MXPA95000679A - New drugs containing compounds of 3-phenilsulfonil-3,7-diazabiciclo (3,3,1) non - Google Patents
New drugs containing compounds of 3-phenilsulfonil-3,7-diazabiciclo (3,3,1) nonInfo
- Publication number
- MXPA95000679A MXPA95000679A MXPA/A/1995/000679A MX9500679A MXPA95000679A MX PA95000679 A MXPA95000679 A MX PA95000679A MX 9500679 A MX9500679 A MX 9500679A MX PA95000679 A MXPA95000679 A MX PA95000679A
- Authority
- MX
- Mexico
- Prior art keywords
- group
- lower alkyl
- compounds
- carbon atoms
- halogen
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 69
- 239000002547 new drug Substances 0.000 title claims abstract 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 62
- 239000002253 acid Substances 0.000 claims abstract description 38
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 28
- 150000007513 acids Chemical class 0.000 claims abstract description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 22
- 230000003288 anthiarrhythmic Effects 0.000 claims abstract description 21
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000011780 sodium chloride Substances 0.000 claims abstract description 19
- 238000007792 addition Methods 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- 150000002367 halogens Chemical class 0.000 claims abstract description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 9
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 8
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 239000000543 intermediate Substances 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract 7
- 210000002216 Heart Anatomy 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 10
- 241001465754 Metazoa Species 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
- 230000033764 rhythmic process Effects 0.000 claims description 6
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000000546 pharmaceutic aid Substances 0.000 claims description 2
- 241001397173 Kali <angiosperm> Species 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229940079593 drugs Drugs 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- 239000000126 substance Substances 0.000 description 20
- BKIMMITUMNQMOS-UHFFFAOYSA-N Nonane Chemical class CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- -1 ex. hydrohalic acids Chemical class 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- 239000000203 mixture Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- OTYXRCFJSSFVRD-UHFFFAOYSA-N 3-butyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane Chemical compound C1NCC2CN(CCCC)CC1C2(C)C OTYXRCFJSSFVRD-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 3
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- 206010070863 Toxicity to various agents Diseases 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
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- 238000000926 separation method Methods 0.000 description 3
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- 238000001291 vacuum drying Methods 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- OYTKINVCDFNREN-UHFFFAOYSA-N 3,4-Diaminopyridine Chemical compound NC1=CC=NC=C1N OYTKINVCDFNREN-UHFFFAOYSA-N 0.000 description 2
- PTPQJKANBKHDPM-UHFFFAOYSA-N 3,7-diazabicyclo[3.3.1]nonane Chemical class C1NCC2CNCC1C2 PTPQJKANBKHDPM-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- UDKDZYOIPADZFO-UHFFFAOYSA-N 4-[(7-butyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)sulfonyl]benzonitrile Chemical compound C1C(C2(C)C)CN(CCCC)CC2CN1S(=O)(=O)C1=CC=C(C#N)C=C1 UDKDZYOIPADZFO-UHFFFAOYSA-N 0.000 description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 2
- 206010003119 Arrhythmia Diseases 0.000 description 2
- 206010007521 Cardiac arrhythmias Diseases 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 210000001308 Heart Ventricles Anatomy 0.000 description 2
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- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 2
- 210000004165 Myocardium Anatomy 0.000 description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- XWJNWIRKHFAHNU-UHFFFAOYSA-N 3-(benzenesulfonyl)-3,7-diazabicyclo[3.3.1]nonane Chemical compound C1C(C2)CNCC2CN1S(=O)(=O)C1=CC=CC=C1 XWJNWIRKHFAHNU-UHFFFAOYSA-N 0.000 description 1
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- NIFGFJOSTUMVNK-UHFFFAOYSA-N 7-butyl-3-(4-imidazol-1-ylphenyl)sulfonyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane Chemical compound C1C(C2(C)C)CN(CCCC)CC2CN1S(=O)(=O)C(C=C1)=CC=C1N1C=CN=C1 NIFGFJOSTUMVNK-UHFFFAOYSA-N 0.000 description 1
