WO2003105844A1 - Medicament combinations of sodium channel blockers and fibrinolytics for treating ischaemic conditions - Google Patents

Abstract

The invention relates to novel medicament combinations based on sodium channel blockers (1) and fibrinolytics (2), to a method for producing the same and to the use thereof for producing medicaments for treating ischaemic conditions.

Description

 DRUG COMBINATIONS OF SODIUM CHANNEL BLOCKERS AND FIBRINOLYTICS FOR TREATING ISCHEMIC CONDITIONS

The invention relates to new drug combinations based on sodium channel blockers 1 and fibrinolytics 2, processes for their preparation and their use for the production of medicaments for the treatment of ischemic conditions.

Description of the invention The invention relates to drug combinations containing one or more, preferably a sodium channel blocker, and one or more, preferably a fibrinolytic 2, optionally in the presence of customary auxiliaries or carriers.

A) Sodium channel blockers 1 which can be used according to the invention: Within the scope of the present invention, the sodium channel blocker (s) are preferably selected from the group consisting of Pirmencol, Sipatrigine, Irampanel, Pilsicainide, Oxcarbazepine, Topiramate, Fosphenytoin, Flunarizine, Ropivacaine, Levobupivacail, Zonisipride, Mexon , Bisaramil, Milacainide, Safinamide, Bupivacaine, Tetrodotoxin, NS 7, the compounds of the general formula 1a

_____ »in what

X is a single bond, -O-, C- | -C4-alkylene, an alkylene bridge with 1 to 8 carbon atoms which may be branched or unbranched and may have one or two oxygen atoms or a nitrogen atom anywhere in the bridge, preferably 0-C- | -C3-alkylene or -0-CH2-CH -0-, -0-CH -CH ₂ -NH-;

R ^{1 is} hydrogen, methyl, ethyl, phenyl;

R ^{2 is} hydrogen, methyl;

R ^{3 is} hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, methoxy;

R ^{4 is} hydrogen, methyl, ethyl;

R ^{5 is} hydrogen, methyl, ethyl;

RO hydrogen, methyl, ethyl; R ^{7 is} tert-butyl, cyclohexyl or phenyl, where phenyl may optionally be substituted by R ⁹ and R ¹ 0, which may be the same or different;

R8 is hydrogen, C- | -C ₄ alkyl; R ^{9 is} hydrogen, methyl, fluorine, chlorine, bromine, methoxy;

R10 is hydrogen, methyl, fluorine, chlorine, bromine, methoxy; can optionally mean in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids;

and the compounds of the general formula Ib.

worin R^"1 ', R²' und R³' gleich oder verschieden, Wasserstoff, Methyl oder Ethyl;

wherein R ^"1 ', R ² ' and R ³ 'are the same or different, hydrogen, methyl or ethyl;

R ⁴ 'is hydrogen, methyl or ethyl;

R ⁵ ', R ⁶ ' and R ⁷ 'are the same or different, hydrogen, methyl or ethyl;

R ⁸ 'and R ⁹ ', the same or different, are hydrogen, fluorine, chlorine, bromine, methyl,

Can mean 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.

Particularly preferred in the context of the present invention are the sodium channel blocker (s) 1 selected from the group consisting of Pirmencol,

Pilsicainide, Sipatrigine, Irampanel, Fosphenytoin, Zonisamide, Mexiletine, Bipridil,

Bisaramil, Milacainide, NS 7, the compounds of general formula 1a wherein

X Ci -C ₃ alkylene, -0-CH ₂ -CH ₂ -0- or -0-CH ₂ -CH ₂ -NH-;

R ^{1 is} hydrogen or methyl; R ^{2 is} hydrogen or methyl;

R ^{3 is} hydrogen or chlorine;

R ^{4 is} hydrogen or methyl;

R ^{5 is} hydrogen or methyl;

R ^{6 is} methyl or ethyl; R ^{7 is} tert-butyl, cyclohexyl or phenyl, where phenyl may optionally be substituted by R ⁹ and R ¹⁰ , which may be the same or different; R ^{8 is} hydrogen; R ^{9 is} hydrogen, methyl, fluorine or chlorine; R ¹ ° is hydrogen, methyl, fluorine or chlorine; can optionally mean in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids;

and the compounds of general formula 1b, wherein

R ^" ! ', R ² ' and R ³ 'the same or different, hydrogen or methyl;

R ⁴ 'is hydrogen or methyl; R ⁵ ', R ⁶ ' and R ⁷ 'are the same or different, hydrogen or methyl, preferably

Methyl;

R ⁸ 'is hydrogen, methyl, hydroxy or methoxy, preferred

Hydrogen or methyl,

R ⁹ 'can be hydrogen or methyl, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable

Acid addition salts.

