JP2005532376A - Novel drug combinations based on sodium channel blockers and magnesium salts - Google Patents

Abstract

The present invention relates to a novel drug combination based on sodium channel blocker (1) and magnesium salt (2). The invention also relates to a process for its production and its use in the manufacture of a medicament for the treatment of ischemic conditions.

Description

The present invention relates to novel drug combinations based on sodium channel blocker 1 and magnesium salt 2 , their preparation methods as well as their use for preparing pharmaceutical compositions for the treatment of ischemic conditions.

The present invention relates to a drug combination comprising one or more, preferably one sodium channel blocker 1 and one or more, preferably one magnesium salt 2 , optionally in the presence of conventional excipients or carriers.

A) Sodium channel blocker 1 which can be used according to the invention
Within the scope of the present invention, preferred sodium channel blockers 1 are pyrmencole, cipatridine, irampanel, pyrushicainide, oxacarbazepine, topiramate, phosphenytoin, flunarizine, ropivacaine, levobupivacaine, zonisamide, mexiletine, bipridil, bisalamyl, miracainide, safinamide, Bupivacaine, tetrodotoxin, NS7, general formula 1a

(Where
X is a single bond, —O, C ₁ -C ₄ -alkylene, alkylene bridge having 1 to 8 carbon atoms, which may be branched or unbranched, and May have one or two oxygen or nitrogen atoms in position), preferably OC ₁ -C ₃ -alkylene or -O-CH ₂ -CH ₂ -O-, -O-CH _2- Represents CH ₂ -NH-
R ¹ represents hydrogen, methyl, ethyl, phenyl,
R ² represents hydrogen, methyl,
R ³ represents hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, methoxy,
R ⁴ represents hydrogen, methyl, ethyl,
R ⁵ represents hydrogen, methyl, ethyl,
R ⁶ represents hydrogen, methyl, ethyl,
R ⁷ represents tert.-butyl, cyclohexyl or phenyl, which may optionally be substituted by R ⁹ and R ¹⁰ (which may be the same or different),
R ⁸ represents hydrogen, C ₁ -C ₄ -alkyl,
R ⁹ represents hydrogen, methyl, fluorine, chlorine, bromine, methoxy,
R ¹⁰ represents hydrogen, methyl, fluorine, chlorine, bromine, methoxy)
(Optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates, but also in the form of the corresponding acid addition salts with free bases or pharmacologically acceptable acids) And general formula 1b

(Where
R ^{1 ′} , R ² ′ and R ³ ′ (which may be the same or different) represent hydrogen, methyl or ethyl;
R ⁴ ′ represents hydrogen, methyl or ethyl,
R ⁵ ′, R ⁶ ′ and R ⁷ ′ (which may be the same or different) represent hydrogen, methyl or ethyl;
R ⁸ 'and R ⁹ ' (which may be the same or different) represent hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxy or methoxy)
Selected from the group consisting of the following compounds (which may be in the form of a racemate, an enantiomer, a diastereomer and a mixture thereof, and may optionally be a pharmacologically acceptable acid addition salt thereof): It has been.

Pirmencol, pyrushicainide, cipatridine, ilampanel, phosphenytoin, zonisamide, mexiletine, bipridil, bisamil, miracainide, NS7, general formula 1a
(Where
X represents C ₁ -C ₃ -alkylene, —O—CH ₂ —CH ₂ —O— or —O—CH ₂ —CH ₂ —NH—,
R ¹ represents hydrogen or methyl,
R ² represents hydrogen or methyl,
R ³ represents hydrogen or chlorine,
R ⁴ represents hydrogen or methyl,
R ⁵ represents hydrogen or methyl,
R ⁶ represents methyl or ethyl,
R ⁷ represents tert.-butyl, cyclohexyl or phenyl, phenyl optionally substituted by R ⁹ and R ¹⁰ (which may be the same or different),
R ⁸ represents hydrogen,
R ⁹ represents hydrogen, methyl, fluorine or chlorine,
R ¹⁰ represents hydrogen, methyl, fluorine or chlorine)
(Optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates, but also in the form of the corresponding acid addition salts with free bases or pharmacologically acceptable acids) And general formula 1b
(Where
R ¹ ′, R ² ′ and R ³ ′ (which may be the same or different) represent hydrogen or methyl;
R ⁴ ′ represents hydrogen or methyl,
R ⁵ ′, R ⁶ ′ and R ⁷ ′ (which may be the same or different) represent hydrogen or methyl, preferably methyl,
R ⁸ ′ represents hydrogen, methyl, hydroxy or methoxy, preferably hydrogen or methyl,
R ⁹ ′ represents hydrogen or methyl)
Selected from the group consisting of the following compounds (which may be in the form of a racemate, an enantiomer, a diastereomer and a mixture thereof, and may optionally be a pharmacologically acceptable acid addition salt thereof): One or more sodium channel blockers 1 are particularly preferred within the scope of the present invention.

