WO2008077170A2 - Benzothioamides, and use thereof for relaxing smooth muscles - Google Patents

Benzothioamides, and use thereof for relaxing smooth muscles Download PDF

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WO2008077170A2
WO2008077170A2 PCT/AT2007/000582 AT2007000582W WO2008077170A2 WO 2008077170 A2 WO2008077170 A2 WO 2008077170A2 AT 2007000582 W AT2007000582 W AT 2007000582W WO 2008077170 A2 WO2008077170 A2 WO 2008077170A2
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substituted
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phenyl
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WO2008077170A3 (en
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Thomas Erker
Norbert Handler
Gerda Brunhofer
Christian Studenik
Pakiza Rawnduzi
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Universität Wien
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/44—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/83—Thioacids; Thioesters; Thioamides; Thioimides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the use of thioamide compounds of the general formula I and subgroups of these thioamide compounds.
  • Compounds with such properties have the potential to be used in the prophylaxis and therapy of numerous disorders associated with seizure disorders and clinical pictures.
  • the inventors surprisingly found in the thioamides of the formula I a new linking group having similar properties to the abovementioned benzanilide derivatives, which has a notable increase in activity over these.
  • the present invention is therefore based on the use of compounds of general formula I.
  • Y is selected from the group consisting of thienyl, pyridyl and
  • each R is hydrogen or a substituent selected from the group consisting of F, Cl, Br, I, OH, OCH 3 , NO 2 , CF 3 , CH 3 , OCF 3 , N (CH 3 ) 2 and SCH 3 , is with the
  • At least one R is not hydrogen
  • X is an unsubstituted or substituted aryl group, wherein one or more ring atoms having a radical selected from the group consisting of F, Cl, Br, I, OH, OCH 3 , NO 2 , CF 3 ,
  • the compounds of the present invention have smooth muscle relaxant activity (e.g., terminal iliac, aortic and pulmonary artery rings).
  • R is selected from the group consisting of F, NO 2 and OCH 3 .
  • At least two radicals R are not hydrogen.
  • R at position 3, 4 and / or 5 is not hydrogen.
  • Another preferred embodiment is characterized by the use of compounds in which X is a phenyl group.
  • X is substituted with a group selected from the group consisting of F, CH 3 , OCH 3 , SCH 3 and N (CH 3 ) 2 .
  • X is at least doubly substituted.
  • the drug is preferably used in indications selected from the group consisting of:
  • spasms and motility disorders of the gastrointestinal tract irritable bowel syndrome, spasms and dyskinesias of the gall and urinary tract, cholecystopathy, dysmenorrhea complaints, convulsions in the genitalia of the female and spasms of the soft tissues during delivery (tocolysis), pylorospasm of the infant, in investigations occurring spasms, such as in gastroduodenal endoscopy or X-ray, arterial hypertension, pulmonary Hypertension, treatment of hypertensive crisis, coronary heart disease, such as chronic stable angina pectoris or vasospastic angina, chronic heart failure, arterial occlusive diseases, such as intermittent claudication, ischemic neurological deficits due to cerebral vasospasm after aneurysmal subarachnoid hemorrhage, brain performance disorders in old age, bronchospasm in bronchial asthma, spastic bronchitis , Status asthmaticus, Raynaud
  • Another aspect of the invention relates to compound groups of the general formula I, which are particularly suitable for the production of medicaments for the indications mentioned.
  • X is an aryl group, preferably a phenyl group, which contains at least one radical selected from the group consisting of F, Cl, Br, I, OH, OCH 3 , NO 2 , CF 3 , CH 3 , OCF 3 ,
  • Preferred compounds of this group are characterized in that the phenyl group Y is at least doubly substituted.
  • phenyl group Y is substituted in simple substitution at position 4 ("para") and in two, preferably identical, substituents at positions 3 and 5 (“meta").
  • Another preferred group are compounds of general formula I.
  • X is an aryl group, preferably phenyl, which is unsubstituted or monosubstituted or polysubstituted by a radical selected from the group consisting of OCH 3 and CH 3 ,
  • Y is at least trisubstituted.
  • X is at least doubly, preferably identically, substituted.
  • Y is thienyl or pyridyl
  • X is substituted twice with a methyl group, preferably at positions 2 and 3.
  • a further preferred embodiment is characterized in that X is substituted twice or three times by a methoxy group, preferably at positions 3, 4 and / or 5.
  • X is monosubstituted or disubstituted by F, preferably at positions 3, 4 and / or 5.
  • the preparation of compounds of general formula I can e.g. be carried out by reacting a carboxylic acid derivative, e.g. a carboxylic acid chloride of general formula II,
  • R has the same meaning as in formula I, in a manner known per se with an amine of the formula H 2 N - X, wherein X has the same meaning as in formula I, to convert a carboxylic acid amide. Thereafter, the carboxylic acid amide with a Thion istsreagens such. B. Lawesson's reagent, converted to the corresponding thioamide and optionally converted by reaction with a physiologically acceptable acid in the acid addition salt.
  • Example I N- (2,4,6-trifluorophenyl) -3,5-dinitrobenzothioamide.
  • Example II N- (2,3-dimethylphenyl) -4-methoxybenzothioamide.
  • Example III N- (3,4,5-Trimethoxyphenyl) -3,5-difluorobenzothioamide.
  • the benzamide is prepared from 3,5-difluorobenzoyl chloride (10 mmol, 1.76 g) and 3,4,5-trimethoxyaniline (10 mmol, 1.83 g). Recrystallization from ethanol gives 2.85 g (88%) of the benzamide.
  • Example IV N- (4-Methylthiophenyl) -3,5-difluorobenzothioamide.
  • the benzamide is prepared from 3,5-difluorobenzoyl chloride (10 mmol, 1.76 g) and 4- (methylthio) aniline (10 mmol, 1.39 g). Recrystallization from ethanol gives 2.57 g (92%) of the benzamide.
  • Example V N- (4-fluorophenyl) -3,5-difluorobenzothioamide.
  • Example VI N- (3,5-Dimethoxyphenyl) - (4-trifluoromethoxy) benzothioamide.
  • the benzamide is prepared from 4- (trifluoromethoxy) benzoyl chloride (10 mmol, 2.24 g) and 3,5-dimethoxyaniline (12 mmol, 1.84 g). Recrystallization from 70% ethanol gives 2.34 g (68%) of the benzamide.
  • Example VII N- (4-Dimethylaminophenyl) -3,5-difluorobenzothioamide.
  • the benzamide is prepared from 3,5-difluorobenzoyl chloride (11 mmol, 1.94 g) and N, N-dimethyl-1,4-phenylenediamine (11 mmol, 1.50 g). Recrystallization from ethanol gives 1.52 g (50%) of the benzamide.
  • Example VIII N- (4-Methylthiophene) -4-fluorobenzothioamide.
  • the benzamide is prepared from 4-fluorobenzoyl chloride (10 mmol, 1.59 g) and 4- (methylthio) aniline (10 mmol, 1.39 g). Recrystallization from ethanol gives 2.08 g (80%) of the benzamide.
  • Example IX N- (3,5-Difluorophenyl) -4-fluorobenzothioamide.
  • Example X N- (3,4,5-T ⁇ methoxyphenvl) -3,5-dinitrobenzothioamide.
  • Example XI N- (2,6-dimethylphenyl) -3,5-dimethoxybenzothioamide.
  • Example XII N- (2,6-dimethylphenyl) -3,4,5-trimethoxybenzothioamide.
  • the benzamide is prepared from 3,4,5-trimethoxybenzoyl chloride (15 mmol, 3.459 g) and 2,6-dimethylaniline (15 mmol, 1.8 ml). Recrystallization from ethanol gives 2.14 g (45.2%) of the benzamide.
  • the benzamide is prepared from 3,4,5-trimethoxybenzoyl chloride (10 mmol, 2.3 g) and benzylamine (10 mmol, 1.07 ml). Recrystallization from ethanol gives 2.02 g (67.12%) of the benzamide.
  • Example XIV N- (2,4-dimethoxybenzyl) -3,4,5-trimethoxybenzothioamide.
  • Example XV N- (2,4-Dimethoxybenzyl) -2- (3,4-dimethoxyphenyl) acetothioamide.
  • 3,4-Dimethoxyphenylacetic acid (10 mmol, 1.96 g) and 1 ml of thionyl chloride are stirred in a dry flask for 92 hours at room temperature and then added at 35 ° C to the water jet vacuum. If no more thionyl chloride is present, 8 ml of abs.
  • Example XVI N- (2,4-Dimethoxybenzyl) -2- (4-methoxyphenyl) acetothioamide.
  • 4-Methoxyphenylacetic acid (10 mmol, 1.66 g) and 1 ml of thionyl chloride are heated in a dry flask for 2 hours under reflux and then attached at 35 ° C to the water jet vacuum. If no more thionyl chloride is present, 8 ml of abs.
  • Example XVII N- (3,4,5-trimethoxyphenyl) -2-thiophenecarbothioamide.
  • the 2-thiophenecarbamide is prepared from thiophene-2-carboxylic acid chloride (5.3 mmol, 0.57 ml) and 3,4,5-trimethoxyaniline (5 mmol, 0.92 g). Recrystallization from 70% ethanol gives 1.45 g (99.1%) of 2-thiophenecarbamide. From 1.26 g of the 2-thiophenecarbamide (4.3 mmol), the 2-thiophenecarbothioamide is prepared.
  • Example XX N- (4-fluorophenyl) -2-thiophenecarbothioamide.
  • Example XXII N- (3,5-Difluorophenyl) -2-thiophenecarbothioamide.
  • Example XXIII N- (3,4,5-trimethoxyphenyl) -thionicotinamide.
  • the nicotinamide is prepared from nicotinic acid hydrochloride (13 mmol, 2.61 g), triethylamine (20 mmol, 1.78 ml) and 3,4,5-trimethoxyaniline (10 mmol, 1.83 g). After recrystallization from 30% ethanol, 2.41 g (83.5%) of the nicotinamide are obtained.
  • the nicotinethioamide is prepared from 1.026 g of the nicotinamide (4.5 mmol). After purification by means of SC (eluent ethyl acetate) and recrystallization in ethanol, 0.253 g are obtained (18.5%) of the desired product. Mp: 190-191 ° C.
  • Example XXIV N- (4-methylthiophenyl) -thionicotinamide.
  • the nicotinamide is prepared from nicotinic acid hydrochloride (6.5 mmol, 1.16 g), triethylamine (10 mmol, 1.39 ml) and 4-methylthioaniline (5 mmol, 0.62 ml). Recrystallization from 50% ethanol gives 0.942 g (67.0%) of the nicotinamide. From 1.10 g of the nicotinamide (4.4 mmol), the nicotinthioamide is prepared. After purification by means of SC (eluent ethyl acetate) and recrystallization in 50% ethanol, 0.474 g (46.19%) of the desired product are obtained. Mp: 140-141 ° C.
  • Example XXV N- (2,3-dimethylphenyl) -thionicotinamide.
  • Example XXVII N - (. 3, 5-Dimethoxyphenyl) -ihionicotinamide.
  • the nicotinamide is prepared from nicotinic acid hydrochloride (12 mmol, 2.14 g), triethylamine (20 mmol, 2.78 ml) and 3,5-dimethoxyaniline (10 mmol, 1.53 g). Recrystallization from ethanol gives 1.956 g (75.8%) of the nicotinamide.
  • test substances were tested for their effect on the contraction force (f c ) of various guinea pig isolated preparations (terminal ilea, aortic rings, pulmonary artery rings, papillary muscle (PM) of the guinea pig heart) and the beat frequency (f) of isolated right atria of the guinea pig heart.
  • the f c terminal iliac, aortic and pulmonary artery rings precontracted with 60 or 90 mmolar KCl solution
  • papillary muscle electrically stimulated, 1 Hz
  • the beating frequency (f) of isolated right atria (RVH) of guinea pig heart became isometric measured. From the concentration-activity curves, the EC 50 values were determined graphically.
  • the compounds according to the invention were investigated in concentrations between 0.1 and 100 ⁇ mol / l.
  • Per compound 6 experiments each were performed on terminal iliac, aortic and pulmonary artery rings. The contraction force on papillary muscles and the Rate of impact on right atria was not significantly reduced.
  • Electron-withdrawing substituents "on both sides” of the thioamide and their arrangement are also decisive for the effect according to the invention.
  • the substances studied show a greater effect on smooth muscle than e.g. the benzamides that have been converted to the thiobenzamides (see Table 2).

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Abstract

The invention relates to the use of a compound of general formula (I), wherein Y is selected from among the group comprising thienyl, pyridyl, and formula (a), wherein each radical R represents hydrogen or a substituent selected from among the group comprising F, Cl, Br, I, OH, OCH3, NO2, CF3, CH3, OCF3, N(CH3)2, and SCH3, provided that at least one radical R does not represent hydrogen, X represents an unsubstituted or substituted aryl group, one or more ring atoms being substituted with a radical selected from among the group comprising F, Cl, Br, I, OH, OCH3, NO2, CF3, CH3, OCF3, N(CH3)2, and SCH3, and n, m = 0 or 1, as well as the salts thereof for producing a medicament for relaxing smooth muscles. Also disclosed are particularly suitable groups of compounds of formula (I).

Description

Benzothioamide und deren Verwendung Benzothioamides and their use
Die Erfindung betrifft die Verwendung von Thioamidverbindungen der allgemeinen Formel I sowie Untergruppen dieser Thioamidverbindungen.The invention relates to the use of thioamide compounds of the general formula I and subgroups of these thioamide compounds.
Vor einiger Zeit wurde festgestellt, dass bestimmte substituierte Benzanilidderivate, wie z.B. N-(2-Hydroxy-5-phenyl)-(2-methoxy-5-chloro)-benzamid, eine relaxierende und dilatierende Wirkung auf die glatte Muskulatur zeigen (Biagi G. et al., European Journal of Medicinal Chemistry 39 (2004): 491-498; Calderone V. et al., European Journal of Medicinal Chemistry 41 (2006): 761-767; Calderone V. et al., European Journal of Medicinal Chemistry 41 (2006): 1421-1429).Some time ago it was found that certain substituted benzanilide derivatives, such as e.g. N- (2-hydroxy-5-phenyl) - (2-methoxy-5-chloro) benzamide, have a smoothing and dilating effect on smooth muscle (Biagi G. et al., European Journal of Medicinal Chemistry 39 (2004 Calderone V. et al., European Journal of Medicinal Chemistry 41 (2006): 761-767; Calderone V. et al., European Journal of Medicinal Chemistry 41 (2006): 1421-1429).
Verbindungen mit derartigen Eigenschaften besitzen das Potential, bei der Prophylaxe und Therapie von zahlreichen mit Krampfzuständen verbundenen Störungen und Krankheitsbildern zur Anwendung zu gelangen.Compounds with such properties have the potential to be used in the prophylaxis and therapy of numerous disorders associated with seizure disorders and clinical pictures.
Von den Erfindern wurde überraschend in den Thioamiden der Formel I eine neue Verbindungsgruppe mit ähnlichen Eigenschaften wie die oben genannten Benzanilidderivate gefunden, welche gegenüber diesen eine beachtenswerte Wirkungssteigerung aufweist.The inventors surprisingly found in the thioamides of the formula I a new linking group having similar properties to the abovementioned benzanilide derivatives, which has a notable increase in activity over these.
Die vorliegende Erfindung ist daher auf die Verwendung von Verbindungen der allgemeinen Formel IThe present invention is therefore based on the use of compounds of general formula I.
