-(benzyloxy)propyll-1,2,3,4,5,6-hexahvdro-5 6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
NH2 /~.~
MIH Me Me Me Me Prepared from compound 2a analogously to Example 1;
melting point: 257 C, [a]o20 = (-) 29,3 (c=1 in MeOH).
io Example 3: (2R,6S,11 R,2GS)-10-Amino-3-[2(2,6-difluorophenyl-methoxv)-progYl-1,2,3,4,5,6-hexahydro-6,11-d imethyl-2,6-methano-3-benzazocine-dihvdrochloride:
NHZ
N F
11H Me Me Me Prepared from compound 2c analogously to Example 1;
melting point: 232 C, [a]p 4.1 (c=1 in MeOH).
Example 4: (2R,6S, 11S, 2"S)-10-Amino-3-f2(2,6-difluoroahenyl-methoxy)-proQyll-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine-dihvdrochloride:
o p 5EMeF
Me Prepared from compound 2d analogously to Example 1;
melting point: 267 C, Ho20 =(-) 2.4 (c=1 in MeOH).
Example 5: (2R,6S, 2"S)-10-Amino-3-f2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihydrochloride:
O \ 1 NHZ / l N F
,,,H Me Me Prepared from compound 2n analogously to Example 1;
melting point: 187 C, [a]o20 = 19.7 (c=1 in MeOH).
Example 6: (2R,6S,2S')-10-Amino-3-f2(2,6-difluorophenyl-methoxy)-butyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride NHOLMe F Me Me Me lo Prepared from compound 2m analogously to Example 1;
melting point: 200 C.
Example 7: (2R,6S,2S')-10-Amino-3-f2(2,6-difluorophenyl-methoxy)-isopentLrll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride NHZ
N F
p Me Me Me Me Me Prepared from compound 2nc analogously to Example 1;
melting point: 274 C, [a]p20 =(-) 21.8 (c=1 in MeOH).
Example 8: (2R,6S)-10-Amino-3-f2(2,6-difluorophenyl-methoxv)-ethyll-1,2 3 4 5 hexahydro-6,11,11-trimethvl-2,6-methano-3-benzazocine-dihvdrochloride F p H
Me _ Me Me Prepared from compound 2f analogously to Example 1;
melting point: 270 C, [a]p =(-) 77.4 (c=1 in MeOH).
Example 9: (2R,6S,2S')-10-Amino-3-f2(benzyloxy)-butyll-1.2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride NHZ
N
H Me Me = Me Me 1o Prepared from compound 21 analogously to Example 1;
melting point: >190 C (decomposition);.
Example 10: (2R,6S)-10-Amino-3-[2(benzyloxy)-ethyll-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihyd rochloride Q
NHZ N/--, O
H
Me Me Me Prepared from compound 2h analogously to Example 1;
melting point: 220 C;.
. =
Example 11: (2R,6S)-10-Amino-3-f2(2-fluorophenyl-methoxv)-ethvll-1,2,3,4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride / ' ~
NH2 ~
N/O F
H
Me = Me Me Prepared from compound 2i analogously to Example 1;
melting point: 220 C;.
Example 12: (2R,6S)-10-Amino-3-f3(2,6-difluorophenyloxy)-propyll-1.2,3,4,5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride F / t ~
NH2 N/"~0 F
H
Me = Me Me io Prepared from compound 2q analogously to Example 1;
melting point: 250 C;.
Example 13: (2R,6S)-10-Amino-3-f4(2,6-difluorophenyl)-butyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride F
NHZ
N F
H
Me Me Me Prepared from compound 2r analogously to Example 1;
melting point: 250 C;.
Example 14: (2R,6S)-10-Amino-3-f2(2,4-difluorophenyl-methoxy)-ethyll-1,2 3 4 5 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride F
NHZ N~/O F
H
Me Me Me Prepared from compound ~ analogously to Example 1;
melting point: 220 C;.
Example 15: (2R,6S)-10-Amino-342(2,6-dimethylphenyl-methoxv)-ethyll-1,2 3 4 5 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride / y \
m NH2 ~
N/ Me H
Me = Me Me lo Prepared from compound 2k analogously to Example 1;
melting point: 245 C;.
Example 16: (2R,6S,2"S,5"S)-10-Amino-3-f5"-phenyl-tetrahydrofuran-2"-yl)methylL
1.2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
H
N H
,= M15 Me ft Prepared from compound 2p analogously to Example 1;
melting point: 253 C, [a]p20 =(-) 135.40 (c=1 in MeOH).
Example 17: (2R.6S,2"R,5"S)-10-Amino-3-f5"-phenyl-tetrahvdrofuran-2"-vl)methyll-1,2,3,4.5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride=
H_ NHZ
N
,,,, H O ,"'H
-Me ~ ~
- Me Me Prepared from compound 2o analogously to Example 1;
5 melting point: 255 C;.
