Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
! A
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S018-801pct.204
SUBSTITUTED 1,2,3,4,5,6-HEXAHYDRO-2,6-METHANO-3-BENZAZOCIN-10-OLS,
METHOD FOR PRODUCING THEM AND THEIR USE AS MEDICAMENTS
The present invention relates to N-(5-phenyl-
tetrahydrofuranyl)methyl- and N-(6-phenyl-
tetrahydropyranyl)methyl-substituted 1,2,3,4,5,6-
hexahydro-2,6-methano-3-benzazocin-10-ols of general
formula 1, processes for preparing them and their use as
medicaments,
OH R1
R4 ~ R2
R3' ~- \ ~ n
R5
R6
wherein
R1 may denote hydrogen, methyl or fluorine;
R2 may denote hydrogen, methyl or fluorine;
n may denote an integer 1 or 2
R3 may denote hydrogen, fluorine, chlorine, bromine,
methyl, ethyl, hydroxy or methoxy;
R4 may denote hydrogen or methyl;
R5 may denote hydrogen or methyl;
R6 may denote hydrogen, methyl or ethyl.
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The preferred compounds of general formula 1 are those
wherein
R1 may denote hydrogen or fluorine;
R2 may denote hydrogen or fluorine;
n may denote the number 1
R3 may denote hydrogen or methyl;
R4 may denote hydrogen or methyl;
R5 may denote hydrogen or methyl;
R6 may denote hydrogen, methyl or ethyl.
The invention relates to the compounds in question,
optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or
racemates and in the form of the free bases or the
corresponding acid addition salts thereof with
pharmacologically acceptable acids - such as for
example acid addition salts with hydrohalic acids -
e.g. hydrochloric or hydrobromic acid - or organic
acids - such as e.g. oxalic, fumaric or diglycolic acid
or methanesulphonic acid.
Biological properties
The compounds claimed are blockers of the voltage-
dependent sodium channel. These are compounds which
displace batrachotoxin (BTX) with a high affinity (Ki
< 1000 nM) competitively or non-competitively from the
binding site on the sodium channel. Such substances
exhibit "use-dependency" while the sodium channels are
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blocked, i.e. in order to bind the substances at the
sodium channel, the sodium channels first have to be
activated. Maximum blockage of the sodium channels is only
achieved after repeated stimulation of the sodium
channels. Consequently, the substances bind preferentially
to sodium channels which are activated a number of times.
As a result, the substances are in a position to become
effective particularly in those parts of the body which
are pathologically overstimulated. The compounds of
general formula 1 according to the invention can thus be
used to treat diseases which are caused by a functional
disorder resulting from overstimulation. These include
diseases such as arrhythmias, spasms, cardiac and cerebral
ischaemias, pain and neurodegenerative diseases of various
origins. These include, for example: 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 infarction,
heart rhythm disorders, angina pectoris, chronic pain,
neuropathic pain and local anaesthesia.
The blocking action on the sodium channel may be
demonstrated by the test system which tests the BTX
binding to the sodium channel [S.W. Postma & W.A.
Catterall, Mol. Pharmacol 25, 219-227 (1984)] as well as
by patch-clamp experiments which 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, 57-65 (1987)].
By a suitable choice of cell system (e.g. neuronal,
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cardiac, DRG cells) it is possible to test the effect of
the substances on different subtypes of sodium channel.
The sodium channel blocking property of the compounds
according to the invention can be demonstrated by the
blocking of the veratridine-induced release of glutamate
[S. Villanueva, P. Frenz, Y. Dragnic, F. Orrego, Brain
Res. 461, 377-380 (1988)]. Veratridine is a toxin which
opens the sodium channel permanently. This leads to an
increased influx of sodium ions into the cell. By means of
the cascade described above, this sodium influx leads to
an increased release of glutamate in the neuronal tissue.
The compounds according to the invention antagonise this
release of glutamate.
The anticonvulsant properties of the substances according
to the invention were demonstrated by their protective
effect against convulsions triggered by a maximum electric
shock in mice [M. A. Rogawski & R.J. Porter, Pharmacol.
Rev. 42, 223-286 (1990)].
Neuroprotective properties were demonstrated by a
protective effect in a rat MCAO model [U. Pschorn & A. J.
Carter, J. Stroke Cerebrovascular Diseases, 6, 93-99
(1996)] and 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)].
Analgesic effects can be investigated in models of
diabetic neuropathy and in a ligature model [C. Courteix,
M. Bardin, C. Chantelauze, J. Lavarenne, A. Eschalier,
Pain 57, 153-160 (1994); C. Courteix, A. Eschalier, J.
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Lavarenne, Pain 53, 81-88 (1993); G. J. Bennett and Y.-K.
Xie, Pain 33, 87-107 (1988)].
