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WO1997022583A1 - Novel 1-phenylalkyl/alkylene-4-(.alpha.-hydroxydiphenylmethyl)-piperidine derivatives and their use as serotonin antagonists - Google Patents

Novel 1-phenylalkyl/alkylene-4-(.alpha.-hydroxydiphenylmethyl)-piperidine derivatives and their use as serotonin antagonists Download PDF

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Publication number
WO1997022583A1
WO1997022583A1 PCT/EP1996/005626 EP9605626W WO9722583A1 WO 1997022583 A1 WO1997022583 A1 WO 1997022583A1 EP 9605626 W EP9605626 W EP 9605626W WO 9722583 A1 WO9722583 A1 WO 9722583A1
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azacyclohexyl
serotonin
derivatives
treatment
diphenylmethanol
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German (de)
French (fr)
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Eckhart Pein
Helmut Ritter
Reinhard Laven
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • the invention relates to the use of l-phenylalkylene-4- (azacyclohexyl) dipheny1-methanol derivatives or phenyletheny1-4- (azacaclohexyl) diphenylmethanol derivatives as serotonin antagonists.
  • Another object of the invention are new l-phenylalkylene-4- (azacyclohexyl) -diphenyl-methanol derivatives and new phenylethylene-4- (azacyc1ohexyl) -diphenylmethanol derivatives.
  • 4-diphenyl-methyl-azacyclohexyl derivatives have very different pharmacodynamic effects.
  • the pharmacodynamic effects include spasmolytic and antisecretory effects (US 3,014,037, US 3,068,237).
  • 4-diphenyl-methyl-azacyclohexyl derivatives can be used as antihistamines (DE 25 06 700 AI, DE 23 03 305 AI, DE 23 03 306 AI, DE 25 03 362 AI, DE 30 07 498 AI, DE 39 17 241 C2).
  • EP-A-0 399 547 discloses 1-phenylalkylene-4- (azacyclohexyl) diphenylmethanol derivatives which correspond to the formula (I) with the exception that the radicals R 1 - R 5 are hydrogen and at least one of them is linear or are branched alkyl radicals with 1-4 carbon atoms, C x -C 3 alkoxy or hydroxy radicals and that A stands for CH 2 .
  • the document also discloses the use of the derivatives mentioned as antihistamines.
  • EP-A-0 208 235 discloses 1-phenylalkylene-4- (azacyclohexyl) phenylmethanol derivatives, which are selective and potent inhibitors of serotonin binding to 5-HT_, and their effect on various diseases such as anorexia nervosa, angina, Raynaud's Phenomenon, coronary vasospasms, migraines as well as their topical anesthetic activity, their anaetic effect and the anti-fibrillatory and anti-arrhythmic effects.
  • J. Med. Chem. 1995, 38, 1196-1202 describes structure-affinity studies with ketanserin analogs with regard to 5-HT 2 - sertonine receptor binding.
  • the invention therefore relates to the use of l-phenylalkylene-4- ( azac y cl ° hexyl) diphenylmethanol derivatives or phenylethenyl-4- (azacyclohexyl) diphenylmethanol derivatives of the general formula
  • R3 > R4 and R5, which are the same or different, for Hydrogen, C- . - C 4 alkyl, C 3 -C 6 cycloalkyl, C- . - C 4 hydroxyalkyl, C x
  • A represents the group (CH;.) -, or -C 2 H 2 -,
  • R6 C-. C 4 alkyl
  • R7 represents a heterocyclic radical derived from piperidine, morpholine or pyrrolidine,
  • X and Y which are the same or different, represent hydrogen or
  • Ci - C 6 alkyl and n is an integer of 1 or 2, and their salts, as serotonin antagonists, or in the treatment of
  • the derivatives used according to the invention can be used, for example, for the treatment of pressor or diatorial vascular effects, serotonin-related spasms, in particular bronchial spasms or vascular spasms, and ischemic attacks.
  • the invention also relates to new 1-phenylalkylene-4- (azacyclohexyl) diphenyl-methanol derivatives or phenylethenyl-4- (azacyclohexyl) diphenylmethanol derivatives of the general formula (I),
  • Rl, R2, R3, R4 and R5 which are the same or different, represent hydrogen or the group -COOH, which may be in the form of a physiologically acceptable salt, -C00R6 -C0R7 or -CONXY, where at least one radical Rl , R2, R3, R4 or R5 is different from hydrogen,
  • A represents the group - (CH 2 H, or -C 2 H 2 -, R6 denotes C x - C 4 alkyl,
  • R7 represents a heterocyclic radical derived from piperidine, morpholine or pyrrolidine, X and Y, which are the same or different, represent hydrogen or Ci - C ⁇ -alkyl, and n denotes the integer 1 or 2.
  • R1, R2, R3, R4 and R5 are, for example, methyl, ethyl, n-propyl, isopropyl, tert-butyl. If one or more of the radicals R1 to R5 are carboxyl groups, these can be present in the form of their salts, in particular in the form of physiologically tolerable salts, for example with alkali metal or
  • Alkaline earth counterions such as lithium, sodium, potassium, calcium, magnesium, but also, for example, iron, ammonium.
  • esterified carboxyl group -C00R6 are methyl ester, ethyl ester, propyl ester and isopropyl ester. If Rl to R5 represent hydroxyalkyl groups, these are, for example, hydroxyethyl or hydroxypropyl groups.
  • Cycloalkyl preferably has 5 or 6 carbon atoms. Ci - C 3 alkoxy is preferred for the alkoxy radical.
  • the heterocyclic groups C0R7 derived from piperidine, morpholine or pyrrolidine are bonded to the carboxyl group via the nitrogen atom to form an amide bond.
  • the heterocyclic radicals can carry conventional substituents such as Ci-Cs- alkyl, C ⁇ -C 6 alkoxy, halogen, C0 2 H, C0 2 R8, C0R8, where R8 is C ⁇ -C ⁇ - alkyl.
  • n is preferably 1.