Figure imgf000003_0001
wobei
Figure imgf000003_0001
in which
Y ausgewählt ist aus der Gruppe bestehend aus Thienyl, Pyridyl undY is selected from the group consisting of thienyl, pyridyl and
Figure imgf000003_0002
wobei jeder Rest R Wasserstoff oder ein Substituent, ausgewählt aus der Gruppe bestehend aus F, Cl, Br, I, OH, OCH3, NO2, CF3, CH3, OCF3, N(CH3)2 und SCH3, ist, mit der
Figure imgf000003_0002
wherein each R is hydrogen or a substituent selected from the group consisting of F, Cl, Br, I, OH, OCH 3 , NO 2 , CF 3 , CH 3 , OCF 3 , N (CH 3 ) 2 and SCH 3 , is with the
Maßgabe, dass mindestens ein Rest R nicht Wasserstoff ist,Provided that at least one R is not hydrogen,
X eine unsubstituierte oder substituierte Arylgruppe ist, wobei ein oder mehrere Ringatome mit einem Rest, ausgewählt aus der Gruppe bestehend aus F, Cl, Br, I, OH, OCH3, NO2, CF3,X is an unsubstituted or substituted aryl group, wherein one or more ring atoms having a radical selected from the group consisting of F, Cl, Br, I, OH, OCH 3 , NO 2 , CF 3 ,
CH3, OCF3, N(CH3)2 und SCH3, substituiert sind, und n, m = O oder 1 , sowie deren Salze zur Herstellung eines Arzneimittels zur Relaxierung glatter Muskulatur gerichtet.CH 3 , OCF 3 , N (CH 3 ) 2 and SCH 3 , and n, m = O or 1, and salts thereof for the preparation of a smooth muscle relaxant drug.
Die erfindungsgemäßen Verbindungen besitzen eine relaxierende Wirkung auf die glatte Muskulatur (z.B. terminale Ilea, Aorta- und Arteria pulmonalis-Ringe).The compounds of the present invention have smooth muscle relaxant activity (e.g., terminal iliac, aortic and pulmonary artery rings).
Bevorzugt werden Verbindungen der allgemeinen Formel I verwendet, bei denen R aus der Gruppe bestehend aus F, NO2 und OCH3 ausgewählt ist.Preference is given to using compounds of the general formula I in which R is selected from the group consisting of F, NO 2 and OCH 3 .
Gemäß einer bevorzugten Ausführungsform sind mindestens zwei Reste R nicht Wasserstoff.According to a preferred embodiment, at least two radicals R are not hydrogen.
Vorzugsweise ist R an der Position 3, 4 und/oder 5 nicht Wasserstoff.Preferably, R at position 3, 4 and / or 5 is not hydrogen.
Eine weitere bevorzugte Ausführungsform ist durch die Verwendung von Verbindungen gekennzeichnet, bei denen X eine Phenylgruppe ist.Another preferred embodiment is characterized by the use of compounds in which X is a phenyl group.
Es ist ferner bevorzugt, dass X mit einem Rest, ausgewählt aus der Gruppe bestehend aus F, CH3, OCH3, SCH3 und N(CH3)2, substituiert ist.It is further preferred that X is substituted with a group selected from the group consisting of F, CH 3 , OCH 3 , SCH 3 and N (CH 3 ) 2 .
Vorzugsweise ist X mindestens zweifach substituiert.Preferably, X is at least doubly substituted.
Das Arzneimittel findet bevorzugt bei Indikationen Anwendung, die ausgewählt sind aus der Gruppe bestehend aus:The drug is preferably used in indications selected from the group consisting of:
Krämpfen und Motilitätsstörungen des Magen-Darm-Trakts, Reizdarmsyndrom, Krämpfen und Dyskinesien der Gallen- und Harnwege, Cholecystopathie, dysmenorrhoischen Beschwerden, Krampfzuständen im Bereich der weiblichen Genitalorgane sowie Spasmen der muskulären Weichteile während der Entbindung (Tokolyse), Pylorospasmus des Säuglings, bei Untersuchungen auftretenden Spasmen, wie bei der Gastroduodenalendoskopie oder Röntgenuntersuchungen, arterieller Hypertonie, pulmonaler Hypertonie, Therapie der hypertonen Krise, koronarer Herzkrankheit, wie chronisch stabiler Angina pectoris oder vasospastischer Angina, chronischer Herzinsuffizienz, arteriellen Verschlusskrankheiten, wie Claudicatio intermittens, ischämischen neurologischen Defiziten infolge zerebraler Vasospasmen nach aneurysmatischer Subarachnoidalblutung, Hirnleistungsstörungen im Alter, Bronchospasmus bei Asthma bronchiale, spastischer Bronchitis, Status Asthmaticus, Morbus Raynaud und gefäßbedingten Waden- oder Zehenkrämpfen.Spasms and motility disorders of the gastrointestinal tract, irritable bowel syndrome, spasms and dyskinesias of the gall and urinary tract, cholecystopathy, dysmenorrhea complaints, convulsions in the genitalia of the female and spasms of the soft tissues during delivery (tocolysis), pylorospasm of the infant, in investigations occurring spasms, such as in gastroduodenal endoscopy or X-ray, arterial hypertension, pulmonary Hypertension, treatment of hypertensive crisis, coronary heart disease, such as chronic stable angina pectoris or vasospastic angina, chronic heart failure, arterial occlusive diseases, such as intermittent claudication, ischemic neurological deficits due to cerebral vasospasm after aneurysmal subarachnoid hemorrhage, brain performance disorders in old age, bronchospasm in bronchial asthma, spastic bronchitis , Status asthmaticus, Raynaud's disease and vaso-occipital or toe cramps.
Ein weiterer Aspekt der Erfindung betrifft Verbindungsgruppen der allgemeinen Formel I, die sich in besonderer Weise zur Herstelllung von Arzneimitteln für die genannten Indikationen eignen.Another aspect of the invention relates to compound groups of the general formula I, which are particularly suitable for the production of medicaments for the indications mentioned.
Bei einer dieser Gruppen handelt es sich um Verbindungen der allgemeinen Formel IOne of these groups are compounds of general formula I.
Figure imgf000005_0001
Figure imgf000005_0001
wobeiin which
X eine Arylgruppe, vorzugsweise Phenylgruppe, ist, welche mit mindestens einem Rest, ausgewählt aus der Gruppe bestehend aus F, Cl, Br, I, OH, OCH3, NO2, CF3, CH3, OCF3,X is an aryl group, preferably a phenyl group, which contains at least one radical selected from the group consisting of F, Cl, Br, I, OH, OCH 3 , NO 2 , CF 3 , CH 3 , OCF 3 ,
N(CH3)2 und SCH3, substituiert ist,N (CH 3 ) 2 and SCH 3 , is substituted,
Y eine Phenylgruppe ist, die mit mindestens einer Gruppe ausgewählt aus F und NO2 substituiert ist, und n, m = 0 oder 1, sowie deren Salze.Y is a phenyl group substituted with at least one group selected from F and NO 2 , and n, m = 0 or 1, and their salts.
Bevorzugte Verbindungen dieser Gruppe sind dadurch gekennzeichnet, dass die Phenylgruppe Y mindestens zweifach substituiert ist.Preferred compounds of this group are characterized in that the phenyl group Y is at least doubly substituted.
Weiters bevorzugt ist, dass die Phenylgruppe Y bei einfacher Substitution an Position 4 („para") und bei zwei, vorzugsweise identischen, Substituenten an den Positionen 3 und 5 („meta") substituiert ist.It is further preferred that the phenyl group Y is substituted in simple substitution at position 4 ("para") and in two, preferably identical, substituents at positions 3 and 5 ("meta").
Vorzugsweise ist bei den Verbindungen dieser Gruppe n,m = O. Ebenfalls bevorzugt ist, dass X dreifach, vorzugsweise mit F oder OCH3, substituiert ist.Preferably, in the compounds of this group n, m = 0. It is likewise preferred that X is substituted in triplicate, preferably with F or OCH 3 .
Eine weitere bevorzugte Gruppe sind Verbindungen der allgemeinen Formel IAnother preferred group are compounds of general formula I.
Figure imgf000006_0001
Figure imgf000006_0001
wobeiin which
X eine Arylgruppe, vorzugsweise Phenylgruppe, ist, welche unsubstiruiert oder mit einem Rest ausgewählt aus der Gruppe bestehend aus OCH3 und CH3 einfach oder mehrfach substituiert ist,X is an aryl group, preferably phenyl, which is unsubstituted or monosubstituted or polysubstituted by a radical selected from the group consisting of OCH 3 and CH 3 ,
Y eine Phenylgruppe ist, die mit einer oder mehreren Methoxygruppen oder OCF3 substituiert ist, und n, m = 0 oder 1 , mit der Maßgabe, dass X+Y insgesamt mindestens drei Substituenten besitzen, sowie deren Salze.Y is a phenyl group substituted with one or more methoxy groups or OCF 3 and n, m = 0 or 1, with the proviso that X + Y in total have at least three substituents, as well as their salts.
Gemäß einer bevorzugten Ausführungsform dieser Verbindungsgruppe ist Y mindestens dreifach substituiert.In a preferred embodiment of this linking group, Y is at least trisubstituted.
Bevorzugt wird auch, dass X mindestens zweifach, vorzugsweise identisch, substituiert ist.It is also preferred that X is at least doubly, preferably identically, substituted.
Vorzugsweise ist bei dieser Verbindungsgruppe n=l und/oder m=l.Preferably, in this connection group, n = 1 and / or m = 1.
Eine weitere Gruppe bevorzugter Verbindungen der allgemeinen Formel I (einschließlich ihrer Salze) ist dadurch gekennzeichnet, dassAnother group of preferred compounds of general formula I (including their salts) is characterized in that
Y Thienyl oder Pyridyl ist,Y is thienyl or pyridyl,
X eine Arylgruppe, vorzugsweise Phenylgruppe, ist, welche mit mindestens einem Rest, ausgewählt aus der Gruppe bestehend aus OCH3, CH3, SCH3 oder F substituiert ist, und n, m = 0 oder 1.X is an aryl group, preferably a phenyl group, which is substituted with at least one radical selected from the group consisting of OCH 3 , CH 3 , SCH 3 or F, and n, m = 0 or 1.
Bevorzugt ist bei dieser Gruppe, dass X zweifach mit einer Methylgruppe, vorzugsweise an den Positionen 2 und 3, substituiert ist. Eine weitere bevorzugte Ausführungsform ist dadurch gekennzeichnet, dass X zweifach oder dreifach mit einer Methoxygruppe, vorzugsweise an den Positionen 3, 4 und/oder 5, substituiert ist.Preferably, in this group, X is substituted twice with a methyl group, preferably at positions 2 and 3. A further preferred embodiment is characterized in that X is substituted twice or three times by a methoxy group, preferably at positions 3, 4 and / or 5.
Eine andere bevorzugte Ausführungsform ist dadurch gekennzeichnet, dass X einfach oder zweifach mit F, vorzugsweise an den Positionen 3, 4 und/oder 5, substituiert ist.Another preferred embodiment is characterized in that X is monosubstituted or disubstituted by F, preferably at positions 3, 4 and / or 5.
Die Herstellung von Verbindungen der allgemeinen Formel I kann z.B. dadurch erfolgen, dass man ein Carbonsäurederivat, z.B. ein Carbonsäurechlorid der allgemeinen Formel II,The preparation of compounds of general formula I can e.g. be carried out by reacting a carboxylic acid derivative, e.g. a carboxylic acid chloride of general formula II,
Figure imgf000007_0001
Figure imgf000007_0001
worin R dieselbe Bedeutung wie in Formel I besitzt, in an sich bekannter Weise mit einem Amin der Formel H2N - X, wobei X dieselbe Bedeutung wie in Formel I besitzt, zu einem Carbonsäureamid umsetzt. Danach wird das Carbonsäureamid mit einem Thionierungsreagens, wie z. B. Lawesson's Reagens, zu dem entsprechenden Thioamid umgesetzt und gegebenenfalls durch Reaktion mit einer physiologisch verträglichen Säure in das Säureadditionssalz übergeführt.wherein R has the same meaning as in formula I, in a manner known per se with an amine of the formula H 2 N - X, wherein X has the same meaning as in formula I, to convert a carboxylic acid amide. Thereafter, the carboxylic acid amide with a Thionierungsreagens such. B. Lawesson's reagent, converted to the corresponding thioamide and optionally converted by reaction with a physiologically acceptable acid in the acid addition salt.
Die Erfindung wird nachfolgend anhand von Beispielen näher erläutert.The invention will be explained in more detail by way of examples.
Beispiele:Examples:
Die Verbindungen I-XIV wurden nach folgender allgemeiner Arbeitsvorschrift hergestellt:The compounds I-XIV were prepared according to the following general procedure:
10 mmol Säurechlorid werden in absolutem Dioxan gelöst und mit 10 mmol des entsprechenden Anilinderivats, ebenfalls gelöst in absolutem Dioxan, versetzt und in einem Scheidetrichter gut durchgeschüttelt. Die Reaktionsmischung wird 10 Minuten lang stehengelassen und dann auf 500 ml Eiswasser gegossen. Der entstandene Niederschlag wird abgenutscht und umkristallisiert oder säulenchromatographisch gereinigt. In einem trockenen Dreihalskolben werden 5 mmol des erhaltenen Benzamids in absolutem THF gelöst und 4 mmol (1,61 g) Lawesson's Reagenz zugegeben. Die Mischung wird mit einem Trockenrohr bis zur vollständigen Umsetzung refluxiert, das THF abrotiert und das Rohprodukt mittels präparativer Säulenchromatographie gereinigt.10 mmol of acid chloride are dissolved in absolute dioxane and treated with 10 mmol of the corresponding aniline derivative, also dissolved in absolute dioxane, and shaken well in a separating funnel. The reaction mixture is allowed to stand for 10 minutes and then poured onto 500 ml of ice water. The resulting precipitate is filtered off and recrystallized or purified by column chromatography. In a dry three-necked flask, dissolve 5 mmol of the resulting benzamide in absolute THF and add 4 mmol (1.61 g) of Lawesson's reagent. The mixture comes with a Drying tube until the reaction is refluxed, the THF is removed by rotary evaporation and the crude product purified by preparative column chromatography.
Die genaue Arbeitsvorschrift der Vorstufen der Verbindungen XV und XVI wird direkt bei den Verbindungen angegeben. Die Synthese des Thioamids dieser Verbindungen erfolgte in der oben beschriebenen Weise.The exact procedure of the precursors of compounds XV and XVI is given directly in the compounds. The synthesis of the thioamide of these compounds was carried out in the manner described above.