According to the invention, the sodium channel blocker (s) 1 are selected from the group consisting of

Fosphenytoin, Zonisamide, Sipatrigine, Irampanel, Mexiletine, NS 7, den

Compounds of the general formula 1a wherein

X Ci -C3 alkylene or -0-CH ₂ -CH ₂ -0-;

R ^{1 is} hydrogen or methyl; R ^{2 is} hydrogen or methyl;

R ^{3 is} hydrogen;

R ^{4 is} hydrogen or methyl;

R ^{5 is} hydrogen or methyl;

Rδ methyl; R ^{7 is} phenyl, which phenyl may optionally be substituted by R ⁹ and R ¹ 0, which may be the same or different;

R ^{8 is} hydrogen;

R ^{9 is} hydrogen, methyl, fluorine or chlorine;

R ^{10 is} hydrogen, methyl, fluorine or chlorine; can optionally mean in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids;

and the compounds of the general formula 1b, in which R ¹ ', R ² ' and R ³ 'are identical or different, hydrogen or methyl; R ⁴ 'is hydrogen or methyl;

R5 ', R6' and R ⁷ 'methyl; R ⁸ 'is hydrogen or methyl, preferably hydrogen;

R ⁹ 'can 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.

C 1 -C 4 -alkyl or Ci-Cs-alkyl generally represents a branched or unbranched hydrocarbon radical having 1 to 4 or 1 to 8 carbon atoms, which is optionally substituted by one or more halogen atoms, preferably fluorine can be, which can be the same or different from each other. The following are examples

Hydrocarbon residues called: 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, preference is given to lower alkyl radicals having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, / so-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1, 1-dimethylethyl.

Correspondingly, alkylene means a branched or unbranched double-bonded hydrocarbon bridge having 1 to 8 carbon atoms, which may optionally be substituted by one or more halogen atoms, preferably fluorine, which may be the same or different from one another.

Alkoxy generally represents a straight-chain or branched hydrocarbon radical bonded via an oxygen atom - one is preferred Lower alkoxy group with 1 to 4 carbon atoms. - The methoxy group is particularly preferred.

Particularly preferred as the compound of the formula 1a is (-) - (1 R, 2 "S) -2- (2" - benzyloxy) propyl-4'-hydroxy-5,9,9-trimethyl-6,7-benzomorphan in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids. This compound is also known as the Crobenetine.

The following compounds of general formula 1b are of particular interest: (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-allyloxypropyl) - 1, 2,3,4,5, δ-hexahydro-6,11, 11-trimethyl-2, 6-methano-3-benzazocin-10-ol hydrochloride.

Accordingly, in the context of the present invention, the component ± is particularly preferably selected from the group consisting of fosphenytoin, zonisamide, sipatrigine, irampanel, mexiletine, NS 7, crobenetine, (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-allyloxypropyl) -1, 2nd , 3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride, particularly preferably crobenetine, (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, with crobenetine being of outstanding importance.

If appropriate, the compounds 1 can be used in the form of their salts, in particular for pharmaceutical use, in the form of their pharmacologically acceptable acid addition salts with an inorganic or organic acid. 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. Mixtures of the aforementioned acids can also be used.

The compounds of formula 1a are known from WO 99/14199. The compounds of formula 1b are not yet known in the prior art. The compounds of the formula 1b which are not yet known in the prior art and can be used according to the invention can be analogous to known compounds Create synthesis methods. Possible synthetic routes to the compounds of the formula V_ are explained below by way of example.

Synthesis Example 1: (2R.-N-Allyloxyethyl-1, 2,3,4.5.6-hexahvdro-6,11.11-trimethyl-2.6- 5 methano-3-benzazocin-10-ol-hydrochloride

1.8 g of allyloxyacetic acid are placed in 15 ml of dichloromethane, mixed 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 ° G and 3.1 g of 1, 2,3,4,5,6-hexahydro-6,11, 11-trimethyl-2,6-methano-3-benzazocin-10-ol are added. The mixture is stirred for 30 minutes at 0 ° C. and for 1 h at RT. Then one time each with 100ml 2nHCL and 100ml 10%

Washed potassium carbonate solution, dried and i.Vac. 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.) The mixture is then heated to 50 ° C., stirred for 1 h, cooled and 1 ml at 0-10 ° C.

15 drops of water were added, the mixture was stirred for 30 minutes, 3 ml of NaOH were added and the mixture was stirred for 30 minutes. The precipitate is suctioned off, the mother liquor is vacuum. concentrated and the residue filtered through a short column. (approx. 75 ml silica gel; dichloromehane 70, ethyl acetate 20, methanol 10). The suitable fractions are evaporated down in vacuo, crystallized from acetone + eth.HCI. Yield 2.8 g (77%), mp: 236 ° C; [α] _D ²⁰ = -78.3 ° (c = 1; methanol). 0

Synthesis Example 2:, 2R, 2 "S.-N- (2-allyloxypropyl, -1, 2,3,4,5,6-hexahvdro-6,11,11-trimethyl-2,6-methano-3-benzazocin -10-ol hvdrochlorid