  • At least one of the radicals R 1 to R 5 is preferably a carboxyl group, its salt or ester
  • the radical R3 is particularly preferably a carboxyl group or its salt or ester.
  • a maximum of two of the radicals R 1 to R 5 are preferably different from hydrogen.
  • A stands for the group —C 2 H 2 -, this can be in the ice or trans configuration.
  • the trans configuration is preferred.
  • the derivatives which can be used according to the invention can be in the form of physiologically acceptable or pharmaceutically acceptable salts, in particular acid addition salts.
  • the salts can be formed with organic and inorganic acids, examples are hydrochloric acid, sulfuric acid, phosphoric acid or carboxylic acids and dicarboxylic acids. Examples of suitable organic acids are
  • Acetic acid fatty acids such as stearic acid, lauric acid, oleic acid or palmitic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, cyclic acidic acid, ascorbic acid, benzoic acid, hydroxamic acid, 4-acidic acid, 4-acidic acid, 4-acidic acid, benzoic acid, 4-acidic acid, 4-acidic acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and hydroxyethanesulfonic acid are also suitable.
  • the salts can be formed in the usual way. Examples of compounds which can be used according to the invention are: 1. 1- (4-methylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol
  • the action of the group of substances shown is exemplified by the action of l- (4-methylphenyl) methyl-4- (azacyclohexyl) -diphenyl-methanol and 4- (azacyclohexyl-diphenylmethanol) -l-methyl-4'-benzoic acid.
  • the experiments were carried out on male NMRI mice with a body weight of 30-35 g.
  • By intradermal injection of 0.1 mg serotonin the capillary permeability is increased, thereby releasing an intravenously injected dye.
  • FIG. 1 shows the influence on the capillary damage caused by intradermal injection of 0.1 ⁇ g serotonin.
  • the effect of the substances examined was methodically determined by recording the breathing resistance as a measure of bronchial spasm with constant breathing volume via the ventilation pressure.
  • a corresponding bronchial spasm was triggered and registered in anesthetized guinea pigs by intracheal application of serotonin.
  • the po administration of 4- (azacyclohexyl-diphenylmethanol) -l-methyl-4 was carried out, for example, for the serotonin-antagonistic activity of the 1-phenylalkylene-4- (azacyclohexyl) -diphenyl-methanol derivatives used according to the invention '-benzoic acid and 1- (4-methylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol compared to terfenadine in doses of 6 mg / kg body weight. Subsequently, further spasms were provoked for up to 5 hours and their extent related to the effect of the reference solution.
  • FIG. 2 shows the relative extent of bronchial spasm in guinea pigs as a function of the time after po treatment with NaCl ⁇ •), 6 mg / kg, terfenadine (I), 6 mg / kg l- (4-methylphenyl) methyl -4- (azacyclohexyl) diphenylmethanol (A), 6 mg / kg 4- (azacyclohexyldiphenylmethanol) l-methyl-4 / -benzoic acid (x); the mean values ⁇ sem are shown.
  • the serotonin-antagonistic activity of the 1-phenylalkylene-4- (azacyclhexyl) -diphenylmethanol derivatives shown is furthermore typically shown both in the isolated vascular preparation of the external carotid artery and in the isolated cardiac disease vessel of the guinea pig, i.e. Corresponding spasms induced by serotonin could be completely inhibited depending on the dose.
  • the newly discovered and unexpected quality of action of the class of substances shown means the possibility of therapeutically influencing disease states in which serotonin is an important mediator.
  • the scope of the claimed derivatives as serotonin antagonists extends to both the human and the entire veterinary field.
  • the l-phenylalkylene-4- (azacyclohexyl) diphenylmethanol derivatives and phenylethenyl 4- (azacyclohexyl) diphenylmethanol derivatives which can be used according to the invention can be administered, for example, orally, parenterally, e.g. administered intravenously, subcutaneously, intramuscularly, intranasally, intratracheally, intraocularly or rectally, and administered in mist or powder form.
  • the doses of the applied substance depend on the type of application and the individual sensitivity of the person to be treated.
  • the dose range extends, for example, from 0.05 to 10 mg / kg / day to achieve the desired effect.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Disclosed are 1-phenylalkylene-4-(azacyclohexyl)-diphenylmethanol derivatives or phenylethenyl-4-(azacyclohexyl)-diphenylmethanol derivatives of general formula (I) in which: R1, R2, R3, R4, R5 can be identical or different and stand for hydrogen, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, hydroxy, -COOH optionally present in the form of a physiologically acceptable salt, -COOR6, COR7 or -CONXY; A stands for -(-CH2-)-n or -C2H2-; R6 stands for C1-C4-alkyl; R7 stands for a heterocyclic group derived from piperidine, morpholine or pyrrolidine; X and Y, which are identical or different, stand for hydrogen or C1-C6-alkyl; and n is a whole number 1 or 2. Also disclosed is the use of said derivatives and their salts as serotonin antagonists or in the treatment of disorders in which serotonin acts as a mediator, or for producing medicaments that act as serotonin antagonists or medicaments suitable for use in the treatment of disorders in which serotonin acts as a mediator.

