Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceutical compositions

A compound selected from the group consisting of:

• (a) (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;
• (b) (2R,6S, 11R,2″S)-10-amino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine dihydrochloride;
• (c) (2R,6S, 11S,2″S)-10-amino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine dihydrochloride;
• (d) (2R,6S)-10-amino-3-[2(2,6-difluorophenylmethoxy)ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride;
• (e) (2R,6S,2″S,5″S)-10-amino-3-[5″-phenyltetrahydrofuran-2″-yl)methyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride;
• (f) (2R,6S,2″S)-10-acetamino-3-[2(2,6-benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine hydrochloride;
• (g) (2R,6S,2″S)-10-acetamino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine hydrochloride;
• (h) (2R,6S,2″S)-10-formylamino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine hydrochloride;
• (i) (2R,6S,2″S)-10-methylamino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride;
• (j) (2R,6S,2″S)-10-dimethylamino-3-[2-(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride;
• (k) (2R,6S,2″S)-10-ethylamino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride;
• (l) (2R,6S,2″S)-10-Fluoro-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine hydrochloride,
• and the pharmacologically acceptable acid addition salts thereof.

A method for preparing a compound of general formula 1

• wherein:
• R1 and R2, which are identical or different, are each hydrogen, C1-C6-alkyl, C1-C6-alkyloxy, OH, F, Cl, or Br;
• R3 is hydrogen, F, Cl, Br, methyl, ethyl, OH, or methoxy;
• R4 and R5, which are identical or different, are each hydrogen, methyl, or ethyl;
• R6 is hydrogen;
• X is NH2;
• A is —(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—,
• the racemates thereof, the enantiomers thereof, the diastereomers thereof, and mixtures thereof, and the pharmacologically acceptable acid addition salts thereof, the method comprising reacting a compound of general formula 3
• wherein the groups R1, R2, R3, R4, R5, R6, and A have the meanings given above, with a source of nitrogen in an aromatic solvent with palladium catalysis.

A method for preparing a compound of general formula 1

• wherein
• R1 and R2, which are identical or different, are each hydrogen, C1-C6-alkyl, C1-C6-alkyloxy, OH, F, Cl, or Br;
• R3 is hydrogen, F, Cl, Br, methyl, ethyl, OH, or methoxy;
• R4 and R5, which are identical or different, are each hydrogen, methyl, or ethyl;
• R6 is hydrogen;
• X is N—(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 is —(CH2)3—, —CH2—CH2—O—, —CH2—O—CH2—, —(CH2)4—, —CH(C1-C6-alkyl)-O—CH213 , —(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—,
• the racemates thereof, the enantiomers thereof, the diastereomers thereof, and mixtures thereof, and the pharmacologically acceptable acid addition salts thereof, the method comprising:
• reacting a compound of formula 1, wherein the groups R1, R2, R3, R4, R5, R6, and A have the meanings given above and X is NH2:
• (a) with a base and an alkylating agent, in a polar organic solvent, to obtain the compound of general formula 1, wherein X is NH—(C1-C6-alkyl) or N(C1-C6-alkyl)2;
• or
• (b) with aldehydes or ketones, with cooling, in the presence of acids, to obtain a Schiff base or an iminium salt and subsequently reducing the Schiff base or the iminium salt obtained with metal hydrides to obtain the compound of general formula 1, wherein X is NH—(C1-C6-alkyl) or N(C1-C6-alkyl)2;
• or
• (c) with an acid chloride or anhydride, in the presence of a base, to obtain the compound of general formula 1, wherein X is NHCO(C1-C6-alkyl);
• or
• (d) with an acid chloride or anhydride, in the presence of a base, to obtain the compound of general formula 1, wherein X is NHCO(C1-C6-alkyl), and subsequently reducing the compound of general formula 1, wherein X is NHCO(C1-C6-alkyl), with a metal hydride, using a Lewis acids as a catalyst, to obtain the compound of general formula 1, wherein X is NH—(C1-C6-alkyl) or N(C1-C6-alkyl)2;
• or
• (e) with formic acid at elevated temperature to obtain the compound of general formula 1, wherein X is NHCOH;
• or
• (f) by diazotization and subsequent decoction with BF4− to obtain the compound of formula 1, wherein X is F.