The presentation is analogous to the procedure according to Example 1. Yield 56%,

Mp: 239 ° C; [] _D ²⁰ = -33.9 ° (c = 1; methanol). 5

Synthesis Example 3: (2R, 2 "S, -N-.2-But-2-enoxypropyl, -1, 2,3, 4,5,6-hexahvdro-6.11.11-trimethyl-2,6-methano -3-benzazocin-10-ol-hydrochloride The preparation is carried out analogously to the procedure of Example 1. Yield 47%, mp: 205 ° C. 0

Example 4: .2R, 2 "S.-N-r2-.2-methyl-propenoxy) -propyπ-1, 2,3,4,5,6-hexahvdro-6,11.11-trimethyl-2,6-methano-3 -benzazocin-10-ol-hydrochloride The preparation is carried out analogously to the procedure of Example 1. Yield 12%, mp: 240 ° C.; [α] _D ²⁰ = -29.6 ° (c = 1; methanol). 5

Example 5: .2R) -N-r2-allyloxy-propyll-1.2.3.4.5.6-hexahvdro-6.11.11-trimethyl-2.6-methano-3-benzazocin-10-ol-hydrochloride

1.9 g (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 methanol and with 3 g of 30% formalin solution and 3 ml of 4 N NaOH were added. The mixture is heated at 50 ° C. for 12 hours and the solvent is drawn off in vacuo. , the residue is mixed with 100 ml of water and extracted twice with 200 ml of ether each time. The organic phase is washed with water, dried and i.Vac. concentrated. The residue is dissolved in 20 ml dichloromethane and added dropwise at RT 1.5 g SOCI ₂ . After 30 min. becomes 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 to 50 ° C. for 2 h, cooled, 1.5 ml of 4N NaOH are added dropwise and the mixture is stirred for 30 min. The precipitate is filtered off with suction and the mother liquor is vacuum. concentrated. The residue is filtered through a short silica gel column (approx. 30 mL silica gel, approx. 250 mL ethyl acetate). ). The suitable fractions are evaporated down in vacuo, crystallized from acetone + eth.HCI. Yield 1.1 g (56%), mp: 212 ° C, [α] _D ²⁰ = - 71.6 ° (c = 1; methanol).

Synthesis Example 6: (2R.2 "S.-N-r2-Allyloxy-propyll-1, 2,3,4,5,6-hexahvdro-6,9,11,11-tetramethyl-2,6-methano-3-benzazocin-10 -ol-hydrochloride The preparation is carried out analogously to the procedure according to Example 5, starting from Example 2. Yield 60%, mp: 215 ° C .; [α] _D ²⁰ = -29.3 ° (c = 1; methanol).

B) Firbrinolytics 2 which can be used according to the invention:

In the context of the present invention, fibrinolytics 2 are preferably selected from the group of plasminogen activators. Of particular interest are old plase (human tissue plasminogen activator, t-PA), tenecteplase, reteplase, streptokinase, urokinase, anistreplase, monteplase, nateplase, duteplase, lanoteplase, silteplase, amediplase and desmoteplase. All of these fibrinolytics are known in the art.

Alteplase (amino acid sequence: GenBank Accession No. AAB59510) is a fibrinolytic approved as a medicament, the production of which by recombinant expression, preferably in cell lines of the Chinese hamster Cricetulus griseus (CHO cells), as well as its pharmaceutical formulation and medical use are described in detail in the prior art (Pennica et al., Nature 301, 214-221 (1983); EP 0 093 619; Andersen et al., Biotechnol Bioeng 70 (1), 25-31 (2000); Dowd et al., Biotechnol Prog 16 ( 5), 786-794 (2000); Fann et al., Biotechnol Bioeng 69 (2), 204-212 (2000); Werner et al., Drug research 48 (8), 870-880 (1998); Wemicke et Will , Anal Biochem 203 (1), 146-150 (1992); Bos et al., Biochim Biophys Acta 1117 (2), 188-192 (1992); Dodd et al., FEBS Lett 209 (1), 13-17 (1986); Matsuo et al., J Chromatogr 369 (2), 391-397 (1986); Einarsson et al., Biochim Biophys Acta 830 (1), 1-10 (1985); Kruithof et al., Biochem J 226 (3), 631- 636 (1985); Nguyen et al., Pharm Biotechnol. 5, 91-134 (1993); The Gusto III Investigators, N Engl J Med. 1997 Oct 16; 337 (16): 1118-23; EP 0 239 292; WO 86/05514).

Tenectepiase (TNK-tPA; T103N, N117Q, KHRR (296-299) AAAA-tPA) is also a drug approved fibrinolytic. Its preparation and use is described in references WO 93/24635; Keyt et al., Proc Natl Acad Sei US S. 1994 Apr 26; 91 (9): 3670-4; Turcasso et Nappi, Ann Pharmacother. 2001 Oct; 35 (10): 1233-40; MacGahan, Issues Emerg Health Technol. 2001 Jan; (t3): 1-6; Davydov et Cheng, Clin Ther. 2001 Jul; 23 (7): 982-97; The Assent II investigators, Lancet. 1999 Aug 28; 354 (9180): 716-22 described in detail.

