TREA

Medicaments for the treatment of cerebral apoplexy

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Information

  • Patent Grant
  • 5070102
  • Patent Number
    5,070,102
  • Date Filed
    Monday, September 10, 1990
    33 years ago
  • Date Issued
    Tuesday, December 3, 1991
    32 years ago
Information
Abstract
A method of treating cerebral apoplexy in a patient in need thereof which comprises administering to said patient a amount effective therefor of a serotonin agonist which has an binding strength of less than 10,000 nmol/l on binding to 5HT.sub.1A receptors.
Description
Claims
  • 1. A method of treating cerebral apoplexy in a patient in need thereof which comprises administering to said patient an amount effective therefor of a serotonin agonist which has a binding strength of less than 10,000 nmol/l on binding to 5HT.sub.1A receptors and is selected from the group consisting of aminotetrahydrobenzindole, indolamine, aminoalkylbenzodioxane, aminotetralin, amino-chroman, amino-thiopyran, indolyl-alkyl-peperidine and tetrahydropyridine] a aminotetrahydrobenzindole of the formula ##STR12## in which X represents H, OCH.sub.3, OH, SCH.sub.3, halogen, CN or CONH.sub.2,
  • R.sup.1 represents hydrogen or C.sub.1 to C.sub.6 alkyl,
  • R.sup.5 has the meaning indicated above for R.sup.1 or represents -Y-Z, where
  • Y represents a straight-chain saturated or unstaurated alkylene chain having up to 6 carbon atoms, and
  • Z represents an amino alkoxy (C.sub.1 to C.sub.6), sulphonamido or carboxamido group or a heterocycle,
  • and a salt thereof and an indolamine of the formula ##STR13## where n represents 1 and
  • R.sup.8 represents CONR.sup.1 R.sup.2 or SO.sub.2 NR.sup.1 R.sup.2, where R.sup.1 and R.sup.2 each independently represent hydrogen or C.sub.1 or C.sub.6 alkyl,
  • R.sup.6 and R.sup.7 are identical or different and denote hydrogen or lower alkyl (C.sub.1 to about C.sub.6),
  • or
  • n represents the number 0,
  • R.sup.8 represents CONR.sup.1 R.sup.2, where R.sup.1 and R.sup.2 have the abovementioned meanings,
  • R.sup.6 and R.sup.7 have the abovementioned meanings,
  • or
  • n represents the number 0,
  • R.sup.8 represents H, OH or OCH.sub.3,
  • R.sup.6 denotes hydrogen or methyl, and
  • R.sup.7 represents the radical ##STR14## where p represents the values 2, 3, 4 or 5, and a salt thereof.
  • 2. The method according to claim 1, wherein the serotonin agonist has 1,000 nmol/l.
  • 3. The method according to claim 1, wherein the serotonin agonist has a binding strength in the range 0.1 to 100 nmol/l.
Priority Claims (1)
Number Date Country Kind
3831888 Sep 1988 DEX
Parent Case Info

This is a division of application Ser. No. 407,161, filed Sept. 14, 1989, now U.S. Pat. No. 4,988,700. The invention relates to the use of active compounds which act as serotonin agonists and have a binding strength of less than 10,000 nmol/l on binding to 5HT.sub.1A receptors for the preparation of medicaments for the treatment of cerebral apoplexy. Cerebral apoplexy (stroke, cerebrovascular accident) is a consequence of a sudden disturbance of blood flow in a region of the human brain with subsequent functional deficits and with corresponding neurological and/or psychological symptoms. Cerebral apoplexy may be caused by brain haemorrhages (for example following a vessel rupture in cases of hypertension, arteriosclerosis and apoplectic aneurysm) and ischaemias (for example due to a hypotensive crisis or embolism). The functional deficits in the brain result in degeneration and/or death of brain cells (Journal of Cerebral Blood Flow and Metabolism 1: 155 to 185 (1981)). The use of active compounds which act as serotonin agonists and have a binding strength of less than 10,000 nmol/l on binding to 5HT.sub.1A receptors for the preparation of medicaments for the treatment of cerebral apoplexy has been found. The active compounds according to the invention surprisingly bring about, both with prophylactic treatment and with treatment (therapeutic) taking place after the cerebral apoplexy, a great reduction in the degeneration and/or the death of brain cells, and they prevent or reduce the functional deficits in the brain. Active compounds which act as serotonin agonists can be identified by determining the inhibition of the forskolin-stimulated adenylate cyclase activity (EC.sub.50 value) by the relevant active compound (J. Pharmacol Exp. Ther. 238, 248-253 (1986)). 