Beispiel I: N-(2, 4, 6-Trifluorphenyl)-3, 5-dinitrobenzothioamid. Das Benzamid wird aus 3,5-Dinitrobenzoesäurechlorid (8,2 mmol, 1,84 g) und 2,4,6- Trifluoranilin (8 mmol, 1,606 g) hergestellt. Nach Umkristallisation aus Ethanol erhält man 1,91 g (70%) des Benzamids. Aus 1,70 g des Benzamids (5 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 30+1) erhält man 1,97 g (79%) des gewünschten Produktes. Fp: 223-225 °C. 1H-NMR (d6-DMSO, 200 MHz): δ 12,25 (s, IH, NH), 9,16-8,96 (m, 3H, Phenyl-H), 7,59-7,33 (m, 2H, Phenyl-H). 13C-NMR (d6-DMSO, 50 MHz): 195,3, 163,7, 159,8 (q, 1Jc1F = 29,1 Hz, 2Jc1F = 64,0 Hz), 155,1 (q, 1Jc1F = 29,1 Hz, 2Jc1F = 64,0 Hz), 147,8, 140,8, 127,6 120,9, 102,2-101,1 (m). MS m/z 357 (M+, 28%), 69 (100%).Example I: N- (2,4,6-trifluorophenyl) -3,5-dinitrobenzothioamide. The benzamide is prepared from 3,5-dinitrobenzoic acid chloride (8.2 mmol, 1.84 g) and 2,4,6-trifluoroaniline (8 mmol, 1.606 g). Recrystallization from ethanol gives 1.91 g (70%) of the benzamide. From 1.70 g of the benzamide (5 mmol), the benzothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 30 + 1), 1.97 g (79%) of the desired product are obtained. Mp: 223-225 ° C. 1 H NMR (d 6 -DMSO, 200 MHz): δ 12.25 (s, IH, NH), 9.16-8.96 (m, 3H, phenyl-H), 7.59-7.33 (m, 2H, phenyl-H). 13 C-NMR (d 6 -DMSO, 50 MHz): 195.3, 163.7, 159.8 (q, 1 Jc 1F = 29.1 Hz, 2 Jc 1F = 64.0 Hz), 155.1 (q, 1 Jc 1 F = 29.1 Hz, 2 Jc 1 F = 64.0 Hz), 147.8, 140.8, 127.6, 120.9, 102.2-101.1 (m). MS m / z 357 (M + , 28%), 69 (100%).
Beispiel II: N-(2, 3-Dimethylphenyl)-4-methoxybenzothioamid. Das Benzamid wird aus 4-Methoxybenzoylchlorid (11 mmol, 1,87 g) und 2,3- Dimethylanilin (11 mmol, 1,34 ml) hergestellt. Nach Umkristallisation aus Ethanol erhält man 1,34 g (48%) des Benzamids. Aus 1,275 g des Benzamids (5 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 20+1) erhält man 0,920 g (68%) des gewünschten Produktes. Fp: 150 °C. 1H-NMR (CDCl3, 200 MHz): δ 8,67 (s, breit, NH), 7,97-7,86 (m, 2H, Phenyl-H), 7,27-7,13 (m, 3H, Phenyl-H), 6,96-7,84 (m, 2H, Phenyl-H), 3,86 (s, 3H, OCH3), 2,33 (s, 3H, CH3), 2,19 (s, 3H, CH3).13C- NMR (CDCl3, 200 MHz): δ 193,0, 138,1, 129,6, 128,7, 126,0, 124,7, 113,6, 55,5, 20,4, 14,2. MS m/z 255 (M+, %).Example II: N- (2,3-dimethylphenyl) -4-methoxybenzothioamide. The benzamide is prepared from 4-methoxybenzoyl chloride (11 mmol, 1.87 g) and 2,3-dimethylaniline (11 mmol, 1.34 ml). Recrystallization from ethanol gives 1.34 g (48%) of the benzamide. From 1,275 g of the benzamide (5 mmol), the benzothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 20 + 1), 0.920 g (68%) of the desired product are obtained. Mp: 150 ° C. 1 H-NMR (CDCl 3 , 200 MHz): δ 8.67 (s, broad, NH), 7.97-7.86 (m, 2H, phenyl-H), 7.27-7.13 (m phenyl-H, 3H,), 6.96 to 7.84 (m, 2H, phenyl-H), 3.86 (s, 3H, OCH 3), 2.33 (s, 3H, CH 3), 2 , 19 (s, 3H, CH 3 ). 13 C-NMR (CDCl 3 , 200 MHz): δ 193.0, 138.1, 129.6, 128.7, 126.0, 124.7, 113.6, 55.5, 20.4, 14 ; 2. MS m / z 255 (M + ,%).
Beispiel III: N-(3, 4, 5-Trimethoxyphenyl)-3, 5-difluorbenzothioamid. Das Benzamid wird aus 3,5-Difluorbenzoylchlorid (10 mmol, 1,76 g) und 3,4,5- Trimethoxyanilin (10 mmol, 1,83 g) hergestellt. Nach Umkristallisation aus Ethanol erhält man 2,85 g (88%) des Benzamids. Aus 1,615 g des Benzamids (5 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 20+1) erhält man 1,06 g (63%) des gewünschten Produktes. Fp: 174-175 0C. 1H-NMR (CDCl3, 200 MHz): δ 9,05 (s, IH, NH), 7,41-7,25 (m, 2H, Phenyl-H), 7,09 (s, 2H, Phenyl- H), 7,07-6,85 (m, IH, Phenyl-H), 3,84 (s, 9H, OCH3). 13C-NMR (CDCl3, 50 MHz): δ 194,3, 162,8 (lJCf=250 Hz), 162,5 ('JcF=250 Hz), 153,2, 136,5, 134,4, 110,0 (JC,F = 26,7 Hz), 106,2 (t, JCF = 26,3 Hz), 100,8, 60,9, 56,2. MS m/z 339 (M+, 45%), 157 (100%).Example III: N- (3,4,5-Trimethoxyphenyl) -3,5-difluorobenzothioamide. The benzamide is prepared from 3,5-difluorobenzoyl chloride (10 mmol, 1.76 g) and 3,4,5-trimethoxyaniline (10 mmol, 1.83 g). Recrystallization from ethanol gives 2.85 g (88%) of the benzamide. The benzothioamide is prepared from 1.615 g of the benzamide (5 mmol). After purification by means of SC (mobile phase toluene / ethyl acetate = 20 + 1), 1.06 g (63%) of the desired product are obtained. Mp 174-175 0 C. 1 H-NMR (CDCl 3, 200 MHz): δ 9.05 (s, IH, NH), 7.41 to 7.25 (m, 2H, phenyl-H), 7 , 09 (s, 2H, phenyl-H), 7.07-6.85 (m, IH, phenyl-H), 3.84 (s, 9H, OCH 3 ). 13 C-NMR (CDCl 3, 50 MHz): δ 194.3, 162.8 ( 1 J Cf = 250 Hz), 162.5 ('Jc F = 250 Hz), 153.2, 136.5, 134.4, 110.0 (J C , F = 26.7 Hz) , 106.2 (t, J C F = 26.3 Hz), 100.8, 60.9, 56.2. MS m / z 339 (M + , 45%), 157 (100%).
Beispiel IV: N-(4-Methylthiophenyl)-3, 5-difluorbenzothioamid. Das Benzamid wird aus 3,5-Difluorbenzoylchlorid (10 mmol, 1,76 g) und 4- (Methylthio)anilin (10 mmol, 1,39 g) hergestellt. Nach Umkristallisation aus Ethanol erhält man 2,57 g (92%) des Benzamids. Aus 1,475 g des Benzamids (5 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 8+2) erhält man 0,58 g (39%) des gewünschten Produktes. Fp: 142-145 °C. 1H-NMR (CDCl3, 200 MHz): δ 8,92 (s, IH, NH), 7,71-7,65 (m, 2H, Phenyl-H), 7,43-7,20 (m, 4H, Phenyl-H), 7,05-6,84 (m, IH, Phenyl-H), 2,50 (s, 3H, SCH3). 13C-NMR (CDCl3, 50 MHz): δ 194,4, 162,4 (1yc,F=249 Hz), 162,1 (7^=249 Hz), 137,1, 136,4, 126,5, 124,2, 110,6 (JC;F = 26,3 Hz), 105,7 (t, Jc,F = 25,6 Hz), 15,7. MS m/z 295 (M+, 46%), 156 (100%).Example IV: N- (4-Methylthiophenyl) -3,5-difluorobenzothioamide. The benzamide is prepared from 3,5-difluorobenzoyl chloride (10 mmol, 1.76 g) and 4- (methylthio) aniline (10 mmol, 1.39 g). Recrystallization from ethanol gives 2.57 g (92%) of the benzamide. The benzothioamide is prepared from 1.475 g of the benzamide (5 mmol). After purification by means of SC (mobile phase toluene / ethyl acetate = 8 + 2), 0.58 g (39%) of the desired product are obtained. Mp: 142-145 ° C. 1 H-NMR (CDCl 3, 200 MHz): δ 8.92 (s, IH, NH), 7.71 to 7.65 (m, 2H, phenyl-H), 7.43 to 7.20 (m , 4H, phenyl-H), 7.05-6.84 (m, IH, phenyl-H), 2.50 (s, 3H, SCH 3 ). 13 C-NMR (CDCl 3, 50 MHz): δ 194.4, 162.4 (1 y c, F = 249 Hz), 162.1 (7 ^ = 249 Hz), 137.1, 136.4, 126.5, 124.2, 110.6 (J C, F = 26.3 Hz), 105.7 (t, Jc, F = 25.6 Hz), 15.7. MS m / z 295 (M + , 46%), 156 (100%).
Beispiel V: N-(4-Fluorphenyl)-3, 5-difluorbenzothioamid.Example V: N- (4-fluorophenyl) -3,5-difluorobenzothioamide.
Das Benzamid wird aus 3,5-Difluorbenzoylchlorid (10 mmol, 1,95 g) und 4-Fluoranilin (10 mmol, 1,11 g) hergestellt. Nach Umkristallisation aus Ethanol erhält man 2,33 g (93%) des Benzamids. Aus 1,255 g des Benzamids (5 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 20+1) erhält man 1,14 g (86%) des gewünschten Produktes. Fp: 136-139 0C. 1H-NMR (CDCl3, 200 MHz): δ 8,96 (s, IH, NH), 7,79-7,58 (m, 2H, Phenyl-H), 7,48-7,28 (m, 2H, Phenyl-H), 7,22-7,05 (m, 2H, Phenyl-H), 7,04-6,83 (m, IH, Phenyl-H). 13C-NMR (CDCl3, 50 MHz): δ 183,5, 162,8 (JC)F = 250,6 Hz), 162,5 (Jc,F = 250,9 Hz), 161,0 (JC,F = 248,0 Hz), 134,4 (JC>F = 3,3 Hz), 126,0 (JC>F = 8,4 Hz), 116,0 (Jc1F = 23,0 Hz), 110,0 (JC,F = 26,7 Hz), 106,4 (t, JC,F = 25,2 Hz). MS m/z 267 (M+, 28%), 157 (100%).The benzamide is prepared from 3,5-difluorobenzoyl chloride (10 mmol, 1.95 g) and 4-fluoroaniline (10 mmol, 1.11 g). Recrystallization from ethanol gives 2.33 g (93%) of the benzamide. From 1,255 g of the benzamide (5 mmol), the benzothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 20 + 1), 1.14 g (86%) of the desired product are obtained. Mp 136-139 0 C. 1 H-NMR (CDCl 3, 200 MHz): δ 8.96 (s, IH, NH), 7.79 to 7.58 (m, 2H, phenyl-H), 7 , 48-7.28 (m, 2H, phenyl-H), 7.22-7.05 (m, 2H, phenyl-H), 7.04-6.83 (m, IH, phenyl-H). 13 C-NMR (CDCl 3, 50 MHz): δ 183.5, 162.8 (J C) F = 250.6 Hz), 162.5 (JC, F = 250.9 Hz), 161.0 ( J C, F = 248.0 Hz), 134.4 (J C> F = 3.3 Hz), 126.0 (J C> F = 8.4 Hz), 116.0 (1F Jc = 23, 0 Hz), 110.0 (J C , F = 26.7 Hz), 106.4 (t, J C , F = 25.2 Hz). MS m / z 267 (M + , 28%), 157 (100%).
Beispiel VI: N-(3, 5-Dimethoxyphenyl)-(4-trifluormethoxy)benzothioamid. Das Benzamid wird aus 4-(Trifluormethoxy)benzoylchlorid (10 mmol, 2,24 g) und 3,5- Dimethoxyanilin (12 mmol, 1,84 g) hergestellt. Nach Umkristallisation aus 70%-igem Ethanol erhält man 2,34 g (68%) des Benzamids. Aus 1,705 g des Benzamids (5 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 20+1) erhält man 1,50 g (84%) des gewünschten Produktes. Fp: 100 °C. 1H-NMR (CDCl3, 200 MHz): δ 8,93 (s, IH, NH), 7,91-7,64 (m, 2H, Phenyl-H), 7,21 (s, 2H, Phenyl-H), 7,13- 6,85 (m, 2H, Phenyl-H), 6,38 (s, IH, Phenyl-H), 3,78 (s, 3H, OCH3). 13C-NMR (CDCl3, 50 MHz): δ 193,4, 160,9, 140,3, 128,4, 120,6, 101,5, 99,2, 55,4. MS m/z 357 (M+, 57%), 356 (100%). Beispiel VII: N-(4-Dimethylaminophenyl)-3, 5-difluorbenzothioamid. Das Benzamid wird aus 3,5-Difluorbenzoylchlorid (11 mmol, 1,94 g) und N,N-Dimethyl- 1,4-phenylendiamin (11 mmol, 1,50 g) hergestellt. Nach Umkristallisation aus Ethanol erhält man 1,52 g (50%) des Benzamids. Aus 1,380 g des Benzamids (5 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 20+1) erhält man 0,85 g (58%) des gewünschten Produktes. Fp: 116-117 °C. 1H-NMR (CDCl3, 200 MHz): δ 8,90 (s, IH, NH), 7,53 (A-Teil eines AB-Systems, JA,B = 8,9 Hz, 2H, Phenyl-H), 7,40-7,25 (m, 2H, Phenyl-H), 7,02-6,84 (m, IH, Phenyl-H), 6,71 (B-Teil eines AB-Systems, JA,B = 8,9 Hz, 2H, Phenyl-H), 2,98 (s, 6H, N(CH3)2). 13C-NMR (CDCl3, 50 MHz): δ 193,6, 162,7 (JC>F = 250,6 Hz), 162,5 (JC,F = 250,6 Hz), 149,4, 127,7, 124,9, 112,0, 110,3-109,7 (m), 105,9 (t, JC,F = 25,2 Hz), 40,5. MS m/z 292 (M+, 75%), 259 (100%).Example VI: N- (3,5-Dimethoxyphenyl) - (4-trifluoromethoxy) benzothioamide. The benzamide is prepared from 4- (trifluoromethoxy) benzoyl chloride (10 mmol, 2.24 g) and 3,5-dimethoxyaniline (12 mmol, 1.84 g). Recrystallization from 70% ethanol gives 2.34 g (68%) of the benzamide. The benzothioamide is prepared from 1.705 g of the benzamide (5 mmol). After purification by means of SC (mobile phase toluene / ethyl acetate = 20 + 1), 1.50 g (84%) of the desired product are obtained. Mp: 100 ° C. 1 H-NMR (CDCl 3 , 200 MHz): δ 8.93 (s, IH, NH), 7.91-7.64 (m, 2H, phenyl-H), 7.21 (s, 2H, phenyl -H), 7.13-6.85 (m, 2H, phenyl-H), 6.38 (s, IH, phenyl-H), 3.78 (s, 3H, OCH 3 ). 13 C-NMR (CDCl 3, 50 MHz): δ 193.4, 160.9, 140.3, 128.4, 120.6, 101.5, 99.2, 55.4. MS m / z 357 (M + , 57%), 356 (100%). Example VII: N- (4-Dimethylaminophenyl) -3,5-difluorobenzothioamide. The benzamide is prepared from 3,5-difluorobenzoyl chloride (11 mmol, 1.94 g) and N, N-dimethyl-1,4-phenylenediamine (11 mmol, 1.50 g). Recrystallization from ethanol gives 1.52 g (50%) of the benzamide. The benzothioamide is prepared from 1.380 g of the benzamide (5 mmol). After purification by means of SC (mobile phase toluene / ethyl acetate = 20 + 1), 0.85 g (58%) of the desired product are obtained. Mp: 116-117 ° C. 1 H-NMR (CDCl 3 , 200 MHz): δ 8.90 (s, IH, NH), 7.53 (A part of an AB system, J A , B = 8.9 Hz, 2H, phenyl) H), 7.40-7.25 (m, 2H, phenyl-H), 7.02-6.84 (m, IH, phenyl-H), 6.71 (B part of an AB system, J A , B = 8.9 Hz, 2H, phenyl-H), 2.98 (s, 6H, N (CH 3 ) 2 ). 13 C-NMR (CDCl 3, 50 MHz): δ 193.6, 162.7 (J C> F = 250.6 Hz), 162.5 (J C, F = 250.6 Hz), 149.4 , 127.7, 124.9, 112.0, 110.3-109.7 (m), 105.9 (t, J C , F = 25.2 Hz), 40.5. MS m / z 292 (M + , 75%), 259 (100%).