It has also been reported that sodium channel blockers can
be used to treat cyclophrenia (manic depressive disorder)
[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.].
Preparation methods
The compounds 1 claimed may be prepared by methods known
per se from the prior art. One possible method of
synthesis is shown in Diagram 1. The methods of
synthesising the nor-1,2,3,4,5,6-hexahydro-2,6-methano-3-
benzazocin-10-ols (2) needed as starting compounds are
described in published German applications 41 21 821, 195
28 472 and 197 40 110. The synthesis component 3 contains
a leaving group X which is preferably iodine, bromine or a
methanesulphonate group. The synthesis of the 5-phenyl-
tetrahydrofuran-2-yl)methyl-iodide is described in the
literature [K. Miura, T. Hondo, S. Okajima, A. Hosomi,
Tetrahedron Lett. 37 (1996) 487-490] for the racemate. The
enantiomerically pure compounds may be prepared
analogously, following these instructions, if the
corresponding chiral 5-hydroxy-5-phenyl-pentene is used as
starting compound [cf. D. Seebach, R.E. Marti, T.
Hintermann; Helv. Chim. Acta, 79 (1996) 1710-1740]. - The
corresponding bromides may be prepared analogously by
using bromine instead of iodine.
The methanesulphonates of the 6-phenyl-tertahydropyran-2-
yl-methanols and 5-phenyl-tetrahydrofuran-2-yl-methanols
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may be prepared from the corresponding alcohols. The
synthesis of 6-phenyl-tetrahydropyran-2-yl-methanol and 5-
phenyl-tetrahydrofuran-2-yl-methanol is described in the
literature [T. Mandai, M. Ueda, K. Kashiwagi, M. Kawada,
J. Tsuji, Tetrahedron Lett., 34 (1993) 111-114; S. Inoki,
T. Mukaiyama, Chemistry Lett. 1990, 67-70].
Diagram 1:
OH H
N
RI
~ ~~ ~- R4
O
R3 ~~~% ~~~.: R5 ~n
R2
R6
2 3
OH R1
R4 ~1 R2
R3 J n
R5
R6
1
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The Examples that follow serve to illustrate the invention
without restricting it to the compounds and processes
disclosed by way of example.
Example 1: (2R, 5S)- and (2S, 5S)-5-Phenyl-
tetrahydrofuran-2-yl)methyl-bromide
1.6 g (10 mmol) of (5S)-5-hydroxy-5-phenyl-pentene are
dissolved in 16 mL of dichloromethane and at 10 to 15 C
1.6 g of bromine in 16 mL dichloromethane is added. The
mixture is left to return to ambient temperature and 2 g
of Na2CO3 (sodium carbonate) and 0.1 g of tetrabutyl
ammoniumsulphate are added. After 1 hour (h) 20 mL of
water are added and the mixture is stirred for another
hour at ambient temperature. The organic phase is
separated off, washed once with 20 mL of 2 N hydrochloric
acid, dried and the solvent is eliminated in vacuo. The
residue is chromatographed on 400 g of silica gel
(cyclohexane/ethyl acetate: 95 : 5). 0.6 g (25 % of
theory) of (2S, 5S)-5-phenyl-tetrahydrofuran-2-yl-methyl-
bromide and 0.7 g (29 % of theory) of (2R, 5S)-5-phenyl-
tetrahydrofuran-2-yl-methyl-bromide are obtained.
Example 2: (5-Phenyl-tetrahydrofuran-2-yl)methyl (2S, 5S)-
methanesulphonate
580 mg (3.3 mmol) of (2S, 5S)-5-phenyl-tetrahydrofuran-2-
yl-methanol are dissolved in 4 mL of pyridine and combined
with 390 mg (3.4 mmol) of inethanesulphonic acid chloride
and stirred for 1 h at 0 C and then for 8 h at ambient
temperature. Next, 30 mL of water and 30 mL of 2 N
hydrochloric acid are added. The mixture is extracted
three times with 20 mL of diethylether, the ethereal phase
is washed once with 50 mL of 10% Na2CO3 solution, dried,
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and the solvent is eliminated in vacuo. The residue is
chromatographed over 20 g of silica gel (cyclohexane/ethyl
acetate: 1 : 1). 450 mg (53% of theory) of the title
compound are obtained as an oil.
