DE10204276A1 - N-Allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceuticals - Google Patents

Abstract

The present invention relates to 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols of general formula 1 wherein the radicals R · 1 ·, R · 2 · R ·3, R ·4 ·, R ·5 ·, R ·6 ·, R ·7 ·, R ·8 · and R ·9 · may have the meanings given in the description and in the claims, processes for their use Manufacture and use as a medicine.

Description

The subject of the envisaged patent application are substituted N-allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols of general formula 1


wherein
R ¹ , R ² and R ^{3 are} identical or different, hydrogen, methyl or ethyl;
R ^{4 is} hydrogen, methyl or ethyl;
R ⁵ , R ⁶ and R ^{7 are} identical or different, hydrogen, methyl or ethyl;
R ⁸ and R ^{9 may be} identical or different and denote hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxy or methoxy,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.

Preference is given to the compounds of general formula 1 in which
R ¹ , R ² and R ^{3 are} identical or different, hydrogen or methyl;
R ^{4 is} hydrogen or methyl;
R ⁵ , R ⁶ and R ^{7 are} identical or different, hydrogen or methyl, preferably methyl;
R ^{8 is} hydrogen, methyl, hydroxy or methoxy, preferably hydrogen or methyl,
R ^{9 may be} hydrogen or methyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.

Particularly, the compounds of general formula 1 , wherein
R ¹ , R ² and R ^{3 are} identical or different, hydrogen or methyl;
R ^{4 is} hydrogen or methyl;
R ⁵ , R ⁶ and R ^{7 are} methyl;
R ^{8 is} hydrogen or methyl, preferably hydrogen;
R ^{9 may be} hydrogen or methyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.

Outstandingly important in the invention are those compounds of the formula 1 which are present in the 1R and, if R ^{4 is} other than hydrogen, the 2 "S configuration, and these stereoisomers which are preferred according to the invention can also be represented by the general formula 1 '


in which the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 may have} the meanings given above represent.

• - (2R)-N-Allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3- benzazocin-10-ol-hydrochlorid;
• - (2R,2"S)-N-(2-Allyloxy-propyl)-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6- methano-3-benzazocin-10-ol-hydrochlorid;

Of particular interest are the following compounds of general formula 1 :

• - (2R) -N-allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride;
• - (2R, 2 "S) -N- (2-allyloxy-propyl) -1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine -10-ol hydrochloride;

Optionally, the compounds of general formula ( 1 ) can be converted into their salts, in particular for pharmaceutical use, into their pharmacologically acceptable acid addition salts with an inorganic or organic acid. Examples of suitable acids are succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid or citric acid. Furthermore, mixtures of the abovementioned acids can be used.

The claimed compounds are blockers of the voltage-dependent sodium channel. These are compounds which displace batrachotoxin (BTX) with high affinity (K _i <500 nM) competitively or non-competitively from the binding site on the sodium channel. Such substances show a "use-dependency" in the blockade of the sodium channels, ie for the binding of the substances to the sodium channel, the sodium channels must first be activated. The maximum blockade of the sodium channels is only achieved after repeated stimulation of the sodium channels. Accordingly, the substances bind preferentially to sodium channels, which are increasingly activated. As a result, the substances are able to be effective preferably in the body regions that are pathologically overstimulated. The compounds of the general formula 1 according to the invention can thus be used in diseases whose cause is due to a malfunction caused by overexcitation. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischemia, pain and neurodegenerative diseases of various origins. For example: epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, cerebral stroke, perinatal asphyxia, cerebellar degeneration, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotension, cardiac infarction, cardiac arrhythmia, angina pectoris, chronic pain, neuropathic pain and local anesthesia.

A further aspect of the invention is therefore directed to the use of compounds of general formula 1 , as medicaments, in particular as medicaments, in which the blockage of the voltage-dependent sodium channel can produce a therapeutic benefit.

Preference is given to the use of the compounds of the general formula 1 according to the invention for the preparation of a medicament for the prevention or treatment of arrhythmias, spasms, cardiac and brain ischemia, pain and neurodegenerative diseases.

Particularly preferred is the above-mentioned use of the compounds of general formula 1 according to the invention for the preparation of a medicament for the prevention or treatment of epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, brain stroke, perinatal asphyxia, degenerations of the cerebellum, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotension, cardiac infarction, cardiac arrhythmia, angina pectoris, chronic pain, neuropathic pain and local anesthesia.

BTX binding to the sodium channel [SW Postma & WA Catterall, Mol. Pharmacol 25 , 219-227 (1984)] as well as patch-clamp experiments in which it can be shown that the present invention is used as a test system for the detection of the sodium channel blocking effect Compounds block the electrically stimulated sodium channel in a "use-dependent" manner [WA Catterall, Trends Pharmacol. Sci., 8 , 57-65 (1987)]. By selecting the cell system (eg neuronal, cardiac, DRG cells), the effect of the substances on different sodium channel subtypes can be investigated.

