MXPA01008507A - 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

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), to a method for producing them and to their use as medicaments.

Description

1,2,3,4,5, 6-HEXAHIDRO-2, 6-METHANE-3-BENZAZOCIN-10-OLES REPLACED WITH N- (5-PHENYL-TETRAHYDROFURANIL) METHYL AND N- (6-PHENYL-TETRAHYDROPYRANIL) METHYL, PROCEDURES FOR PREPARING THEM AND EMPLOYING THEM AS PHARMACEUTICAL COMPOSITIONS DESCRIPTION OF THE INVENTION The present invention relates to 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-oles substituted with N- (5-phenyl-tetrahydrofuranyl) methyl and N- (6-phenyl-tetrahydropyranyl) methyl of general formula 1, to processes for preparing them, and to their use as medicaments, wherein R1 can mean hydrogen, methyl or fluorine; R "can mean hydrogen, methyl or fluorine, n can mean a whole number 1 or 2, RJ can mean hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxy or methoxy, R4 can be hydrogen or methyl; REF: 131288 R5 can mean hydrogen or methyl; R6 can mean hydrogen, methyl or ethyl; Preferred are compounds of the general formula 1, in which R 1 can mean hydrogen or fluorine; R2 can mean hydrogen or fluorine; n can mean the number 1; RJ can mean hydrogen or methyl; R4 can mean hydrogen or methyl; R5 can mean hydrogen or methyl; R "can mean hydrogen, methyl or ethyl- Subject of the invention are the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, as well as in the form of the free bases or the corresponding salts by addition of acids, with pharmacologically harmless acids - such as, for example, salts by addition of acids with the hydrohalic acids - for example hydrochloric or hydrobromic acid - or organic acids - such as, for example, oxalic, fumaric or diglycolic acid or methanesulfonic acid.

Biological Properties The claimed compounds are blockers of the voltage-dependent sodium channel. In this case, these are compounds that displace the batrachotoxin (PTX) with a high affinity (Ki <1000 nM), competitively or non-competitively, from the binding site in the sodium channel. Such substances show a "dependence of use" on the blocking of the sodium channels, that is to say that in order to join the substances in the sodium channel, the sodium channels must first be activated. The maximum blockage of sodium channels is only achieved after repeated stimulation of the sodium channels. Accordingly, the substances bind in preference to the sodium channels that are activated several times. With this, the substances are able to be particularly effective in parts of the body that are pathologically overstimulated. The compounds of general formula 1 according to the invention can thus be used in the case of diseases whose cause is based on a functional disorder resulting from overstimulation. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischemias, pains as well as neurodegenerative diseases of various origins. For example, there may be mentioned: epilepsy, hypoglycemia, hypoxia, anoxia, cerebral trauma, cerebral edema, cerebral attack, perinatal asphyxia, degenerations of the cerebellum, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclofrenia, haphotonia , cardiac infarction, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain, as well as local anesthesia. As a test system for the detection of the blocking action on the sodium channel serves the binding of BTX to the sodium channel [S.W. Postma and W.A. Catterall, Mol. Pharmacol. 25, 219-227 (1984)], as well as by patch-clamping experiments, in which it can be demonstrated that the compounds according to the invention cluck the electrically stimulated sodium channel, in a "use-dependent" manner] [ WA Catterall, Trends Pharmacol. Sci., 8_, 57-65 (1987)]. By choosing the cellular system (for example neuronal, cardiac, DRG cells) it is possible to investigate the effect of substances on different sodium channel subtypes. The blocking property of the sodium channel of the compounds according to the invention can be detected by blocking the release of glutamate induced by veratridine [S. Villanueva, P. Frenz, Y. Dragnic, F.