Description

NEUE l-PHENYLALKYL/ALKYLEN-4-(.ALPHA.-HYDROXYDIPHENYLMETHYL)-PIPERIDIN DERIVATIVE UND IHRE VERWENDUNG ALS SEROTONIN ANTAGONISTEN. NEW L-PHENYLALKYL / ALKYLEN-4 - (.ALPHA.-HYDROXYDIPHENYLMETHYL) -PIPERIDINE DERIVATIVE AND THEIR USE AS SEROTONIN ANTAGONISTS.

Gegenstand der Erfindung ist die Verwendung von l-Phenylalkylen-4- (azacyclohexyl)-dipheny1-methanol-Derivaten oder Phenyletheny1-4- (azacaclohexyl )-diphenylmethanol-Derivaten als Serotonin-Antagonisten. Einen weiteren Gegenstand der Erfindung bilden neue l-Phenylalkylen-4- (azacyclohexyl)-diphenyl-methanol-Derivate und neue Phenyletheπyl-4- (azacyc1ohexyl)-diphenylmethanol-Derivate.The invention relates to the use of l-phenylalkylene-4- (azacyclohexyl) dipheny1-methanol derivatives or phenyletheny1-4- (azacaclohexyl) diphenylmethanol derivatives as serotonin antagonists. Another object of the invention are new l-phenylalkylene-4- (azacyclohexyl) -diphenyl-methanol derivatives and new phenylethylene-4- (azacyc1ohexyl) -diphenylmethanol derivatives.

Es ist bekannt, daß 4-Diphenyl-methyl-azacyclohexyl-Derivate sehr unterschiedliche pharmakodynamische Wirkungen entfalten. Die pharmakodynamisehen Wirkungen umfassen spasmolytische und antisekretorische Effekte (US 3 014 037, US 3 068 237). Weiterhin ist bekannt, daß 4-Diphenyl-methyl-azacyclohexyl-Derivate als Antihistaminika verwendbar sind (DE 25 06 700 AI, DE 23 03 305 AI, DE 23 03 306 AI, DE 25 03 362 AI, DE 30 07 498 AI, DE 39 17 241 C2).It is known that 4-diphenyl-methyl-azacyclohexyl derivatives have very different pharmacodynamic effects. The pharmacodynamic effects include spasmolytic and antisecretory effects (US 3,014,037, US 3,068,237). It is also known that 4-diphenyl-methyl-azacyclohexyl derivatives can be used as antihistamines (DE 25 06 700 AI, DE 23 03 305 AI, DE 23 03 306 AI, DE 25 03 362 AI, DE 30 07 498 AI, DE 39 17 241 C2).

Aus EP-A-0 399 547 sind l-Pheny1alkylen-4-(azacyclohexyl)- diphenylmethanol-derivate bekannt, die der Formel (I) entsprechen mit der Ausnahme, daß die Reste Rl - R5 für Wasserstoff und mindestens einer davon für lineare oder verzweigte Alkylreste mit 1 - 4 Kohlenstoffatomen, Cx-C3-Alkoxy- oder Hydroxy-Reste stehen und daß A für CH2 steht. Ferner ist in diesem Dokument die Verwendung der genannten Derivate als Antihistaminika offenbart.EP-A-0 399 547 discloses 1-phenylalkylene-4- (azacyclohexyl) diphenylmethanol derivatives which correspond to the formula (I) with the exception that the radicals R 1 - R 5 are hydrogen and at least one of them is linear or are branched alkyl radicals with 1-4 carbon atoms, C x -C 3 alkoxy or hydroxy radicals and that A stands for CH 2 . The document also discloses the use of the derivatives mentioned as antihistamines.

EP-A-0 208 235 offenbart l-Phenylalkylen-4-(azacyclohexyl)- phenylmethanolderivate, die selektive und potente Inhibitoren der Serotoninbindung an 5-HT_,-darstellen sowie deren Wirkung auf verschiedene Erkrankungen wie Anorexia nervosa, Angina, Raynaud's Phänomen, Koronarvasospasmen, Migräne sowie ihre topische anästhetische Aktivität, ihren anaigetischen Effekt und die anti-fibrillatorische und anti-arrhytmische Wirkung.EP-A-0 208 235 discloses 1-phenylalkylene-4- (azacyclohexyl) phenylmethanol derivatives, which are selective and potent inhibitors of serotonin binding to 5-HT_, and their effect on various diseases such as anorexia nervosa, angina, Raynaud's Phenomenon, coronary vasospasms, migraines as well as their topical anesthetic activity, their anaetic effect and the anti-fibrillatory and anti-arrhythmic effects.

J. Med. Chem. 1995, 38, 1196 - 1202 beschreibt Struktur-Affinitäts- Untersuchungen mit Ketanserin-Analoga in Hinblick auf die 5-HT2- Sertonin-Rezeptor-Bindung.J. Med. Chem. 1995, 38, 1196-1202 describes structure-affinity studies with ketanserin analogs with regard to 5-HT 2 - sertonine receptor binding.