The sodium channel blocking property of the compounds of the invention can be demonstrated by the blockade of veratridine-induced glutamate release [S. Villauneva, P. Frenz, Y. Dragnic, F. Orrego, Brain Res. 461 , 377-380 (1988)]. Veratridine is a toxin that permanently opens the sodium channel. This leads to an increased influx of sodium ions into the cell. This sodium influx leads to an increased release of glutamate in neuronal tissue. By the compounds according to the invention, this glutamate release can be antagonized.

Neuroprotective properties were demonstrated by protective action in a rat MCAO model [U. Pschorn & AJ Carter, J. Stroke Cerebrovascular Diseases, 6 , 93-99 (1996)] and a malonate-induced lesion model [MF Beal, Annals of Neurology, 38 , 357-366 (1995) and JB Schulz, RT Matthews, DR Henshaw and MF Beal, Neuroscience, 71 , 1043-1048 (1996)].

Analgesic effects can be found in models of diabetic neuropathy as well as in a ligature model [C. Courteix, M. Bardin, C. Chantelauze, J. Lavarenne, A. Eschalier, Pain 57, 153-160 (1994); C. Courteix, A. Eschalier, J. Lavarenne, Pain 53, 81-88 (1993); G.J. Bennett & Y.-K. Xie, Pain 33, 87-107 (1988)].

It has also been described that sodium channel blocker for the therapy of cyclophrenia (Manic depressive illness) can be used [J. R. Calabrese, C. Bowden, M.J. Woyshville; Psychopharmacology: The Fourth Generation of Progress (Eds .: D.E. Bloom and D.J. Kupfer) 1099-1111. New York: Raven Press Ltd.].

The compounds 1 according to the invention can be prepared in analogy to known synthesis methods. One possible synthetic route is shown in Scheme 1. The 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine-10-ols ( 2 ) characterized as starting compounds in Scheme 1 are obtainable according to synthesis methods known from the prior art. In this regard, reference is made to European Patent Application EP-A-521422 and International Patent Applications WO 97/06146 and WO 99/14199. Scheme 1

The synthesis unit 3 contains a leaving group X, which is preferably chlorine, bromine, hydroxyl or a methoxy or ethoxy radical. For a detailed explanation of the synthesis of the compounds of the formula 1 according to the invention, reference is made to the experimental working instructions described below.

A possible access to compounds of formula 1 , in which R ^{9 is} methyl, is outlined in Scheme 2. Scheme 2

For a detailed explanation of the synthesis of the compounds of formula 1 according to Scheme 2 according to the invention, reference is also made to the experimental working instructions described below.

The following examples serve to illustrate the invention without, however, limiting it to the compounds and methods disclosed by way of example. Example 1 (2R) -N-Allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride

1.8 g of allyloxyacetic acid are initially charged in 15 ml of dichloromethane, admixed with 4.8 g of TBTU and 7.5 ml of ethyldiisopropylamine and stirred at RT for 15 min. It is then cooled to -5 ° C and 3.1 g of 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol was added. The mixture is stirred for 30 min at 0 ° C, and 1 h at RT. Then it is washed once each with 100 ml of 2NHCL and 100 ml of 10% potassium carbonate solution, dried and i. Vak. concentrated. The residue is taken up in 50 ml of THF and added dropwise under nitrogen to a suspension of 1.0 g of lithium aluminum hydride in 50 ml of THF. (Temp. Rises to 35 ° C) Then it is warmed to 50 ° C, stirred for 1 h, cooled and added dropwise at 0-10 ° C 1 ml of water, stirred for 30 min, added 3 ml of NaOH and stirred for 30 min. The precipitate is filtered off with suction, the mother liquor i. Vak. concentrated and the residue filtered through a short column. (About 75 ml of silica gel, dichloromethane 70, ethyl acetate 20, methanol 10). The appropriate fractions are i. Concentrated, from acetone + eth. HCl crystallizes. Yield 2.8 g (77%), mp: 236 ° C; [α] _D ²⁰ = -78.3 ° (c = 1, methanol). Example 2 (2R, 2 "S) -N- (2-Allyloxy-propyl) -1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-one benzazocin-10-ol hydrochloride

The preparation is analogous to the procedure of Example 1. Yield 56%, mp.: 239 ° C; [α] _D ²⁰ = -33.9 ° (c = 1, methanol). Example 3 (2R, 2 "S) -N- (2-But-2-enoxy-propyl) -1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6- methano-3-benzazocin-10-ol hydrochloride