Example 18: (2R,6S,2"S)-10-Acetamino-3-f2(2,6-benzyloxy)propyll-1 2 3 4 5 6-hexahYdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride:
HN Me I \ .~H
/ Me Me Me 1o 2 mL of acetic anhydride are added to 1.1 g (2.4 mmol) of (2R,6S,2"S)-10-amino-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride (Example 2) and 5 mL of triethylamine in 50 mL of dichloromethane and the mixture is stirred for 0.5 h at room temperature. It is then evaporated down in vacuo, combined with 100 mL of ether and washed twice with 15 mL of water. The organic phase is dried, the solvent is eliminated in vacuo, the residue is taken up in ether and the hydrochloride is precipitated with ethereal HCI.
Yield: 0.8 g (73%), melting point: >100 C, [a]p20 = (-) 56.5 (c=1 in MeOH).
Example 19: (2R,6S.2"S)-10-Acetamino-3-f2(2,6-difluorophenyl-methoxy)-propyll-20 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride=
F / , HN J~ Me N/~( O ~
F
\ ,H 1Me I / Me Me Me Prepared from Example 1 analogously to Example 18;
melting point: 125 C, [a]p20 =(-) 58,7 (c=1 in MeOH).
Example 20: (2R,6S,2"S)-10-Formylamino-3-f2(2,6-difluorophenyl-methoxv)-propyl]_ 1 ,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride=
F
l~H O N F
HN p õH Me Me = Me Me 0.5 g (1.2 mmol) of (2R,6S,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine (Example 1) are combined with 10 mL of 97% formic acid and refluxed for 1 h. The mixture is then evaporated down in vacuo, the residue is combined with ice and 50 mL of ammonia and extracted twice with 50 mL of ethyl acetate. The combined organic phase is washed with 30 mL of water, dried and the solvent is eliminated in vacuo. The lo residue is taken up in ether and the hydrochloride is precipitated with ethereal HCI.
Yield: 0.3 g (52%), melting point: amorphous, [a]D 20 = (-) 41.6 (c=1 in MeOH).
Example 21: (2R,6S,2"S)-10-methylamino-3-f2(2,6-difluorophenyl-methoxv)-propyll-1,2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride=
HN'Me O 9 N F
H Me Me = Me Me 1.0 g (2.4 mmol) of (2R,6S,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine (Example 1) are dissolved in 10 mL of ethyl acetate, and 1 mL of triethylamine and 1 mL of trifluoroacetic acid anhydride is added. After 10 min the mixture is washed twice with 10 mL of water, the organic phase is dried and the solvent is eliminated in vacuo.
The residue is taken up in 10 mL of dimethylacetamide and 0.5 g of NaH is added.
After 15 min. 1 mL of methyliodide is added and the mixture is stirred for 1 h at 50 C.
Then the solvent is eliminated in vacuo, the residue is combined with 20 mL of methanol and 2 mL of 20% NaOH and stirred for 30 min. at 60 C. The solution is once more evaporated down in vacuo, the residue is combined with 50 mL of water and extracted twice with 100 mL of ether. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue is chromatographed on silica gel. The appropriate fractions are combined and the hydrochloride is precipitated with ethereal HCI. Yield: 0.4 g (35%), melting point: 243 C, [a]p20 =(-) 20.5 (c=1 in MeOH).
Example 22: (2R,6S,2"S)-10-dimethylamino-3-f2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
Me,, NMe OF P
N F
.,,1H Me Me = Me Me A suspension of 0.4 g (1 mmol) of (2R,6S,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-1o benzazocine (Example 1) and 0.3 g of NaBH4 in 7 mL of THF is added batchwise to a solution of 0.6 mL of 37% formalin and 1.2 mL of 3N H2SO4 cooled to -10 C.
After it has all been added, the mixture is left to react for 10 min, ammonia is added and the resulting mixture is extracted twice with 20 mL of ethyl acetate. The organic phase is dried, the solvent is eliminated in vacuo, the residue is taken up in ether and the hydrochloride is precipitated with ethereal HCI. Yield: 0.5 g (97%), melting point:
125 C, [a]o = (-) 20.0 (c=1 in MeOH).
Example 23: (2R,6S,2"S)-10-ethylamino-3-(2(2,6-difluorophenvl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
HN'Et OF P
N F
,,,1H Me Me = Me Me 1.1 g (2.4 mmol) of (2R,6S,2"S)-10-acetamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine (Example 1) are dissolved in 30 mL of THF, combined with 0.5 g of NaBH4 and 1.5 mL of BF3-etherate and refluxed for 6 h. The mixture is allowed to cool, 30 mL
of MeOH and 60 mL of 2 N HCI are added and the resulting mixture is refluxed for a further 30 min. Then the solvent is eliminated in vacuo, the residue is combined with conc. ammonia and extracted twice with 30 mL of ethyl acetate. The combined organic phase is washed once with 20 mL of water, dried and the solvent is eliminated in vacuo. The residue is taken up in acetone and the hydrochloride is precipitated with ethereal HCI. Yield: 0.95 g(89 l0), melting point: 242 C, [a]p20 =(-) 24.8 (c=1 in MeOH).