The production of the reteplase, which is also approved as a medicament, and its pharmaceutical formulations and uses are described in references WO 90/03497; WO 91/08765, WO 91/08766, and Noble et McTavish, Drugs. 1996 Oct; 52 (4): 589-605. Production, pharmaceutical formulation and medical use of lanoteplase are described in references WO 87/04722 and WO 90/08557. Production, pharmaceutical formulation and medical use of desmoteplase are described in references WO 90/09438 and WO 97/29188. The preparation, pharmaceutical formulation and medical use of the anistreplase approved as a medicament is described in references EP 0 028489, Fears, Semin Thromb Hemost 15 (2), 129-139 (1989); Anderson et al., Circulation. 1991 Jan; 83 (1): 126-40; Been et al., Int J Cardiol. 1986 Apr; 11 (1): 53-61; Marder et al., Ann Intern Med. 1986 Mar; 104 (3): 304-10; Walker et al, Thromb Haemost. 1984 Apr 30; 51 (2): 204-6, and Matsuo et al, Thromb Res Suppl. 1981 Nov 15; 24 (4): 347-58. Urokinase is described in EP 0 143 949, EP 0 154 272, EP 0 303 028, and EP 0 620 279.

The literature describes a large number of further plasminogen activators which can be used as component 2 for the combination according to the invention.

In the context of the present invention, fibrinolytics 2 are particularly preferably selected from the group consisting of old plase (t-PA), tenectepiase, reteplase, streptokinase, urokinase, anistreplase, monoplase and nateplase. Fibrinolytics 2 which are particularly preferred according to the invention are selected from the group of old plase (t-PA), tenectepiase, reteplase, urokinase and anistreplase, where Alteplase, Tenectepiase and Reteplase, particularly preferably Alteplase, are of outstanding importance according to the invention.

C) Use of the drug combinations according to the invention from 1 and 2: The present invention further relates to the use of the combinations according to the invention of one or more, preferably a sodium channel blocker 1 _, and one or more, preferably a fibrinolytic 2 for the preparation of a medicament for the treatment of ischemic conditions of different Genesis. The present invention preferably relates to the use of the combinations according to the invention of one or more, preferably a sodium channel blocker, and one or more, preferably a fibrinolytic, 2 for the manufacture of a medicament for the treatment of cardiac or cerebral ischemia, particularly preferably for the treatment of stroke. Of particular importance in the context of the present invention is the use of the combinations according to the invention of one or more, preferably a sodium channel blocker 1 and one or more, preferably a fibrinolytic 2 for the treatment of ischemic stroke, particularly preferably of acute, ischemic stroke.

The present invention further relates to a method for the treatment of ischemic conditions of different origins, which is characterized in that a combination according to the invention of one or more, preferably a sodium channel blocker, and one or more, preferably a fibrinolytic, 2 is applied. The present invention preferably relates to a method for the treatment of cardiac or cerebral ischemia, particularly preferably stroke, according to the invention preferably furthermore ischemic stroke, particularly preferably acute, ischemic stroke, which is characterized in that a combination according to the invention of one or more, preferably one Sodium channel blocker _ and one or more, preferably a fibrinolytic 2 is applied.

The present invention further relates to the use of one or more, preferably a sodium channel blocker, for the production of a medicament for the combined treatment of ischemic conditions of different origins with one or more, preferably a fibrinolytic, 2. The present invention preferably relates to the use mentioned above for the production of a Medicament for the combined treatment of cardiac or brain ischemia, particularly preferably for the treatment of stroke with one or more, preferably a fibrinolytic 2. Of particular importance in the context of The present invention is the above use for the combined treatment of ischemic stroke, particularly preferably of acute, ischemic stroke with one or more, preferably one fibrinolytic 2.

The present invention further relates to a method for the treatment of ischemic conditions of different origins, which is characterized in that one or more, preferably a sodium channel blocker, and one or more, preferably a fibrinolytic, 2 simultaneously or sequentially in a single or two separate, preferably in two separate dosage forms can be applied. The present invention preferably relates to a method for the treatment of cardiac or brain ischemia, particularly preferably of stroke, according to the invention preferably further of ischemic stroke, particularly preferably of acute, ischemic stroke, which is characterized in that one or more, preferably a sodium channel blocker, and a or more, preferably one fibrinolytic 2, can be administered simultaneously or sequentially in a single or two separate, preferably in two separate, dosage forms.