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- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003458 sulfonic acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 230000004873 systolic arterial blood pressure Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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Abstract
The present invention relates to new drugs containing fonil-3,7-diazabicyclo [3.3.1] nonane, tetrasubstituted in 3,7,9,9 for the preparation of medicaments, which have antiarrhythmic activity, and new tetrasubstituted compounds in 3,7,9,9 having antiarrhythmic activity, of the general formula la, wherein R 8 signifies an alkyl group with 1-6 carbon atoms or a cycloalkylalkyl group with 4-7 carbon atoms, R 2 means lower alkyl, and R3 means lower alkyl, or R2 and R3 together form an alkylene chain with 3-6 carbon atoms, R4 represents cyano, a group R6-O-CO, wherein R6 means lower alkyl, a group R7-S2-NH , wherein R7 signifies lower alkyl, or a group R8-CO-NH, wherein R8 signifies lower alkyl or a phenyl group, which is optionally substituted with halogen, cyano, nitro, or a radical R9-SO2, wherein R9 is lower alkyl, or an imidazolyl radical disposed in 4-position of the phenyl ring, and R 5 means hydrogen or halogen, and their salts by addition of physiologically compatible acids, as well as processes and intermediates for their preparation
Description
-2-NEW MEDICINES CONTAINING COMPOUNDS OF 3-FENILSULFONIL-3,7-DIAZABICICLO (3,3,1) NONANO. D E S C R I P C L I N D E L A N N E N C E N
The present invention relates to new medicaments containing 3,7-diazabicyclo [3, 3, 1 hexane tetrasubstituted in 3,7,9,9 compounds, which carry in position 3 a substituted phenylsulfonyl radical in the ring of phenyl, and its salts as substances having antiarrhythmic activity as well as new 3-phenylsulfonyl compounds 1-3, 7-diazabicyclol3, 3, 1 Jnonano tetrasust in 3,7,9,9, with antiarrhythmic properties, and procedures and intermediate products for the preparation of these compounds. 3-Sulfonyl-3,7-diazabicyclo [3, 3, 1] nonane derivatives, which exert an effect in the gastrointestinal tract, are known from the publication document for German patent application DE-OS 37.22.134. regulator on the mobility of the stomach. The invention is based on the mission of developing new active substances that have antiarrhythmic activity and pharmaceutical preparations with an improved effect profile. In addition, the invention is based on the mission to develop new 3,7-diazabicyclo [3, 3, 1] nonane compounds with valuable pharmacological properties. It was finally discovered that a group of 3,7-diazabicyclo [3, 3, 1] nonane compounds substituted in the 3-position with a substituted 3-phenylsulfonyl radical have valuable pharmacological properties for the treatment of heart rhythm disorders and they present a profile of antiarrhythmic effects, which makes them suitable for the treatment of heart rhythm disorders, especially of tachycardic arrhythmias. According to the invention, as antiarrhythmic active substances for the production of pharmaceutical preparations having antiarrhythmic activity for the treatment of heart rhythm disorders in higher mammalian animals and humans, 3-phenylsulfo-nil-3,7-diazabicyclo compounds are used [ 3, 3, l] nonane of the general formula I
(see formula I)
wherein R means an alkyl group with 1-6 carbon atoms or a cycloalkylalkyl group with 4-7 carbon atoms,
R 2 means lower alkyl, and R means lower alkyl, or R 2 and R 3 together form an alkylene chain with 3-6 carbon atoms, R 4 represents halogen, nitro, trifluoromethyl or cyano, a group R 6-0-CO, in wherein R6 means lower alkyl, a group R7-S02-NH, wherein R7 signifies alkyl. 4-lower, or a group R -CO-NH, wherein R8 means lower alkyl or a phenyl group, which is optionally substituted with halogen, cyano, nitro, or with a radical R9-S02, wherein R9 is alkyl lower, or represents an imidazolyl radical arranged in 4-position of the phenyl ring, and R5 means hydrogen or halogen, and their salts by addition of physiologically compatible acids. If in the compounds of the formula I R represents an alkyl group, it may be straight or branched chain and contain from 1 to 6, preferably from 3 to 5, especially 4 carbon atoms. A cycloalkylalkyl group R may contain from 4 to 9, preferably from 4 to 7 carbon atoms. Particularly suitable radicals R are alkyl radicals having 3 to 5 carbon atoms.