Example 24: (2R,6S,2"S)-10-Fluoro-3-[2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride:
F
N F
0 p -IH Me Me = Me Me 1.5 g (3.6 mmoi) of (2R,6S,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine (Example 1) are io placed in 30 mL of dioxan, combined with 3 g of NOBF4 in 30 mL of dioxan and stirred for 1 h at 90 C. Then the solvent is eliminated in vacuo, the residue is combined with 50 mL of ethyl acetate and washed once with 30 mL of dilute ammonia and once with 30 mL of water. The combined organic phase is dried, the solvent is eliminated in vacuo and the residue is chromatographed on silica gel. The appropriate fractions are combined and the hydrochloride is precipitated with ethereal HCI. Yield: 0.5 g (33%), melting point: 190 C, [a]D 20 =(-) 27.3 (c=1 in MeOH).
Example 25: (2R,6S,2"S)-10-Amino-7-methyl-3-f2-(2,6-difluorophenyl-methoxy)-propyll-1.2,3,4,5,6-hexahydro-6,11.11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
NH2 0F p N~ F
H Me Me Me Me Me Prepared from 2s analogously to Example 1;
melting point: 236 C;.
Example 26: (2R,6S,2"S)-10-Amino-7-methyl-3-[2-(benzyloxy)propv4]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-d ihydrochloride:
~1 NH2 0 \
AMN Me Me e Me M
e Prepared from 2t analogously to Example 1;
melting point: 227 C, [a]o20 = (-) 31,8 (c=1 in MeOH).
Example 27: (2R,6S,2"S)-10-Formylamino-7-methyl-3-f2-(benzyloxy)propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride:
I HN H ~ o/ , ~
N
,,H Me Me = Me Me Me Prepared from Example 26 analogously to Example 20;
melting point: 141 C;.
Example 28: (2R,6S,2"S)-10-Formylamino-7-methvl-3-(2-(2,6-difluorophenyl-methoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
J~.
HN H OF P
N F
H Me Me Me Me Me Prepared from Example 28 analogously to Example 20;
melting point: >105 C C (decomposition), [a]D 20 = (-)42,2 (c=1 in MeOH);.
Example 29: (2R,6S,2"S)-10-methylamino-7-methyl-3-f2-(benzvloxy)propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihyd rochloride=
HN'Me ~O 0 N
'H Me Me - Me Me Me Prepared from Example 26 analogously to Example 21;
5 melting point: >100 C (decomposition);.
Example 30: (2R,6S,2"S)-10-methylamino-7-methvl-3-l2-(2,6-difluorophenvl-methoxy)propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethvl-2,6-methano-3-benzazocine-dihydrobromide:
HN'Me O
N~ F
õI~H Me Me Me 10 Me Me Prepared from Example 25 analogously to Example 21;
melting point: 221 C (decomposition), [a]p = (-)29,4 (c=1 in MeOH);.
Example 31: (2R,6S,2"S)-10-Amino-8-methyl-3-f2-(benzyloxy)propyll-1 2 3 4 5 6-T5 hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride=
NH2 N~
\ õ11H Me MeI Me Me Me Prepared analogously to Example 1; melting point: 250 C;.
Example 32: (2R,6S. 2"S)-10-Amino-7-chloro-3-f2(benzyloxv)-nropyIj-1 2 3 4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride:
N
,, Me Me - Me CI Me 4.5 g (10 mmol) of (2R,6S,2"S)-10-amino-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride (Example 2) are dissolved in 90 mL of MeOH and 90 mL of glacial acetic acid, 1.45 g of NCS
(N-chloro-succinimide) are added and the mixture is stirred for 4 h at room temperature. Then the solvent is eliminated in vacuo, the residue is taken up in 100 mL of aqueous ammonia solution and extracted twice with 50 mL of ethyl acetate.
lo The combined organic phase is dried, the solvent is eliminated in vacuo and the residue is chromatographed on silica gel. The appropriate fractions are evaporated down in vacuo and the hydrochloride is precipitated with ethereal HCI.
Yield: 1.3 g (27%); melting point: 222 C, [a]o =(-)17.4 (c=1 in MeOH);.
Example 33: (2R,6S, 2"S)-10-Amino-7,9-dichloro-3-f2(benzyloxy)-propyll-1 ,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
NH2 aN
CI
\Me Me Me C1 Me Prepared together with Example 32;
Separation by chromatography produces:
Yield: 0.6 g (12%); melting point: 197 C, [a]p20 = 11,0 (c=1 in MeOH);.
Example 34: (2R,6S, 2"S)-10-Amino-7-chloro-3-f2(2,6-difluorophenyl-methoxv)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
F /
~
NH2 ~ \
F
UNII'-~
I \ H H Me Me - Me CI Me Prepared from Example 1 analogously to Example 32;
melting point: 247 C;.
Example 35: (2R,6S, 2"S)-10-Amino-7-bromo-3-f2(benzyloxv)-propyll-1,2,3 4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
N
U
õ~
'H Me *Me Br Me Prepared from Example 2 analogously to Example 32 using NBS;
melting point: 215 C, [aJo20 =(-)17.3 (c=1 in MeOH);.