Ferner wurde in Chem. Pharm. Bull. 35 4637-4641 (1987) offenbart, daß PiPeridyl-4-(α,α-diphenyl-methanol)-Derivate und chemisch nahestehende Verbindungen eine cerebral gefäßerweiternde Wirkung durch musculotrop- spasmolytische Eigenschaften entfalten.Further Pharm was in. Chem. Bull. 35 4637-4641 (1987) discloses that Pi P he idyl-4- (α, α-diphenyl-methanol) derivatives and chemically related compounds, a cerebral vasodilator effect by spasmolytic properties musculotrop- unfold.

Es wurde nunmehr überraschenderweise gefunden, daß bestimmte 1- Phenylalky1en-4-(azacyclohexyl)-dipheny1-methanol-Derivate sowie Phenylethenyl-4-(azacyclohexyl)-diphenyImethanol-Derivate eine serotonin-antagonistische Wirkung aufweisen.It has now surprisingly been found that certain 1-phenylalkylene-4- (azacyclohexyl) -dipheny-1-methanol derivatives and phenylethenyl-4- (azacyclohexyl) -diphenyImethanol derivatives have a serotonin-antagonistic effect.

Die Erfindung betrifft daher die Verwendung von l-Phenylalkylen-4- (azacycl°hexyl)-diphenylmethanol-Derivaten oder Phenylethenyl-4- (azacyclohexyl)-diphenylmethanol-Derivaten der allgemeinen FormelThe invention therefore relates to the use of l-phenylalkylene-4- ( azac y cl ° hexyl) diphenylmethanol derivatives or phenylethenyl-4- (azacyclohexyl) diphenylmethanol derivatives of the general formula

Figure imgf000004_0001
Figure imgf000004_0001

in derin the

' ' R3> R4 und R5, die gleich oder verschieden sind, für Wasserstoff, C-. - C4-Alkyl, C3-C6-Cyc1oalkyl , C-. - C4-Hydroxyalkyl, Cx '' R3 > R4 and R5, which are the same or different, for Hydrogen, C- . - C 4 alkyl, C 3 -C 6 cycloalkyl, C- . - C 4 hydroxyalkyl, C x

- C_-Alkoxy, Hydroxy, die Gruppe -COOH, die in Form eines physiologisch vertraglichen Salzes vorliegen kann, -C00R6, -C0R7, oder- C_-alkoxy, hydroxy, the group -COOH, which can be in the form of a physiologically acceptable salt, -C00R6, -C0R7, or

-CONXY stehen,-CONXY stand,

A fur die Gruppe (CH;.)--, oder -C2H2- steht,A represents the group (CH;.) -, or -C 2 H 2 -,

R6 C-. - C4-Alkyl bedeutet,R6 C-. C 4 alkyl,

R7 fur einen von Piperidin, Morpholin oder Pyrrolidin abgeleiteten heterocyclischen Rest steht,R7 represents a heterocyclic radical derived from piperidine, morpholine or pyrrolidine,

X und Y, die gleich oder verschieden sind, fur Wasserstoff oderX and Y, which are the same or different, represent hydrogen or

Ci - C6-Alkyl stehen, und n eine ganze Zahl von 1 oder 2 bedeutet, sowie von deren Salzen, als Serotonin-Antagonisten, bzw. bei der Behandlung vonCi - C 6 alkyl, and n is an integer of 1 or 2, and their salts, as serotonin antagonists, or in the treatment of

Krankheitszustanden, bei denen Serotonin als Mediator wirkt, sowie zurConditions in which serotonin acts as a mediator, as well as

Herstellung von Arzneimitteln, die als Serotonin-Antagonisten wirken, bzw. zur Herstellung von Arzneimitteln zur Behandlung vonManufacture of medicinal products that act as serotonin antagonists or for the manufacture of medicinal products for the treatment of

Krankheitszustanden, bei denen Serotonin als Mediator wirkt.Conditions in which serotonin acts as a mediator.

Die erfindungsgemaß verwendeten Derivate können beispielsweise zur Behandlung von pressorischen oder di tatorischen Gefäßwirkungen, serotoninbedingten Spasmen, insbesondere Bronchialspasmen oder Gefaßspasmen, sowie ischämischen Attacken verwendet werden.The derivatives used according to the invention can be used, for example, for the treatment of pressor or diatorial vascular effects, serotonin-related spasms, in particular bronchial spasms or vascular spasms, and ischemic attacks.

Die Erfindung betrifft auch neue l-Phenylalkylen-4-(azacyclohexyl)- diphenyl-methanol-Derivate oder Phenylethenyl-4-(azacyclohexyl)- diphenylmethanol-Derivate der allgemeinen Formel (I),The invention also relates to new 1-phenylalkylene-4- (azacyclohexyl) diphenyl-methanol derivatives or phenylethenyl-4- (azacyclohexyl) diphenylmethanol derivatives of the general formula (I),

O oO o

^ > (I)

Figure imgf000005_0001
in der Rl, R2, R3, R4 und R5, die gleich oder verschieden sind, für Wasserstoff oder die Gruppe -COOH, die in Form eines physiologisch verträglichen Salzes vorliegen kann, -C00R6 -C0R7 oder -CONXY stehen, wobei mindestens ein Rest Rl, R2, R3, R4 oder R5 von Wasserstoff verschieden ist, ^> (I)
Figure imgf000005_0001
in the Rl, R2, R3, R4 and R5, which are the same or different, represent hydrogen or the group -COOH, which may be in the form of a physiologically acceptable salt, -C00R6 -C0R7 or -CONXY, where at least one radical Rl , R2, R3, R4 or R5 is different from hydrogen,

A für die Gruppe -(CH2H, oder -C2H2- steht, R6 Cx - C4-Alkyl bedeutet,A represents the group - (CH 2 H, or -C 2 H 2 -, R6 denotes C x - C 4 alkyl,

R7 für einen von Piperidin, Morpholin oder Pyrrolidin abgeleiteten heterocyclischen Rest steht, X und Y, die gleich oder verschieden sind, für Wasserstoff oder Ci - Cβ-Alkyl stehen, und n die ganze Zahl von 1 oder 2 bedeutet.R7 represents a heterocyclic radical derived from piperidine, morpholine or pyrrolidine, X and Y, which are the same or different, represent hydrogen or Ci - C β -alkyl, and n denotes the integer 1 or 2.