If the substituents R and R represent lower alkyl, these alkyl groups can be straight chain or branched, and contain from 1 to 4, preferably from 1 to 3 carbon atoms, and especially methyl. If "Rr and R form an alkylene group in common, it can contain from 3 to 6, preferably from 4 to 5, carbon atoms, especially where the compounds in which R 2 and R 1 are each lower alkyl, especially methyl If the substituent R contains an lower alkyl group, it may be straight or branched chain and contain 1 to, especially 1 to 3, carbon atoms, and may preferably represent the methyl group. Preferably, the substituent represents cyano or an imidazolyl radical disposed in 4-position of the phenyl ring. As salts by the addition of pharmacologically acceptable acids of the compounds of formula I, for example, their salts with inorganic acids, e.g. ex. hydrohalic acids, especially hydrochloric acid, sulfuric acid or phosphoric acid, or with organic iaia, p. ex. lower aliphatic monocarboxylic or dicarboxylic acids such as malonic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, acetic acid or citric acid, or with organic sulphonic acids, for example (lower alkane) sulphonic acids such as methanesulfonic acid or acids benzenesulfonic compounds optionally substituted with halogen or lower alkyl in the benzene ring, such as p-toluenesulfonic acid.
The subject of the invention are novel medicaments containing the compounds of the formula I as pharmacologically active substances, which have antiarrhythmic activity. So far, no 3-phenylsulfonyl-3,7-diazabicyclo [3, 3, 1] nonane of the general formula has been described in the literature.
(see formula la)
wherein R means an alkyl group with 1-6 carbon atoms or a cycloalkylalkyl group with 4-7 carbon atoms,
R 2 if it is a lower alkyl, and R 3 is lower alkyl, or R? 2 and RJ "i form in common an alkylene chain with 3-6 carbon atoms, R4 represents cyano, a group R -0-C0, in which R6 means lower alkyl, a group R7-S02-NH, in the that R means lower alkyl, or a group R8-CO-NH, wherein R means lower alkyl or a phenyl group, which is optionally substituted with halogen, cyano, nitro, or with a radical R9-S02, wherein R9 is lower alkyl, or an imidazolyl radical arranged in 4-position of the phenyl ring, and R5 signifies hydrogen or halogen, and their salts by addition of physiologically compatible acids, and constitute new and valuable pharmacological active substances, which are also subject of the present invention. The other compounds of the formula I used according to the invention as active substances having antiarrhythmic activity fall within the range of the compounds described in DE-OS 37.22.134 mentioned above, and are known to from this In accordance with the invention, the 3-phenylsul-fonyl-3,7-diazabicyclo [3, 3, 1] nonane compounds of the formula I and their salts by addition of acids are obtained in a manner known per se , a) for the preparation of compounds of the general formula
(see formula le),
wherein R1, R, R and R5 have the above meanings and R represents halogen, nitro, trifluoromethyl or cyano, a group R -0-C0, in which R ° has the above meaning, a group R -S02-NH , at
'7 that R has the above meaning, or a group R8'-CO-NH, in which R8' means lower alkyl, by reacting compounds of the general formula II
(see formula II)
wherein R 1, R and R "have the above meanings, with compounds of the general formula III (see formula III),
wherein R4 '' 'and 5 have the above meanings and Y represents a reactive group, or b) for the preparation of compounds of the general formula
(see the formula le)
where R 1, R2, R3 and RJ •? they have the above meanings, reacting compounds of the general formula IV
(see formula IV)
1 • > c wherein R, R, R and R have the above meanings, with imidazole of the formula V
(see formula V) or c) for the preparation of compounds of the general formula Id
(see formula Id) - 9 - in which R 1, R 2 *, RJ 3 and R 3 have the meanings Q above and R ° means a phenyl group, which is optionally substituted with halogen, cyano, nitro or with a radical R - S02, wherein R9 is lower alkyl, acylating compounds of the general formula VI
(see formula VI)
wherein R1, R, R and R5 have the above meanings, with acid or acid derivatives capable of reacting of the general formula VII
(see formula VII)
wherein R possesses the above meanings and X signifies hydroxy or a reactive group, and optionally by transforming the free compounds having the formula I into their salts by the addition of acids, or by transforming the salts by addition of acids into the free compounds having the formula I. The reaction of the sulfonic acid derivatives of the formula III with the 3,7-diazabicyclo [3, 3, 1] non-nano compounds of the formula II according to process variant a) can be carried out according to customary methods for the formation of sulfone gone by acylation. Examples of suitable reactive derivatives are halides, preferably sulphonic acid chlorides, and sulfonic acid anhydrides of the formula 11 Ib.