D.1) Application of the pharmaceutical combinations according to the invention from 1 and 2: The pharmaceutical combinations according to the invention can contain the active constituents 1 and 2 in a single or in two separate administration forms. In the combinations of zonisamides, mexiletines, NS 7, crobenetine, (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-allyloxypropyl) -1, 2,3,4,5,6-hexahydro-6,11, 11 - trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride as component 1 with Alteplase (t-PA), tenectepiase, reteplase, urokinase or anistreplase as component 2, the two components are preferably in two separate dosage forms Example in the form of a so-called kit.Separate forms of administration of the two components 1 and 2 are described in detail in the sections below.

The application of the combination of 1 and 2 according to the invention in the context of the abovementioned use and in the context of the abovementioned method can be carried out by simultaneous administration of the combination of 1 and 2 or, if 1 and 2 are present, in different administration forms by simultaneous or sequential administration of the components 1 and 2 take place. Sequential in the context of the present invention is to be understood as any application of components _ or 2 that does not take place simultaneously. With simultaneous application in particular also understood the type of application in which at least one of components 1 and 2 is administered for example by means of an infusion over a longer period of time and the other component is also used during this application interval. If both components _ and 2 are administered by infusion over a longer period of time, it also means in the sense of the present invention that the infusion intervals overlap at least briefly.

In particular in the therapy of the ischemic stroke preferred in the context of the present invention, particularly preferably in the treatment of acute ischemic stroke, components 1 and 2 are preferably administered simultaneously or at least at a short time interval, i.e. for example within an hour. Treatment with the pharmaceutical combinations according to the invention is particularly effective here if it takes place within a very short time after the onset of the stroke. The therapy is particularly preferably started at the latest within about 5 hours, particularly preferably within 4 hours, further preferably within 3 hours after the onset of the stroke.

D.2) Pharmaceutical Formulation and Application of Component 1: In the context of the present invention, the compounds 1. can be administered orally, transdermally, by inhalation or parenterally. The compounds are present as active constituents in customary dosage forms, for example in compositions which essentially consist of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as tablets, dragees, capsules, wafers, powders, solutions, suspensions, emulsions , Syrups, suppositories, transdermal systems etc. An effective dose of the compounds _, in particular the compounds of the formulas 1a_ and 1b, is between 1 and 1000, preferably between 1 and 500, particularly preferably between 5-300 mg / dose in the case of oral administration , with intravenous, subcutaneous or intramuscular use between 0.001 and 100, preferably between 0.1 and 70 mg per dose.

It is in particular possible to use component 1 according to the invention as an infusion solution, preferably in a physiological saline solution or

Use brine. In the case of an infusion, for example 10-100 mg / h, preferably 25-60 mg / h of the compound _ can be used. The latter application form is of outstanding importance according to the invention. When applying compound 1 crobenetine, which is particularly preferred according to the invention, intravenous administration as an infusion is particularly preferred. Here, preferably between 10 and 60 mg (based on the free base crobenetine) are used per dose. It is possible to administer crobenetine as a component of the pharmaceutical combination according to the invention at different time intervals with different dosages per therapy. For example, crobenetine can be applied as component _ initially in a dose of 20-70 mg, preferably 30 to 60 mg, particularly preferably 50 mg over a period of about 30 minutes to 2 hours, preferably over 45 to 90 minutes, particularly preferably over an hour become. This first application of component 1. Crobenetine can then be followed by further applications in doses of, for example, 5 to 50 mg, preferably 10 to 40 mg, particularly preferably 20 to 30 mg over a period of 2 to 8 hours, preferably 3 to 7 hours preferably connect for 4 to 6 hours. If necessary, this second application of component 1 crobenetine can be followed by others.

Special embodiments of formulations which can be administered parenterally are described below, which can be used in particular in the compounds of the formulas 1a and 1b which are particularly preferably used according to the invention as sodium channel blockers 1.

These formulations comprise at least one compound of the formula 1a or 1b or one of its pharmaceutically acceptable salts and a cyclodextrin derivative, in particular gamma-cyclodextrin (γ-CD), hydroxypropyl-gamma-cyclodextrin (HP-γ-CD), hydroxypropyl-beta -cyclodextrin (HP-ß-CD) or sulfobutyl ether-beta-cyclodextrin (SBE-ß-CD). The preferred cyclodextrin derivative is hydroxypropyl-γ-cyclodextrin. Hydroxypropyl-γ-cyclodextrin with a molar degree of substitution from 0.5 to 0.7 is commercially available, for example, from Wacker-Chemie GmbH, D-Burghausen, under the name “CAVASOL® W8 HP Pharma”. “CAVASOL® W8 HP Pharma "is particularly preferred for these pharmaceutical compositions. In addition to the compound of formula 1a or 1b and the cyclodextrin derivative, the pharmaceutical compositions according to the invention intended for parenteral use can contain hydroxy acids such as malic acid, lactic acid, tartaric acid or citric acid. If appropriate, they also contain customary auxiliaries and carriers, such as the isotonic agents glucose, mannitol or sodium chloride or sodium acetate or sodium acetate trihydrate as a buffer in combination with acetic acid or a citric acid / phosphate buffer consisting, for example, of citric acid and disodium hydrogen phosphate or Disodium hydrogen phosphate dihydrate. Water is usually used as the solvent for injections.