Beispiel VIII: N-(4-Methvlthiophenvl)-4-fluorbenzothioamid.Example VIII: N- (4-Methylthiophene) -4-fluorobenzothioamide.
Das Benzamid wird aus 4-Fluorbenzoylchlorid (10 mmol, 1,59 g) und 4-(Methylthio)anilin (10 mmol, 1,39 g) hergestellt. Nach Umkristallisation aus Ethanol erhält man 2,08 g (80%) des Benzamids. Aus 1,305 g des Benzamids (5 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 8+2) erhält man 0,780 g (56%) des gewünschten Produktes. Fp: 148-152 °C. 1H-NMR (CDCl3, 200 MHz): δ 8,95 (s, breit, IH, NH), 7,89-7,76 (m, 2H, Phenyl-H), 7,75-7,53 (m, 2H, Phenyl-H), 7,36-7,19 (m, 2H, Phenyl-H), 7,18-6,96 (m, 2H, Phenyl-H), 2,49 (s, 3H, SCH3). 13C-NMR (CDCl3, 50 MHz): δ 135,9, 129,0-128,8 (m), 126,7, 124,2, 115,5 (JCjF = 22,0 Hz), 15,7. MS m/z 277 (M+, 25%), 139 (100%).The benzamide is prepared from 4-fluorobenzoyl chloride (10 mmol, 1.59 g) and 4- (methylthio) aniline (10 mmol, 1.39 g). Recrystallization from ethanol gives 2.08 g (80%) of the benzamide. The benzothioamide is prepared from 1.305 g of the benzamide (5 mmol). After purification by means of SC (mobile phase toluene / ethyl acetate = 8 + 2), 0.780 g (56%) of the desired product are obtained. Mp: 148-152 ° C. 1 H-NMR (CDCl 3 , 200 MHz): δ 8.95 (s, broad, IH, NH), 7.89-7.76 (m, 2H, phenyl-H), 7.75-7.53 (m, 2H, phenyl-H), 7.36-7.19 (m, 2H, phenyl-H), 7.18-6.96 (m, 2H, phenyl-H), 2.49 (s, 3H, SCH 3 ). 13 C-NMR (CDCl 3, 50 MHz): δ 135.9, 129.0 to 128.8 (m), 126.7, 124.2, 115.5 (J = 22.0 Hz CJF), 15 , 7th MS m / z 277 (M + , 25%), 139 (100%).
Beispiel IX: N-(3, 5-Difluorphenyl)-4-fluorbenzothioamid.Example IX: N- (3,5-Difluorophenyl) -4-fluorobenzothioamide.
Das Benzamid wird aus 4-Fluorbenzoylchlorid (10 mmol, 1,76 g) und 3,5-Difluoranilin (10 mmol, 1,29 g) hergestellt. Nach Umkristallisation aus 70%-igem Ethanol erhält man 2,25 g (90%) des Benzamids. Aus 1,255 g des Benzamids (5 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 20+1) erhält man 0,84 g (63%) des gewünschten Produktes. Fp: 145 °C. 1H-NMR (CDCl3, 200 MHz): δ 8,93 (s, IH, NH), 7,83-7,76 (m, 2H, Phenyl-H), 7,40-7,37 (m, 2H, Phenyl-H), 7,10 (t, JH>H = 8,6 Hz, 2H, Phenyl-H), 6,97-6,68 (tt, JH;H = 8,6 Hz, JH)F = 2,3 Hz, IH, Phenyl-H). 13C-NMR (CDCl3, 50 MHz): δ 186,9, 164,7 (JC,F = 253,6 Hz), 163,0 (JC)F = 248,5 Hz), 162,8 (JC)F = 248,5 Hz), 148,8, 140,8, 129,0 (JC,F = 8,8 Hz), 115,8 (JC>F = 21,8 Hz), 106,5 (JC>F = 29,5 Hz), 102,2 (t, Jc,F = 25,5 Hz). MS m/z 267 (M+, 19%), 139 (100%).The benzamide is prepared from 4-fluorobenzoyl chloride (10 mmol, 1.76 g) and 3,5-difluoroaniline (10 mmol, 1.29 g). Recrystallization from 70% ethanol gives 2.25 g (90%) of the benzamide. From 1,255 g of the benzamide (5 mmol), the benzothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 20 + 1), 0.84 g (63%) of the desired product are obtained. Mp: 145 ° C. 1 H-NMR (CDCl 3 , 200 MHz): δ 8.93 (s, IH, NH), 7.83-7.76 (m, 2H, phenyl-H), 7.40-7.37 (m , 2H, phenyl-H), 7.10 (t, J H> H = 8.6 Hz, 2H, phenyl-H), 6.97-6.68 (tt, J H, H = 8.6 Hz , J H) F = 2.3 Hz, IH, phenyl-H). 13 C-NMR (CDCl 3 , 50 MHz): δ 186.9, 164.7 (J C, F = 253.6 Hz), 163.0 (J C) F = 248.5 Hz), 162.8 (J C) F = 248.5 Hz), 148.8, 140.8, 129.0 (J C, F = 8.8 Hz), 115.8 (J C> F = 21.8 Hz), 106.5 (J C> F = 29.5 Hz), 102.2 (t, Jc, F = 25.5 Hz). MS m / z 267 (M + , 19%), 139 (100%).
Beispiel X: N-(3, 4, 5-Tήmethoxyphenvl)-3,5-dinitrobenzothioamid. Das Benzamid wird aus 3,5-Dinitrobenzoylchlorid (10 mmol, 2,300 g) und 3,4,5- Trimethoxyanilin (10 mmol, 1,83 g) hergestellt. Nach Umkristallisation aus Ethanol erhält man 2,98 g (79%) des Benzamids. Aus 1,900 g des Benzamids (5 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 8+2) erhält man 1,70 g (86%) des gewünschten Produktes. Fp: 202-210 °C. 1H-NMR (CDCl3, 200 MHz): δ 11,58 (s, breit, IH, NH), 9,05 (s, 3H, Phenyl-H), 7,25 (s, 2H, Phenyl- H), 3,87 (s, 9H, OCH3). 13C-NMR (CDCl3, 50 MHz): δ 190,8, 152,8, 147,6, 145,3, 135,0, 127,5, 119,3, 101,0, 60,7, 56,0. MS m/z 393 (M+, 25%), 139 (100%).Example X: N- (3,4,5-Tήmethoxyphenvl) -3,5-dinitrobenzothioamide. The benzamide is prepared from 3,5-dinitrobenzoyl chloride (10 mmol, 2.300 g) and 3,4,5-trimethoxyaniline (10 mmol, 1.83 g). Recrystallization from ethanol gives 2.98 g (79%) of the benzamide. From 1,900 g of the benzamide (5 mmol), the benzothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 8 + 2), 1.70 g (86%) of the desired product are obtained. Mp: 202-210 ° C. 1 H-NMR (CDCl 3, 200 MHz): δ 11.58 (s, broad, IH, NH), 9.05 (s, 3H, phenyl-H), 7.25 (s, 2H, phenyl H ), 3.87 (s, 9H, OCH 3 ). 13 C-NMR (CDCl 3, 50 MHz): δ 190.8, 152.8, 147.6, 145.3, 135.0, 127.5, 119.3, 101.0, 60.7, 56 , 0th MS m / z 393 (M + , 25%), 139 (100%).
Beispiel XI: N-(2, 6-Dimethylphenyl)-3, 5-dimethoxybenzothioamid. Das Benzamid wird aus 3,5-Dimethoxybenzoylchlorid (10 mmol, 2,006 g) und 2,6- Dimethylanilin (10 mmol, 1,3 ml) hergestellt. Nach Umkristallisation aus Ethanol erhält man 1,35 g (47,4%) des Benzamids. Aus 1,351 g des Benzamids (4,74 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 8+2) erhält man 1,2 g (85,7%) des gewünschten Produktes. Fp: 114 0C. 1H-NMR (CDCl3, 200 MHz): δ 8,65 (s, IH, NH), 7,22-7,09 (m, 3H, Phenyl-H), 7,04 (d, JH>H=2,3 Hz, 2H, Phenyl-H), 6,62-6,53 (t, IH, Phenyl-H), 3,84 (s, 6H, OCH3), 2,28 (s, 6H, CH3). 13C-NMR (CDCl3, 50 MHz): δ 199,0, 160,7, 143,6, 136,1, 135,5, 128,4, 128,4, 104,9, 103,1, 55,6, 18,0. MS m/z 301 (M+, 13%), 286 (100%).Example XI: N- (2,6-dimethylphenyl) -3,5-dimethoxybenzothioamide. The benzamide is prepared from 3,5-dimethoxybenzoyl chloride (10 mmol, 2.006 g) and 2,6-dimethylaniline (10 mmol, 1.3 mL). Recrystallization from ethanol gives 1.35 g (47.4%) of the benzamide. From 1.351 g of the benzamide (4.74 mmol), the benzothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 8 + 2), 1.2 g (85.7%) of the desired product are obtained. Mp 114 0 C. 1 H-NMR (CDCl 3, 200 MHz): δ 8.65 (s, IH, NH), 7.22 to 7.09 (m, 3H, phenyl-H), 7.04 (d, J H> H = 2.3Hz, 2H, phenyl-H), 6.62-6.53 (t, IH, phenyl-H), 3.84 (s, 6H, OCH 3 ), 2 , 28 (s, 6H, CH 3 ). 13 C-NMR (CDCl 3, 50 MHz): δ 199.0, 160.7, 143.6, 136.1, 135.5, 128.4, 128.4, 104.9, 103.1, 55 , 6, 18,0. MS m / z 301 (M + , 13%), 286 (100%).
Beispiel XII: N-(2, 6-Dimethylphenyl)-3, 4, 5 -trimethoxy benzothioamid. Das Benzamid wird aus 3,4,5-Trimethoxybenzoylchlorid (15 mmol, 3,459 g) und 2,6- Dimethylanilin (15 mmol, 1,8 ml) hergestellt. Nach Umkristallisation aus Ethanol erhält man 2,14 g (45,2%) des Benzamids. Aus 1,828 g des Benzamids (5,8 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 8+2) erhält man 1,42 g (73,7%) des gewünschten Produktes. Fp: 209 °C. 1H-NMR (CDCl3, 200 MHz): δ 8,64 (s, IH, NH), 7,30-7,11 (m, 5H, Phenyl-H), 3,94 (s, 6H, OCH3), 3,89 (s, 3H, OCH3), 2,31 (s, 6H, CH3). 13C-NMR (CDCl3, 50 MHz): δ 198,7, 153,0, 137,1, 136,3, 135,5, 128,5, 128,4, 104,4, 60,9, 56,3, 18,1. MS m/z 331 (M+, 19%), 316 (100%).Example XII: N- (2,6-dimethylphenyl) -3,4,5-trimethoxybenzothioamide. The benzamide is prepared from 3,4,5-trimethoxybenzoyl chloride (15 mmol, 3.459 g) and 2,6-dimethylaniline (15 mmol, 1.8 ml). Recrystallization from ethanol gives 2.14 g (45.2%) of the benzamide. The benzothioamide is prepared from 1.828 g of the benzamide (5.8 mmol). After purification by means of SC (mobile phase toluene / ethyl acetate = 8 + 2), 1.42 g (73.7%) of the desired product are obtained. Mp: 209 ° C. 1 H-NMR (CDCl 3, 200 MHz): δ 8.64 (s, IH, NH), 7.30-7.11 (m, 5H, phenyl-H), 3.94 (s, 6H, OCH 3 ), 3.89 (s, 3H, OCH 3 ), 2.31 (s, 6H, CH 3 ). 13 C-NMR (CDCl 3, 50 MHz): δ 198.7, 153.0, 137.1, 136.3, 135.5, 128.5, 128.4, 104.4, 60.9, 56 , 3, 18,1. MS m / z 331 (M + , 19%), 316 (100%).
Beispiel XIII: N-Benzyl-3, 4, 5-trimethoxybenzothioamid.Example XIII: N-Benzyl-3,4,5-trimethoxybenzothioamide.
Das Benzamid wird aus 3,4,5-Trimethoxybenzoylchlorid (10 mmol, 2,3 g) und Benzylamin (10 mmol, 1,07 ml) hergestellt. Nach Umkristallisation aus Ethanol erhält man 2,02 g (67,12%) des Benzamids. Aus 1,726 g des Benzamids (5,73 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 8+2) erhält man 1,30 g (71,75%) des gewünschten Produktes. Fp: 122 0C. 1H-NMR (CDCl3, 200 MHz): δ 7,81 (s, IH, NH), 7,39 (s, 5H, Phenyl-H), 6,95 (s, 2H, Phenyl-H), 4,99 (d, JH,H =5,3 Hz, 2H, CH2), 3,85 (s, 6H, OCH3), 3,80 (s, 3H, OCH3). 13C-NMR (CDCl3, 50 MHz): δ 198,7, 152,8, 140,5, 137,4, 136,1, 128,9, 128,3, 128,1, 104,2, 60,7, 56,2, 51,0. MS m/z 317 (M+, 75%), 91 (100%).The benzamide is prepared from 3,4,5-trimethoxybenzoyl chloride (10 mmol, 2.3 g) and benzylamine (10 mmol, 1.07 ml). Recrystallization from ethanol gives 2.02 g (67.12%) of the benzamide. The benzothioamide is prepared from 1.726 g of the benzamide (5.73 mmol). After purification by means of SC (mobile phase toluene / ethyl acetate = 8 + 2), 1.30 g (71.75%) of the desired product are obtained. Mp 122 0 C. 1 H-NMR (CDCl 3, 200 MHz): δ 7.81 (s, IH, NH), 7.39 (s, 5H, phenyl-H), 6.95 (s, 2H , Phenyl-H), 4.99 (d, J H , H = 5.3 Hz, 2H, CH 2 ), 3.85 (s, 6H, OCH 3 ), 3.80 (s, 3H, OCH 3 ). 13 C-NMR (CDCl 3, 50 MHz): δ 198.7, 152.8, 140.5, 137.4, 136.1, 128.9, 128.3, 128.1, 104.2, 60 , 7, 56,2, 51,0. MS m / z 317 (M + , 75%), 91 (100%).