Example 36: (2R,6S, 2"S)-10-Amino-7,9-dibromo-3-f2(benzyloxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochioride:
n'z'~
NH2 ~ ~
):* 1H
Br Me Me Br Me Prepared together with Example 35 analogously to Example 33;
melting point: 177 C, [a]o20 = 11.5 (c=1 in MeOH);.
Example 37: (2R,6S, 2"S)-10-Amino-7-bromo-3-f2(2,6-difluorophenyi-methoxv)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
N F
Me (LI-f(.IH
Me _ Me Br Me Prepared from Example 1 analogously to Example 32 using NBS;
melting point: 233 C, [a]p20 =(-)20.5 (c=1 in MeOH);.
Example 38: (2R,6S, 2"S)-10-Amino-7,9-dibromo-3-f2(2,6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-io dihydrochloride:
F / ' NH2 0\
N F
Br Me ,,,H
Me : Me Br Me Prepared together with Example 37 analogously to Example 36;
melting point: 236 C, [a]p20 = 5,9 (c=1 in MeOH);.
Example 39: (2R,6S, 2"S)-10-Amino-9-bromo-3-f2(2,6-difluorophenvl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride:
F
NH0 Br )JaN
Me F
Me = Me Me Prepared together with Example 37 analogously to Example 32;
melting point: 252 C, [a]D 20 =(-)14,6 (c=1 in MeOH);.
Example 40: (2R,6S,2"S)-10-Amino-7-fluoro-3-[2-(benzvloxy)propyl)-1 2 3 4 5 6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihvdrochloride=
o NHZ
H Me Me Me F Me Prepared from 2v analogously to Example 1;
melting point: 150 C;.
Example 41: (2R,6S,2"S,5"S)-10-Amino-7-methyl-3-f5"-phenyl-tetrahydrofuran-2"-Yl)methyll-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2 6-methano-3-benzazocine-dihydrochloride:
H
N H
aNNI
H p H
~ / -Me = Me Me Me Prepared from 2u analogously to Example 1;
melting point: 250 C;.
Example 42: (2R,6S,2"S,5"S)-10-methvlamino-7-methvl-3-f5"-phenvl-tetrahydrofuran-2"-vl)methvll-1,2,3,4,5,6-hexahydro-6 11 11-trimethyl-2 6-methano-3-benzazocine-dihvdrochloride:
HN" Me H
N
H p Me Me Me Me Prepared from Example 41 analogously to Example 21;
melting point: 250 C;.
Example 43: (2R,6S,2"S,5"S)-10-Formvlamino-7-methvl-3-f5"-phenvl-tetrahydrofuran-2"-yl)methyll-1,2,3,4,5,6-hexahvdro-6 11 11-trimethvl-2 6-methano-3-benzazocine-dihvdrochloride:
Prepared from Example 41 analogously to Example 20;
melting point: 250 C;.
Example 44: (2R,6S, 2"S)-10-Amino-7-trifluoromethyl-3-f2(benzyloxv)-propyl1 1,2,3,4,5,6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihvdrochloride=
NHZ
õ..H Me CF3 Me Prepared from 2w analogously to Example 1;
5 melting point: 165 C;.
Example 45: (2R,6S, 2"S)-10-Amino-7-(4-methylphenyl)-3-f2(2 6-difluorophenyl-methoxy)-propyll-1,2,3,4,5,6-hexahydro-6-methyl-2,6-methano-3-benzazocine-dihydrochioride:
N~ F
1,1H Me Me = Me Me 10 Me Prepared from 2x analogously to Example 1;
melting point: 219 C, [a]p20 =(-)19.5 (c=1 in MeOH).
15 The compounds according to the invention may be administered orally, transdermally, nasally, by inhalation or parenterally. The compounds according to the invention occur as active ingredients in conventional preparations, for example in compositions which consist essentially of an inert pharmaceutical carrier and an effective dose of the active substance, such as for example tablets, coated tablets, 20 capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal systems etc.. An effective dose of the compounds according to the invention is between 1 and 1000, preferably between 1 and 500, most preferably between 5-300 mg/dose for oral administration, and between 0.001 and 50, preferably between 0.1 and 10 mg/dose for intravenous, subcutaneous or 25 intramuscular administration. For inhalation, according to the invention, solutions containing 0.01 to 1.0, preferably 0.1 to 0.5 % active substance are suitable.
For administration by inhalation the use of powders is preferred. It is also possible to use the compounds according to the invention as a solution for infusion, preferably in a physiological saline or nutrient saline solution.
The compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances. Suitable preparations include for example tablets, capsules, suppositories, solutions, elixirs, emulsions or 1o dispersible powders.
Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers.
Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g of. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Solutions for injection are prepared in the usual way, e.g of. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.
Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
A therapeutically effective daily dose is between 1 and 1000 mg, preferably 10 mg per adult.