The molar ratio of the compound of formula 1a or 1b to cyclodextrin in these formulations is, for example, between 1: 1 and 1: 5. A molar ratio of 1: 2.5 to 1: 3.5 is preferred. In the presence of hydroxy acid, this molar ratio according to the invention is preferably between 1: 0.5 and 1: 3; a molar ratio of 1: 0.5 to 1: 1.5 is particularly preferred. These formulations are particularly preferably used when crobenetine is applied as component 1.

In addition to the formulations described above, comprising at least one compound of the formula 1a or 1b or one of its pharmaceutically acceptable salts and a cyclodextrin derivative, formulations for parenteral administration which are in addition to a compound of the formula 1a or 1b or a their pharmaceutically acceptable salts containing mannitol as an adjuvant. The amount of mannitol is preferably chosen so that an isotonic solution is obtained.

If appropriate, these pharmaceutical compositions also contain other customary auxiliaries and excipients such as, for example, an acetic acid / acetate buffer consisting of acetic acid and sodium acetate or sodium acetate trihydrate or a citric acid / phosphate buffer consisting e.g. from citric acid and disodium hydrogen phosphate or disodium hydrogen phosphate dihydrate. The amount of the buffer components is usually chosen so that a certain pH value and a certain buffer capacity is achieved. Water is usually used as the solvent for injections.

In addition to the isotonance mannitol, the pharmaceutical composition preferably contains an acetic acid / acetate buffer. A 0.005 to 0.05 molar, preferably a 0.005 to 0.02 molar acetic acid / acetate buffer with a pH of 3.8 to 5 is particularly preferred, a 0.01 molar acetic acid / acetate is very particularly preferred. Buffer with a pH of around 4. The concentration given here refers to the total concentration of acetic acid and acetate; the ratio of acetic acid to acetate results from the desired pH. The specified pH value is measured both in the pure bufferais and in the finished solution for injection or infusion. These formulations are particularly preferably used when crobenetine is used as component ±. D.2.1) Pharmaceutical formulation examples of component 1:

Formulation example 1:

Crobenetine hydrochloride 767 mg

HpγCD *) 10000 mg

Mannitol 11000 mg

Acetic acid 99% 125.25 mg

Sodium acetate trihydrate 56.5 mg

Water for injections ad 250 ml

*) for example "CAVASOL ® W8 HP Pharma" from Wacker

Formulation example 2:

Crobenetine hydrochloride 383.5 mg γCD 5000 mg

NaCI 2250 mg

Water for injections ad 250 ml

Formulation example 3:

Crobenetine hydrochloride 767 mg

HPßCD 7500mg

Mannitol 12500 mg

Acetic acid 99% 125.25 mg

Sodium acetate tri hydrate 56.5 mg

Water for injections ad 250 ml

Formulation example 4:

Crobenetine hydrochloride 767 mg

SBESSCD 5000 mg

Mannitol 12500 mg

Acetic acid 99% 125.25 mg

Sodium acetate trihydrate 56.5 mg

Water for injections ad 250 ml Formulation example 5:

Crobenetine hydrochloride 767 mg

HPγCD 2500 mg

Citric acid 708 mg

Mannitol 12500 mg

Acetic acid 99% 125.25 mg

Sodium acetate trihydrate 56.5 mg

Water for injections ad 250 ml

Formulation example 6:

Crobenetine hydrochloride 767 mg γCD 2500 mg

Tartaric acid 138.25 mg

NaCI 2250 mg

Water for injections ad 250 ml

Formulation example 7 (solution for infusion (acetate buffer pH 4))

Croebentine hydrochloride 274 mg

Mannitol 25000 mg acetic acid 99% 250.5 mg

Sodium acetate trihydrate 113.0 mg

Water for injections ad 500 ml

Formulation example 8 (infusion solution (acetate buffer pH 4.5))

Crobenetine hydrochloride 274 mg

Mannitol 25000 mg

Acetic acid 99% 180.0 mg

Sodium acetate trihydrate 265.0 mg water for injections ad 500 ml

Formulation example 9 (solution for infusion (acetate buffer pH 4))

Crobenetine hydrochloride 383.6 mg

Mannitol 25000 mg acetic acid 99% 501.0 mg

Sodium acetate trihydrate 226.0 mg

Water for injections ad 500 ml Formulation example 10 (solution for infusion (acetate buffer pH 4))

Crobenetine hydrochloride 767 mg

Mannitol 11000 mg

Acetic acid 9% 125.25 mg sodium acetate trihydrate 56.5 mg

Water for injections ad 250 ml

Formulation example 11 (solution for infusion (acetate buffer pH 4.5)) Crobenetine hydrochloride 767 mg mannitol 25000 mg

Acetic acid 99% 90.0 mg

Sodium acetate trihydrate 132.5 mg

Water for injections ad 500 ml

Formulation example 12 (solution for infusion (acetate buffer pH 4))

Crobenetine hydrochloride 219.1 mg

Mannitol 5000 mg

Acetic acid 99% 50.1 mg

Sodium acetate trihydrate 22.6 mg water for injections ad 100 ml

The amount of the active ingredient administered can be controlled by administration of a certain volume of one of the solutions described above. For example, the daily application of 100 ml of a solution according to Example 1 corresponds to a dose of 280 mg crobenetine daily.