5HT.sub.1A ligands which act as agonists or partial agonists inhibit forskolin-stimulated adenylate cyclase. Active compounds which reduce the enzyme activity act as serotonin agonists or partial serotonin agonists. The said adenylate cyclase inhibition test can be carried out as follows, for example: Rat hippocampus membranes are incubated under suitable conditions with .alpha.-.sup.32 P-ATP and forskolin in the absence and presence of compounds according to the invention. After the reaction has been stopped, the radioactively labelled cyclic AMP is isolated and quantitatively determined. The enzyme activity is calculated from this. The binding strength (inhibition constant or K.sub.i value) is a measure of the interactions between an active compound and the 5HT.sub.1A seroton in receptors (Molecular Pharmacology 16, 687-699 (1979); J. Neurochem. 36, 220-226, 1981). The binding strength can be determined as follows, for example: Calf hfppocampus membranes are incubated with .sup.3 H-serotonin in the presence and absence of substances according to the invention. The reaction is stopped by filtration, and the radioactivity remaining on the filters is measured. IC.sub.50 values and inhibition constants K.sub.i are calculated from the resulting displacement plots. Preferred active compounds which act as serotonin agonists and have a binding strength of less than 10,000 nmol/l on binding to 5HT.sub.1A receptors are described, for example, in SCRIP's Serotonin Report, PJB Publications (1988) and by J. Fozard, Trends in Pharmacological Sciences 8, 501 (1987). These include, for example, compounds from the following classes of substances Particularly preferred from the group of aryl- and hetaryl-piperazines are the 2-pyrimidinyl-1-piperazine derivatives of the formula I ##STR1## and the aryl-1-picerazine derivatives of the formula II ##STR2## in which n represents one of the numbers 2, 3, 4, 5 or 6, Others which may also be mentioned are (+)-N-[2-[4-[2,3-dihydro-2-(hydroxymethyl)-1,4-benzodioxin-5-yl]-1-piperazinyl]ethyl]-4-fluorobenzamide hydrochloride(INN: flesinoxan hydrochloride) and 6-[[3-[4-[o-methoxyphenyl]-1-piperazinyl]propyl]amino]-1,3-dimethyluracil [INN: urapidil]. The following active compounds may be mentioned by way of example: 8-[4-N-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl]-8-azaspiro[4.5]-decane-7,9-dione hydrochloride(INN: buspirone), 4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl]-2,6-piperidinedione hydrochloride (INN: gepirone), 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)-butyl)-1,2-benzoisothiazol-3(2H)-one 1,1-dioxide hydrochloride (INN: ipsapirone), 3a,4,4a,6a,7,7a-hexahydro-2-[4-[4-(2- pyrimidinyl)-1-piperazinyl]-butyl]-4,7-etheno-1H-cyclobutano[f]isoindole-1,3(2H)-dione dihydrochloride sesquihydrate (WY-47,846), N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butly]-bicyclo[2.2.1]heptane-2,3-di-exo-carboximide (SM 3997), 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl-propyl)-1,2-benzoisothiazol-3-(2H)-one 1,1-dioxide hydrochloride, 3-butyl-9,9-dimethyl-7-[4-[4-[2-methoxyphenyl)-1-piperazinyl]butyl]-3,7-diazabicyclo[3,2,1]nonane-2,4,6,8-tetraone (KC 9172). Ipsapirone is particularly preferred. The piperazine derivatives are kdown per se (DE-A-3,321,969; Fozard, Trends in Pharmacological Sciences 8, 501 (1987); Scrip Report, PJB Publications (1988); EP-A 82,402; EP-A 220,873, DE-A 3,529,872; DE-A 3,248,160) and can be prepared, for example, by reacting an appropriate benzothiazole with (piperazinyl)pyrimidines. Particularly preferred from the group of tetrahydrobenzindoles are the 1,3,4,5-tetrahydrobenz[c,d]indoles of the formula 8 4-(N,N-dipropylamino)-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole, 4-[4-(N-1,2-benzisothiazol-3(2H)-one 1,1-dioxido)]butylamino-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole hydrochloride. Examples of heterocyclic radicals which may be mentioned are 1,1-dioxido-3-oxo-2H-1,2-benzisothiazol-2-yl or 4,4- dimethyl-2,6-dioxopiperidin-1-yl. Of these, 4-(N,N-dipropylamino)-6-methoxy-1,3,4,5-tetrahydrobenz[c,d]indole