Beispiel XIV: N-(2,4-Dimethoxybenzyl)-3,4,5-trimethoxybenzothioamid. Das Benzamid wird aus 3,4,5-Trimethoxybenzoylchlorid (10 mmol, 2,31 g) und 2,4- Dimethoxybenzylamin (10 mmol, 1,67 g) hergestellt. Nach Umkristallisation aus Ethanol erhält man 1,873 g (51,88 %) des Benzamids. Aus 1,60 g des Benzamids (4,4 mmol) wird das Benzothioamid hergestellt. Nach Reinigung mittels SC (Laufinittel Toluol/ Ethylacetat = 6+4) erhält man 0,376 g (22,79 %) des gewünschten Produktes. Fp: 115 °C. 1H-NMR (CDCl3, 200 MHz): δ 7,95 (s, breit, IH, NH), 7,32 (d, JH,H=8,7 Hz, IH, Phenyl-H), 6,95 (s, 2H, Phenyl-H), 6,51-6,45 (m, 2H, Phenyl-H), 4,92 (d, JH,H=5,2 Hz, 2H, CH2), 3,87 (s, 6H, OCH3), 3,86 (s, 3H, OCH3), 3,84 (s, 3H, OCH3), 3,81 (s, 3H, OCH3). 13C-NMR (CDCl3, 50 MHz): δ 197,5,161,0, 158,7, 152,8, 140,4, 137,7, 131,5, 116,4, 104,2, 104,1, 98,7, 60,8, 56,2, 55,3, 46,7. MS m/z 377 (M+, 23%), 151 (100%).Example XIV: N- (2,4-dimethoxybenzyl) -3,4,5-trimethoxybenzothioamide. The benzamide is prepared from 3,4,5-trimethoxybenzoyl chloride (10 mmol, 2.31 g) and 2,4-dimethoxybenzylamine (10 mmol, 1.67 g). Recrystallization from ethanol gives 1.873 g (51.88%) of the benzamide. From 1.60 g of the benzamide (4.4 mmol), the benzothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 6 + 4), 0.376 g (22.79%) of the desired product are obtained. Mp: 115 ° C. 1 H-NMR (CDCl 3 , 200 MHz): δ 7.95 (s, broad, IH, NH), 7.32 (d, J H , H = 8.7 Hz, IH, phenyl-H), 6 , 95 (s, 2H, phenyl-H), 6.51-6.45 (m, 2H, phenyl-H), 4.92 (d, J H, H = 5.2 Hz, 2H, CH 2 ) , 3.87 (s, 6H, OCH 3), 3.86 (s, 3H, OCH 3), 3.84 (s, 3H, OCH 3), 3.81 (s, 3H, OCH 3). 13 C-NMR (CDCl 3, 50 MHz): δ 197,5,161,0, 158.7, 152.8, 140.4, 137.7, 131.5, 116.4, 104.2, 104.1 , 98.7, 60.8, 56.2, 55.3, 46.7. MS m / z 377 (M + , 23%), 151 (100%).
Beispiel XV: N-(2,4-Dimethoxvbenzvl)-2-(3,4-dimethoxyphenyl)acetthioamid. 3,4-Dimethoxyphenylessigsäure (10 mmol, 1,96 g) und 1 ml Thionylchlorid werden in einem trockenen Kolben 92 Stunden bei Raumtemperatur gerührt und anschließend bei 35°C an das Wasserstrahlvakuum angehängt. Ist kein Thionylchlorid mehr vorhanden, werden 8 ml abs. Dioxan und 2,4-Dimethoxybenzylamin (10 mmol, 1,5 ml) zugegeben. Nach Umkristallisation aus 40% Ethanol erhält man 0,489 g (14,17 %) des Acetamids. Aus 0,40 g des Acetamids (1,15 mmol) wird das Acetthioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 7+3) erhält man 0,173 g (43,25%) des gewünschten Produktes. Fp: 98 °C. 1H-NMR (CDCl3, 200 MHz): δ 7,63 (s, breit, IH, NH), 7,25-7,12 (m, IH, Phenyl-H), 6,84 (d, JH,H = 8,0 Hz, IH, Phenyl-H), 6,80-6,65 (m, 2H, Phenyl-H), 6,45- 6,34 (m, 2H, Phenyl-H), 4,74 (d, JH,H=5,4 Hz, 2H, CH2), 4,07 (s, 2H, CH2), 3,88 (s, 6H, OCH3), 3,80 (s, 3H, OCH3), 3,78 (s, 3H, OCH3), 3,58 (s, 3H, OCH3). 13C-NMR (CDCl3, 50 MHz): δ 200,7, 160,8, 158,4, 149,3, 148,5, 131,0, 127,0, 122,0, 116,3, 112,4, 111,3, 103,8, 98,4, 55,9, 55,8, 55,3, 54,9, 52,6, 46,1. MS m/z 361 (M+, 20%), 151 (100%).Example XV: N- (2,4-Dimethoxybenzyl) -2- (3,4-dimethoxyphenyl) acetothioamide. 3,4-Dimethoxyphenylacetic acid (10 mmol, 1.96 g) and 1 ml of thionyl chloride are stirred in a dry flask for 92 hours at room temperature and then added at 35 ° C to the water jet vacuum. If no more thionyl chloride is present, 8 ml of abs. Dioxane and 2,4-dimethoxybenzylamine (10mmol, 1.5ml). Recrystallization from 40% ethanol gives 0.489 g (14.17%) of the acetamide. From 0.40 g of the acetamide (1.15 mmol), the acetothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 7 + 3), 0.173 g (43.25%) of the desired product are obtained. Mp: 98 ° C. 1 H-NMR (CDCl 3 , 200 MHz): δ 7.63 (s, broad, IH, NH), 7.25-7.12 (m, IH, phenyl-H), 6.84 (d, J H , H = 8.0 Hz, IH, phenyl-H), 6.80-6.65 (m, 2H, phenyl-H), 6.45-6.34 (m, 2H, phenyl-H), 4.74 (d, J H , H = 5.4 Hz, 2H, CH 2 ), 4.07 (s, 2H, CH 2 ), 3.88 (s, 6H, OCH 3 ), 3.80 ( s, 3H, OCH 3 ), 3.78 (s, 3H, OCH 3 ), 3.58 (s, 3H, OCH 3 ). 13 C-NMR (CDCl 3, 50 MHz): δ 200.7, 160.8, 158.4, 149.3, 148.5, 131.0, 127.0, 122.0, 116.3, 112 , 4, 111.3, 103.8, 98.4, 55.9, 55.8, 55.3, 54.9, 52.6, 46.1. MS m / z 361 (M + , 20%), 151 (100%).
Beispiel XVI: N-(2, 4-Dimethoxybenzyl)-2-(4-methoxyphenyl)acetthioamid. 4-Methoxyphenylessigsäure (10 mmol, 1,66 g) und 1 ml Thionylchlorid werden in einem trockenen Kolben 2 Stunden unter Rückfluss erhitzt und anschließend bei 35°C an das Wasserstrahlvakuum angehängt. Ist kein Thionylchlorid mehr vorhanden, werden 8 ml abs. Dioxan, 2,4-Dimethoxybenzylamin (10 mmol, 1,5 ml) und Triethylamin (10 mmol, 1,01 ml) zugegeben. Nach Umkristallisation aus Ethanol erhält man 1,485 g (47,14 %) des Acetamids. Aus 0,85 g des Acetamids (2,6 mmol) wird das Acetthioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 8+2) erhält man 0,322 g (37,44%) des gewünschten Produktes. Fp: 71 0C. 1H-NMR (CDCl3, 200 MHz): δ 7,61 (s, IH, NH), 7,30-7,06 (m, 4H, Phenyl-H), 6,93-6,83 (m, 2H, Phenyl-H), 6,45-6,34 (m, 2H, Phenyl-H), 4,73 (d, JH,H=5,4 Hz, 2H, CH2), 4,06 (s, 2H, CH2), 3,80 (s, 3H, OCH3), 3,78 (s, 3H, OCH3), 3,59 (s, 3H, OCH3). 13C-NMR (CDCl3, 50 MHz): δ 200,9, 160,8, 159,0 158,4, 131,0, 130,8, 126,6, 116,3, 114,3, 103,8, 98,5, 55,3, 55,2, 55,0, 52,1, 46,2, 39,2. MS m/z 331 (M+, 31%), 151 (100%).Example XVI: N- (2,4-Dimethoxybenzyl) -2- (4-methoxyphenyl) acetothioamide. 4-Methoxyphenylacetic acid (10 mmol, 1.66 g) and 1 ml of thionyl chloride are heated in a dry flask for 2 hours under reflux and then attached at 35 ° C to the water jet vacuum. If no more thionyl chloride is present, 8 ml of abs. Dioxane, 2,4-dimethoxybenzylamine (10mmol, 1.5ml) and triethylamine (10mmol, 1.01ml). Recrystallization from ethanol gives 1.485 g (47.14%) of the Acetamide. From 0.85 g of the acetamide (2.6 mmol), the acetothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 8 + 2), 0.322 g (37.44%) of the desired product are obtained. Mp: 71 0 C. 1 H-NMR (CDCl 3, 200 MHz): δ 7.61 (s, IH, NH), 7.30 to 7.06 (m, 4H, phenyl-H), 6.93 -6.83 (m, 2H, phenyl-H), 6.45-6.34 (m, 2H, phenyl-H), 4.73 (d, J H , H = 5.4 Hz, 2H, CH 2 ), 4.06 (s, 2H, CH 2 ), 3.80 (s, 3H, OCH 3 ), 3.78 (s, 3H, OCH 3 ), 3.59 (s, 3H, OCH 3 ) , 13 C-NMR (CDCl 3, 50 MHz): δ 200.9, 160.8, 159.0 158.4, 131.0, 130.8, 126.6, 116.3, 114.3, 103, 8, 98.5, 55.3, 55.2, 55.0, 52.1, 46.2, 39.2. MS m / z 331 (M + , 31%), 151 (100%).
Allgemeine Arbeitsvorschrift für Beispiel XVII - XXII:General Procedure for Example XVII - XXII:
5 mmol Anilinderivat werden in 20 ml 2N NaOH suspendiert/ emulgiert und mit 5,3 mmol des Thiophensäurechlorids versetzt und in einem Scheidetrichter 15 Minuten gut durchgeschüttelt. Der entstandene Niederschlag wird abgenutscht und in einem geeigneten Alkohol umkristallisiert. In einem trockenen Dreihalskolben werden 4 mmol des erhaltenen Benzamids in absolutem THF gelöst und 3,44 mmol (1,39 g) Lawesson's Reagenz zugegeben. Die Mischung wird mit einem Trockenrohr so lange refluxiert, bis keine weitere Umsetzung mehr mittels DC erkennbar ist. Anschließend wird das THF abrotiert und das Rohprodukt mittels präparativer Säulenchromatographie gereinigt und in einem geeigneten Alkohol umkristallisiert.5 mmol of aniline derivative are suspended / emulsified in 20 ml of 2N NaOH and admixed with 5.3 mmol of thiophene chloride and thoroughly shaken in a separating funnel for 15 minutes. The resulting precipitate is filtered off with suction and recrystallized in a suitable alcohol. In a dry three-necked flask, dissolve 4 mmol of the resulting benzamide in absolute THF and add 3.43 mmol (1.39 g) of Lawesson's reagent. The mixture is refluxed with a drying tube until no further reaction is recognizable by means of TLC. The THF is then removed by rotary evaporation and the crude product is purified by preparative column chromatography and recrystallized in a suitable alcohol.
Beispiel XVII: N-(3, 4, 5-Trimethoxyphenyl)-2-thiophencarbothioamid. Das 2-Thiophencarbamid wird aus Thiophen-2-carbonsäurechlorid (5,3 mmol, 0,57 ml) und 3,4,5-Trimethoxyanilin (5 mmol, 0,92 g) hergestellt. Nach Umkristallisation aus 70 % Ethanol erhält man 1,45 g (99,1 %) des 2-Thiophencarbamids. Aus 1,26 g des 2- Thiophencarbamids (4,3 mmol) wird das 2-Thiophencarbothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 6+4) und Umkristallisation aus Methanol erhält man 0,771 g (58,0 %) des gewünschten Produktes. Fp: 105-107 °C. 1H- NMR (d6-DMSO, 200 MHz): δ 11,44 (s, breit, IH, NH), 7,94-7,79 (m, 2H, aromat. H), 7,30- 7,10 (m, 3H, aromat. H), 3,77 (s, 6H, OCH3), 3,68 (s, 3H, OCH3). 13C-NMR (dό-DMSO, 50 MHz): δ 186,4, 152,7 (2C), 148,6, 135,8, 135,5, 135,0, 128,4, 125,0, 102,7 (2C), 60,3, 56,2 (2C). MS m/z 309 (M+, 20%), 127 (100%).Example XVII: N- (3,4,5-trimethoxyphenyl) -2-thiophenecarbothioamide. The 2-thiophenecarbamide is prepared from thiophene-2-carboxylic acid chloride (5.3 mmol, 0.57 ml) and 3,4,5-trimethoxyaniline (5 mmol, 0.92 g). Recrystallization from 70% ethanol gives 1.45 g (99.1%) of 2-thiophenecarbamide. From 1.26 g of the 2-thiophenecarbamide (4.3 mmol), the 2-thiophenecarbothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 6 + 4) and recrystallization from methanol, 0.771 g (58.0%) of the desired product are obtained. Mp: 105-107 ° C. 1 H NMR (d 6 -DMSO, 200 MHz): δ 11.44 (s, broad, IH, NH), 7.94-7.79 (m, 2H, aromat. H), 7.30-7 , 10 (m, 3H, aromatic H), 3.77 (s, 6H, OCH 3 ), 3.68 (s, 3H, OCH 3 ). 13 C-NMR (d ό -DMSO, 50 MHz): δ 186.4, 152.7 (2C), 148.6, 135.8, 135.5, 135.0, 128.4, 125.0, 102.7 (2C), 60.3, 56.2 (2C). MS m / z 309 (M + , 20%), 127 (100%).
Beispiel XVIII: N-(4-Methvlthiovhenvl)-2-thiovhencarbothioamid.Example XVIII: N- (4-methylthiovhenvl) -2-thiovhenecarbothioamide.
Das 2-Thiophencarbamid wird aus Thiophen-2-carbonsäurechlorid (5,3 mmol, 0,57 ml) und 4-Methylthioanilin (5 mmol, 0,61 ml) hergestellt. Nach Umkristallisation aus 70 % Ethanol erhält man 1,138 g (91,4 %) des 2-Thiophencarbamids. Aus 0,67 g des 2-Thiophencarbamids (2,7 mmol) wird das 2-Thiophencarbothioamid hergestellt. Nach Reinigung mittels SC (Laufinittel Toluol/ Ethylacetat = 20+1) und Umkristallisation aus 70 % Ethanol erhält man 0,506 g (70,6 %) des gewünschten Produktes. Fp: 136-138 °C. 1H-NMR Cd6-DMSO, 200 MHz): δ 11,50 (s, breit, IH, NH), 7,90-7,58 (m, 4H, aromat. H), 7,38-7,10 (m, 3H, aromat. H), 2,50 (s, 3H, SCH3). 13C-NMR (d6-DMSO, 50 MHz): δ 186,6, 148,4, 136,7, 136,3, 135,0, 128,4, 126,0 (2C), 125,7 (2C), 125,2, 15,0. MS m/z 265 (M+, 24%), 127 (100%).The 2-thiophenecarbamide is prepared from thiophene-2-carboxylic acid chloride (5.3 mmol, 0.57 ml) and 4-methylthioaniline (5 mmol, 0.61 ml). Recrystallization from 70% ethanol gives 1.138 g (91.4%) of 2-thiophenecarbamide. From 0.67 g of 2-thiophenecarbamide (2.7 mmol), the 2-thiophenecarbothioamide is prepared. After cleaning by SC (Running toluene / ethyl acetate = 20 + 1) and recrystallization from 70% ethanol to obtain 0.506 g (70.6%) of the desired product. Mp: 136-138 ° C. 1 H-NMR Cd 6 -DMSO, 200 MHz): δ 11.50 (s, broad, IH, NH), 7.90-7.58 (m, 4H, aromat. H), 7.38-7, 10 (m, 3H, aromatic H), 2.50 (s, 3H, SCH 3 ). 13 C-NMR (d 6 -DMSO, 50 MHz): δ 186.6, 148.4, 136.7, 136.3, 135.0, 128.4, 126.0 (2C), 125.7 ( 2C), 125.2, 15.0. MS m / z 265 (M + , 24%), 127 (100%).