D.3) Pharmaceutical formulation and application of component 2:

The one used in the combination according to the invention

Fibrinolytic 2 is usually a polypeptide that must be administered parenterally. The application can take place in particular by intravenous, intraarterial, intramuscular, intra- or subcutaneous injection, but administration by inhalation of a powder or aerosol is also possible. Typical formulations are freeze-dried preparations (lyophilisates) of the polypeptide, which are reconstituted with a solution for injection or infusion immediately before administration. The reconstitution solution can be water or a buffered aqueous solution. However, the formulation can also consist of an aqueous solution, which is preferably buffered with a physiologically compatible buffer and can additionally contain conventional stabilizers, solubilizers, and preservatives. Examples of common auxiliaries for such Solid or liquid formulations are alkali hydrogen phosphate / alkali dihydrogen phosphate, sodium chloride, serum albumin, polyoxyethylene sorbitan monolaurate (Tween ^® 20), polyoxyethylene sorbitan monooleate (Tween ^® 80), ethylenediamine tetraacetate (EDTA), sucrose, mannitol, dextran alkanol, and amino acid

5 (the latter only for liquid formulations). The application is usually parenteral, preferably by intravenous injection or infusion. The mode of application and dosage depend on the fibrinolytic chosen, in particular on its specific biological activity and half-life in the blood plasma. Alteplase, which has a relatively short half-life, is typically administered in a total dose of 100 mg as follows: 10-15 mg as an intravenous bolus, followed by an intravenous infusion of 50 mg over a period of 30 to 60 minutes, followed by another infusion of 60-180 minutes up to the maximum dose. Tenectepiase has a longer half-life and can therefore be used as a single bolus based on body weight up to a maximum dose of

15 50 mg can be administered. Reteplase, which has a medium half-life and a lower specific activity, is administered as an intravenous double bolus every 30 minutes at a dose of 10 units (560 mg) per bolus. The person skilled in the art knows how to find suitable dosages for a new medicament. The person skilled in the art can use formulation and

Dose information from the literature references mentioned above.

D.3.1) Pharmaceutical formulation examples of component 2: Formulations of component 2 are known in the prior art and are available on the market. Below are some of the commercially available ones

Formulations that can be used according to the invention are listed by way of example and for clarification.

Alteplase: (powder and solvent for solution for injection / infusion)

Composition: Alteplase 10 mg / 20 mg / 50 mg / 100 mg. further components: arginine, phosphoric acid, polysorbate 80.

Water for injections.

5 Tenectepiase: (powder and solvent for solution for injection) Composition: Tenectepiase 8,000 U / 10,000 U (40 mg / 50 mg), other components: arginine, phosphoric acid, polysorbate 20.

Water for injections 8 ml / 10 ml. Reteplase: (powder and solvent for solution for injection) Composition: Reteplase 0.56 g (equivalent to 10 units). further components: tranexamic acid, potassium monohydrogen phosphate,

Phosphoric acid, sucrose, polysorbate 80. Water for injections 10 ml.

Streptokinase: (dry substance for infusion solution)

Composition: highly purified streptokinase 250,000 IU / 750,000 IU /

1500000 I.E. as dry matter. further components: human albumin, sodium L-hydrogen glutamate 1 H 0,

Polygelin.

Streptokinase: (oral tablets)

Composition: streptokinase 10,000 IU, streptodomase 2500- 10,000 IU. other ingredients: magnesium stearate, calcium hydrogen phosphate,

Cornstarch, Arabic gum.

Urokinase: (dry matter) Composition: Urokinase 500 000 I.U. further components: sodium monohydrogen phosphate,

Sodium dihydrogen phosphate, human albumin.

Urokinase: (dry matter) Composition: Urokinase (human) 500,000 IU other ingredients: sodium dihydrogen phosphate, sodium monohydrogen phosphate, sodium chloride, dextran 40.

Anistreplase: (dry substance and solvent for intravenous injection) Composition .: 209-230 mg dry substance with anistreplase 29.55-

30.03 mg. further components: 4-amidinophenyl (p-anisate) -HCI 0.15-0.17 mg,

Dimethyl sulfoxide 1-2 mg, aminocaproic acid 1.2-1.6 mg, D-mannitol, human albumin, lysine-1 HCl, sodium hydroxide, glycerol, aqua ad injectabilia.