The preparation is analogous to the procedure of Example 1. Yield 47%, mp.: 205 ° C Example 4 (2R, 2 "S) -N- [2- (2-methyl propenoxy) propyl] -1,2,3 , 4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride

The preparation is analogous to the procedure of Example 1. Yield 12%, mp. 240 ° C; [α] _D ²⁰ = -29.6 ° (c = 1, methanol). Example 5 (2R) -N- [2-Allyloxy-propyl] -1,2,3,4,5,6-hexahydro-6,11,11-trimetrimethyl-2,6-methano-3-benzazocine-10 ol hydrochloride

1.9 g of (2R) -N-allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride ( Example 1) are dissolved in 40 mL of methanol and treated with 3 g of 30% formalin solution and 3 mL of 4 N NaOH. The mixture is heated for 12 hours at 50 ° C, the solvent is drawn i. Vak. , the residue is combined with 100 ml of water and extracted twice with 200 ml of ether. The organic phase is washed with water, dried and i. Vak. concentrated. The residue is dissolved in 20 ml of dichloromethane and 1.5 g of SOCl _{2 are} added dropwise at RT. After 30 min. will i. Vak. concentrated, the residue taken up in 20 ml of THF and added dropwise under nitrogen to a suspension of 0.5 g of lithium aluminum hydride in 20 ml of terahydrofuran. The mixture is then heated for 2 h at 50 ° C, cooled, 1.5 mL of 4N NaOH was added dropwise and stirred for 30 min. The precipitate is filtered off and the mother liquor i. Vak. concentrated. The residue is filtered through a short silica gel column (about 30 mL silica gel, about 250 mL ethyl acetate).). The appropriate fractions are i. V., crystallized from acetone + eth. HCl. Yield 1.1 g (56%), mp: 212 ° C, [α] _D ²⁰ = -71.6 ° (c = 1, methanol). Example 6 (2R, 2 "S) -N- [2-Allyloxy-propyl] -1,2,3,4,5,6-hexahydro-6,9,11,11-tetramethyl-2,6-methano 3-benzazocin-10-ol hydrochloride

The preparation is analogous to the procedure of Example 5 starting from Example 2. Yield 60%, mp. 215 ° C; [α] _D ²⁰ = -29.3 ° (c = 1, methanol).

The compounds according to the invention can be administered orally, transdermally, by inhalation or parenterally. The compounds according to the invention are in this case as active ingredients in conventional dosage forms, for example in Compositions consisting essentially of an inert pharmaceutical Carrier and an effective dose of the drug exist, such as Tablets, dragees, capsules, wafers, powders, solutions, suspensions, Emulsions, syrups, suppositories, transdermal systems etc. An effective dose the compounds of the invention is in an oral application between 1 and 1000, preferably between 1 and 500, more preferably between 5-300 mg / dose, during intravenous, subcutaneous or intramuscular administration between 0.001 and 50, preferably between 0.1 and 10 mg / dose. For inhalation are according to the invention suitable solutions which are 0.01 to 1.0, preferably 0.1 to 0.5% Active ingredient included. For inhalative application is the use of powders prefers. Because of its special physicochemical properties it is furthermore possible, the compounds according to the invention as infusion solution, preferably in a physiological saline or saline solution use. In an infusion 10-100 mg / h could preferably 25-60 mg / h to Application come. The latter application form is according to the invention of outstanding importance.

The compounds according to the invention can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active agents, are used. suitable Examples of applications are tablets, capsules, suppositories, solutions, Juices, emulsions or dispersible powders. Appropriate tablets can for example, by mixing the active substance (s) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as Starch or gelatin, lubricants, such as magnesium stearate or talc, and / or Means for achieving the depot effect, such as carboxymethylcellulose, Cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Accordingly, dragees by coating analogous to the tablets produced cores with commonly used in dragée coatings agents, For example Kollidon or shellac, gum arabic, talc, titanium dioxide or Sugar, to be produced. To achieve a depot effect or to avoid of incompatibilities, the core can also consist of several layers. Similarly, the Dragéehülle to achieve a depot effect from several layers are those mentioned above in the tablets Excipients can be used.

Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or Sugar as well as a taste-improving agent, e.g. B. flavorings, such as vanillin or orange extract. You can also use suspension aids or Thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example Condensation products of fatty alcohols with ethylene oxide, or protective substances such as Hydroxybenzoates.

Injection solutions are in the usual manner, for. B. with the addition of Preservatives, such as p-hydroxybenzoates, or stabilizers, such as Alkali salts of ethylenediaminetetraacetic acid and in injection bottles or ampoules bottled.