(see formula Illb)
where R and R5 have the above meanings. Thus, the reactive group Y in the compounds of the formula III can mean, for example, halogen, especially chloro, or a substituted phenylsulfonyloxy group in the phenyl ring with
A l I I C. "R 'and R. The acylation can be carried out in an inert solvent under the reaction conditions at temperatures between 0 ° C and the boiling temperature of the solvent. Suitable solvents are halogenated hydrocarbons such as dichloromethane or chloroform, aromatic hydrocarbons such as benzene, toluene or chlorobenzene, cyclic ethers such as tetrahydrofuran or dioxane, dimethylformamide, or mixtures of these solvents. The acylation can be carried out, if desired, in the presence of an acid binding agent. Suitable acid-binding agents are inorganic bases, especially alkali metal carbonates, or organic bases, especially (lower alkyl) tertiary amines and pyridines, such as, for example, triethylamine or 4-dimethylamino-pyridine.
The reaction of compounds of formula IV with imidazole according to process variant b) can be carried out in a manner known per se in an inert organic solvent under the reaction conditions, at elevated temperatures, for example at temperatures between 70 and 150 ° C. Suitable solvents are dimethyl sulfoxide, dimethylformamide and acetonitrile. Conveniently, compounds of the formula IV are reacted with about 3 to 6 equivalents of an imidazole. In general, it is advantageous to work with the addition of 1-3 equivalents of an inorganic base, for example of an alkali metal carbonate. The reaction of the amino compounds of the formula VI with the acids or acid derivatives of the formula VII according to the process variant c) can be carried out according to customary methods for the acylation of aniline derivatives. Suitable acid derivatives of formula III, which are capable of reacting, are in particular halogenides, preferably acid chlorides and acid anhydrides. The reaction of such acid derivatives with the compounds of the formula VI can be carried out under the reaction conditions which are usual for the formation of amides, for example under the reaction conditions indicated above for variant a) of the process. If acids of the formula VII are used, the reaction can be carried out conveniently in the presence of a coupling reagent which is known from the chemistry of the peptides as appropriate for the formation of amides. As examples of coupling reagents, which favor the formation of amides with the free acids, reacting with the respective acid in situ with the formation of an acid derivative capable of reacting, especially alkylcarbodiimides, carbonyldiimidazole and N- (lower alkyl) salts will be mentioned. -2-halogen-non-pyridinium such as N-methyl-2-chloro-pyridinium iodide. The reaction in the presence of a coupling reagent can conveniently be carried out in an inert organic solvent, for example a halogenated hydrocarbon and / or an aromatic hydrocarbon, optionally in the presence of an acid-binding amine. The compounds of the formula I can be isolated from the reaction mixture and purified in a manner known per se. The acid addition salts can be converted in the customary manner to the free bases and these, if desired, can be converted in a known manner into pharmacologically compatible acid addition salts. In the case that in the compounds of the formula I the substituents R 2 and R 3 are different, the compounds contain a center of chirality and can be presented in two optically active forms or as a racemate. The present invention encompasses both the racemic mixtures as well as the optical-13 -isomers of these compounds of the formula I. The optically active compounds can be obtained from the racemic mixtures in a manner known per se by means of customary separation methods., for example by chromatographic separation in the presence of chiral separation materials or by fractional crystallization of appropriate salts with optically active acids. The pure compounds for the enantiomers can also be prepared by synthesis from corresponding pure compounds with respect to the enantiomers, which have the formula II. The starting compounds of the formula II are known from DE-OS 37.22.134 and / or can be prepared in a manner known per se according to the methods described in this DE-OS document or analogously to the methods described therein. publication. The starting compounds of the formula III are known or can be prepared in a manner known per se. For example, aromatic compounds of the general formula IX can be converted
(see formula IX)
A I I I? wherein R and R have the above meanings, in a known manner, by means of chlorosulfonic acid and / or sulfonyl chloride, in the corresponding 14-substituted-benzenesulfochlorides of the formula III. The starting compounds of the formula IV can be obtained by reacting compounds of the formula II with sulphonic acid derivatives of the general formula VIII
(see formula VIII)
