CA2362697C - Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols, method for producing them and their use as medicaments - Google Patents

Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols, method for producing them and their use as medicaments Download PDF

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CA2362697C
CA2362697C CA002362697A CA2362697A CA2362697C CA 2362697 C CA2362697 C CA 2362697C CA 002362697 A CA002362697 A CA 002362697A CA 2362697 A CA2362697 A CA 2362697A CA 2362697 C CA2362697 C CA 2362697C
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mixture
racemate
isomer
compound
free base
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Matthias Grauert
Hans Briem
Matthias Hoffmann
Adrian Carter
Thomas Weiser
Wolf-Dietrich Bechtel
Rainer Palluk
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Boehringer Ingelheim Pharma GmbH and Co KG
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Abstract

The 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) (see formula 1) to a method for producing them and to their use as medicaments with sodium channel blocking activity, and related therapeutic functions.

Description

! A

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, R4 ~ R2 R3' ~- \ ~ n 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.
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 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, 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.
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 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 R4 ~1 R2 R3 J n 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, 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-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 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.
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

Claims (20)

CLAIMS:
1. 1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocin-10-ols of general formula 1 wherein R1 is hydrogen, methyl or fluorine;
R2 is hydrogen, methyl or fluorine;
n is 1 or 2;

R3 is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxy or methoxy;

R4 is hydrogen or methyl;

R5 is hydrogen or methyl; and R6 is hydrogen, methyl or ethyl; or an optical isomer thereof, a mixture of enantiomers thereof, a racemate thereof, a free base thereof or a pharmacologically acceptable acid addition salt thereof.
2. A compound, isomer, mixture, racemate, free base or salt according to claim 1, wherein R1 is hydrogen or fluorine;
R2 is hydrogen or fluorine;

n is 1;

R3 is hydrogen or methyl;
R4 is hydrogen or methyl;
R5 is hydrogen or methyl;

R6 is hydrogen, methyl or ethyl.
3. A process for preparing a compound of general formula 1 wherein a norbenzomorphane derivative of general formula 2 wherein R3, R4, R5 and R6 are defined as in claim 1, is reacted with a tetrahydrofuran or hexahydropyran derivative of general formula 3 wherein R1, R2 and n are defined as in claim 1 or 2 and X
represents a leaving group which is optionally substituted by a secondary amino group and the end product is optionally purified and isolated.
4. A pharmaceutical composition comprising a compound, isomer, mixture, racemate, free base or salt according to claim 1 or 2 and a pharmaceutically acceptable excipient or carrier.
5. A pharmaceutical composition according to claim 4, formulated as a solution for infusion.
6. A pharmaceutical composition according to claim 5, comprising from 0.001 to 5 wt.% of the compound, isomer, mixture, racemate, free base or salt based on the total mass of the pharmaceutical composition.
7. A pharmaceutical composition according to claim 5, comprising from 0.001 to 3 wt.% of the compound, isomer, mixture, racemate, free base or salt based on the total mass of the pharmaceutical composition.
8. A pharmaceutical composition according to claim 5, comprising from 0.01 to 1 wt.% of the compound, isomer, mixture, racemate, free base or salt based on the total mass of the pharmaceutical composition.
9. A pharmaceutical composition according to any one of claims 4 to 8 for therapeutic treatment of functional disorders caused by overstimulation.
10. A pharmaceutical composition according to any one of claims 4 to 8 for therapeutic treatment of an arrhythmia, a spasm, cardiac ischemia, cerebral ischaemia, pain or a neurodegenerative disorder.
11. A pharmaceutical composition according to any one of claims 4 to 8 for therapeutic treatment of 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, a heart rhythm disorder, angina pectoris, chronic pain, and neuropathic pain.
12. Use of a compound, isomer, mixture, racemate, free base or salt according to claim 1 or 2 in preparing a pharmaceutical composition for therapeutic treatment of functional disorders caused by overstimulation.
13. Use of a compound, isomer, mixture, racemate, free base or salt according to claim 1 or 2 in preparing a pharmaceutical composition for therapeutic treatment of an arrhythmia, a spasm, cardiac ischemia, cerebral ischaemia, pain or a neurodegenerative disorder.
14. Use of a compound, isomer, mixture, racemate, free base or salt according to claim 1 or 2 in preparing a pharmaceutical composition for therapeutic treatment of 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, a heart rhythm disorder, angina pectoris, chronic pain, and neuropathic pain.
15. Use of a compound, isomer, mixture, racemate, free base or salt according to claim 1 or 2 for therapeutic treatment of functional disorders caused by overstimulation.
16. Use of a compound, isomer, mixture, racemate, free base or salt according to claim 1 or 2 for therapeutic treatment of an arrhythmia, a spasm, cardiac ischemia, cerebral ischaemia, pain or a neurodegenerative disorder.
17. Use of a compound, isomer, mixture, racemate, free base or salt according to claim 1 or 2 for therapeutic treatment of 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, a heart rhythm disorder, angina pectoris, chronic pain, and neuropathic pain.
18. A compound, isomer, mixture, racemate, free base or salt according to claim 1 or 2 for therapeutic treatment of functional disorders caused by overstimulation.
19. A compound, isomer, mixture, racemate, free base or salt according to claim 1 or 2 for therapeutic treatment of an arrhythmia, a spasm, cardiac ischemia, cerebral ischaemia, pain or a neurodegenerative disorder.
20. A compound, isomer, mixture, racemate, free base or salt according to claim 1 or 2 for therapeutic treatment of 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, a heart rhythm disorder, angina pectoris, chronic pain, and neuropathic pain.
CA002362697A 1999-02-23 2000-02-12 Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols, method for producing them and their use as medicaments Expired - Fee Related CA2362697C (en)