Phosphenytoin, zonisamide, cipatridine, ilampanel, mexiletine, NS7, general formula 1a
(Where
X represents C ₁ -C ₃ -alkylene or —O—CH ₂ —CH ₂ —O—,
R ¹ represents hydrogen or methyl,
R ² represents hydrogen or methyl,
R ³ represents hydrogen,
R ⁴ represents hydrogen or methyl,
R ⁵ represents hydrogen or methyl,
R ⁶ represents methyl,
R ⁷ represents phenyl, which may be optionally substituted by R ⁹ and R ¹⁰ (which may be the same or different);
R ⁸ represents hydrogen,
R ⁹ represents hydrogen, methyl, fluorine or chlorine,
R ¹⁰ represents hydrogen, methyl, fluorine or chlorine)
(Optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates, but also in the form of the corresponding acid addition salts with free bases or pharmacologically acceptable acids) And general formula 1b
(Where
R ¹ ′, R ² ′ and R ³ ′ (which may be the same or different) represent hydrogen or methyl;
R ⁴ ′ represents hydrogen or methyl,
R ⁵ ', R ⁶ ' and R ⁷ 'represent methyl,
R ⁸ ′ represents hydrogen or methyl, preferably hydrogen,
R ⁹ ′ represents hydrogen or methyl)
Selected from the group consisting of the following compounds (which may be in the form of a racemate, an enantiomer, a diastereomer and a mixture thereof, and may optionally be a pharmacologically acceptable acid addition salt thereof): One or more sodium channel blockers 1 are particularly preferred within the scope of the present invention.

C ₁ -C ₄ -alkyl or C ₁ -C ₈ -alkyl generally represents a branched or unbranched hydrocarbon group having 1 to 4 or 1 to 8 carbon atoms, optionally containing one or more halogens It may be substituted by atoms (which may be the same or different from each other), preferably fluorine. The following hydrocarbon groups are mentioned as examples: methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1- Methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl preferable.
Thus, alkylene represents a branched or unbranched double bond hydrocarbon bridge having from 1 to 8 carbon atoms, optionally containing one or more halogen atoms (which may be the same or different from each other). Optionally substituted with fluorine.
Alkoxy generally represents a straight or branched hydrocarbon group bonded through an oxygen atom, and a lower alkoxy group having 1 to 4 carbon atoms is preferred. A methoxy group is particularly preferred.

Particularly preferred compounds of the formula 1a are (-)-(1R, 2 "S) -2- (2" -benzyloxy) propyl-4 in the form of the corresponding acid addition salts with free bases or pharmacologically acceptable acids. '-Hydroxy-5,9,9-trimethyl-6,7-benzomorphane. This compound is also known by the name clobenetin.
The following compounds of general formula 1b are particularly important: (2R) -N-allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano -3-Benzazocin-10-ol hydrochloride and (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 hydrochloride.
Therefore, within the scope of the present invention, component 1 is phosphenytoin, zonisamide, cypatridine, ilampanel, mexiletine, NS7, clobenetine, (2R) -N-allyloxyethyl-1,2,3,4,5,6- Hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride and (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 hydrochloride, most preferably clobenetine, (2R) -N-allyloxyethyl-1,2 , 3,4,5,6-Hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride and (2R, 2 ”S) -N- (2-allyloxy- Most preferred is selected from the group consisting of (propyl) -1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride Clobenetin is of particular importance.