In der vorstehenden allgemeinen Formel (I) sind Rl, R2, R3, R4 und R5 beispielsweise Methyl, Ethyl, n-Propyl, Isopropyl, tert.-Butyl. Falls einer oder mehrere der Reste Rl bis R5 Carboxylgruppen sind, können diese in Form ihrer Salze vorliegen, insbesondere in Form von physiologisch verträglichen Salzen, beispielsweise mit Alkali- oderIn the above general formula (I), R1, R2, R3, R4 and R5 are, for example, methyl, ethyl, n-propyl, isopropyl, tert-butyl. If one or more of the radicals R1 to R5 are carboxyl groups, these can be present in the form of their salts, in particular in the form of physiologically tolerable salts, for example with alkali metal or

Erdalkaligegenionen, wie Lithium, Natrium, Kalium, Calcium, Magnesium, aber auch beispielsweise Eisen, Ammonium. Beispiele für die veresterte Carboxylgruppe -C00R6 sind Methylester, Ethylester, Propylester, Isopropylester. Stellen Rl bis R5 Hydroxyalkylgruppen dar, so sind dies beispielsweise Hydroxyethyl- oder Hydroxypropylgruppen. C3-Cβ-Alkaline earth counterions, such as lithium, sodium, potassium, calcium, magnesium, but also, for example, iron, ammonium. Examples of the esterified carboxyl group -C00R6 are methyl ester, ethyl ester, propyl ester and isopropyl ester. If Rl to R5 represent hydroxyalkyl groups, these are, for example, hydroxyethyl or hydroxypropyl groups. C 3 -C β -

Cycloalkyl weist bevorzugt 5 oder 6 C-Atome auf. Für den Alkoxyrest ist Ci - C3 Alkoxy bevorzugt.Cycloalkyl preferably has 5 or 6 carbon atoms. Ci - C 3 alkoxy is preferred for the alkoxy radical.

Die von Piperidin, Morpholin oder Pyrrolidin abgeleiteten heterocyclischen Reste der Gruppe C0R7 sind über das Stickstoffatom unter Bildung einer Amidbindung an die Carboxylgruppe gebunden. Die heterocyclischen Reste können übliche Substitutenten tragen wie Ci-Cs- Alkyl, Cι-C6-Alkoxy, Halogen, C02H, C02R8, C0R8, wobei R8 für Cχ-Cβ- Alkyl steht.The heterocyclic groups C0R7 derived from piperidine, morpholine or pyrrolidine are bonded to the carboxyl group via the nitrogen atom to form an amide bond. The heterocyclic radicals can carry conventional substituents such as Ci-Cs- alkyl, C ι -C 6 alkoxy, halogen, C0 2 H, C0 2 R8, C0R8, where R8 is Cχ-C β - alkyl.

In der vorstehenden Formel (I) ist n bevorzugt 1.In the above formula (I), n is preferably 1.

Bei den neuen erfindungsgemäßen Derivaten stellt mindestens einer der Reste Rl bis R5 bevorzugt eine Carboxylgruppe, deren Salz oder Ester dar. Besonders bevorzugt ist der Rest R3 eine Carboxylgruppe bzw. deren Salz oder Ester.In the new derivatives according to the invention, at least one of the radicals R 1 to R 5 is preferably a carboxyl group, its salt or ester The radical R3 is particularly preferably a carboxyl group or its salt or ester.

Bevorzugt sind höchstens zwei der Reste Rl bis R5 von Wasserstoff verschieden.A maximum of two of the radicals R 1 to R 5 are preferably different from hydrogen.

Falls A fur die Gruppe -C2H2- steht, so kann diese in eis- oder trans¬ Konfiguration vorliegen. Die trans-Konfiguration ist bevorzugt.If A stands for the group —C 2 H 2 -, this can be in the ice or trans configuration. The trans configuration is preferred.

Die erfindungsgemaß verwendbaren Derivate können in Form von physiologisch vertraglichen oder pharmazeutisch zulässigen Salzen, insbesondere von Saureadditionssalzen vorliegen. Die Salze können mit organischen und anorganischen Sauren gebildet werden, Beispiele sind Salzsaure, Schwefelsaure, Phosphorsaure oder Carbonsäuren und Dicarbonsauren. Beispiele für geeignete organische Sauren sindThe derivatives which can be used according to the invention can be in the form of physiologically acceptable or pharmaceutically acceptable salts, in particular acid addition salts. The salts can be formed with organic and inorganic acids, examples are hydrochloric acid, sulfuric acid, phosphoric acid or carboxylic acids and dicarboxylic acids. Examples of suitable organic acids are