where Y and R have the above meanings. The reaction can be carried out under the conditions indicated above for the reaction of compounds of the formula II with compounds of the formula III. The compounds of the formula VI are new compounds, which constitute valuable intermediates for the preparation of pharmacologically active compounds. The compounds of the formula VI can be obtained by separating by hydrolysis the acyl group R ° -CO- from corresponding compounds of the formula I, in which R represents an acylammo radical R ° -CO-NH-, in which R It has the previous meaning. The hydrolysis can be carried out in a manner known per se in acidic or alkaline conditions. It was finally discovered, with surprise, that the group of the compounds of formula I and their salts by addition of physiologically compatible acids, which are used according to the invention, have antiarrhythmic effects. These compounds have especially antiarrhythmic properties of the class III and produce an extension of the effective refractory time in the heart, which leads to a prolongation of the QT interval in the electrocardiogram. The compounds have a favorable profile of effects with good compatibility, prolonged duration of effect and such a high selectivity of the antiarrhythmic effect against the bradycardic and hypotensive properties, that in the range of the doses that have an antiarrhythmic activity no therapeutically undesired influence appears about heart rate and / or blood pressure. The compounds are distinguished by the fact that the antiarrhythmic effect is especially pronounced under tachycardic conditions. The antiarrhythmic effects of the compounds can be checked in standardized pharmacological test methods.
Description of pharmacological research methods. 1. Determination of the minimum toxic dose Male mice weighing 20 to 25 g are administered orally (p.o.) maximum doses of 300 mg / kg of the test substance. The animals are observed for 3 hours carefully regarding symptoms of toxicity. All the symptoms and fatal cases are recorded over a period of 72 hours after the application. The symptoms - 16 - are also observed and recorded. When death or strong toxic symptoms are observed, smaller doses are administered to other mice until no more toxic symptoms appear. The lowest dose, which causes death or strong toxic symptoms, is indicated in Table A below as the minimum toxic dose. The numbers of Examples indicated in Table A refer to the following Preparation Examples. Table A
2. In vivo investigation of the antiarrhythmic properties of substances under tachycardic conditions in narcotized guinea pigs. The effects of the substances on the effective refractory time period (= ERP) and on blood pressure in the case of intravenous (i.v.) application with an increased heart rate, were investigated in narcotized guinea pigs. The animals were inserted into the right ventricle, through a jugular vein, a bipolar excitatory catheter, mediating complete narcosis. Through it he kept the animals' heart rate, by electrical excitation throughout the investigation, at approximately 150% of his normal heart rate. In the other jugular vein a cannula was introduced for the i.v. of the test substances. During the investigation, systolic and diastolic arterial blood pressures (= SAP and DAP) were measured in a carotid artery by means of a manometer (Statham pressure transducer). The test substances were applied i.v. in increasing doses (cumulatively). Before the application of the first dose and in each case at 8 minutes after each administration of a dose, the ERP was determined by a double pulse protocol. The dose with which an ERP prolongation was reached at 115% of the starting value was calculated as an effective dose (= ERP-DE115). As effective doses for a hypotensive effect, the dose at which the SAP had been decreased to 85% of its starting value (= SAP-DE85) and the dose at which the DAP had been decreased to 85% of its value were calculated. of departure (= DAP-DE85). In the following Table B the results obtained with the method described above are reproduced. The numbers of Examples indicated for the test substances refer to the Preparation Examples given below.
Table B
The prolongation effect of the refractory period of time, which the substances have, can also be verified in in vitro tests by determining the functional refractory time period in the isolated papillary muscle of the right ventricle of guinea pigs. The above results of the tests show that the compounds of the formula I possess antiarrhythmic effects and clearly prolong the effective refractory period of the cardiac muscle (myocardium) and that an effective hypotensive effect of the substances appears only with doses that they are considerably higher than the effective doses for the prolongation of the refractory period of time. By virtue of its profile of effects described above, the substances are suitable for the control of tachycardic disorders of the heart rhythm (premature beats, flutter and flutter of the ventricle) and can find use for the prophylaxis and treatment of disorders of the "19" heart rhythm in higher mammalian animals and humans. In particular, the substances are suitable for preventing the appearance of tachyarrhythmias, that is, arrhythmias that are coupled with an increase in heart rate.