If necessary, Compound 1 may be used in the form of a salt thereof, and may be used in the form of a pharmacologically acceptable acid addition salt with an inorganic or organic acid, particularly for pharmaceutical use. Suitable acids for this include, for example, 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. It is also possible to use mixtures of the above acids.
Compounds of formula 1a are known from WO 99/14199. The compound of formula 1b is not yet known in the prior art.
Compounds of formula 1b that may be used according to the invention and are not yet known in the prior art can be prepared in analogy to synthetic methods known per se. Possible synthetic methods for compounds of formula 1b are described below as examples.
Synthesis Example 1: (2R) -N-allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol 1.8 g of allyloxyacetic acid hydrochloride is added to 15 ml of dichloromethane, combined with 4.8 g of TBTU and 7.5 ml of ethyldiisopropylamine, and stirred at room temperature for 15 minutes. The mixture was 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 To do. The mixture is stirred at 0 ° C. for 30 minutes and at room temperature for 1 hour. It is then washed once with 100 ml of 2N HCl and once with 100 ml of 10% potassium carbonate solution, dried and evaporated in vacuo. The residue is taken up in 50 ml THF and added dropwise to a suspension of 1.0 g lithium aluminum hydride in 50 ml THF under nitrogen atmosphere (temperature rises to 35 ° C.). It was then heated to 50 ° C., stirred for 1 hour, cooled, 1 ml of water was added dropwise at 0-10 ° C., the mixture was stirred for 30 minutes, NaOH 3 ml was added, and the mixture was stirred for 30 minutes To do. The precipitate is filtered off with suction, the mother liquor is evaporated in vacuo and the residue is filtered through a short column (about 75 ml of silica gel; dichloromethane 70, ethyl acetate 20, methanol 10). Appropriate fractions are evaporated in vacuo and crystallized with acetone + ethereal HCl.
Yield 2.8 g (77%), melting point: 236 ° C .; [α] _D ²⁰ = −78.3 ° (c = 1; methanol)

Synthesis Example 2: (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 hydrochloride This is prepared analogously to the method described in Example 1.
Yield 56%, melting point: 239 ° C .; [α] _D ²⁰ = −33.9 ° (c = 1; methanol)
Synthesis 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 This is prepared analogously to the method described in Example 1.
Yield 47%, melting point: 205 ° C
Synthesis Example 4: (2R, 2 "S) -N- [2- (2-Methyl-propeneoxy) -propyl] -1,2,3,4,5,6-hexahydro-6,11,11- Trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride This is prepared analogously to the method described in Example 1.
Yield 12%, melting point: 240 ° C .; [α] _D ²⁰ = −29.6 ° (c = 1; methanol)
Synthesis Example 5: (2R) -N- [2-allyloxy-propyl] -1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine -10-ol hydrochloride
(2R) -N-allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride (Example) 1) Dissolve 1.9 g in 40 ml of methanol and combine with 3 g of 30% formalin solution and 3 ml of 4N NaOH. The mixture is heated to 50 ° C. for 12 hours, the solvent is removed in vacuo, 100 ml of water are added to the residue and it is extracted twice with 200 ml of ether. The organic phase is washed with water, dried and evaporated in vacuo. The residue is dissolved in 20 ml of dichloromethane and 1.5 g of SOCl ₂ is added dropwise at room temperature. After 30 minutes it is evaporated in vacuo, the residue is taken up in 20 ml of THF and added dropwise to a suspension of 0.5 g of lithium aluminum hydride in 20 ml of tetrahydrofuran under a nitrogen atmosphere. It is then heated to 50 ° C. for 2 hours, cooled, 1.5 ml of 4N NaOH are added dropwise and the mixture is stirred for 30 minutes. The precipitate is filtered off with suction and the mother liquor is evaporated in vacuo. The residue is filtered through a short silica gel column (silica gel about 30 ml; ethyl acetate about 250 ml). Appropriate fractions are evaporated in vacuo and crystallized with acetone + ethereal HCl.
Yield 1.1 g (56%), melting point: 212 ° C .; [α] _D ²⁰ = −71.6 ° (c = 1; methanol)
Synthesis 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-Benzuazoshin-10 in a manner similar to the method ol hydrochloride described in example 5, which is prepared starting from example 2 60% yield, mp: 215 ° C.; [α] _D ²⁰ = -29.3 ° (c = 1; methanol)

B) Magnesium salt 2 which can be used according to the invention
Within the scope of the present invention, magnesium adipate, magnesium L-aspartate, magnesium carbonate, magnesium hydrogen aspartate, magnesium hydrogen citrate, magnesium hydrogen glutamate, magnesium sulfate, magnesium chloride, trimagnesium dicitrate and magnesium acetate A magnesium salt 2 selected from the group consisting of
Within the scope of the present invention, a magnesium salt 2 selected from the group consisting of magnesium sulfate, magnesium chloride and magnesium acetate is particularly preferred, and magnesium sulfate is particularly important according to the present invention.
C) Use of the Drug Combinations 1 and 2 of the Present Invention The present invention further provides one or more, preferably one sodium channel blocker 1 and one, for preparing a pharmaceutical composition for the treatment of ischemic symptoms of various origins. Above, preferably relates to the use of a combination of the invention of a kind of magnesium salt 2 . Preferably, the present invention is one or more, preferably one sodium channel blocker 1 and one for preparing a pharmaceutical composition for the treatment of cardiac or cerebral ischemia, most preferably for the treatment of stroke and traumatic brain injury. Above, preferably relates to the use of a combination of the invention of a kind of magnesium salt 2 . The use of one or more, preferably one sodium channel blocker 1 and one or more, preferably one magnesium salt 2 combination of the present invention for the treatment of ischemic stroke, most preferably acute ischemic stroke, is within the scope of the present invention. Is particularly important within.
The present invention further comprises a method for treating ischemic symptoms of various origins, characterized in that one or more, preferably one sodium channel blocker 1 and one or more, preferably one magnesium salt 2 combination of the present invention is administered. About. Preferably, the present invention is administered cardiac ischemia or cerebral ischemia, characterized in that one or more, preferably one sodium channel blocker 1 and one or more, preferably one magnesium salt 2 combination of the present invention is administered. Most preferably a stroke, more preferably according to the present invention relates to a method for the treatment of ischemic stroke, most preferably acute ischemic stroke.