Orrego, Brain Res. 461., 377-380 (1988)]. Veratridine is a toxin that permanently opens the sodium channel. With this, an increased inflow of sodium ions to the cell occurs. By means of the cascade described above, this influx of sodium leads to an increased release of glutamate in the neuronal tissue. The glutamate release can be antagonized by the compounds according to the invention. The anticonvulsive properties of the substances according to the invention were confirmed by a protective effect against convulsions caused by a maximum electrical shock in mice [M.A. Rogawski and R.J. Porter, Pharmacol. Rev. 4_2, 223-286 (1990)]. The neuroprotective properties were confirmed by a protective effect in a YCAO model of rats [U. Pschorn and A.J. Carter, J. Stroke Cerebrovascular Diseases, 6_, 93-99 (1996)] and a model of malonate-induced injury [M.F. Beal, Annals of Neurology, 38, 357-66 (1995) and J.B. Schultz, R.T. Matthews, D.R. Henshaw and Y.F. Beal, Neuroscience, 7_1, 1043-48 (1996)]. The analgesic effects can be investigated in models of diabetic neuropathy, as well as in a ligature model [C. Courteix, M. Bardin, C. Chantelauze, J. Lavarenne, A. Eschalier, Pain 57, 153-60 (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 further been described that sodium channel blockers can be used for the therapy of cyclophrenia (manic depressive illness), J.R. Calabrese, C. Bowden, M.J. Woyshville, in: Psychopharmacology: The Fourth Generation of Progress (compilers: D.E. Bloom and D.J. Kupfer), 1099-1111. New York, Raven Press Ltd.].

PREPARATION PROCEDURES The claimed compounds 1 can be prepared by methods known per se from the prior art. A possible synthesis route is represented in Scheme 1. The syntheses of the nor- 1,2,3,4,5,6-hexahydro-2,6-methane-3-benzazocin-1-oles (2), necessary as starting material, are described in German publication reports 41 21 821, 195 28 472 and 197 40 110. Component 3 of the synthesis contains a leaving group X which is preferably iodo, bromo or a methanesulfonate radical. The synthesis of 5-phenyl-tetrahydrofuranylmethyl iodide is described in the literature [K. Miura, T. Hondo, S. Okajima, A. Hosomi, Tetrahedron Lett. 37, (1996) 487-90] for the racemate. The pure compounds for the enantiomers can be prepared in an analogous manner, following this prescription, if starting from the corresponding chiral 5-hydroxy-5-phenyl-pentene as [see D. Seebach, R.E. Marti, T. Hintermann; Helv. Chim. Acta 7_9 (1996) 1710-1740]. The corresponding bromides can be prepared in an analogous way, if bromine is used instead of iodine. The methanesulfonates of the 6-phenyl-tetrahydropyran-2-yl-methanes and 5-phenyl-tetrahydrofuran-2-yl-methanes can 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].

Reaction Scheme I The following Examples serve to explain the invention in more detail, but without limiting 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, are mixed with 1.6 g of bromine in 16 ml of dichloromethane. The mixture is allowed to return to room temperature and 2 g of Na 2 CO 3 (sodium carbonate) and 0,1 g of tetrabutylammonium sulfate are added. After 1 hour (h), add 20 ml of water and stir at room temperature for another hour. The organic phase is separated, washed once with 20 ml of 2N hydrochloric acid, dried and the solvent removed 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) bromide are obtained. , 5S) -5-phenyl-tetrahydrofuran-2-yl-methyl.

Example 2: (5S, 5S) -methanesulfonic acid (5-phenyl-tetrahydrofuran-2-yl) metal ester 580 mg (3.3 mmol) of (2S, 5S) -5-phenyl-tetrahydrofuran-2-yl- Ethanol are dissolved in 4 ml of pyridine and mixed with 390 mg (3.4 mmol) of methanesulfonic acid chloride and stirred for 1 h at 0 ° C and then for 8 h at room temperature. Then, 30 ml of water and 30 ml of 2 N hydrochloric acid are added. It is extracted three times in each case with 20 ml of diethyl ether, the ether phase is washed once with 50 ml of 10% Na 2 CO 3 solution, it is dried, and the solvent is removed in vacuo. The residue is chromatographed on 20 g of silica gel (cyclohexane / ethyl acetate, 1: 1). 450 mg (53% of theory) of the title compound are obtained in the form of an oil.