Essigsaure, Fettsauren wie Stearinsaure, Laurinsäure, Olsaure oder Palmitinsaure, Glykolsäure, Milchsaure, Brenztraubensaure, Malonsäure, Bernsteinsaure, Fumarsaure, Apfelsäure, Weinsäure, Zitronensaure, Cyc1amensaure, Ascorbinsäure, Benzoesäure, 4-Hydroxybenzoesaure, Zimtsaure, Salicylsaure, Mandelsäure; es sind auch Sulfonsäuren geeignet wie Methansulfonsäure, Ethansulfonsaure und Hydroxyethansulfonsaure. Die Salze können auf übliche Weise gebildet werden. Beispiele für erfindungsgemaß verwendbare Verbindungen sind: 1. l-(4-Methylphenyl)methyl-4-(azacyclohexyl)-diphenyl-methanolAcetic acid, fatty acids such as stearic acid, lauric acid, oleic acid or palmitic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, cyclic acidic acid, ascorbic acid, benzoic acid, hydroxamic acid, 4-acidic acid, 4-acidic acid, 4-acidic acid, benzoic acid, 4-acidic acid, 4-acidic acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and hydroxyethanesulfonic acid are also suitable. The salts can be formed in the usual way. Examples of compounds which can be used according to the invention are: 1. 1- (4-methylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol

2. 1-(4-Methylphenyl)dimethyl-4-(azacyclohexyl)-diphenyl-methanol2. 1- (4-methylphenyl) dimethyl-4- (azacyclohexyl) diphenyl-methanol

3. 1-(4-Ethylphenyl)methyl-4-(azacyclohexyl)-diphenyl-methanol3. 1- (4-ethylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol

4. 1-(4-Isopropylphenyl)methyl-4-(azacyclohexyl)-diphenyl-methanol4. 1- (4-isopropylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol

5. 2-(4-tert. -Buty1phenyl)methy1-4-(azacyclohexyl)-diphenyl-methanol 6. l-(4-Propylphenyl)methyl-4-(azacyclohexyl)-diphenyl-methanol5. 2- (4-tert-Butylphenyl) methy1-4- (azacyclohexyl) diphenyl-methanol 6. 1- (4-propylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol

7. l-(3-Methylphenyl)methyl-4-(azacyclohexyl)-diphenyl-methanol7. 1- (3-methylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol

8. l-(2-Methylphenyl)methyl-4-(azacyclohexyl)-diphenyl-methanol8. 1- (2-methylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol

9. l-(3-Ethylphenyl)methyl-4-(azacyclohexyl)-diphenyl-methanol9. 1- (3-ethylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol

10. l-(2-Ethylphenyl)methyl-4-(azacyclohexyl)-diphenyl-methanol 11. l-(2-Propylphenyl)methyl-4-(azacyclohexyl)-diphenyl-methanol10. 1- (2-ethylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol 11. 1- (2-propylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol

12. l - (3-Propylphenyl )methyl-4- (azacyclohexyl ) -diphenyl-methanol12. l - (3-Propylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol

13. 1-(4-Methylphenyl)tπmethylen-4-(azacyclohexyl)-dipheny1-methanol 14. 1-(2,4-Dimethylphenyl)methy1-4-(azacyclohexyl)-diphenyl methanol13. 1- (4-methylphenyl) tπmethylene-4- (azacyclohexyl) dipheny1-methanol 14. 1- (2,4-Dimethylphenyl) methyl 1-4- (azacyclohexyl) diphenyl methanol

15. 1-(3,4-Dimethylphenyl )methy1-4-(azacyclohexyl)-diphenyl-methanol15. 1- (3,4-Dimethylphenyl) methyl 1-4- (azacyclohexyl) diphenyl-methanol

16. 4-(Azacyclohexyl-diphenylmethanol )-l-methyl-3' -benzoesäure16. 4- (Azacyclohexyl-diphenylmethanol) -l-methyl-3 '-benzoic acid

17. 4-(Azacyclohexyl-diphenylmethanol)-l-methyl-2'-benzoesäure 18. 4-(Azacyclohexyl-diphenylmethanol)-l-methyl-4'-benzoesäure17. 4- (azacyclohexyl-diphenylmethanol) -l-methyl-2'-benzoic acid 18. 4- (azacyclohexyl-diphenylmethanol) -l-methyl-4'-benzoic acid

19. 4-(Azacyclohexyl-diphenylmethanol)-l-methyl-4'-benzoesaure- ethylester19. 4- (Azacyclohexyl-diphenylmethanol) -l-methyl-4'-benzoic acid ethyl ester

20. 4-(Azacyclohexyl-diphenylmethanol)-l-methy1-4'-benzoesaure- methylester 21. 4-(Azacyclohexyl-diphenylmethanol)-l-methy1-4'-benzoesaure- Natriumsalz20. 4- (Azacyclohexyl-diphenylmethanol) -l-methy1-4'-benzoic acid methyl ester 21. 4- (Azacyclohexyl-diphenylmethanol) -l-methy1-4'-benzoic acid sodium salt

22. 4-(Azacyclohexyl-diphenylmethanol)-l-methyl-4'-benzoesaure- Kaliumsalz22. 4- (Azacyclohexyl-diphenylmethanol) -l-methyl-4'-benzoic acid potassium salt