The invention further relates to the use of one or more, preferably one channel blocker 1 , for preparing a pharmaceutical composition for combined treatment of ischemic symptoms of various origins with one or more, preferably one magnesium salt 2. . The present invention preferably comprises a pharmaceutical composition for preparing a combined treatment of cardiac ischemia or cerebral ischemia with one or more, preferably one magnesium salt 2 , most preferably for the treatment of stroke and traumatic brain injury. Regarding use. Of particular importance within the scope of the present invention is this use for combined treatment of one or more, preferably one, magnesium salt 2 for ischemic stroke, most preferably acute ischemic stroke.
The present invention further includes one or more, preferably one sodium channel blocker 1 and one or more, preferably one magnesium salt 2 , simultaneously in one single formulation or two separate formulations, preferably two separate formulations. The present invention relates to a method for treating ischemic symptoms of various origins characterized by being administered sequentially. The present invention is preferably characterized in that one or more, preferably one sodium channel blocker 1 and one or more, preferably one magnesium salt 2, are administered simultaneously or sequentially in one single formulation or in two separate formulations. The invention relates to a method for treating cardiac ischemia or cerebral ischemia, most preferably stroke and traumatic brain injury, more preferably according to the invention ischemic stroke, most preferably acute ischemic stroke.

D.1) Administration of drug combinations 1 and 2 of the present invention The drug combinations of the present invention may comprise active ingredients 1 and 2 in one single formulation or in two separate formulations. Zonisamide, mexiletine, NS7, clobenetine as component 1 , (2R) -N-allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano- 3-Benzazocin-10-ol hydrochloride or (2R, 2 "S) -N- (2-allyloxy-propyl) -1,2,3,4,5,6-hexahydro-6,11,11-trimethyl- In the combination of 2,6-methano-3-benzazocin-10-ol hydrochloride and magnesium sulfate, magnesium chloride or magnesium acetate as component 2 (these are particularly important according to the invention), the two components are one One of the formulations or two are preferably contained in separate formulations. separate formulations may also separate formulations may also be. the two components 1 and 2 to the extent that is referred to as the so-called kit of the present invention of the present invention are described in detail in Section D.2 and D.3 section. component 1 and formulations capable of containing both components in a single formulation 2, for example, D.4 It described.
A combination of 1 and 2 of the present invention is a combination of components 1 and 2 administered simultaneously within the scope of use and within the method, or if 1 and 2 are present in different formulations. Administration may be by administering 1 and 2 simultaneously or sequentially. The term sequential within the scope of the present invention refers to a method of administering component 1 or 2 that does not occur simultaneously. Simultaneous administration means a method of administration in which at least one of components 1 and 2 is administered, for example, by infusion over a long period of time, and another component is used during this period. If the two components 1 and 2 are both administered by infusion over a long period of time, the term simultaneous for the purposes of the present invention means that the infusion periods overlap for at least a short time.
Especially when treating ischemic strokes (this is a preferred indication within the scope of the present invention), most preferably when treating acute ischemic strokes, components 1 and 2 may be simultaneous or at least within a short time, eg Preferably they are given to each other within one hour. Treatment with the drug combination of the present invention is particularly effective when it is given as quickly as possible after a stroke has occurred. The treatment is preferably initiated at the latest within about 6 hours after the stroke has occurred, most preferably within 4 hours, more preferably within 3 hours.