The doses to be used may be individually different and vary naturally depending on the type of condition to be treated, the substance used and the manner of application. However, in general, medicinal forms with an active substance content of 0.5 to 100, especially 1 to 25 mg, per individual dose are suitable for application in higher mammalian animals, especially humans. As medicaments, the compounds of formula I can be contained together with conventional pharmaceutical adjuvants in galenical preparations such as, for example, tablets, capsules, suppositories or solutions. These galenic preparations can be produced according to methods known per se, with use of customary solid or liquid carriers, such as, for example, lactose, starch or talc or liquid paraffins and / or with the use of customary pharmaceutical auxiliaries, for example tablet disintegrating agents, dissolution inducers (solubilizers) or preservatives. The following Examples should explain the invention in greater detail, but without limiting its extension in any way.
- 20"Example 1: 7- (n-Butyl) -3- [(4-cyanophenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo [3.3.1] nonane To a solution of 2.37 g of 7- (n-butyl) -9,9-dimethyl-3,7-diazabicyclo [3, 3, 1] nonane in 30 ml of dichloromethane was added dropwise, by cooling with ice, a solution of 2.5 g of 4-cyanobenzenesulfonic acid chloride in 20 ml of dichloromethane, then cooling with ice was suppressed and the reaction mixture was stirred for one hour at room temperature, in this case, the hydrochloride of the title compound it was separated as a white precipitate, the crystals were filtered with suction and dried at 60 ° C in a vacuum drying oven to obtain 2.5 g of 7- (n-butyl) -3- hydrochloride. (4-cyanophenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo [3, 3, 1] nonane with a melting point of 98 to 99 ° C.
Example 2; 7- (n-Butyl-3 - [(4-acetylaminophenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo [3.3.1] onan To a solution of 39.3 g of 7- ( n-butyl) -9,9-dimethyl-3,7-diazabicyclo [3, 3, 1] nonane and 29 ml of triethylamine in 700 ml of dichloromethane was added dropwise, while cooling with ice, a solution of , 7 g of 4-acetamidosulfonic acid chloride in 100 ml of dichloromethane The reaction mixture was stirred for another 2 hours at room temperature, then water was added to the reaction mixture to carry out the treatment and the mixture was stirred. The mixture was extracted twice with dichloromethane, the combined dichloromethane phases were dried with magnesium sulfate and concentrated., 4 g of 7- (n-butyl) -3 - [(4-acetylaminophenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo [3.3.1] nonane. 2.9 g of the title base was dissolved in 20 ml of ethyl acetate. To the solution was added, while cooling with ice, a solution of 1.1 g of tartaric acid in 20 ml of acetone. In this case, the hydrogen tartrate of the title compound resulted in a crystalline state. The crystals were filtered with suction and dried at 50 ° C in a vacuum drying oven. 3.6 g of the mono-hydrogen tartrate of the title compound were obtained with a melting point of 130 ° C.
Example 3; 7- (n-Butyl) -3- [(4- (imidazol-1-yl) -phenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo [3.3.1] nonane A) A a solution of 7.8 g of 7- (n-butyl) -9,9-dimethyl-3,7-diazabicyclo [3, 3, 1] nonane in 40 ml of dichloromethane was added dropwise, while cooling with ice, a solution of 7.2 g of 4-fluorobenzenesulfonic acid chloride in 10 ml of dichloromethane. The cooling was then suppressed with ice and the reaction mixture was stirred at room temperature for 1 hour. For the treatment, an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extracted twice with dichloromethane. The combined dichloromethane extracts were dried with magnesium sulfate and concentrated. 12.9 g of 7- (n-butyl) -3 - [(4-fluorophenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo [3.3.1] nonane were obtained. B) 12.9 g of the product obtained above, 5.8 g of potassium carbonate and 2 g of imidazole in 200 ml of dimethylsulfoxide were heated at 120 ° C for 10 hours. Then, the reaction mixture was cooled, the potassium carbonate was removed by filtration and the filtrate was concentrated. The remaining residue was mixed with an aqueous solution of sodium hydroxide and extracted twice with dichloromethane. The combined dichloromethane extracts were dried with magnesium sulfate and concentrated. The crude title compound, remaining as oily residue, was purified by chromatography on alumina clay, using acetic acid ethyl ester as the elution agent. 4.2 g of 7- (n-butyl) -3 - [(4- (imidazol-1-yl) -phenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo were obtained [3.3 , 1] nonane with a melting point of 148 to 150 ° C.