Beispiel XIX: N-(2, 3-Dimethylphenyl)-2-thiophencarbothioamid.Example XIX: N- (2,3-dimethylphenyl) -2-thiophenecarbothioamide.
Das 2-Thiophencarbamid wird aus Thiophen-2-carbonsäurechlorid (5,3 mmol, 0,57 ml) und 2,3-Dimethylanilin (5 mmol, 0,61 ml) hergestellt. Nach Umkristallisation aus Ethanol erhält man 0,99 g (85,5 %) des 2-Thiophencarbamids. Aus 0,972 g des 2-Thiophencarbamids (4,2 mmol) wird das 2-Thiophencarbothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 9+1) und Umkristallisation aus Ethanol erhält man 0,918 g (88,4 %) des gewünschten Produktes. Fp: 146-147,5 °C. 1H-NMR (d6-DMSO, 200 MHz): δ 11,43 (s, IH, NH), 7,99-7,77 (m, 2H, aromat. H), 7,30-7,00 (m, 4H, aromat. H), 2,29 (s, 3H, CH3), 2,08 (s, 3H, CH3). 13C-NMR (d6-DMSO, 50 MHz): δ 187,8, 147,4, 138,5, 137,6, 134,7, 133,7, 129,1, 128,5, 125,9, 125,6, 125,0, 20,2, 14,2. MS m/z 247 (M+, 14%), 232 (100%).The 2-thiophenecarbamide is prepared from thiophene-2-carboxylic acid chloride (5.3 mmol, 0.57 ml) and 2,3-dimethylaniline (5 mmol, 0.61 ml). Recrystallization from ethanol gives 0.99 g (85.5%) of 2-thiophenecarbamide. From 0.972 g of the 2-thiophenecarbamide (4.2 mmol), the 2-thiophenecarbothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 9 + 1) and recrystallization from ethanol, 0.918 g (88.4%) of the desired product are obtained. Mp: 146-147.5 ° C. 1 H NMR (d 6 -DMSO, 200 MHz): δ 11.43 (s, IH, NH), 7.99-7.77 (m, 2H, aromat. H), 7.30-7.00 (m, 4H, aromat H), 2.29 (s, 3H, CH 3 ), 2.08 (s, 3H, CH 3 ). 13 C NMR (d 6 -DMSO, 50 MHz): δ 187.8, 147.4, 138.5, 137.6, 134.7, 133.7, 129.1, 128.5, 125.9 , 125.6, 125.0, 20.2, 14.2. MS m / z 247 (M + , 14%), 232 (100%).
Beispiel XX: N-(4-Fluorphenyl)-2-thiophencarbothioamid.Example XX: N- (4-fluorophenyl) -2-thiophenecarbothioamide.
Das 2-Thiophencarbamid wird aus Thiophen-2-carbonsäurechlorid (5,6 mmol, 0,60 ml) und 4-Fluoranilin (5,3 mmol, 0,50 ml) hergestellt. Nach Umkristallisation aus 70 % Ethanol erhält man 1,238 g (99,92 %) des 2-Thiophencarbamids. Aus 1,005 g des 2- Thiophencarbamids (4,5 mmol) wird das 2-Thiophencarbothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 20+1) und Umkristallisation aus 70 % Ethanol erhält man 0,501 g (46,9 %) des gewünschten Produktes. Fp: 153-154 0C. 1H- NMR (d6-DMSO, 200 MHz): δ 11,54 (s, IH, NH), 7,97-7,80 (m, 2H, aromat. H), 7,78-7,60 (m, 2H, aromat. H), 7,39-7,17 (m, 3H, aromat. H). 13C-NMR (de-DMSO, 50 MHz): δ 187,2, 160,2 ('^=244 Hz), 148,1, 136,0 (4JC,F=3 Hz), 135,1, 128,5, 127,6 (3Jc,F=8 Hz), 125,3, 115,5 (2Jc,F=23 Hz). MS m/z 237 (M+, 39%), 127 (100%).The 2-thiophenecarbamide is prepared from thiophene-2-carboxylic acid chloride (5.6 mmol, 0.60 ml) and 4-fluoroaniline (5.3 mmol, 0.50 ml). After recrystallization from 70% ethanol, 1.238 g (99.92%) of 2-thiophenecarbamide are obtained. From 1.005 g of the 2-thiophenecarbamide (4.5 mmol), the 2-thiophenecarbothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 20 + 1) and recrystallization from 70% ethanol, 0.501 g (46.9%) of the desired product are obtained. Mp 153-154 0 C. 1 H NMR (d 6 -DMSO, 200 MHz): δ 11.54 (s, IH, NH), 7.97 to 7.80 (m, 2H, aromat. H) , 7.78-7.60 (m, 2H, aromat. H), 7.39-7.17 (m, 3H, aromat. H). 13 C-NMR (de-DMSO, 50 MHz): δ 187.2, 160.2 ('^ = 244 Hz), 148.1, 136.0 ( 4 J C , F = 3 Hz), 135.1 , 128.5, 127.6 ( 3 Jc, F = 8 Hz), 125.3, 115.5 ( 2 Jc, F = 23 Hz). MS m / z 237 (M + , 39%), 127 (100%).
Beispiel XXI: N-(3, 5-Dimethoxyphenyl)-2-thiophencarbothioamid.Example XXI: N- (3,5-dimethoxyphenyl) -2-thiophenecarbothioamide.
Das 2-Thiophencarbamid wird aus Thiophen-2-carbonsäurechlorid (5,3 mmol, 0,57 ml) und 3,5-Dimethoxyanilin (5 mmol, 0,77 g) hergestellt. Nach Umkristallisation aus 70 % Ethanol erhält man 0,67 g (50,7 %) des 2-Thiophencarbamids. Aus 0,584 g des 2-Thiophencarbamids (2,2 mmol) wird das 2-Thiophencarbothioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 20+1) und Umkristallisation aus 80 % Ethanol erhält man 0,577 g (93,9 %) des gewünschten Produktes. Fp: 110-111 0C. 1H-NMR (d6-DMSO, 200 MHz): δ 11,44 (s, IH, NH), 8,10-7,79 (m, 2H, aromat. H), 7,34-7,19 (m, IH, aromat. H), 7,15-6,98 (m, 2H, aromat. H) 6,54-6,40 (m, IH, aromat. H), 3,76 (s, 6H, OCH3). 13C-NMR Cd6-DMSO, 50 MHz): δ 186,8, 160,4 (2C), 148,7, 141,3, 135,2, 128,5, 125,2, 103,2 (2C), 98,5, 55,6 (2C). MS m/z 279 (M+, 27%), 127 (100%).The 2-thiophenecarbamide is prepared from thiophene-2-carboxylic acid chloride (5.3 mmol, 0.57 ml) and 3,5-dimethoxyaniline (5 mmol, 0.77 g). Recrystallization from 70% ethanol gives 0.67 g (50.7%) of 2-thiophenecarbamide. From 0.584 g of the 2-thiophenecarbamide (2.2 mmol), the 2-thiophenecarbothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 20 + 1) and recrystallization from 80% ethanol, 0.577 g (93.9%) of the desired product are obtained. Mp 110-111 0 C. 1 H-NMR (d 6 -DMSO, 200 MHz): δ 11.44 (s, IH, NH), 8.10-7.79 (m, 2H, aromatic H), 7.34-7.19 (m, IH, aromatic H), 7 , 15-6.98 (m, 2H, aromatic H) 6.54-6.40 (m, IH, aromat H), 3.76 (s, 6H, OCH 3 ). 13 C NMR Cd 6 -DMSO, 50 MHz): δ 186.8, 160.4 (2C), 148.7, 141.3, 135.2, 128.5, 125.2, 103.2 (2C ), 98.5, 55.6 (2C). MS m / z 279 (M + , 27%), 127 (100%).
Beispiel XXII: N-(3, 5-Difluorphenyl)-2-thiophencarbothioamid.Example XXII: N- (3,5-Difluorophenyl) -2-thiophenecarbothioamide.
Das 2-Thiophencarbamid wird aus Thiophen-2-carbonsäurechlorid (5,3 mmol, 0,57 ml) und 3,5-Difluoranilin (5 mmol, 0,65 g) hergestellt. Nach Umkristallisation aus 70 % Ethanol erhält man 0,94 g (78,8 %) des 2-Thiophencarbamids. Aus 0,844 g des 2-Thiophencarbamids (3,5 mmol) wird das 2-Thiophencarbothioamid hergestellt. Nach Reinigung mittels SC (Laufinittel Toluol/ Ethylacetat = 20+1) und Umkristallisation aus 80 % Ethanol erhält man 0,273 g (30,6 %) des gewünschten Produktes. Fp: 151-155 °C. 1H-NMR (d6-DMSO, 200 MHz): δ 11,64 (s, IH, NH), 8,00-7,80 (m, 2H, aromat. H), 7,75-7,50 (m, 2H, aromat. H), 7,35-7,07 (m, 2H, aromat. H). 13C-NMR (d6-DMSO, 50 MHz): δ 187,7, 162,3 ?JCjr2M Hz), 162,0 (1JCI^M Hz), 148,3, 142,1 (3Jc,F=13 Hz), 135,8, 128,5, 125,9, 108,0 (2JClF=29 Hz, 4Jc,F=6 Hz, 2C), 101,8 (2JC;F=26 Hz). MS m/z 255 (M+, 25%), 127 (100%).The 2-thiophenecarbamide is prepared from thiophene-2-carboxylic acid chloride (5.3 mmol, 0.57 ml) and 3,5-difluoroaniline (5 mmol, 0.65 g). Recrystallization from 70% ethanol gives 0.94 g (78.8%) of 2-thiophenecarbamide. From 0.844 g of the 2-thiophenecarbamide (3.5 mmol), the 2-thiophenecarbothioamide is prepared. After purification by means of SC (mobile phase toluene / ethyl acetate = 20 + 1) and recrystallization from 80% ethanol, 0.273 g (30.6%) of the desired product are obtained. Mp: 151-155 ° C. 1 H-NMR (d 6 -DMSO, 200 MHz): δ 11.64 (s, IH, NH), 8.00-7.80 (m, 2H, aromat. H), 7.75-7.50 (m, 2H, aromatic H), 7.35-7.07 (m, 2H, aromatic H). 13 C-NMR (d 6 -DMSO, 50 MHz): δ 187.7, 162.3 J C jr 2 M Hz), 162.0 ( 1 J CI ^ M Hz), 148.3, 142.1 ( 3 Jc , F = 13 Hz), 135.8, 128.5, 125.9, 108.0 ( 2 J ClF = 29 Hz, 4 Jc, F = 6 Hz, 2C), 101.8 ( 2 J C; F = 26 Hz). MS m / z 255 (M + , 25%), 127 (100%).
Allgemeine Arbeitsvorschrift für Beispiel XXIII - XXVII:General procedure for example XXIII - XXVII:
10 mmol Anilinderivat werden in einem trockenen Dreihalskolben in absolutem THF gelöst und mit 10 mmol des Nicotinsäurechlorids sowie 20 mmol Triethylamin versetzt. Die Mischung wird mit einem Trockenrohr so lange refluxiert, bis keine weitere Umsetzung mehr mittels DC erkennbar ist. Anschließend wird das Lösungsmittel abrotiert, das Rohprodukt zunächst mit 2N NaOH angelöst und gegen Ethylacetat ausgeschüttelt. Die vereinten organischen Phasen werden hierauf mit 2N NaOH und Wasser gewaschen und anschließend das Lösungsmittel im Vakuum entfernt. Der so erhaltene Rückstand wird umkristallisiert. In einem trockenen Dreihalskolben werden 5 mmol des erhaltenen Benzamids in absolutem THF gelöst und 4 mmol (1,61 g) Lawesson's Reagenz zugegeben. Die Mischung wird mit einem Trockenrohr so lange refluxiert, bis keine weitere Umsetzung mehr mittels DC erkennbar ist. Anschließend wird das THF abrotiert, das Rohprodukt mittels präparativer Säulenchromatographie gereinigt und umkristallisiert.10 mmol aniline derivative are dissolved in a dry three-necked flask in absolute THF and treated with 10 mmol of nicotinic acid chloride and 20 mmol of triethylamine. The mixture is refluxed with a drying tube until no further reaction is recognizable by means of TLC. The solvent is then removed by rotary evaporation, the crude product is first dissolved with 2N NaOH and shaken out against ethyl acetate. The combined organic phases are then washed with 2N NaOH and water and then the solvent is removed in vacuo. The residue thus obtained is recrystallized. In a dry three-necked flask, dissolve 5 mmol of the resulting benzamide in absolute THF and add 4 mmol (1.61 g) of Lawesson's reagent. The mixture is refluxed with a drying tube until no further reaction is recognizable by means of TLC. Subsequently, the THF is spun off, the crude product purified by preparative column chromatography and recrystallized.
Beispiel XXIII: N-(3,4,5-Trimethoxyphenyl)-thionicotinamid.Example XXIII: N- (3,4,5-trimethoxyphenyl) -thionicotinamide.
Das Nicotinamid wird aus Nicotinsäurehydrochlorid (13 mmol, 2,61 g), Triethylamin (20 mmol, 1,78 ml) und 3,4,5-Trimethoxyanilin (10 mmol, 1,83 g) hergestellt. Nach Umkristallisation aus 30% Ethanol erhält man 2,41 g (83,5 %) des Nicotinamids. Aus 1,026 g des Nicotinamids (4,5 mmol) wird das Nicotinthioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Ethylacetat) und Umkristallisation in Ethanol erhält man 0,253 g (18,5 %) des gewünschten Produktes. Fp: 190-191 °C. 1H-NMR Cd6-DMSO, 200 MHz): δ 11,93 (s, IH, NH), 8,92 (d, JH,H=1,9 Hz, IH, aromat. H), 8,70-8,67 (m, IH, aromat. H), 8,17- 8,11 (m, IH, aromat. H), 7,39 (s, 2H, aromat. H), 3,77 (s, 6H, OCH3), 3,69 (s, 3H, OCH3). 13C-NMR (d6-DMSO, 50 MHz): δ 193,9, 152,5 (2C), 151,2, 147,5, 138,7, 135,7, 135,6, 135,1, 123,1, 101,4 (2C), 60,2, 56,0 (2C). MS m/z 304 (M+, 67%), 122 (100%).The nicotinamide is prepared from nicotinic acid hydrochloride (13 mmol, 2.61 g), triethylamine (20 mmol, 1.78 ml) and 3,4,5-trimethoxyaniline (10 mmol, 1.83 g). After recrystallization from 30% ethanol, 2.41 g (83.5%) of the nicotinamide are obtained. The nicotinethioamide is prepared from 1.026 g of the nicotinamide (4.5 mmol). After purification by means of SC (eluent ethyl acetate) and recrystallization in ethanol, 0.253 g are obtained (18.5%) of the desired product. Mp: 190-191 ° C. 1 H-NMR Cd 6 -DMSO, 200 MHz): δ 11.93 (s, IH, NH), 8.92 (d, J H , H = 1.9 Hz, IH, aromat. H), 8, 70-8.67 (m, IH, aromatic H), 8.17-8.11 (m, IH, aromatic H), 7.39 (s, 2H, aromatic H), 3.77 (s , 6H, OCH 3 ), 3.69 (s, 3H, OCH 3 ). 1 3 C NMR (d 6 -DMSO, 50 MHz): δ 193.9, 152.5 (2C), 151.2, 147.5, 138.7, 135.7, 135.6, 135.1 , 123.1, 101.4 (2C), 60.2, 56.0 (2C). MS m / z 304 (M + , 67%), 122 (100%).