D.2) Pharmaceutical formulation and administration of component 1 Within the scope of the present invention, component 1 may be administered orally, transdermally, by inhalation or parenterally. Component 1 is a conventional formulation, for example a composition consisting essentially of an inert pharmaceutical carrier and an effective dose of an active substance, such as a tablet, coated tablet, capsule, lozenge, powder, solution, suspension, emulsion, syrup, It exists as an active ingredient in suppositories and transdermal systems. Effective doses of Compound 1 , especially the compounds of Formulas 1a and 1b , are 1-1000 mg / dose, preferably 1-500 mg / dose, most preferably 5-300 mg / dose for oral administration, and intravenous, subcutaneous or intramuscular 0.001-100 mg / dose for administration, preferably 0.1-70 mg / dose.
It is particularly possible to use component 1 according to the invention as an infusion solution, preferably in physiological saline or nutrient saline solution. In the injection, for example, 10-100 mg / hour, preferably 20-60 mg / hour of Compound 1 may be used. This latter method of administration is of particular importance according to the invention.
Most preferably, Compound 1 clobenetine (which is particularly preferred according to the invention) is administered intravenously by infusion. Preferably 10-60 mg (based on free base clobenetine) is administered per dose. It is also possible to administer clobenetine as component 1 of the drug combination of the present invention at different doses and at different time intervals for each treatment. For example, clobenetine is initially given as component 1 at a dose of 20-70 mg, preferably 30-60 mg, most preferably 50 mg over a period of about 30 minutes to 2 hours, preferably 45 to 90 minutes, most preferably 1 hour. May be. This initial administration of component 1 clobenetine is then followed over a period of 2 to 8 hours, preferably 3 to 7 hours, most preferably 4 to 6 hours, for example 5 to 50 mg, preferably 10 to 40 mg, most preferably A dose of 20-30 mg may also be administered. If desired, others may be administered following this second administration of component 1 clobenetine.
Some specific embodiments of formulations for parenteral administration are described below, which may be used in particular for compounds of formulas 1a and 1b , which are particularly preferred for use as sodium channel blocker 1 .

These formulations comprise at least one compound of formula 1a or 1b or one of its pharmaceutically acceptable salts and cyclodextrin derivatives, in particular γ-cyclodextrin (γ-CD), hydroxypropyl-γ-cyclodextrin (HP-γ- CD), hydroxypropyl-β-cyclodextrin (HP-β-CD) or sulfobutyl ether-β-cyclodextrin (SBE-β-CD). A preferred cyclodextrin derivative is hydroxypropyl-γ-cyclodextrin. Hydroxypropyl-γ-cyclodextrin with a molar substitution level of 0.5 to 0.7 is sold, for example, by the trade name “Kabasol® W8 HP Pharma” by Wacker-Chemie GmbH (D-Burghausen). “Cabasol® W8 HP Pharma” is particularly preferred for these pharmaceutical compositions.
Apart from the compound of formula 1a or 1b and the cyclodextrin derivative, the pharmaceutical composition intended for parenteral use according to the invention may comprise a hydroxy acid, for example malic acid, lactic acid, tartaric acid or citric acid. They are also optionally used in conventional excipients and carriers such as isotonic glucose, mannitol or sodium chloride or sodium acetate or sodium acetate trihydrate as a buffer combined with acetic acid or, for example, citric acid and phosphorus. A citric acid / phosphate buffer consisting of disodium hydrogen phosphate or disodium hydrogen phosphate dihydrate may also be included. The solvent used is usually water for injection.
The molar ratio of the compound of formula 1a or 1b to cyclodextrin is, for example, 1: 1 to 1: 5 in these formulations. A molar ratio of 1: 2.5 to 1: 3.5 is preferred. In the presence of a hydroxy acid, this molar ratio is preferably 1: 0.5 to 1: 3 according to the invention. A molar ratio of 1: 0.5 to 1: 1.5 is particularly preferred. Most preferably, these formulations are used with clovenine as component 1 .

Apart from the above formulations comprising at least one compound of formula 1a or 1b or one of its pharmaceutically acceptable salts and a cyclodextrin derivative, an equivalently preferred formulation for parenteral use according to the invention is a compound of formula 1a or 1b or a compound thereof In addition to a pharmaceutically acceptable salt, the preparation contains mannitol as an excipient. The amount of mannitol is preferably selected so as to obtain an isotonic solution. These pharmaceutical compositions also optionally contain other conventional excipients and carriers such as acetic acid / acetate buffer consisting of acetic acid and sodium acetate or sodium acetate trihydrate or e.g. citric acid and hydrogen phosphate A citric acid / phosphate buffer consisting of disodium or disodium hydrogen phosphate dihydrate may be included. Usually, the amount of buffer component is chosen to obtain a special pH value and a special buffer capacity. The solvent used is usually water for injection.
The pharmaceutical composition preferably comprises an acetic acid / acetate buffer in addition to the isotonic agent mannitol. Particularly preferred is 0.005-0.05 molar, preferably 0.005-0.02 molar acetic acid / acetate buffer having a pH of 3.8-5, most preferably 0.01 molar acetic acid / acetate buffer having a pH value of about 4. Particularly preferred. The specified concentrations relate to the total concentration of acetic acid and acetate. The ratio of acetic acid to acetate results from the desired pH. The specified pH is measured both in pure buffer and in the finished solution for injection or infusion.
These formulations are particularly preferably used when clobenetine is used as component 1 .