_-23 -Example 4: 7- (n-Butyl) -3- [(4- (4-cyanobenzoylamino) -phenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo [3.3.1 ] nonane A) 5.1 g of 7- (n-butyl) -3 - [(4-acetylaminophenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo [3] were heated at reflux for 6 hours. , 3, 1] nonane (about its preparation, see Example 2) and 1.5 g of potassium hydroxide in 100 ml of ethanol. Then the reaction mixture was cooled, water was added and extracted twice with diethyl ether. The combined ether extracts were dried with magnesium sulfate and concentrated. 4.0 g of 7- (n-butyl) -3 - [(4-aminophenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo [3, 3, 1] nonane were obtained, which were used without further purification in the next reaction step. B) 1.4 g of the product obtained above and 0.63 g of 4-cyanobenzoyl chloride in 20 ml of dichloromethane were dissolved. The reaction mixture was allowed to react at room temperature for 1 hour. For the treatment, the reaction mixture was adjusted to the alkaline margin by the addition of an aqueous solution of sodium hydroxide. Then the aqueous phase was separated and extracted twice with dichloromethane. The combined dichloromethane phases were dried with magnesium sulfate and concentrated. The crude title compound, obtained as a crystalline residue, was recrystallized from diethyl ether, and the obtained crystals were dried at 24-60 ° C in a vacuum drying oven. 1.3 g of 7- (n-butyl) -3 - [(4- (4-cyanobenzoylamino) -phenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo [3.3.1] were obtained. ] nonane, which has a melting point of 145 ° C. According to the processes described in the preceding Examples, the compounds of the formula I which are indicated in the following Table can also be prepared.
.25 -
Im = imidazol-l-yl, phen = phenyl, n = normal, i = iso, Cyp = cyclopropyl, Cyh = cyclohexyl, HCl = hydrochloride, HTa = hydrogen tartrate, B = base, HMa = hydrogenomalonate
26
C \ l
- 29 - Example I: Tablets containing 7- (n-butyl) -3 - [(4-cyanophenyl) -sulfonyl] -9, -dimethyl-3,7-diazabicyclohydrochloride- [3,3,1] nonane Tablets having the following composition per tablet were prepared:
7- (n-Butyl) -3- [(4-cyanophenyl) -sulfonyl] -9,9-dimethyl-3,7-diazabicyclo [3, 3, 1] nonane 20 mg hydrochloride
Corn starch 60 mg
Lactose 135 mg
Gelatin (as a 10% solution) 6 mg The active substance, corn starch and lactose were thickened with 10 gelatin solution. The pulp was crumbled and the resulting granulate was placed on an appropriate sheet and dried at 45 ° C. The dried granulation was conducted through a shredding machine and mixed with the following other coadjuvant substances in a mixing apparatus:
Talc 5 mg Magnesium stearate 5 mg Corn starch 9 mg
and then compressed to form 240 mg tablets.