Example 3: (2R, 6S, 2R ', 5' S) -N- [(5'-phenyl-tetrahydrofuran-2'-yl) methyl] -1,2,3,4,5,6-hexahydro hydrochloride -6, 11, 11-trimethyl-2,6-methane-3-benzazocin-10-ol 0.5 g (2.15 mmol) of (2R, 6S) -1, 2, 3,, 5, 6 hexahydro-6, 11, 11-trimethyl-2,6-methane-3-benzazocin-10-ol and 0.5 g (11 mmol) of (2R, 5S) -5-phenyl-tetrahydrofuran-2-yl- bromide methyl are dissolved in 3 ml of 1,3-dimethyltetrahydropyrimidinone and mixed with 1 g of K2CO (potassium carbonate). It is heated for a period of 4 h at a temperature in the range of 80 90 ° C, allow to cool, mix with 100 ml of water and extract twice with 100 ml of ethyl acetate each (ethyl ester of acetic acid). The combined organic extracts are washed three times with 100 ml of water, dried and freed from the solvent in vacuo. The residue is chromatographed on 30 g of silica gel (cyclohexane / ethyl acetate). The appropriate fractions are collected, the solvent is removed 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 (548 of the theoretical value) of the title compound are obtained, in the form of crystals of mp: 174 ° C, [a] 20 D = (-) 47.0 ° (c = 1 in methanol ). By analogy to Example 3, they were prepared, among others, in addition: Hydrochloride. of (2R, 6S, 2S ', 5' S) -N- [(5'-phenyl-tetrahydrofuran-2'-yl) ethyl] -! 2, 3, 4, 5, 6-hexahydro-6, 11 , 11-trimethyl-2,6-methane-3-bezazocin-10-ol: mp: 253 ° C, [] 20 D = (-) 55.3 ° (c = 1 in methanol). Hydrochloride of (2R, 6S, 2R ', 5'R) -N- [(5'-phenyl-tetrahydrofuran-2'-yl) methyl] -! 2, 3, 4, 5, 6-hexahydro-6, 11, 11-trimethyl-2,6-methane-3-benzazocin-10-ol: pf : 157 ° C and Hydrochloride of (2R, 6S, 2S ', 5' R) -N- [(5'-phenyl-tetrahydrofuran-2'-yl) methyl] -! 2, 3, 4, 5, 6 hexahydro-6, 11, 11-trimethyl-2,6-methane-3-benzazocin-10-ol: mp: 169 ° C. The (2R, 5R) - and (2S, 5R) -5-phenyl-tetrahydrofuran-2-yl-methyl iodide was used as a mixture of isomers and the corresponding diastereoisomers were separated by chromatography.

Example 4: (2RS, 6S, 2S ', 5' S) -N- [(5'-phenyl-tetrahydrofuran-2'-yl) methyl] -! 2, 3, 4, 5, 6-hexahydro hydrochloride -6,7-dimethyl-2,6-methane-3-benzazocin-10-ol 440 mg (1.7 mmol) of (2RS, 6RS) -1, 2, 3, 4, 5, 6-hexahydro-6 , 7-dimethyl-2,6-methane-3-benzazocin-10-ol and 350 mg (1.6 mmol) of (2S, 5S) -methanesulfonic acid (5-phenyl-tetrahydrofuran-2-yl) methyl ester they are dissolved in 3 ml of 1,3-dimethyltetrahydropyrimadinone and mixed with 1 g of K2CO3. It is heated for a period of 5 h at a temperature in the range of 80-90 ° C, allowed to cool, mixed with 100 ml of water and extracted twice with each 100 ml of ethyl acetate. The combined organic phases are washed three times with 100 ml of water, dried and concentrated in vacuo. The residue is chromatographed on 30 g of silica gel (cyclohexane / ethyl acetate, 3: 1). The appropriate fractions are collected, the solvent is removed 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 diastereoisomers, m.p .: 155 ° C.

Pharmaceutical preparations The following are some examples of pharmaceutical preparations with the active substance: Tablets: active substance according to the general formula 1_ 20 mg magnesium stearate 1 mg lactose 190 mg Injectable solution: active substance according to the general formula 1_ 0.3 mg sodium chloride 0.8 mg benzalkonium chloride 0.01 mg water for injection up to 100 ml A solution similar to the above is suitable for nasal administration in a spray, or in combination with an apparatus that generates an aerosol, with a particle size preferably between 2 and 6 μm, for its administration through the lungs.