D.2.1) Examples of component 1 pharmaceutical formulations
Formulation Example 1
Clobenetine hydrochloride 767mg
HpγCD *) 10000mg
Mannitol 11000mg
Acetic acid 99% 125.25mg
Sodium acetate trihydrate 56.5mg
250ml water for injection
*) For example, “Cabasol (registered trademark) W8 HP Pharma” manufactured by Wacker
Formulation Example 2
Clobenetine hydrochloride 383.5mg
γCD 5000mg
NaCl 2250mg
250ml water for injection

Formulation Example 3
Clobenetine hydrochloride 767mg
HPβCD 7500mg
Mannitol 12500mg
Acetic acid 99% 125.25mg
Sodium acetate trihydrate 56.5mg
250ml water for injection
Formulation Example 4
Clobenetine hydrochloride 767mg
SBEβCD 5000mg
Mannitol 12500mg
Acetic acid 99% 125.25mg
Sodium acetate trihydrate 56.5mg
250ml water for injection
Formulation Example 5
Clobenetine hydrochloride 767mg
HPγCD 2500mg
Citric acid 708mg
Mannitol 12500mg
Acetic acid 99% 125.25mg
Sodium acetate trihydrate 56.5mg
250ml water for injection
Formulation Example 6
Clobenetine hydrochloride 767mg
γCD 2500mg
Tartaric acid 138.25mg
NaCl 2250mg
250ml water for injection

Formulation Example 7 (Injection solution (acetate buffer pH 4))
Clobenetine hydrochloride 274mg
Mannitol 25000mg
Acetic acid 99% 250.5mg
Sodium acetate trihydrate 113.0mg
500ml water for injection
Formulation Example 8 (Solution for injection (acetate buffer pH 4.5))
Clobenetine hydrochloride 274mg
Mannitol 25000mg
Acetic acid 99% 180.0mg
Sodium acetate trihydrate 265.0mg
500ml water for injection
Formulation Example 9 (Injection solution (acetate buffer pH 4))
Clobenetine hydrochloride 383.6mg
Mannitol 25000mg
Acetic acid 99% 501.0mg
Sodium acetate trihydrate 226.0mg
500ml water for injection

Formulation Example 10 (Solution for injection (acetate buffer pH 4))
Clobenetine hydrochloride 767mg
Mannitol 11000mg
Acetic acid 99% 125.25mg
Sodium acetate trihydrate 56.5mg
250ml water for injection
Formulation Example 11 (Solution for injection (acetate buffer pH 4.5))
Clobenetine hydrochloride 767mg
Mannitol 25000mg
Acetic acid 99% 90.0mg
Sodium acetate trihydrate 132.5mg
500ml water for injection
Formulation Example 12 (Solution for injection (acetate buffer pH 4))
Clobenetine hydrochloride 219.1mg
Mannitol 5000mg
Acetic acid 99% 50.1mg
Sodium acetate trihydrate 22.6mg
100ml water for injection
The amount of active substance provided can be adjusted by administering one particular volume of the solution. For example, daily administration of 100 ml of the solution of Example 1 corresponds to a daily dose of 280 mg of clobenetine.

D.3) Pharmaceutical formulation and administration of component 2 Magnesium salt 2 used within the scope of the combination of the present invention may be administered orally or parenterally within the scope of the present invention, with parenteral administration being particularly preferred. It may be administered in particular by intravenous, intraarterial, intramuscular, intradermal or subcutaneous injection. A typical formulation is an aqueous solution for injection or injection, which may optionally contain further stabilizers, solubilizers and preservatives as additional components.
Typically, within the scope of the present invention, a total of 30-120 millimoles, preferably about 50-100 millimoles, more preferably about 70-90 millimoles of magnesium is administered per dose. The substance is administered, for example, in the form of an infusion administered over a period of about 6-48 hours, preferably about 12-36 hours, more preferably about 18-30 hours. Within this period, the dose can vary for each time interval. For example, in the first interval, about 5 to 25 millimole, preferably about 10 to 20 millimole of magnesium may be administered over a period of about 5 minutes to 1 hour, preferably about 10 to 30 minutes. In the second interval, 25-100 millimolar, preferably about 40-80 millimolar, more preferably about 50-70 millimolar magnesium, for example, about 5-48 hours, preferably about 12-36 hours, more preferably about It is administered over a period of 20-28 hours. However, the dose and duration of administration may vary from those described above as guidelines, depending on the patient and clinical situation. In principle, it may be desirable to adjust the magnesium dose and duration of administration so that the resulting plasma level of magnesium is about 1.5 to 2.5 times, preferably about 2 times above the natural plasma level of magnesium. . For example, component 2 may also be administered by one or more injections.