is particularly preferred. The tetrahydrobenzindole derivatives are known per se (DE-A 3,346,573; EP-A 153,083; EP-A 162,695) and can be prepared, for example, by reacting 4-amino-6-methoxy1,3,4,5-tetrahydrobenz[c,d]indole and 2-(4-bromobutyl)1,2-benzisothiazol-3(2H)-one 1,1-dioxide. Particularly preferred from the group of indolamines are the tryptamine derivatives of the formula ##STR4## where n represents 1 and The following active compounds may be mentioned by way of example: 5-carboxamidotryptamine, N,N-dipropyl-5-carboxamidotryptamine, 3-(2-aminoethyl)-1H-indole-5-(N-methyl)acetamide (AH 25 086), 3-(2-dimethylaminoethyl)-1H-indole-5-(N-methyl)methanesulphonamide (GR 43 175), 3-(2-[4-[2-(1,2-benzisothiazole-3(2H)-one 1,1-dioxido)]butyl]amino)ethyl-5-methoxy-1H-indole. Of these, N,N-dipropyl-5-carboxamidotryptamine and 3-(2- dimethylaminoethyl)-1H-indole-5-(N-methyl)methanesulphonamide are particularly preferred. The tryptamine derivatives are known per se (Fozard, Trends in Pharmacological Sciences 8, 501 (1987); Scrip's Serotonin Report, PJB Publications (1988); EP-A 236,930; DE-A 3,131,728; DE-A 2,940,687, DE-A 3,320,521) and can be prepared, for example, by reacting 3-(2-bromoethyl)-1H-indole-5-(N-methyl)methanesulphonamide with dimethylamine. Particularly preferred from the group of aminoalkyl-benzodioxanes are the 2-aminomethyl derivatives of the formula ##STR6## where A and B represent H or together represent --CH.dbd.CH--CH.dbd.CH-- and form a ring, The following active compounds may be mentioned by way of example: Of these, 2-[4-(1,4-benzodioxan-2-ylmethylamino)butyl]1,2-benzisothiazol-3(2H)-one 1,1-dioxide is particularly preferred. The 2-aminomethyl-benzodioxane derivatives are known per se (EP-A 236,930; Fozard, Trends in Pharmacological Sciences 8, 501 (1987); Scrip's Serotonin Report, PJB Publications (1988); EP 170,213) and can be prepared, for example, by reacting 2-aminomethylbenzodioxane with 2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide. Particularly preferred from the group of amino-tetralins are the 2-amino derivatives of the formula ##STR8## where R.sup.12 represents H or CH.sub.3, R.sup.1 and R.sup.5 have the abovementioned meaning, and when R.sup.12 is H, The following active compounds may be mentioned by way of example: Of these, 2-(N,N-dipropylamino)-8-hydroxy-1,2,3,4-tetrahydronaphthalene is particularly preferred. The aminotetralin derivatives are known per se (EP-A 41,488; EP-A 236,930; Arvidsson et al. J. Med. Chem. 30, 2105, 1987) and can be prepared, for example, by reacting 8-methoxy-2-tetralone with dipropylamine under reducing conditions. Examples from the group of amino-chromans and -thiopyrans which are preferred are the 3-aminochroman and -thiopyran derivatives of the formula ##STR9## where W represents oxygen or sulphur, R.sup.13 and R.sup.14 have the meaning indicated for R.sup.1 and R.sup.2, represent aralkyl (C.sub.7 to C.sub.18) or together form a carbocyclic ring (C.sub.4 to C.sub.7), and The following active compounds may be mentioned by way of example: 3-N,N-dipropylamino-5-hydroxy-thiochroman, 3-N,N-dipropylamino-5-ethoxy-thiochroman, 3-N,N-dipropylamino-5-ethoxychroman. Of these, 3-N,N-dipropylamino-5-hydroxy-thiochroman is particularly preferred. The 3-aminochroman and -thiopyran derivatives are known per se (EP-A 222,996) and can be prepared, for example, by reacting 3,4-dihydro-5-methoxy-2H-benzothiopyran-3-amine with propyl iodide. Particularly preferred from the group of indolylalkylpiperidines are the 1-[2-(3-indolyl)]ethyl derivatives of the formula ##STR10## where R.sup.16 represents H, halogen, methyl, CN or CONH.sub.2, and The following active compounds may be mentioned by way of example: Of these, The 1-[2-(3-indolyl)]ethyl-piperidine derivatives are known per se (DE-A 3,430,284) and can be prepared, for example, by reacting 1-{2-[3-(5-bromo)indolyl]}ethyl-2,6-dimethylpiperidine with sodium cyanide. Examples from the group of tetrahydropyridines which are preferred are the indolyl-tetrahydropyridine derivatives of the formula ##STR11## where R.sup.19 represents H, OCH.sub.3, O-ethyl, O-propyl or halogen, The following active compounds may be mentioned by way of example: Of these, 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole is particularly preferred. The indolyl-tetrahydropyridine derivatives are known per se (EP-A 3,199; SCRIP's Serotonin Report, PJB Publications (1988); Fozard, Trends in Pharmacological Sciences 8, 501 (1987)) and can be prepared, for example, by reacting 4-piperidone with 5-methoxyindole. The present invention likewise relates to medicaments for the treatment of cerebral apoplexy, which contain one or more active compounds which act as serotonin agonists and have a binding strength of less than 10,000 nmol/l on binding to 5HT.sub.1A receptors. The medicaments according to the invention generally contain 0.01 to 20% by weight, preferably 0.1 to 10% by weight, of the active compound(s), based on the composition. The active compounds according to the invention can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable vehicles or solvents. The formulations are prepared, for example, by extending the active compounds with solvents and/or vehicles, optionally with the use of emulsifiers and/or dispersing agents, and, for example, when using water as a diluent, organic solvents can optionally be used as auxiliary solvents. Examples of auxiliaries which may be mentioned are: water, non-toxic organic solvents, such as paraffins (for example petroleum fractions), vegetable oils (for example groundnut oil/sesame oil), alcohols (for example ethyl alcohol and glycerol) and glycols (for example propylene glycol and polyethylene glycol), solid vehicles, such as, for example, natural rock powders (for example kaolins, aluminas, talc and chalk), synthetic rock powders (for example highly disperse silica and silicates) and sugars (for example sucrose, lactose and glucose), emulsifiers (for example polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkylsulphonates and arylsulphonates), dispersing agents (for example lignin, sulphite waste liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (for example magnesium stearate, talc, stearic acid and sodium lauryl sulphate). Administration is effected in the customary manner, preferably orally or parenterally, in particular perlingually or intravenously. In the case of oral administration, tablets can, of course, also contain, in addition to the vehicles mentioned, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additional substances, such as starch, preferably potato starch, gelatine and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulphate and talc can also be used when making tablets. In the case of aqueous suspensions, the active compounds can be mixed with various flavor-improving agents or colorants in addition to the abovementioned auxiliaries. In the case of parenteral administration, solutions of the active compounds, employing suitable liquid vehicles, can be used. In general, it has proved advantageous, in the case of intravenous administration, to administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg, body weight to achieve effective results, and in the case of oral administration, the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg, body weight. Nevertheless, it can at times be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight or of the nature of the administration method, but also because of the individual behavior towards the medicament, or the nature of the formulation of the medicament and the time or interval over which the administration takes place. Thus it can suffice in some cases to manage with less than the above-mentioned minimum amount, whilst in other cases the upper limit mentioned must be exceeded. Where relatively large amounts are administered, it can be advisable to divide these into several individual administrations over the course of the day. The mode of action of the active compounds according to the invention for the preventive and subsequent treatment of cerebral apoplexy can be indentified using the method of focal cerebral ischaemia in the rat as stroke model (Middle Cerebral Artery Occlusion (MCA)). Reference: A. Tamura et al.; J. Cerebral Blood Flow and Metab. 1, 53-60, 1981. The treatment of cerebral apoplexy with the active compounds according to the invention represents a new and surprising treatment principle.

Divisions (1)
Number Date Country
Parent 407161 Sep 1989