The Examples which follow illustrate the present invention without restricting its scope:
Examples of pharmaceutical formulations A) Tablets per tablet active substance 300 mg lactose 240 mg corn starch 340 mg polyvinylpyrrolidone 45 mg magnesium stearate 15 mg 940 mg The finely ground active substance, lactose and some of the com starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the 3o remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.
B) Tablets per tablet active substance 80 mg corn starch 190 mg lactose 55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodium-carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
C) Coated tablets per coated tablet Active substance 5 mg Corn starch 41.5 mg Lactose 30 mg Polyvinylpyrrolidone 3 mg Magnesium stearate 0.5 mg 80 mg The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45 C and the granules are then passed through the same screen. After the magnesium stearate has been mixed in, convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine. The tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc. The finished coated tablets are polished with wax.
D) Capsules per capsule Active substance 1 50 mg Corn starch 268.5 mg Magnesium stearate 1.5 mg 420 mg The substance and corn starch are mixed and moistened with water. The 1o moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The finished mixture is packed into size 1 hard gelatine capsules.
E) Ampoule solution active substance 50 mg sodium chloride 50 mg water for inj. 5 ml 2o The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain mg, 25 mg and 50 mg of active substance.
F) Suppositories Active substance 50 mg Solid fat 1650 mg 1700 mg The hard fat is melted. At 40 C the ground active substance is homogeneously dispersed. It is cooled to 38 C and poured into slightly chilled suppository moulds.
Claims (22)
1. A compound of general formula 1 or a racemate thereof, an enantiomer thereof, a diastereomer thereof or a pharmacologically acceptable acid addition salt thereof, wherein R1 and R2 independently denote hydrogen, C1-C6-alkyl, C1-C6-alkyloxy, OH, F, Cl or Br;
R3 and R3' independently denote hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which is unsubstituted or substituted by a group selected from among F, Cl, Br, methyl, ethyl, OH, CF3 and methoxy;
R4, R5 and R6 independently denote hydrogen, methyl or ethyl, X denotes NH2, NH- (C1-C6-alkyl) , N(C1-C6-alkyl)2, the two C1-C6-alkyl groups of which are identical or different, NH-COH, NH-CO (C1-C6-alkyl) or F;
A denotes - (CH2)3-, -CH2-CH2-O-, -CH2-O-CH2-, -(CH2)4-, -CH(C1-C6-alkyl)-O-CH2-, -(CH2)2-O-CH2-, -(CH2)3-O-, -(CH2)5-, -CH2-O-(CH2)3-, -(CH2)2-O-(CH2)2-, -(CH2)3-O-CH2-, -(CH2)4-O-, -CH2-O-CH2-CH2-O-,
R3 and R3' independently denote hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which is unsubstituted or substituted by a group selected from among F, Cl, Br, methyl, ethyl, OH, CF3 and methoxy;
R4, R5 and R6 independently denote hydrogen, methyl or ethyl, X denotes NH2, NH- (C1-C6-alkyl) , N(C1-C6-alkyl)2, the two C1-C6-alkyl groups of which are identical or different, NH-COH, NH-CO (C1-C6-alkyl) or F;
A denotes - (CH2)3-, -CH2-CH2-O-, -CH2-O-CH2-, -(CH2)4-, -CH(C1-C6-alkyl)-O-CH2-, -(CH2)2-O-CH2-, -(CH2)3-O-, -(CH2)5-, -CH2-O-(CH2)3-, -(CH2)2-O-(CH2)2-, -(CH2)3-O-CH2-, -(CH2)4-O-, -CH2-O-CH2-CH2-O-,
2. A compound, racemate, enantiomer, diastereomer or salt according to claim 1, wherein R1 and R2 independently denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, OH, F, Cl or Br;
R3 and R3' independently denote hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which is unsubstituted or substituted by a group selected from among F, Cl, Br and methyl;
R4, R5 and R6 independently denote hydrogen or methyl;
X denotes NH2, NH-(methyl), N(methyl)2, NH-(ethyl), N(ethyl)2, NH-COH, NH-COMe or F;
A denotes -CH2-CH2-O-, -CH2-O-CH2-, -CH (methyl) -O-CH2-, -CH (ethyl) -O-CH2-, -CH (isopropyl) -O-CH2-, -(CH2)2-O-CH2-, -(CH2)3-O-, -CH2-O-(CH2)3-, -(CH2)2-O-(CH2)2-, -(CH2)3-O-CH2-, -(CH2)4-O-, -CH2-O-CH2-CH2-O-,
R3 and R3' independently denote hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which is unsubstituted or substituted by a group selected from among F, Cl, Br and methyl;
R4, R5 and R6 independently denote hydrogen or methyl;
X denotes NH2, NH-(methyl), N(methyl)2, NH-(ethyl), N(ethyl)2, NH-COH, NH-COMe or F;
A denotes -CH2-CH2-O-, -CH2-O-CH2-, -CH (methyl) -O-CH2-, -CH (ethyl) -O-CH2-, -CH (isopropyl) -O-CH2-, -(CH2)2-O-CH2-, -(CH2)3-O-, -CH2-O-(CH2)3-, -(CH2)2-O-(CH2)2-, -(CH2)3-O-CH2-, -(CH2)4-O-, -CH2-O-CH2-CH2-O-,
3. A compound, racemate, enantiomer, diastereomer or salt according to claim 2, wherein one or both of R3 and R3' are substituted by methyl.