D.3.1) Example of pharmaceutical preparation of component 2:
a) Injection solution:
Magnesium sulfate 1000mg
10ml water for injection
b) Injection solution:
Magnesium sulfate 2000mg
10ml water for injection
c) Concentrated solution for injection (to prepare solution for injection):
Magnesium sulfate 5000mg
10ml water for injection
In the formulation examples given above, the information relates to the anhydrous form of magnesium sulfate.

D.4) Examples of pharmaceutical formulations containing components 1 and 2
Formulation Example 1 (Injection solution (acetate buffer pH 4))
Clobenetine hydrochloride 274mg
Mannitol 25000mg
Acetic acid 99% 250.5mg
Sodium acetate trihydrate 113.0mg
Magnesium sulfate 500mg
500ml water for injection
Formulation Example 2 (Injection solution (acetate buffer pH 4.5))
Clobenetine hydrochloride 274mg
Mannitol 25000mg
Acetic acid 99% 180.0mg
Sodium acetate trihydrate 265.0mg
Magnesium sulfate 500mg
500ml water for injection
Formulation Example 3 (Injection solution (acetate buffer pH 4))
Clobenetine hydrochloride 274mg
Mannitol 25000mg
Acetic acid 99% 250.5mg
Sodium acetate trihydrate 113.0mg
Magnesium sulfate 1000mg
500ml water for injection
Formulation Example 4 (Solution for injection (acetate buffer pH 4.5))
Clobenetine hydrochloride 274mg
Mannitol 25000mg
Acetic acid 99% 180.0mg
Sodium acetate trihydrate 265.0mg
Magnesium sulfate 1000mg
500ml water for injection

Formulation Example 5 (Injection solution (acetate buffer pH 4))
Clobenetine hydrochloride 274mg
Mannitol 25000mg
Acetic acid 99% 250.5mg
Sodium acetate trihydrate 113.0mg
Magnesium sulfate 3000mg
500ml water for injection
Formulation Example 6 (Solution for injection (acetate buffer pH 4.5))
Clobenetine hydrochloride 274mg
Mannitol 25000mg
Acetic acid 99% 180.0mg
Sodium acetate trihydrate 265.0mg
Magnesium sulfate 3000mg
500ml water for injection
Formulation Example 7 (Injection solution (acetate buffer pH 4))
Clobenetine hydrochloride 274mg
Mannitol 25000mg
Acetic acid 99% 250.5mg
Sodium acetate trihydrate 113.0mg
Magnesium sulfate 5000mg
500ml water for injection
Formulation Example 8 (Solution for injection (acetate buffer pH 4.5))
Clobenetine hydrochloride 274mg
Mannitol 25000mg
Acetic acid 99% 180.0mg
Sodium acetate trihydrate 265.0mg
Magnesium sulfate 5000mg
500ml water for injection
In the above formulation examples, the information relates to anhydrous magnesium sulfate.

Claims (10)

A drug combination comprising one or more, preferably one sodium channel blocker 1 and one or more, preferably one magnesium salt 2 , optionally in the presence of a normal excipient or carrier. 1 Pirumenkoru, Shipatorijin, Iramupaneru, Pirushikainido, oxcarbazepine, topiramate, fosphenytoin, flunarizine, ropivacaine, levobupivacaine, zonisamide, mexiletine, Bipurijiru, Bisaramiru, Mirakainido, safinamide, bupivacaine, tetrodotoxin, NS7, Formula 1a