R1- R2_ / R3 - ° 2-GC le
VII
Claims (4)
- R means hydrogen or halogen, and their salts by addition of physiologically compatible acids, intended for the treatment of heart rhythm disorders in higher mammalian animals and humans. 2. New drugs according to claim 1, characterized in that they contain compounds, in which R means an alkyl group with 3-5 carbon atoms, and R and R each signify lower alkyl. 3.- New drugs according to one of the preceding claims characterized by the fact that they contain compounds, in which R represents cyano or an imidazolyl radical arranged in position 4 of the phenyl ring. 4.- New drugs as antiarrhythmic agents, characterized in that they contain an antiarrhythmic-effective amount of a compound according to claim 1, and the usual pharmaceutical adjuvants and / or carrier materials. 5.- Compounds of the formula the - 4 - wherein R 1 means an alkyl group with 1-6 carbon atoms or a cycloalkylalkyl group with 4-7 carbon atoms,
- 2 R means lower alkyl, and RJ means lower alkyl, or R * and RJ form in common an alkylene chain with 3-6 carbon atoms, represents cyano, a group R -0-C0, wherein R ° means alkyl lower, a group R -S02-NH, wherein R means lower alkyl, or a group R ^ -CO-NH, wherein R means lower alkyl or a phenyl group, which is optionally substituted by halogen, cyano, nitro , or with a radical R 9_-SCr0a2, aell, qru ?? ae RD? 3 is lower alkyl, or an imidazolyl radical arranged in position 4 of the phenyl ring, and R5 means hydrogen or halogen, and their salts by addition of acids physiologically compatible. 6. - Process for the preparation of compounds of the general formula -35- wherein R means an alkyl group with 1-6 carbon atoms or a cycloalkylalkyl group with 4-7 carbon atoms, R 2"means lower alkyl, and R 3 means lower alkyl, or R 2 and 3 form in common an alkylene chain with 3-6 carbon atoms, R 4 'represents cyano, a group R? - 0-C0, in which Rf? means lower alkyl, a group R7-S02-NH, wherein R means lower alkyl, or a group R8-CO-NH, or wherein R means lower alkyl or a phenyl group, which is optionally substituted by halogen, cyano , nitro, or with a radical R -S02, in which R is lower alkyl, or an imidazolyl radical disposed in 4-position of the phenyl ring, and R means hydrogen or halogen, and their salts by addition of physiologically compatible acids, characterized by the fact that a) for the preparation of compounds of the general formula Ib (Ib) - 36 - in which R 1, R2, RJ3 and R35 have the above meanings and 4", represents cyano, a group R -0-C0-, in which R has the above meaning, a group R 7 -S02-NH, in which R 7 has the above meaning, Q / Q / or a group R ° -CO-NH, in which R means lower alkyl, compounds of the general formula II are reacted wherein R 1, R and R 3 have the above meanings, with compounds of the general formula Illa wherein R and R have the above meanings and Y represents a reactive group, or - 37 - for the preparation of compounds of the general formula wherein R 1, R 2, R 3 and R 5 have the above meanings, compounds of the general formula IV are reacted wherein R 1, R 2, R 3 and s 5 have the above meanings, with imidazole of the formula V (V) - 38 - for the preparation of compounds of the general formula Id
- 3 c in which RJ and RJ have the above meanings and R, ° 8 'represents a phenyl group which is optionally substituted by halogen, nitro, or with QQ a radical R -S02, in which it is lower alkyl, compounds are acylated of the general formula VI wherein R 1, R "2, R 3 and R 5 have the above meanings, with acids or with acid derivatives capable of reacting of the general formula VII X-CO-Rβ '(VII) -39- wherein R has the above meanings and X signifies hydroxy or a reactive group, and optionally the free compounds having the formula Ia are converted into their salts by the addition of acids, or the salts are transformed by the addition of acids into the free compounds having the formula la. p.p. Kali Chemie Pharma GmbH -.40 - EXTRACT OF THE INVENTION. New drugs containing fonil-3,7-diazabicyclo [3, 3, 1 Jnonano, tetrasubstituted in 3,7,9,9, for the preparation of drugs, which have antiarrhythmic activity, and new tetrasubstituted compounds in 3,7 are described , 9.9 which have antiarrhythmic activity, of the general formula R means an iaguilo group with 1-6 carbon atoms or a cycloalkylalkyl group with 4-7 carbon atoms, R means lower alkyl, and R means lower alkyl, or R 2 and R 1 form in common an alkylene chain with 3- 6 carbon atoms, R represents cyano, a group R -0-CO, wherein R means lower alkyl, a group RS, -NH, wherein R means lower alkyl, or a group R -CO-NH, or wherein R means lower alkyl or a phenyl group, which is optionally substituted with halogen, qq cyano, nitro, or with a radical R -SO, in which R is lower alkyl, or an imidazolyl radical disposed in
- 4-position of the phenyl ring, and RD means hydrogen or halogen, and their salts by the addition of physiologically compatible acids, as well as processes and intermediates for their preparation.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE4402931A DE4402931A1 (en) | 1994-02-01 | 1994-02-01 | New drugs containing 3-phenylsulfonyl-3,7-diazabicyclo [3,3,1] nonane compounds |
DEP4402931.4 | 1994-02-01 |
Publications (2)
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MX9500679A MX9500679A (en) | 1998-03-31 |
MXPA95000679A true MXPA95000679A (en) | 1998-10-15 |
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