The one or more active substances or combinations of active substances containing capsules can be prepared, for example, by the Ingredients with inert carriers, such as lactose or sorbitol, and mixes in Encapsulating gelatin capsules.

Suitable suppositories can be, for example, by mixing with it provided carriers, such as neutral fats or polyethylene glycol or its derivatives.

A therapeutically effective daily dose is between 1 and 2500 mg, preferably 100-1000 mg per adult.

The following examples illustrate the present invention without, however, limiting its scope: Pharmaceutical Formulation Examples A) tablets per tablet active substance 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg

The finely ground active substance, lactose and part of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of suitable shape and size. B) tablets per tablet active substance 80 mg corn starch 190 mg lactose 55 mg Microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium carboxymethyl 23 mg magnesium stearate 2 mg 400 mg

The finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, mixed and pressed the mixture into tablets of suitable size. C) Dragées per dragée active substance 5.0 mg corn starch 41.5 mg lactose 30.0 mg polyvinylpyrrolidone 3.0 mg magnesium stearate 0.5 mg 80.0 mg

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is forced through a sieve with 1 mm mesh size, dried at about 45 ° C and then strikes the granules through the same sieve. After admixing with magnesium stearate, curved tablet cores having a diameter of 6 mm are pressed on a tableting machine. The dragee cores thus produced are coated in a known manner with a layer consisting essentially of sugar and talc. The finished dragees are polished with wax. D) capsules per capsule active substance 50.0 mg corn starch 268.5 mg magnesium stearate 1.5 mg 320.0 mg

Substance and cornstarch are mixed and moistened with water. The moist mass is sieved and dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is filled into hard gelatine capsules size 1. E) Ampoule solution active substance 50 mg sodium chloride 50 mg Aqua pro inj. 5 ml

The active ingredient is dissolved at its own pH or optionally at pH 5.5 to 6.5 in water and treated with sodium chloride as isotonic, the resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed , The vials contain 5 mg, 25 mg and 50 mg active ingredient. F) Suppositories active substance 50 mg Adeps solidus 1650 mg 1700 mg

The hard fat is melted. At 40 ° C, the ground active substance homogeneously dispersed. It is cooled to 38 ° C and slightly pre-cooled Suppository forms poured out.

Claims (9)

1. Compounds of the general formula 1


wherein
R ¹ , R ² and R ^{3 are} identical or different, hydrogen, methyl or ethyl;
R ^{4 is} hydrogen, methyl or ethyl;
R ⁵ , R ⁶ and R ^{7 are} identical or different, hydrogen, methyl or ethyl;
R ⁸ and R ^{9 may be} identical or different and denote hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxy or methoxy,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts. 2. Compounds of general formula 1 according to claim 1, wherein
R ¹ , R ² and R ^{3 are} identical or different, hydrogen or methyl;
R ^{4 is} hydrogen or methyl;
R ⁵ , R ⁶ and R ^{7 are} identical or different, hydrogen or methyl, preferably methyl;
R ^{8 is} hydrogen, methyl, hydroxy or methoxy, preferably hydrogen or methyl,
R ^{9 may be} hydrogen or methyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts. 3. Compounds of general formula 1 according to claim 1 or 2, wherein
R ¹ , R ² and R ^{3 are} identical or different, hydrogen or methyl;
R ^{4 is} hydrogen or methyl;
R ⁵ , R ⁶ and R ^{7 are} methyl;
R ^{8 is} hydrogen or methyl, preferably hydrogen;
R ^{9 may be} hydrogen or methyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts. 4. Compounds of general formula 1 according to claim 1, 2 or 3, characterized in that they are in the 1R and, unless R ⁴ is hydrogen, further in the 2 "S configuration. 5. Pharmaceutical preparation characterized by a content of one of the compounds of formula 1 according to any one of claims 1 to 4 in addition to conventional excipients and carriers. 6. Use of one of the compounds of formula 1 according to any one of claims 1 to 4 as a medicament. 7. Use of one of the compounds of formula 1 according to any one of claims 1 to 4 for the manufacture of a medicament for the prevention or treatment of diseases or disorders in which the blockage of the voltage-dependent sodium channel can develop a therapeutic benefit. 8. Use of one of the compounds of formula 1 according to any one of claims 1 to 4 for the manufacture of a medicament for the prevention or treatment of arrhythmias, spasms, cardiac and cerebral ischemia, pain and neurodegenerative diseases. 9. Use of any of the compounds of formula 1 according to any one of claims 1 to 4 for the manufacture of a medicament for the prevention or treatment of epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, brain stroke, perinatal asphyxia, degenerations of the cerebellum, amyotrophic lateral Sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotension, cardiac infarction, cardiac arrhythmia, angina pectoris, chronic pain, neuropathic pain or local anesthesia.