Solution for infusion A solution of xylitol or 5% by weight saline, containing, for example, the active substance at a concentration of 2 mg / ml, is adjusted to a pH value of approximately 4, using an acetate buffer of sodium. Solutions for infusions of this type can have a content of an active substance according to general formula 1, based on the total mass of the pharmaceutical preparation, in a range of 0.001 to 5% by weight, preferably in a range of 0.001 to 3. % by weight, and particularly preferably in a range of 0.01 to 1% by weight.

Capsules for inhalation The active substance according to the general formula _1 is packaged in micronized form in hard gelatin capsules (particle size, essentially between 2 and 6 μm), possibly with the addition of micronized support substances, for example lactose. For the inhalation serve the usual devices for inhalation of powders. They are packaged in each capsule, for example, between 0.2 and 20 mg of active substance and from 0 to 40 mg of lactose.

Spray for inhalation active substance according to the general formula 1. 1 part soya lecithin 0.2 parts propellant gas mixture up to 100 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (12)

1. Having described the invention as above, the content of the following claims is claimed as property: 1. 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-oles of general formula 1, characterized in that: R1 can mean hydrogen, methyl or fluorine; R2 can mean hydrogen, methyl or fluorine; n can mean an integer 1 or 2; RJ can mean hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxy or methoxy; R can mean hydrogen or methyl; R5 can mean hydrogen or methyl; RD can mean hydrogen, methyl or ethyl; the respective compounds, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, as well as in the form of the free bases or the corresponding salts by addition of acids, with pharmacologically harmless acids. 2. Compounds of general formula _1 according to claim 1, characterized in that
2. R1 can mean hydrogen or fluorine; R2 can mean hydrogen or fluorine; n can mean the number 1; R3 can mean hydrogen or methyl; R4 can mean hydrogen or methyl; c RJ can mean hydrogen or methyl; R6 can be hydrogen, methyl or ethyl, the respective compounds, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, as well as in the form of the free bases or the corresponding salts by addition of acids, with acids pharmacologically harmless.
3. 3. Process for preparing compounds of general formula 1 characterized in that a norbenzomorphan derivative of general formula 2 wherein R3, R4, R5 and R6 can have the meaning mentioned in claims 1 or 2, is reacted with a tetrahydrofuran or hexahydropyran derivative of general formula 3 wherein R1, R2 and n can have the meaning mentioned in claims 1 or 2, and X represents a leaving group substitutable with a secondary amino group, and the final product is eventually purified and isolated.
4. 4. Pharmaceutical preparation, characterized by a content in one of the compounds according to any of claims 1 or 2, and their salts by addition of acids, together with adjuvants and usual support substances.
5. 5. Pharmaceutical preparation according to claim 4, characterized in that it is formulated as a solution for infusion.
6. 6. Pharmaceutical preparation according to claim 5, characterized in that the content of active substance is within the range of 0.001 to 5% by weight, based on the total mass of the pharmaceutical preparation.
7. 7. Pharmaceutical preparation according to claim 6, characterized in that the content of active substance is within the range of 0.001 to 3% by weight, based on the total mass of the pharmaceutical preparation.
8. 8. Pharmaceutical preparation according to claim 7, characterized in that the content of active substance is within the range of 0.01 to 1% by weight, based on the total mass of the pharmaceutical preparation.
9. 9. Use of compounds according to any of claims 1 or 2, as medicaments.
10. 10. Use of compounds according to any of claims 1 or 2, for preparing a medicament for the therapeutic treatment of functional disorders caused by overstimulation.
11. 11. Use of compounds according to any of claims 1 or 2, for preparing a pharmaceutical composition for the therapeutic treatment of arrhythmias, spasms, cardiac and cerebral ischemia, pain as well as neurodegenerative diseases of various origins.
12. 12. Use of compounds according to claim 11, for preparing a medicament for the therapeutic treatment of epilepsy, hypoglycemia, hypoxia, anoxia, cerebral trauma, cerebral edema, cerebral attack, perinatal asphyxia, degenerations of the cerebellum, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarction, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain as well as local anesthesia.