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DE19907874.2 1999-02-23
DE19907874A DE19907874A1 (en) 1999-02-23 1999-02-23 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
PCT/EP2000/001160 WO2000050421A1 (en) 1999-02-23 2000-02-12 Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols, method for producing them and their use as medicaments

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CA (1) CA2362697C (en)
CO (1) CO5170499A1 (en)
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US6355652B1 (en) 1999-11-27 2002-03-12 Boehringer Ingelheim Pharma Kg Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceutical compositions
DE19957156A1 (en) * 1999-11-27 2001-05-31 Boehringer Ingelheim Pharma 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
US20030045449A1 (en) * 2001-08-15 2003-03-06 Pfizer, Inc. Pharmaceutical combinations for the treatment of neurodegenerative diseases
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
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
AR069545A1 (en) * 2007-11-16 2010-02-03 Boehringer Ingelheim Pharma DERIVATIVES OF ARIL AND HETEROARILCARBONILO OF RELATED BENZOMORPHANS AND RELATED STRUCTURES, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS, OBTAINING THEMSELVES, THEIR USE IN THE TREATMENT OF DISEASES MEDIATED BY THE INHIBITION OF THE HIDDEN AND DISEASE
JP7289119B2 (en) * 2019-02-15 2023-06-09 国立大学法人千葉大学 Method for Synthesizing Optically Active Substituted Tetrahydrofuran Derivatives

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GB1575009A (en) * 1976-06-21 1980-09-17 Acf Chemiefarma Nv 6,7-benzomorphan derivatives
AU524600B2 (en) * 1976-09-22 1982-09-23 Sterling Drug Inc. 2,6-methano-3-benzazocines
JPS5513253A (en) * 1978-07-15 1980-01-30 Res Inst For Prod Dev Cis-3-aralkyl substituted-8-benzoylthio-6,11-dimethyl-2,6- methano-1,2,3,4,5,6-hexahydro-3-benzazocine or its acid addition salt
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CA2362697A1 (en) 2000-08-31
WO2000050421A1 (en) 2000-08-31
UY26022A1 (en) 2000-09-29
DE50000560D1 (en) 2002-10-31
EP1157020A1 (en) 2001-11-28
PE20001487A1 (en) 2001-01-18
JP2002537393A (en) 2002-11-05
CO5170499A1 (en) 2002-06-27
ES2183786T3 (en) 2003-04-01
AR022718A1 (en) 2002-09-04
DK1157020T3 (en) 2003-01-27
PT1157020E (en) 2003-01-31
DE19907874A1 (en) 2000-08-24
EP1157020B1 (en) 2002-09-25
ATE224890T1 (en) 2002-10-15

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