23. 4-(Azacyclohexyl-diphenylmethanol)-l-[ethenyl-2-(4'-benzoesäure)] Der Nachweis der überraschenden und unerwarteten besonderen Wirkung der genannten l-Phenylalkylen-4-(azacyclohexyl)-diphenylmethanol-Derivate und Phenylethenyl-(4-azacyclohexyl)-diphenylmethanol-Derivate ergibt sich aus der pharmakologischen Wirkung der beschriebenen Verbindungen im Vergleich gegenüber dem Dimethylethylphenyl-4- (hydroxydiphenylmethyl)-l-piperidin-butanol), INN: Terfenadin.23. 4- (Azacyclohexyl-diphenylmethanol) -l- [ethenyl-2- (4'-benzoic acid)] Evidence of the surprising and unexpected special effect of the l-phenylalkylene-4- (azacyclohexyl) -diphenylmethanol derivatives and phenylethenyl- (4-azacyclohexyl) diphenylmethanol derivatives result from the pharmacological action of the compounds described in comparison with dimethylethylphenyl-4- (hydroxydiphenylmethyl) -l-piperidine-butanol), INN: terfenadine.

Beispielhaft für die Wirkungsweise der aufgezeigten Substanzgruppe ist die Wirkung des l-(4-Methylphenyl)methyl-4-(azacyclohexyl)-diphenyl- methanols sowie der 4-(Azacyclohexyl-diphenylmethanol)-l-methyl-4'- benzoesäure. Die Experimente wurden an männlichen NMRI-Mäusen mit einem Körpergewicht von 30 - 35 g durchgeführt. Durch intradermale Injektion von 0,1 mg Serotonin wird die Kapillarpermeabilität erhöht und dadurch die Freisetzung eines intravenös injizierten Farbstoffes bewirkt. Als Maß der seretonin- antagonistischen Aktivität wird die Hemmung der photometrisch bestimmten Farbstoffkonzentration eines bestimmten Hautareals gegenüber einer verarbreichten Kochsalz- sowie Terfenadin-Losung gemessen. In Fig. 1 ist die Beeinflussung der durch intradermale Injektion von 0,1 μg Serotonin erzeugten Kapillarschädigung dargestellt.The action of the group of substances shown is exemplified by the action of l- (4-methylphenyl) methyl-4- (azacyclohexyl) -diphenyl-methanol and 4- (azacyclohexyl-diphenylmethanol) -l-methyl-4'-benzoic acid. The experiments were carried out on male NMRI mice with a body weight of 30-35 g. By intradermal injection of 0.1 mg serotonin, the capillary permeability is increased, thereby releasing an intravenously injected dye. As a measure of the seretonin-antagonistic activity, the inhibition of the photometrically determined dye concentration of a certain area of the skin is measured compared to a solution of common salt and terfenadine. FIG. 1 shows the influence on the capillary damage caused by intradermal injection of 0.1 μg serotonin.

Die Fig. 1 stellt den Farbaustritt in durch 0,1 μg Serotonin induzierten Quaddeln 30 Minuten nach p.o.-Behandlung mit 1. NaCl, 2. Cyproheptadin, 3. Terfenadin 3 mg/kg, 4. + 5. l-(4-Methylphenyl)methyl- 4-(azacyclohexyl)-diphenylmethanol 3 mg/kg bzw. 6 mg/kg, 6. 4- (Azacyclohexyl-diphenylmethanol)-l-methyl-4' -benzoesäure 6 mg/kg, dar. Die Werte sind als Mittelwerte ± s.e.m. angegeben.1 shows the color leakage in wheals induced by 0.1 μg serotonin 30 minutes after po treatment with 1. NaCl, 2. Cyproheptadin, 3. terfenadine 3 mg / kg, 4. + 5. l- (4-methylphenyl) methyl- 4- (azacyclohexyl) -diphenylmethanol 3 mg / kg or 6 mg / kg, 6. 4- (azacyclohexyl-diphenylmethanol ) -l-methyl-4 '-benzoic acid 6 mg / kg. The values are given as mean values ± sem.

Es zeigte sich überraschend und unerwartet eine ausgeprägte serotonin- antagonistische Wirkung der l-Phenylalkylen-4-(azacyclohexyl)- diphenylmethanol-Derivate im Vergleich zu dem Piperidinoalkohol-Derivat Terfenadin.Surprisingly and unexpectedly, a pronounced serotonin-antagonistic effect of the 1-phenylalkylene-4- (azacyclohexyl) diphenylmethanol derivatives was shown in comparison to the piperidino alcohol derivative terfenadine.

Die serotonin-antagonistische Wirkung der aufgezeigten 1-Phenylalkylen- 4-(azacyclohexyl)diphenylmethanol-Derivate war besonders überraschend, da für das strukturverwandte Terfenadin in der Literatur ein Serotoninantagonismus verneint wird (Cheng, H. C. Woodward, J. K.: Arznm. Forsch. 32, 1160-1166, 1982).The serotonin-antagonistic effect of the 1-phenylalkylene-4- (azacyclohexyl) diphenylmethanol derivatives shown was particularly surprising, since serotonin antagonism is denied in the literature for the structurally related terfenadine (Cheng, HC Woodward, JK: Arznm. Forsch. 32, 1160 -1166, 1982).