Beispiel XXIV: N-(4-Methvlthiophenyl)-thionicotinamid.Example XXIV: N- (4-methylthiophenyl) -thionicotinamide.
Das Nicotinamid wird aus Nicotinsäurehydrochlorid (6,5 mmol, 1,16 g), Triethylamin (10 mmol, 1,39 ml) und 4-Methylthioanilin (5 mmol, 0,62 ml) hergestellt. Nach Umkristallisation aus 50% Ethanol erhält man 0,942 g (67,0 %) des Nicotinamids. Aus 1,10 g des Nicotinamids (4,4 mmol) wird das Nicotinthioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Ethylacetat) und Umkristallisation in 50 % Ethanol erhält man 0,474 g (46,19 %) des gewünschten Produktes. Fp: 140-141 °C. 1H-NMR (d6-DMSO, 200 MHz): δ 11,64 (s, IH, NH), 8,62 (d, JH,H=1,3 Hz, IH, aromat. H), 8,40-8,34 (m, IH, aromat. H), 7,85- 7,81 (m, IH, aromat. H), 7,50 (A-Teil eines AB-Systems, d, JA,B=8,6 Hz, 2H, aromat. H), 7,20-7,14 (m, IH, aromat. H), 7,01 (B-Teil eines AB-Systems, d, JA)B=8,6 Hz, 2H, aromat. H), 2,18 (s, 3H, SCH3). 13C-NMR ((I6-DMSO, 50 MHz): δ 194,2, 151,2, 147,6, 138,3, 136,83, 136,2, 135,1, 125,9 (2C), 124,4 (2C), 123,1, 14,8. MS m/z 260 (M+, 24%), 122 (100%).The nicotinamide is prepared from nicotinic acid hydrochloride (6.5 mmol, 1.16 g), triethylamine (10 mmol, 1.39 ml) and 4-methylthioaniline (5 mmol, 0.62 ml). Recrystallization from 50% ethanol gives 0.942 g (67.0%) of the nicotinamide. From 1.10 g of the nicotinamide (4.4 mmol), the nicotinthioamide is prepared. After purification by means of SC (eluent ethyl acetate) and recrystallization in 50% ethanol, 0.474 g (46.19%) of the desired product are obtained. Mp: 140-141 ° C. 1 H NMR (d 6 -DMSO, 200 MHz): δ 11.64 (s, IH, NH), 8.62 (d, J H , H = 1.3 Hz, IH, aromat. H), 8 , 40-8.34 (m, IH, aromat H), 7.85-7.81 (m, IH, aromat H), 7.50 (A part of an AB system, d, J A , B = 8.6 Hz, 2H, aromatic H), 7.20-7.14 (m, IH, aromatic H), 7.01 (B part of an AB system, d, J A) B = 8.6 Hz, 2H, aromat. H), 2.18 (s, 3H, SCH 3 ). 13 C-NMR ((I 6 -DMSO, 50 MHz): δ 194.2, 151.2, 147.6, 138.3, 136.83, 136.2, 135.1, 125.9 (2C) , 124.4 (2C), 123.1, 14.8, MS m / z 260 (M + , 24%), 122 (100%).
Beispiel XXV: N-(2, 3-Dimethylphenyl)-thionicotinamid.Example XXV: N- (2,3-dimethylphenyl) -thionicotinamide.
Das Nicotinamid wird aus Nicotinsäurehydrochlorid (6 mmol, 0,89 g), Triethylamin (10 mmol, 1,39 ml) und 2,3-Dimethylanilin (5 mmol, 0,61 ml) hergestellt. Nach Umkristallisation aus Wasser erhält man 0,495 g (43,98 %) des Nicotinamids. Aus 0,904 g des Nicotinamids (4 mmol) wird das Nicotinthioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 2+8) und Umkristallisation in 80 % Ethanol erhält man 0,508 g (52,48 %) des gewünschten Produktes. Fp: 127-129 °C. 1H-NMR (d6-DMSO, 200 MHz): δ 11,35 (s, IH, NH), 8,70-8,55 (m, IH, aromat. H), 8,30-8,27 (m, IH, aromat. H), 7,84-7,78 (m, IH, aromat. H), 7,12-7,06 (m, IH, aromat. H), 6,77-6,66 (m, 3H, aromat. H), 1,88 (s, 3H, CH3), 1,69 (s, 3H, CH3). 13C-NMR (dό-DMSO, 50 MHz): δ 195,9, 151,5, 147,6, 138,5, 137,5, 137,0, 135,1, 133,2, 129,0, 125,9, 125,0, 123,2, 20,0, 14,1. MS m/z 242 (M+, 11%), 227 (100%).The nicotinamide is prepared from nicotinic acid hydrochloride (6 mmol, 0.89 g), triethylamine (10 mmol, 1.39 ml) and 2,3-dimethylaniline (5 mmol, 0.61 ml). Recrystallization from water gives 0.495 g (43.98%) of the nicotinamide. From 0.904 g of nicotinamide (4 mmol), the nicotinthioamide is produced. After purification by means of SC (mobile phase toluene / ethyl acetate = 2 + 8) and recrystallization in 80% ethanol, 0.508 g (52.48%) of the desired product are obtained. Mp: 127-129 ° C. 1 H NMR (d 6 -DMSO, 200 MHz): δ 11.35 (s, IH, NH), 8.70-8.55 (m, IH, aromat H), 8.30-8.27 (m, IH, aromatic H), 7.84-7.78 (m, IH, aromatic H), 7, 12-7.06 (m, IH, aromatic H), 6.77-6, 66 (m, 3H, aromatic H), 1.88 (s, 3H, CH 3 ), 1.69 (s, 3H, CH 3 ). 13 C-NMR (d ό -DMSO, 50 MHz): δ 195.9, 151.5, 147.6, 138.5, 137.5, 137.0, 135.1, 133.2, 129.0 , 125.9, 125.0, 123.2, 20.0, 14.1. MS m / z 242 (M + , 11%), 227 (100%).
Beispiel XXVI: N-(4-Fluorphenyl)-thionicotinamid.Example XXVI: N- (4-fluorophenyl) -thionicotinamide.
Das Nicotinamid wird aus Nicotinsäurehydrochlorid (11 mmol, 1,96 g), Triethylamin (20 mmol, 2,78 ml) und 4-Fluoranilin (10 mmol, 0,95 ml) hergestellt. Nach Umkristallisation aus 20 % Ethanol erhält man 1,621 g (75 %) des Nicotinamids. Aus 1,72 g des Nicotinamids (4 mmol) wird das Nicotinthioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 2+8) und Umkristallisation in 80 % Ethanol erhält man 0,508 g (52,48 %) des gewünschten Produktes. Fp: 127-129 0C. 1H-NMR (d6-DMSO, 200 MHz): δ 12,00 (s, IH, NH), 8,97 (d, JH,H=1,8 Hz, IH, aromat. H), 8,71-8,68 (m, IH, aromat. H), 8,20-8,16 (m, IH, aromat. H), 7,90-7,83 (m, 2H, aromat. H), 7,54-7,48 (m, IH, aromat. H), 7,35-7,26 (m, 2H, aromat. H). 13C-NMR (de-DMSO, 50 MHz): δ 195,3, 160,3 (1JΓ C,F^244 HZ), 151,7, 147,9, 138,5, 136,5 (4JClF=2,9 Hz), 135,5, 126,6 (3JC,F=8,4 Hz), 123,5, 115,7 (2JC,F=22,7 Hz). MS m/z 232 (M+, 36%), 122 (100%).The nicotinamide is prepared from nicotinic acid hydrochloride (11 mmol, 1.96 g), triethylamine (20 mmol, 2.78 ml) and 4-fluoroaniline (10 mmol, 0.95 ml). After recrystallization from 20% ethanol, 1.621 g (75%) of the nicotinamide are obtained. From 1.72 g of nicotinamide (4 mmol), the nicotinthioamide is produced. After purification by means of SC (mobile phase toluene / ethyl acetate = 2 + 8) and recrystallization in 80% ethanol, 0.508 g (52.48%) of the desired product are obtained. Mp 127-129 0 C. 1 H-NMR (d 6 -DMSO, 200 MHz): δ 12.00 (s, IH, NH), 8.97 (d, J H, H = 1.8 Hz, H, aromatic H), 8.71-8.68 (m, IH, aromatic H), 8.20-8.16 (m, IH, aromatic H), 7.90-7.83 (m , 2H, aromatic H), 7.54-7.48 (m, IH, aromatic H), 7.35-7.26 (m, 2H, aromatic H). 13 C-NMR (de-DMSO, 50 MHz): δ 195.3, 160.3 ( 1 J Γ C, F ^ 244 HZ), 151.7, 147.9, 138.5, 136.5 ( 4 J Cl F = 2.9 Hz), 135.5, 126.6 ( 3 J C , F = 8.4 Hz), 123.5, 115.7 ( 2 J C , F = 22.7 Hz). MS m / z 232 (M + , 36%), 122 (100%).
Beispiel XXVII: N-(.3, 5-Dimethoxyphenyl)-ihionicotinamid.Example XXVII: N - (. 3, 5-Dimethoxyphenyl) -ihionicotinamide.
Das Nicotinamid wird aus Nicotinsäurehydrochlorid (12 mmol, 2,14 g), Triethylamin (20 mmol, 2,78 ml) und 3,5-Dimethoxyanilin (10 mmol, 1,53 g) hergestellt. Nach Umkristallisation aus Ethanol erhält man 1,956 g (75,8 %) des Nicotinamids. Aus 1,548 g des Nicotinamids (4,8 mmol) wird das Nicotinthioamid hergestellt. Nach Reinigung mittels SC (Laufmittel Toluol/ Ethylacetat = 2+8) und Umkristallisation in 70 % Ethanol erhält man 0,192 g (11,67 %) des gewünschten Produktes. Fp: 122-125 °C. . 1H-NMR (d6-DMSO, 200 MHz): δ 11,93 (s, IH, NH), 8,91 (d, JH,H=1,9 Hz, IH, aromat. H), 8,70-8,66 (m, IH, aromat. H), 8,15-8,11 (m, IH, aromat. H), 7,53-7,46 (m, IH, aromat. H), 7,21 (d, JH,H=2,1 Hz, 2H, aromat. H), 6,47-6,44 (m, IH, aromat. H), 3,76 (s, 6H, OCH3). 13C-NMR (dό-DMSO, 50 MHz): δ 194,3, 159,9 (2C), 150,8, 147,2, 141,1, 138,4, 134,8, 122,8, 101,5 (2C), 98,1, 55,1 (2C). MS m/z 274 (M+, 49%), 122 (100%).The nicotinamide is prepared from nicotinic acid hydrochloride (12 mmol, 2.14 g), triethylamine (20 mmol, 2.78 ml) and 3,5-dimethoxyaniline (10 mmol, 1.53 g). Recrystallization from ethanol gives 1.956 g (75.8%) of the nicotinamide. The nicotinethioamide is prepared from 1.548 g of the nicotinamide (4.8 mmol). After purification by means of SC (mobile phase toluene / ethyl acetate = 2 + 8) and recrystallization in 70% ethanol, 0.192 g (11.67%) of the desired product are obtained. Mp: 122-125 ° C. , 1 H NMR (d 6 -DMSO, 200 MHz): δ 11.93 (s, IH, NH), 8.91 (d, J H , H = 1.9 Hz, IH, aromat. H), 8 , 70-8.66 (m, IH, aromatic H), 8.15-8.11 (m, IH, aromatic H), 7.53-7.46 (m, IH, aromatic H), 7.21 (d, J H , H = 2.1 Hz, 2H, aromatic H), 6.47-6.44 (m, IH, aromatic H), 3.76 (s, 6H, OCH 3 ). 13 C-NMR (d ό -DMSO, 50 MHz): δ 194.3, 159.9 (2C), 150.8, 147.2, 141.1, 138.4, 134.8, 122.8, 101.5 (2C), 98.1, 55.1 (2C). MS m / z 274 (M + , 49%), 122 (100%).
Pharmakologische Daten:Pharmacological data:
Die Testsubstanzen wurden hinsichtlich ihrer Wirkung auf die Kontraktionskraft (fc) verschiedener isolierter Präparate des Meerschweinchens (terminale Ilea, Aortenringe, Arteria pulmonalis-Ringe, Papillarmuskel (PM) des Meerschweinchenherzens) sowie auf die Schlagfrequenz (f) isolierter rechter Vorhöfe des Meerschweinchenherzens untersucht. Die fc terminaler Ilea, Aortenringe und Arteria pulmonalis-Ringe (vorkontrahiert mit 60 bzw. 90 mmolarer KCl-Lösung) sowie von Papillarmuskeln (elektrisch stimuliert, 1 Hz) und die Schlagfrequenz (f) isolierter rechter Vorhöfe (RVH) des Meerschweinchenherzens wurden isometrisch gemessen. Aus den Konzentrations-Wirkungskurven wurden die EC50- Werte graphisch ermittelt.The test substances were tested for their effect on the contraction force (f c ) of various guinea pig isolated preparations (terminal ilea, aortic rings, pulmonary artery rings, papillary muscle (PM) of the guinea pig heart) and the beat frequency (f) of isolated right atria of the guinea pig heart. The f c terminal iliac, aortic and pulmonary artery rings (precontracted with 60 or 90 mmolar KCl solution) and papillary muscle (electrically stimulated, 1 Hz) and the beating frequency (f) of isolated right atria (RVH) of guinea pig heart became isometric measured. From the concentration-activity curves, the EC 50 values were determined graphically.
Die erfindungsgemäßen Verbindungen wurden in Konzentrationen zwischen 0,1 und 100 μmol/1 untersucht. Pro Verbindung wurden je 6 Versuche an terminalen Ilea, Aorten- und Arteria pulmonalis-Ringen durchgeführt. Die Kontraktionskraft an Papillarmuskeln und die Schlagfrequenz an rechten Vorhöfen wurde nicht signifikant reduziert. Bei einigen Substanzen wurde eine EC50 an Aortenringen, Arteria pulmonalis-Ringen bzw. terminalen Ilea in Konzentrationen zwischen 0,112 und 100 μmol/1 erreicht (siehe Tabellen 1 und 2).The compounds according to the invention were investigated in concentrations between 0.1 and 100 μmol / l. Per compound, 6 experiments each were performed on terminal iliac, aortic and pulmonary artery rings. The contraction force on papillary muscles and the Rate of impact on right atria was not significantly reduced. For some substances, an EC 50 of aortic rings, pulmonary arterial rings, and terminal iliacs, respectively, was reached in concentrations between 0.112 and 100 μmol / l (see Tables 1 and 2).
