Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-30
2002-03-12
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S097000
Reexamination Certificate
active
06355652
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines of general formula 1
wherein
R
1
and R
2
which may be identical or different denote hydrogen, C
1
-C
6
-alkyl, C
1
-C
6
-alkyloxy, OH, F, Cl, or Br;
R
3
may denote hydrogen, F, Cl, Br, methyl, ethyl, OH, or methoxy;
R
4
, R
5
, and R
6
, which may be identical or different, may denote hydrogen, methyl, or ethyl;
X may denote NH
2
, NH-(C
1
-C
6
-alkyl), N(C
1
-C
6
-alkyl)
2
, the two C
1
-C
6
-alkyl groups of which may be identical or different, NH—COH, NH—CO(C
1
-C
6
-alkyl), or F;
A may denote —(CH
2
)
3
—, —CH
2
—CH
2
—O—, —CH
2
—O—CH
2
—, —(CH
2
)
4
—, —CH(C
1
-C
6
-alkyl)-O—CH
2
—, —(CH
2
)
2
—O—CH
2
—, —(CH
2
)
3
—O—, (CH
2
)
5
—, —CH
2
—O—(CH
2
)
3
—,
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:
R
1
and R
2
which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, OH, F, Cl, or Br;
R
3
may denote hydrogen, F, methyl, ethyl, OH, or methoxy;
R
4
, R
5
, and R
6
, which may be identical or different, may denote hydrogen or methyl;
X may denote NH
2
, NH-(methyl), N(methyl)
2
, NH-(ethyl), N(ethyl)
2
, NH—COH, NH—COMe, or F;
A may denote —CH
2
—CH
2
—O—, —CH
2
—O—CH
2
—, —CH(methyl)-O—CH
2
—, CH(ethyl)-O—CH
2
—, —CH(isopropyl)-O—CH
2
—, —(CH
2
)
2
—O—CH
2
—, —(CH
2
)
3
—O—, —CH
2
—O—(CH
2
)
3
—, —(CH
2
)
2
—O—(CH
2
)
2
—, —(CH
2
)
3
—O—CH
2
—, —(CH
2
)
4
—O—, —CH
2
—O—CH
2
—CH
2
—
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:
R
1
and R
2
which may be identical or different, may denote hydrogen or F;
R
3
may denote hydrogen or methyl;
R
4
, R
5
, and R
6
, which may be identical or different, may denote hydrogen or methyl;
X may denote NH
2
, NH-(methyl), N(methyl)
2
, NH—COH, or NH—COMe;
A may denote —CH(methyl)-O—CH
2
—, —CH
2
—O—CH
2
—, or
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:
R
1
and R
2
which may be identical or different may denote hydrogen or F;
R
3
may denote hydrogen;
R
4
, R
5
, and R
6
, which may be identical or different, may denote hydrogen or methyl;
X may denote F;
A may denote —CH(methyl)-O—CH
2
—,
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 interest are compounds of general formula 1 selected from the group comprising:
(2R,6S,2S′)-10-amino-3-[2(2,6-difluorophenylmethoxy)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-6,11,11trimethyl-2,6-methano-3-benzazocine dihydrochloride;
(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;
(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;
(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;
(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;
(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-difluorophenylmethoxy)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-difluorophenylmethoxy)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-difluorophenylmethoxy)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-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride; and
(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.
C
1
-C
6
-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.
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 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, sulfuric 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 (K
i
<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, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotrophic 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 anesthesia.
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
Carter Adrian
Ensinger Helmut
Gaida Wolfram
Grauert Matthias
Mierau Joachim
Aulakh Charanjit S.
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Raymond Robert P.
Stempel Alan R.
LandOfFree
Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2869761