Example 3: (2R,6S,2R',5'S)-N-[5'-phenyl-tetrahydrofuran-
2'-yl)methyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-
methano-3-benzazocin-10-ol-hydrochloride
0.5 g (2.15 mmol) of (2R, 6S) -l, 2, 3, 4, 5, 6-hexahydro-
6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol and 0.5 g
(11 mmol) of (2R, 5S)-5-phenyl-tetrahydrofuran-2-
yl)methyl-bromide are dissolved in 3 mL of 1,3-
dimethyltetrahydropyrimidinone and 1 g of K2CO3 (potassium
carbonate) is added. The mixture is heated for a period of
4 h to a temperature in the range from 80-90 C, left to
cool, mixed with 100 mL of water and extracted twice with
100 mL of ethyl acetate. The combined organic extracts are
washed three times with 100 mL of water, dried, and freed
from solvent in vacuo. The residue is chromatographed over
30 g of silica gel (cyclohexane/ethyl acetate). The
appropriate fractions are collected, the solvent is
eliminated in vacuo, the residue is taken up in 50 mL of
ether and the hydrochloride is precipitated with ethereal
hydrochloric acid. In this way, 0.5 g (54% of theory) of
the title compound is obtained in the form of crystals;
melting point: 174 C, [a]p20 =(-) 47.0 (c=1 in
methanol).
The following is prepared analogously to Example 3:
(2R,6S,2S',5'S)-N-[5'-phenyl-tetrahydrofuran-2'-
yl)methyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-
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methano-3-benzazocin-10-ol-hydrochloride; melting point:
253 C, [a]o20 = (-) 55.3 (c=1 in methanol).
(2R, 6S, 2R' , 5' R) -N- [5' -Phenyl-tetrahydrofuran-2' -
yl)methyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-
methano-3-benzazocin-l0-ol-hydrochloride; melting point:
157 C and
(2R,6S,2S',5'R)-N-[5'-Phenyl-tetrahydrofuran-2'-
yl)methyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-
methano-3-benzazocin-10-ol-hydrochloride; melting point:
169 C.
(2R, 5R)- and (2S, 5R)-5-phenyl-tetrahydrofuran-2-
yl)methyl-iodide were used as the mixture of isomers and
the corresponding diastereomers were separated by
chromatography.
Example 4: (2RS,6RS,2S',5'S)-N-[5'-Phenyl-tetrahydrofuran-
2'-yl)methyl]-1,2,3,4,5,6-hexahydro-6,7-dimethyl-2,6-
methano-3-benzazocin-10-ol-hydrochloride
440 mg (1.7 mmol) of (2RS,6RS)-1,2,3,4,5,6-hexahydro-6,7-
dimethyl-2,6-methano-3-benzazocin-10-ol and 350 mg (1.6
mmol) of (5-phenyl-tetrahydrofuran-2-yl)methyl (2S, 5S)-
methanesulphonate are dissolved in 3 mL of 1,3-
dimethyltetrahydropyrimidinone and 1 g of K2CO3 is added.
The mixture is heated to a temperature in the range from
80-90 C over a period of 5 h, left to cool, 100 mL of
water are added and the resulting mixture is extracted
twice with 100 mL of ethyl acetate. The combined organic
phases are washed three times with 100 mL of water, dried,
and evaporated down in vacuo. The residue is
chromatographed over 30 g of silica gel (cyclohexane/ethyl
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acetate 3 : 1). The required fractions are collected, the
solvent is eliminated in vacuo, the residue is taken up in
50 mL of ether and the hydrochloride is precipitated with
ethereal hydrochloric acid. Yield: 370 mg (53%) of a 1:1
mixture of diastereomers, melting point: 155 C.
Pharmaceutical Preparations
The following are some examples of pharmaceutical
preparations containing the active substance:
Tablets:
active substance of general formula 1 20 mg
magnesium stearate 1 mg
lactose 190 mg
Injectable solution
active substance of general formula 1 0.3 mg
sodium chloride 0.8 g
benzalkonium chloride 0.01 mg
water for injections ad 100 ml
A solution similar to that shown above is suitable for
nasal administration in a spray, or in conjunction with
a device which produces an aerosol with a particle size
preferably between 2 and 6 M, for administration via
the lungs.
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Solution for infusion
A 5% by weight xylitol or saline solution which
contains the active substance in a concentration of 2
mg/ml, for example, is adjusted to a pH of about 4
using a sodium acetate buffer.
Infusible solutions of this kind may contain an active
substance according to general formula 1 in an amount,
based on the total mass of the pharmaceutical preparation,
in the range from 0.001 to 5 wt.%, preferably in the range
from 0.001 to 3 wt.% and most preferably in the range from
0.01 to 1 wt.%.
Capsules for inhalation
The active substance according to general formula 1 in
micronised form (particle size substantially between 2
and 6 M) is packed into hard gelatine capsules,
optionally with the addition of micronised carrier
substances, such as lactose. It can be inhaled using
conventional equipment for powder inhalation. Between
0.2 and 20 mg of active substance and 0 to 40 mg of
lactose are packed into each capsule.
Aerosol for Inhalation
active substance of general formula 1 1 part
soya lecithin 0.2 parts
propellent gas mixture ad 100