Zur Aufklärung des möglichen Wirkmechanismus dieser Verbindungen kann aus den Experimenten geschlossen werden, dass die relaxierende Wirkung durch NO-Freisetzung aus dem Endothel sowie durch Aktivierung der KATP - Kanäle zustande kommt (Fig. 1, 2).To elucidate the possible mechanism of action of these compounds, it can be concluded from the experiments that the relaxant action is due to NO release from the endothelium as well as activation of the K ATP channels (FIGS. 1, 2).
Fig. 1 illustriert die Beeinflussung der Vasodilatation, hervorgerufen durch Beispiel I (4 μM) bei Zugabe von 100 μM Nitro-L-Arginin (Inhibitor der eNOS) an vorkontrahierten Aortaringen; Max. Kontraktion wurde mit 90 mM KCl hervorgerufen (Kontrolle), n = 3.Figure 1 illustrates the effect of vasodilation induced by Example I (4 μM) on addition of 100 μM nitro-L-arginine (inhibitor of eNOS) to precontracted aorta rings; Max. Contraction was induced with 90 mM KCl (control), n = 3.
Fig. 2 illustriert die signifikante Beeinflussung der Vasodilatation, hervorgerufen durch Beispiel I (4 μM) bei Zugabe von 30 μM Glibenclamid (KAτp-Antagonist) an vorkontrahierten Aortaringen; Max. Kontraktion wurde mit 90 mM KCl hervorgerufen (Kontrolle). * P < 0,05; n = 3.Figure 2 illustrates the significant effect of vasodilation elicited by Example I (4 μM) on addition of 30 μM glibenclamide (K A τp antagonist) to precontracted aorta rings; Max. Contraction was caused by 90 mM KCl (control). * P <0.05; n = 3.
Fig. 3 illustriert die Beeinflussung der Vasodilatation, hervorgerufen durch Beispiel I (4 μM) bei Zugabe von 100 μM Glibenclamid (KATP- Antagonist) an vorkontrahierten Aortaringen; Max. Kontraktion wurde mit 90 mM KCl hervorgerufen (Kontrolle), n = 3.Figure 3 illustrates the effect of vasodilation induced by Example I (4 μM) on addition of 100 μM glibenclamide (K ATP antagonist) to precontracted aorta rings; Max. Contraction was induced with 90 mM KCl (control), n = 3.
Diese Ergebnisse geben Hinweise darauf, dass die stark vasodilatierende Wirkung der Verbindungen der Formel I aufgrund einer kontrollierten H2S-Freisetzung zu Stande kommt.These results indicate that the strong vasodilating effect of the compounds of formula I due to a controlled H 2 S release comes about.
Elektronenziehende Substituenten „auf beiden Seiten" des Thioamids sowie deren Anordnung sind für die erfindungsgemäße Wirkung mit ausschlaggebend.Electron-withdrawing substituents "on both sides" of the thioamide and their arrangement are also decisive for the effect according to the invention.
Tabelle 1Table 1
Figure imgf000018_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000019_0001
Die untersuchten Substanzen zeigen aber eine stärkere Wirkung auf die glatte Muskulatur als z.B. die Benzamide, die zu den Thiobenzamiden umgesetzt wurden (siehe Tabelle 2).However, the substances studied show a greater effect on smooth muscle than e.g. the benzamides that have been converted to the thiobenzamides (see Table 2).
Tabelle 2Table 2
Aufgrund dieser Ergebnisse ist mit einem vorteilhaften Einsatz der erfindungsgemäßen Verbindungen bei der Behandlung zahlreicher mit Krampfzuständen verbundener Störungen und Erkrankungen zu rechnen. On the basis of these results, an advantageous use of the compounds according to the invention in the treatment of numerous disorders and disorders associated with convulsive states is to be expected.

Claims

Patentansprüche : Claims:
1. Verwendung einer Verbindung der allgemeinen Formel I1. Use of a compound of general formula I.
Figure imgf000020_0001
wobei
Figure imgf000020_0001
in which
Y ausgewählt ist aus der Gruppe bestehend aus Thienyl, Pyridyl undY is selected from the group consisting of thienyl, pyridyl and
Figure imgf000020_0002
Figure imgf000020_0002
wobei jeder Rest R Wasserstoff oder ein Substituent, ausgewählt aus der Gruppe bestehend aus F, Cl, Br, I, OH, OCH3, NO2, CF3, CH3, OCF3, N(CH3)2 und SCH3, ist, mit derwherein each R is hydrogen or a substituent selected from the group consisting of F, Cl, Br, I, OH, OCH 3 , NO 2 , CF 3 , CH 3 , OCF 3 , N (CH 3 ) 2 and SCH 3 , is with the
Maßgabe, dass mindestens ein Rest R nicht Wasserstoff ist,Provided that at least one R is not hydrogen,
X eine unsubstituierte oder substituierte Arylgruppe ist, wobei ein oder mehrere Ringatome mit einem Rest, ausgewählt aus der Gruppe bestehend aus F, Cl, Br, I, OH, OCH3, NO2, CF3,X is an unsubstituted or substituted aryl group, wherein one or more ring atoms having a radical selected from the group consisting of F, Cl, Br, I, OH, OCH 3 , NO 2 , CF 3 ,
CH3, OCF3, N(CH3)2 und SCH3, substituiert sind, und n, m = O oder 1 , und deren Salze zur Herstellung eines Arzneimittels zur Relaxierung glatter Muskulatur.CH 3 , OCF 3 , N (CH 3 ) 2 and SCH 3 , and n, m = O or 1, and salts thereof for the preparation of a smooth muscle relaxant drug.
2. Verwendung nach Anspruch 1, dadurch gekennzeichnet, dass R aus der Gruppe bestehend aus F, NO2 und OCH3 ausgewählt ist.2. Use according to claim 1, characterized in that R is selected from the group consisting of F, NO 2 and OCH 3 .
3. Verwendung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass mindestens zwei Reste R nicht Wasserstoff sind.3. Use according to claim 1 or 2, characterized in that at least two radicals R are not hydrogen.
4. Verwendung nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass R an der Position 3, 4 und/oder 5 nicht Wasserstoff ist.4. Use according to one of claims 1 to 3, characterized in that R at the position 3, 4 and / or 5 is not hydrogen.
5. Verwendung nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass X eine Phenylgruppe ist. 5. Use according to one of claims 1 to 4, characterized in that X is a phenyl group.
6. Verwendung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass X mit einem Rest, ausgewählt aus der Gruppe bestehend aus F, CH3, OCH3, SCH3 und N(CH3)2, substituiert ist.6. Use according to any one of claims 1 to 5, characterized in that X is substituted by a radical selected from the group consisting of F, CH 3 , OCH 3 , SCH 3 and N (CH 3 ) 2 .
7. Verwendung nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass X mindestens zweifach substituiert ist.7. Use according to one of claims 1 to 6, characterized in that X is at least doubly substituted.
8. Verwendung gemäß einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass das Arzneimittel bei Indikationen Anwendung findet, die ausgewählt sind aus der Gruppe bestehend aus:8. Use according to any one of claims 1 to 7, characterized in that the drug is used in indications which are selected from the group consisting of:
Krämpfen und Motilitätsstörungen des Magen-Darm-Trakts,Convulsions and motility disorders of the gastrointestinal tract,
Reizdarmsyndrom,Irritable bowel syndrome,
Krämpfen und Dyskinesien der Gallen- und Harnwege,Cramps and dyskinesias of the bile and urinary tract,
Cholecystopathie, dysmenorrhoischen Beschwerden,Cholecystopathy, dysmenorrhea complaints,
Krampfzuständen im Bereich der weiblichen Genitalorgane sowie Spasmen der muskulärenSpasms in the area of the female genital organs and spasms of the muscular
Weichteile während der Entbindung (Tokolyse),Soft tissues during delivery (tocolysis),
Pylorospasmus des Säuglings, bei Untersuchungen auftretenden Spasmen, wie bei der Gastroduodenalendoskopie oderPylorospasm of the infant, spasm occurring during examinations, such as in gastroduodenal endoscopy or
Röntgenuntersuchungen, arterieller Hypertonie, pulmonaler Hypertonie,X-ray examinations, arterial hypertension, pulmonary hypertension,
Therapie der hypertonen Krise, koronarer Herzkrankheit, wie chronisch stabiler Angina pectoris oder vasospastischerTreatment of hypertensive crisis, coronary heart disease, such as chronic stable angina or vasospastic
Angina, chronischer Herzinsuffizienz, arteriellen Verschlusskrankheiten, wie Claudicatio intermittens, ischämischen neurologischen Defiziten infolge zerebraler Vasospasmen nach aneurysmatischer Subarachnoidalblutung,Angina, chronic heart failure, arterial occlusive diseases, such as intermittent claudication, ischemic neurological deficits due to cerebral vasospasm after aneurysmal subarachnoid hemorrhage,
Hirnleistungsstörungen im Alter,Brain disorders in old age,
Bronchospasmus bei Asthma bronchiale, spastischer Bronchitis,Bronchospasm in bronchial asthma, spastic bronchitis,
Status Asthmaticus,Status asthmaticus,
Morbus Raynaud und gefäßbedingten Waden- oder Zehenkrämpfen. Raynaud's disease and vessel-related calf or toe cramps.
9. Verbindung der allgemeinen Formel I9. Compound of the general formula I
Figure imgf000022_0001
Figure imgf000022_0001
wobeiin which
X eine Arylgruppe, vorzugsweise Phenylgruppe, ist, welche mit mindestens einem Rest, ausgewählt aus der Gruppe bestehend aus F, Cl, Br, I, OH, OCH3, NO2, CF3, CH3, OCF3,X is an aryl group, preferably a phenyl group, which contains at least one radical selected from the group consisting of F, Cl, Br, I, OH, OCH 3 , NO 2 , CF 3 , CH 3 , OCF 3 ,
N(CH3)2 und SCH3, substituiert ist,N (CH 3 ) 2 and SCH 3 , is substituted,
Y eine Phenylgruppe ist, die mit mindestens einer Gruppe ausgewählt aus F und NO2 substituiert ist, und n, m = O oder 1 , sowie deren Salze.Y is a phenyl group substituted with at least one group selected from F and NO 2 , and n, m = O or 1, and their salts.
10. Verbindung nach Anspruch 9, dadurch gekennzeichnet, dass die Phenylgruppe Y mindestens zweifach substituiert ist.10. A compound according to claim 9, characterized in that the phenyl group Y is at least doubly substituted.
11. Verbindung nach Anspruch 9 oder 10, dadurch gekennzeichnet, dass die Phenylgruppe Y bei einfacher Substitution an Position 4 („para") und bei zwei, vorzugsweise identischen, Substituenten an den Positionen 3 und 5 („meta") substituiert ist.11. A compound according to claim 9 or 10, characterized in that the phenyl group Y is substituted in simple substitution at position 4 ("para") and two, preferably identical, substituents at positions 3 and 5 ("meta").
12. Verbindung nach einem der Ansprüche 9 bis 11, dadurch gekennzeichnet, dass n,m = 0.12. A compound according to any one of claims 9 to 11, characterized in that n, m = 0.
13. Verbindung nach einem der Ansprüche 9 bis 11, dadurch gekennzeichnet, dass X dreifach, vorzugsweise mit F oder OCH3, substituiert ist.13. A compound according to any one of claims 9 to 11, characterized in that X is trisubstituted, preferably substituted by F or OCH 3 .
14. Verbindung der allgemeinen Formel I14. Compound of the general formula I
Figure imgf000022_0002
Figure imgf000022_0002
wobei X eine Arylgruppe, vorzugsweise Phenylgruppe, ist, welche unsubstituiert oder mit einemin which X is an aryl group, preferably phenyl group, which is unsubstituted or with a
Rest ausgewählt aus der Gruppe bestehend aus OCH3 und CH3 einfach oder mehrfach substituiert ist,Radical selected from the group consisting of OCH 3 and CH 3 is monosubstituted or polysubstituted,
Y eine Phenylgruppe ist, die mit einer oder mehreren Methoxygruppen oder OCF3 substituiert ist, und n, m = 0 oder 1 , mit der Maßgabe, dass X+Y insgesamt mindestens drei Substituenten besitzen, sowie deren Salze.Y is a phenyl group substituted with one or more methoxy groups or OCF 3 and n, m = 0 or 1, with the proviso that X + Y in total have at least three substituents, as well as their salts.
15. Verbindung nach Anspruch 14, dadurch gekennzeichnet, dass Y mindestens dreifach substituiert ist.15. A compound according to claim 14, characterized in that Y is substituted at least three times.
16. Verbindung nach Anspruch 14 oder 15, dadurch gekennzeichnet, dass X mindestens zweifach, vorzugsweise identisch, substituiert ist.16. A compound according to claim 14 or 15, characterized in that X is at least twice, preferably identical, substituted.
17. Verbindung nach einem der Ansprüche 14 bis 16, dadurch gekennzeichnet, dass n=l und/oder m=l.17. A compound according to any one of claims 14 to 16, characterized in that n = 1 and / or m = l.
18. Verbindung der allgemeinen Formel I18. Compound of the general formula I
Figure imgf000023_0001
Figure imgf000023_0001
wobeiin which
Y Thienyl oder Pyridyl ist,Y is thienyl or pyridyl,
X eine Arylgruppe, vorzugsweise Phenylgruppe, ist, welche mit mindestens einem Rest, ausgewählt aus der Gruppe bestehend aus OCH3, CH3, SCH3 oder F substituiert ist, und n, m = 0 oder 1 , sowie deren Salze.X is an aryl group, preferably phenyl, which is substituted with at least one radical selected from the group consisting of OCH 3 , CH 3 , SCH 3 or F, and n, m = 0 or 1, and salts thereof.
19. Verbindung nach Anspruch 18, dadurch gekennzeichnet, dass X zweifach mit einer Methylgruppe, vorzugsweise an den Positionen 2 und 3, substituiert ist. 19. A compound according to claim 18, characterized in that X is substituted twice with a methyl group, preferably at the positions 2 and 3.
20. Verbindung nach Anspruch 18, dadurch gekennzeichnet, dass X zweifach oder dreifach mit einer Methoxygruppe, vorzugsweise an den Positionen 3, 4 und/oder 5, substituiert ist.20. A compound according to claim 18, characterized in that X is substituted twice or three times with a methoxy group, preferably at the positions 3, 4 and / or 5.
21. Verbindung nach Anspruch 18, dadurch gekennzeichnet, dass X einfach oder zweifach mit F, vorzugsweise an den Positionen 3, 4 und/oder 5, substituiert ist.21. A compound according to claim 18, characterized in that X is monosubstituted or disubstituted by F, preferably at the positions 3, 4 and / or 5, is substituted.
22. Verwendung nach Anspruch 1 oder 8, dadurch gekennzeichnet, dass die Verbindung der allgemeinen Formel I eine Verbindung gemäß einem der Ansprüche 9-21 ist. 22. Use according to claim 1 or 8, characterized in that the compound of general formula I is a compound according to any one of claims 9-21.
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