Claims

 claims 1) Pharmaceutical combinations containing one or more, preferably a sodium channel blocker 1 and one or more, preferably a fibrinolytic 2, optionally in the presence of customary auxiliaries or carriers. 2) Pharmaceutical combinations according to claim 1, characterized in that _ is selected from the group consisting of Pirmencol, Sipatrigine, Irampanel, Pilsicainide, Oxcarbazepine, Topiramate, Fosphenytoin, Flunarizine, Ropivacaine, Levobupivacaine, Zonisamide, Mexiletine, Bipridilain, Bisideamil, Bisaramil Safinamide, Bupivacaine, Tetrodotoxin, NS 7, the compounds of the general FormeMa

1a wherein X is a single bond, -O-, -C-C-4-alkylene, an alkylene bridge with 1 to 8 carbon atoms which can be branched or unbranched and anywhere in the bridge one or two oxygen atom (s) or one May have nitrogen atom, preferably 0-C- ^* -C3-alkylene or -0-CH ₂ -CH ₂ -0-, -0-CH -CH ₂ -NH-; R1 is hydrogen, methyl, ethyl, phenyl; R ^{2 is} hydrogen, methyl; R ^{3 is} hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, methoxy; R ^{4 is} hydrogen, methyl, ethyl; R5 is hydrogen, methyl, ethyl; R6 is hydrogen, methyl, ethyl; R7 is tert-butyl, cyclohexyl or phenyl, where phenyl may optionally be substituted by R ⁹ and R ¹⁰ , which may be the same or different; R ^{8 is} hydrogen, C- ^* -C4 alkyl; R ^{9 is} hydrogen, methyl, fluorine, chlorine, bromine, methoxy; R10 is hydrogen, methyl, fluorine, chlorine, bromine, methoxy; can optionally mean in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids; and the compounds of general formula 1b.

wherein R1 ', R ² ' and R ³ 'are the same or different, hydrogen, methyl or ethyl; w R ⁴ 'is hydrogen, methyl or ethyl; R ⁵ ', R ⁸ ' and R ⁷ 'are the same or different, hydrogen, methyl or ethyl; R ⁸ 'and R ⁹ ' may mean the same or different hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxy or methoxy, optionally in the form of their racemates, their enantiomers, their 15 diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable acid addition salts , 3) drug combinations according to claim 2, characterized in that 1 is selected from the group consisting of Pirmencol, Pilsicainide, Sipatrigine, 0 Irampanel, Fosphenytoin, Zonisamide, Mexiletine, Bipridil, Bisaramil, Milacainide, NS 7, the compounds of general formula 1a wherein X Ci -C ₃ alkylene, -0-CH ₂ -CH ₂ -0- or -0-CH ₂ -CH ₂ -NH-; R ^{1 is} hydrogen or methyl; R ^{2 is} hydrogen or methyl; 5 R ^{3 is} hydrogen or chlorine; _R 4 is hydrogen or methyl; R5 is hydrogen or methyl; R ^{8 is} methyl or ethyl; R ^{7 is} tert-butyl, cyclohexyl or phenyl, where phenyl may optionally be substituted by R ⁹ and R ^{1 0} , which may be the same or different; R ^{8 is} hydrogen; R ^{9 is} hydrogen, methyl, fluorine or chlorine; _R 10 is hydrogen, methyl, fluorine or chlorine; can optionally mean in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids; and the compounds of the general formula 1b, in which R ^"1 ', R ² ' and R ³ ', identical or different, are hydrogen or methyl; R ⁴ ' is hydrogen or methyl; R ⁵ ', R ⁸ ' and R ⁷ 'are the same or different, hydrogen or methyl, preferably methyl; R ⁸ 'is hydrogen, methyl, hydroxy or methoxy, preferred Can be hydrogen or methyl, R ⁹ '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) drug combinations according to one of claims 1 to 3, characterized in that 2 is selected from the group of plasminogen activators. 5) drug combinations according to claim 4, characterized in that 2 is selected from the group consisting of old plase (human tissue plasminogen activator, t-PA), tenectepiase, reteplase, streptokinase, urokinase, anistreplase, monteplase, nateplase, duteplase, lanoteplase, silteplase , Amediplase and Desmoteplase. 6) Pharmaceutical combinations according to one of claims 1 to 5, characterized in that the active ingredients 1 and 2 are contained in a single, or in two separate, preferably in two separate dosage forms. 7) Use of a drug combination according to one of claims 1 to 6 for the manufacture of a medicament for the treatment of ischemic conditions of different origins. 8) Use according to claim 7, for the manufacture of a medicament for the treatment of cardiac or brain ischemia, particularly preferably for the treatment of stroke. 9) Use of one or more, preferably a sodium channel blocker 1_ for the manufacture of a medicament for the combined treatment of ischemic conditions of different origins with one or more, preferably a fibrinolytic 2. 10) Use according to claim 9, characterized in that 1 is selected from the group of compounds according to claim 2 and further characterized in that 2 is selected from the group of compounds according to claim 4.