(Where
X is a single bond, —O, C ₁ -C ₄ -alkylene, alkylene bridge having 1 to 8 carbon atoms, which may be branched or unbranched, and May have one or two oxygen or nitrogen atoms in position), preferably OC ₁ -C ₃ -alkylene or -O-CH ₂ -CH ₂ -O-, -O-CH _2- Represents CH ₂ -NH-
R ¹ represents hydrogen, methyl, ethyl, phenyl,
R ² represents hydrogen, methyl,
R ³ represents hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, methoxy,
R ⁴ represents hydrogen, methyl, ethyl,
R ⁵ represents hydrogen, methyl, ethyl,
R ⁶ represents hydrogen, methyl, ethyl,
R ⁷ represents tert.-butyl, cyclohexyl or phenyl, which may optionally be substituted by R ⁹ and R ¹⁰ (which may be the same or different),
R ⁸ represents hydrogen, C ₁ -C ₄ -alkyl,
R ⁹ represents hydrogen, methyl, fluorine, chlorine, bromine, methoxy,
R ¹⁰ represents hydrogen, methyl, fluorine, chlorine, bromine, methoxy)
(Optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates, but also in the form of the corresponding acid addition salts with free bases or pharmacologically acceptable acids) And general formula 1b

(Where
R ^{1 ′} , R ² ′ and R ³ ′ (which may be the same or different) represent hydrogen, methyl or ethyl;
R ⁴ ′ represents hydrogen, methyl or ethyl,
R ⁵ ′, R ⁶ ′ and R ⁷ ′ (which may be the same or different) represent hydrogen, methyl or ethyl;
R ⁸ 'and R ⁹ ' (which may be the same or different) represent hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxy or methoxy)
Selected from the group consisting of the following compounds (which may be in the form of a racemate, an enantiomer, a diastereomer and a mixture thereof, and may optionally be a pharmacologically acceptable acid addition salt thereof): The drug combination according to claim 1, wherein 1 is pirmencol, pyrushicainide, cipatridine, ilampanel, phosphenytoin, zonisamide, mexiletine, bipridil, bisamil, miracainide, NS7, general formula 1a
(Where
X represents C ₁ -C ₃ -alkylene, —O—CH ₂ —CH ₂ —O— or —O—CH ₂ —CH ₂ —NH—,
R ¹ represents hydrogen or methyl,
R ² represents hydrogen or methyl,
R ³ represents hydrogen or chlorine,
R ⁴ represents hydrogen or methyl,
R ⁵ represents hydrogen or methyl,
R ⁶ represents methyl or ethyl,
R ⁷ represents tert.-butyl, cyclohexyl or phenyl, phenyl optionally substituted by R ⁹ and R ¹⁰ (which may be the same or different),
R ⁸ represents hydrogen,
R ⁹ represents hydrogen, methyl, fluorine or chlorine,
R ¹⁰ represents hydrogen, methyl, fluorine or chlorine)
(Optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates, but also in the form of the corresponding acid addition salts with free bases or pharmacologically acceptable acids) And general formula 1b
(Where
R ¹ ′, R ² ′ and R ³ ′ (which may be the same or different) represent hydrogen or methyl;
R ⁴ ′ represents hydrogen or methyl,
R ⁵ ′, R ⁶ ′ and R ⁷ ′ (which may be the same or different) represent hydrogen or methyl, preferably methyl,
R ⁸ ′ represents hydrogen, methyl, hydroxy or methoxy, preferably hydrogen or methyl,
R ⁹ ′ represents hydrogen or methyl)
Selected from the group consisting of the following compounds (which may be in the form of a racemate, an enantiomer, a diastereomer and a mixture thereof, and may optionally be a pharmacologically acceptable acid addition salt thereof): The drug combination according to claim 2, wherein 2 is selected from the group consisting of magnesium adipate, magnesium L-aspartate, magnesium carbonate, magnesium hydrogen L-aspartate, magnesium hydrogen citrate, magnesium hydrogen glutamate, magnesium sulfate, magnesium chloride, trimagnesium dicitrate and magnesium acetate The drug combination according to claim 1, wherein the drug combination is characterized in that 5. A drug combination according to claim 4, wherein 2 is selected from the group consisting of magnesium sulfate, magnesium chloride and magnesium acetate. 6. A drug combination according to one of claims 1 to 5, characterized in that the active ingredients 1 and 2 are contained in a single formulation or in two separate formulations.   Use of a drug combination according to one of claims 1 to 6 for the preparation of a pharmaceutical composition for the treatment of ischemic symptoms of various origins.   Use according to claim 7 for the preparation of a pharmaceutical composition for the treatment of cardiac or cerebral ischemia, most preferably for the treatment of stroke and traumatic brain injury. Use of one or more, preferably one sodium channel blocker 1 , for preparing a pharmaceutical composition for combined treatment of ischemic symptoms of various origins comprising one or more, preferably one magnesium salt 2 . 1 is characterized in that selected from the compound of claim 2, further 2 characterized in that it is selected from among the claims 4 compounds described, the use of claim 9, wherein.