4. A compound, racemate, enantiomer, diastereomer or salt according to claim 1, wherein R1 and R2 independently denote hydrogen or F;
R3 and R3' independently denote hydrogen, F, Cl, Br, CF3 or methyl;
R4, R5 and R6 independently denote hydrogen or methyl;
X denotes NH2, NH-(methyl), N(methyl)2, NH-COH, NH-COMe or F;
A denotes -CH (methyl)-O-CH2-, -CH2-O-CH2- or
R3 and R3' independently denote hydrogen, F, Cl, Br, CF3 or methyl;
R4, R5 and R6 independently denote hydrogen or methyl;
X denotes NH2, NH-(methyl), N(methyl)2, NH-COH, NH-COMe or F;
A denotes -CH (methyl)-O-CH2-, -CH2-O-CH2- or
5. A compound, racemate, enantiomer, diastereomer or salt according to claim 1, wherein R1 and R2 independently denote hydrogen or F;
R3 and R3' independently denote hydrogen, F, Cl, Br, CF3 or methyl;
R4, R5 and R6 independently denote hydrogen or methyl;
X denotes NH2, NH-(methyl) or NH-COH;
A denotes -CH(methyl)-O-CH2-, -CH2-O-CH2- or
R3 and R3' independently denote hydrogen, F, Cl, Br, CF3 or methyl;
R4, R5 and R6 independently denote hydrogen or methyl;
X denotes NH2, NH-(methyl) or NH-COH;
A denotes -CH(methyl)-O-CH2-, -CH2-O-CH2- or
6. A compound, racemate, enantiomer, diastereomer or salt according to claim 1, wherein R1 and R2 independently denote hydrogen or F;
R3 and R3' each denote hydrogen;
R4, R5 and R6 independently denote hydrogen or methyl;
X denotes F;
A denotes -CH(methyl)-O-CH2-.
R3 and R3' each denote hydrogen;
R4, R5 and R6 independently denote hydrogen or methyl;
X denotes F;
A denotes -CH(methyl)-O-CH2-.
7. A pharmaceutical composition comprising a compound, racemate, enantiomer, diastereomer or salt according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier or diluent.
8. A pharmaceutical composition according to claim 7 for treatment of a disease or a disorder wherein a blockage of a voltage-dependent sodium channel is of therapeutic value.
9. A pharmaceutical composition according to claim 7 for treatment or prevention of an arrhythmia, a spasm, cardiac and cerebral ischaemia, pain or a neurodegenerative disease.
10. A pharmaceutical composition according to claim 7 for treatment or prevention of epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, a cardiac rhythm disorder, angina pectoris, chronic pain, neuropathic pain or for local anaesthesia.
11. Use of a compound, racemate, enantiomer, diastereomer or salt according to any one of claims 1 to 6 in preparing a pharmaceutical composition for prevention or treatment of a disease or disorder in which blockage of a voltage-dependent sodium channel is of therapeutic value.
12. Use of a compound, racemate, enantiomer, diastereomer or salt according to any one of claims 1 to 6 in preparing a pharmaceutical composition for prevention or treatment of an arrhythmia, a spasm, cardiac and cerebral ischaemia, pain or a neurodegenerative disease.
13. Use of a compound, racemate, enantiomer, diastereomer or salt according to any one of claims 1 to 6 in preparing a pharmaceutical composition for prevention or treatment of epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, a cardiac rhythm disorder, angina pectoris, chronic pain, neuropathic pain or for local anaesthesia.
14. Use of a compound, racemate, enantiomer, diastereomer or salt according to any one of claims 1 to 6 for prevention or treatment of a disease or disorder in which blockage of a voltage-dependent sodium channel is of therapeutic value.
15. Use of a compound, racemate, enantiomer, diastereomer or salt according to any one of claims 1 to 6 for prevention or treatment of an arrhythmia, a spasm, cardiac and cerebral ischaemia, pain or a neurodegenerative disease.
16. Use of a compound, racemate, enantiomer, diastereomer or salt according to any one of claims 1 to 6 for prevention or treatment of epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, a cardiac rhythm disorder, angina pectoris, chronic pain, neuropathic pain or for local anaesthesia.
17. A compound, racemate, enantiomer, diastereomer or salt according to any one of claims 1 to 6 for prevention or treatment of a disease or disorder in which blockage of a voltage-dependent sodium channel is of therapeutic value.
18. A compound, racemate, enantiomer, diastereomer or salt according to any one of claims 1 to 6 for prevention or treatment of an arrhythmia, a spasm, cardiac and cerebral ischaemia, pain or a neurodegenerative disease.
19. A compound, racemate, enantiomer, diastereomer or salt according to any one of claims 1 to 6 for prevention or treatment of epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, a cardiac rhythm disorder, angina pectoris, chronic pain, neuropathic pain or for local anaesthesia.
20. A process for preparing a compound of general formula 1 wherein R1, R2, R3, R3, R4, R5, R6 and A are as defined in any one of claims 1 to 6, and X denotes NH2, wherein a compound of general formula 3 wherein R1, R2, R3, R3', R4, R5, R6 and A are as defined in any one of claims 1 to 5 are reacted with a source of nitrogen in an aromatic solvent with palladium catalysis.
21. An intermediate compound of general formula 3 wherein the groups R1, R2, R3, R3', R4, R5, R6 and A are as defined in any one of claims 1 to 6.
22. A process for preparing a compound of general formula 1 wherein R1, R2, R3, R3, R4, R5, R6 and A are as defined in any one of claims 1 to 5, wherein a compound of general formula 1 wherein X denotes NH2:
a) is reacted with a base and a corresponding alkylating agent, in a polar organic solvent, to form a compound of general formula 1 wherein X denotes NH-(C1-C6-alkyl) or N(C1-C6-alkyl)2;
b) is reacted with an aldehyde or a ketone, with cooling, in the presence of an acid, and a Schiff base or iminium salt thus forming an intermediate which is subsequently reduced with a metal hydride to form a compound of general formula 1 wherein X denotes NH-(C1-C6-alkyl) or N(C1-C6-alkyl)2;
c) is reacted, in the presence of a base, with an acid chloride or anhydride to form a compound of general formula 1 wherein X denotes NHCO(C1-C6-alkyl);
d) a compound of formula 1 wherein X denotes NHCO(C1-C6-alkyl), obtained according to step c), is then reduced with a metal hydride, using a Lewis acid as a catalyst, to obtain a compound of general formula 1 wherein X denotes NH-(C1-C6-alkyl) or N(C1-C6-alkyl)2;
e) is converted at elevated temperature into a compound of general formula 1 wherein X denotes NHCOH by reacting with formic acid, or f) is reacted by diazotisation and subsequent decoction with BF4- to form a compound of formula 1 wherein X denotes F.
a) is reacted with a base and a corresponding alkylating agent, in a polar organic solvent, to form a compound of general formula 1 wherein X denotes NH-(C1-C6-alkyl) or N(C1-C6-alkyl)2;
b) is reacted with an aldehyde or a ketone, with cooling, in the presence of an acid, and a Schiff base or iminium salt thus forming an intermediate which is subsequently reduced with a metal hydride to form a compound of general formula 1 wherein X denotes NH-(C1-C6-alkyl) or N(C1-C6-alkyl)2;
c) is reacted, in the presence of a base, with an acid chloride or anhydride to form a compound of general formula 1 wherein X denotes NHCO(C1-C6-alkyl);
d) a compound of formula 1 wherein X denotes NHCO(C1-C6-alkyl), obtained according to step c), is then reduced with a metal hydride, using a Lewis acid as a catalyst, to obtain a compound of general formula 1 wherein X denotes NH-(C1-C6-alkyl) or N(C1-C6-alkyl)2;
e) is converted at elevated temperature into a compound of general formula 1 wherein X denotes NHCOH by reacting with formic acid, or f) is reacted by diazotisation and subsequent decoction with BF4- to form a compound of formula 1 wherein X denotes F.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19957156A DE19957156A1 (en) | 1999-11-27 | 1999-11-27 | New amino and fluoro substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine derivatives useful in treatment of e.g. arrythmias, spasms, ischaemia, pain and neurodegenerative disorders |
| DE19957156.2 | 1999-11-27 | ||
| PCT/EP2000/011585 WO2001051471A1 (en) | 1999-11-27 | 2000-11-21 | Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and the use thereof as medicaments |
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| Publication Number | Publication Date |
|---|---|
| CA2383114A1 CA2383114A1 (en) | 2001-07-19 |
| CA2383114C true CA2383114C (en) | 2008-06-17 |
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| CA002383114A Expired - Fee Related CA2383114C (en) | 1999-11-27 | 2000-11-21 | Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceutical compositions |
Country Status (33)
| Country | Link |
|---|---|
| EP (1) | EP1235809B1 (en) |
| JP (1) | JP2003519687A (en) |
| KR (1) | KR20020058042A (en) |
| CN (1) | CN1177825C (en) |
| AR (1) | AR026586A1 (en) |
| AT (1) | ATE254108T1 (en) |
| AU (1) | AU5789701A (en) |
| BG (1) | BG106682A (en) |
| BR (1) | BR0015786A (en) |
| CA (1) | CA2383114C (en) |
| CO (1) | CO5251469A1 (en) |
| CZ (1) | CZ20022120A3 (en) |
| DE (2) | DE19957156A1 (en) |
| DK (1) | DK1235809T3 (en) |
| EA (1) | EA005681B1 (en) |
| EE (1) | EE200200267A (en) |
| ES (1) | ES2210036T3 (en) |
| HK (1) | HK1052176A1 (en) |
| HR (1) | HRP20020460A2 (en) |
| HU (1) | HUP0204169A3 (en) |
| IL (1) | IL149607A0 (en) |
| MX (1) | MXPA02003822A (en) |
| NO (1) | NO20022457D0 (en) |
| NZ (1) | NZ519758A (en) |
| PL (1) | PL355493A1 (en) |
| PT (1) | PT1235809E (en) |
| SK (1) | SK9302002A3 (en) |
| TR (1) | TR200302031T4 (en) |
| UA (1) | UA72566C2 (en) |
| UY (1) | UY26448A1 (en) |
| WO (1) | WO2001051471A1 (en) |
| YU (1) | YU37902A (en) |
| ZA (1) | ZA200204056B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE10204276A1 (en) * | 2002-02-02 | 2003-08-07 | Boehringer Ingelheim Pharma | N-Allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceuticals |
| US6683089B2 (en) | 2002-02-02 | 2004-01-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | N-allyoxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine-10-ols |
| JP6400592B2 (en) * | 2012-11-09 | 2018-10-03 | パーデュー、ファーマ、リミテッド、パートナーシップ | Benzomorphan analogs and uses thereof |
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| DE4121821A1 (en) * | 1991-07-02 | 1993-01-14 | Boehringer Ingelheim Kg | NEW BENZOMORPHANE AND ITS USE AS A MEDICAMENT |
| US5354758A (en) * | 1992-12-16 | 1994-10-11 | Japan Tobacco Inc. | Benzomorphans useful as NMDA receptor antagonists |
| DE19740110A1 (en) * | 1997-09-12 | 1999-03-18 | Boehringer Ingelheim Pharma | New hydroxy substituted benzomorphan derivatives |
| DE19907874A1 (en) * | 1999-02-23 | 2000-08-24 | Boehringer Ingelheim Pharma | New N-substituted hexahydro-2,6-methano-3-benzazocin-10-ol derivatives, as tension-dependent sodium channel blockers useful for treating e.g. arrhythmia, spasms, pain or neurodegenerative diseases |
-
1999
- 1999-11-27 DE DE19957156A patent/DE19957156A1/en not_active Withdrawn
-
2000
- 2000-11-21 PT PT00993781T patent/PT1235809E/en unknown
- 2000-11-21 SK SK930-2002A patent/SK9302002A3/en unknown
- 2000-11-21 CA CA002383114A patent/CA2383114C/en not_active Expired - Fee Related
- 2000-11-21 JP JP2001551853A patent/JP2003519687A/en active Pending
- 2000-11-21 DE DE50004455T patent/DE50004455D1/en not_active Expired - Fee Related
- 2000-11-21 ES ES00993781T patent/ES2210036T3/en not_active Expired - Lifetime
- 2000-11-21 NZ NZ519758A patent/NZ519758A/en unknown
- 2000-11-21 CZ CZ20022120A patent/CZ20022120A3/en unknown
- 2000-11-21 UA UA2002065301A patent/UA72566C2/en unknown
- 2000-11-21 BR BR0015786-4A patent/BR0015786A/en not_active Expired - Fee Related
- 2000-11-21 WO PCT/EP2000/011585 patent/WO2001051471A1/en not_active Application Discontinuation
- 2000-11-21 EE EEP200200267A patent/EE200200267A/en unknown
- 2000-11-21 EP EP00993781A patent/EP1235809B1/en not_active Expired - Lifetime
- 2000-11-21 AU AU57897/01A patent/AU5789701A/en not_active Abandoned
- 2000-11-21 DK DK00993781T patent/DK1235809T3/en active
- 2000-11-21 YU YU37902A patent/YU37902A/en unknown
- 2000-11-21 HU HU0204169A patent/HUP0204169A3/en unknown
- 2000-11-21 CN CNB008162530A patent/CN1177825C/en not_active Expired - Fee Related
- 2000-11-21 KR KR1020027006752A patent/KR20020058042A/en not_active Application Discontinuation
- 2000-11-21 PL PL00355493A patent/PL355493A1/en not_active Application Discontinuation
- 2000-11-21 MX MXPA02003822A patent/MXPA02003822A/en unknown
- 2000-11-21 TR TR2003/02031T patent/TR200302031T4/en unknown
- 2000-11-21 AT AT00993781T patent/ATE254108T1/en not_active IP Right Cessation
- 2000-11-21 EA EA200200491A patent/EA005681B1/en not_active IP Right Cessation
- 2000-11-21 IL IL14960700A patent/IL149607A0/en unknown
- 2000-11-23 AR ARP000106183A patent/AR026586A1/en not_active Suspension/Interruption
- 2000-11-24 CO CO00090163A patent/CO5251469A1/en not_active Application Discontinuation
- 2000-11-24 UY UY26448A patent/UY26448A1/en not_active Application Discontinuation
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2002
- 2002-05-09 BG BG106682A patent/BG106682A/en active Pending
- 2002-05-22 ZA ZA200204056A patent/ZA200204056B/en unknown
- 2002-05-24 NO NO20022457A patent/NO20022457D0/en not_active Application Discontinuation
- 2002-05-24 HR HR20020460A patent/HRP20020460A2/en not_active Application Discontinuation
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2003
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