Da Serotonin als biogenes Amin ein entscheidender Mediator anaphylaktischer Reaktionen vom Sofort-Typ (Typ 1) ist, wurde am Modell des durch Serotonin induzierten Bronchialspasmus am Meerschweinchen untersucht, welche Wirkungen die beschriebenen l-Phenylalkylen-4- (azacyclhexyl)-diphenylmethanol-Derivate auf die Spasmus in-vivo zeigen.Since serotonin as a biogenic amine is a decisive mediator of anaphylactic reactions of the immediate type (type 1), the model of the bronchial spasm induced by serotonin in guinea pigs was used to investigate the effects of the described l-phenylalkylene-4- (azacyclhexyl) diphenylmethanol derivatives which show spasm in vivo.

Methodisch wurde durch Erfassung des Atemwiderstandes als Maß für einen Bronchialspasmus bei konstantem Atemvolumen über den Beatmungsdruck die Wirkung der untersuchten Substanzen erfaßt. An narkotisierten Meerschweinchen wurde ein entsprechender Bronchialspasmus durch intracheale Applikation von Serotonin ausgelöst und registriert. Nach zwei Kontraktionsreizen (Referenzwerte) erfolgte beispielhaft für die serotonin-antagonistische Aktivität der erfindungsgemäß verwendeten 1- Phenylalkylen-4-(azacyclohexyl)-diphenyl-methanol-Derivate, die p.o. Gabe von 4-(Azacyclohexyl-diphenylmethanol)-l-methyl-4'-benzoesäure sowie von 1-(4-Methylphenyl)methyl-4-(azacyclohexyl)-diphenyl-methanol im Vergleich zu Terfenadin in den Dosierungen von 6 mg/kg Körpergewicht. Anschließend wurden bis zu 5 h weitere Spasmen provoziert und deren Ausmaß auf die Wirkung der Referenzlösung bezogen. Die serotonin-antagonistische Wirkung der genannten l-Phenylalkylen-4- (azacyclohexyl)diphenylmethanol-Derivate trat rasch ein und hatte nach 100 min. das Maximum, d.h. eine völlige Blockade des Spasmus erreicht (Fig. 2). Terfenadin zeigte demgegenüber keinerlei Serotonin- antagonistische Aktivität im Vergleich zur Negativkontrolle.The effect of the substances examined was methodically determined by recording the breathing resistance as a measure of bronchial spasm with constant breathing volume via the ventilation pressure. A corresponding bronchial spasm was triggered and registered in anesthetized guinea pigs by intracheal application of serotonin. After two contraction stimuli (reference values), the po administration of 4- (azacyclohexyl-diphenylmethanol) -l-methyl-4 was carried out, for example, for the serotonin-antagonistic activity of the 1-phenylalkylene-4- (azacyclohexyl) -diphenyl-methanol derivatives used according to the invention '-benzoic acid and 1- (4-methylphenyl) methyl-4- (azacyclohexyl) diphenyl-methanol compared to terfenadine in doses of 6 mg / kg body weight. Subsequently, further spasms were provoked for up to 5 hours and their extent related to the effect of the reference solution. The serotonin-antagonistic effect of the l-phenylalkylene-4- mentioned (Azacyclohexyl) diphenylmethanol derivatives occurred rapidly and had after 100 min. reached the maximum, ie a complete blockage of the spasm (Fig. 2). In contrast, terfenadine showed no serotonin-antagonistic activity in comparison to the negative control.

In der Fig. 2 wird das relative Ausmaß des Bronchialspasmus am Meerschweinchen in Abhängigkeit von der Zeit nach p.o. -Behandlung mit NaCl {•), 6 mg/kg, Terfenadin (I), 6 mg/kg l-(4-Methylphenyl)methyl-4- (azacyclohexyl)-diphenylmethanol (A), 6 mg/kg 4-(Azacyclohexyl- diphenylmethanol)l-methyl-4/-benzoesäure (x) angegeben; es sind die Mittelwerte ± s.e.m. dargestellt.2 shows the relative extent of bronchial spasm in guinea pigs as a function of the time after po treatment with NaCl {•), 6 mg / kg, terfenadine (I), 6 mg / kg l- (4-methylphenyl) methyl -4- (azacyclohexyl) diphenylmethanol (A), 6 mg / kg 4- (azacyclohexyldiphenylmethanol) l-methyl-4 / -benzoic acid (x); the mean values ± sem are shown.

Die dargestellte serotonin-antagonistische Wirksamkeit der 1- Phenylalkylen-4-(azacyclhexyl)-diphenylmethanol-Derivate zeigt sich weiterhin in typischer Weise sowohl am isolierten Gefäßpräparat der A. carotis externa als auch am isolierten Herzkrankzgefäß des Meerschweinchens, d.h. entsprechende durch Serotonin induzierte Spasmen konnten dosisabhängig vollständig inhibiert werden.The serotonin-antagonistic activity of the 1-phenylalkylene-4- (azacyclhexyl) -diphenylmethanol derivatives shown is furthermore typically shown both in the isolated vascular preparation of the external carotid artery and in the isolated cardiac disease vessel of the guinea pig, i.e. Corresponding spasms induced by serotonin could be completely inhibited depending on the dose.

Die überraschende Serotonin-antagonistische Wirksamkeit der aufgezeigten 1-Phenylalkylen-4-(azacyclohexyl)-diphenylmethanol- Derivate ist um so bemerkenswerter, als die genannten Substanzen praktisch keine strukturelle Verwandtschaft zu den bisher bekannten Serotoninantagonisten wie Methysergid, Ondansetron oder Cyproheptadin aufweisen.The surprising serotonin-antagonistic effectiveness of the 1-phenylalkylene-4- (azacyclohexyl) diphenylmethanol derivatives shown is all the more remarkable since the substances mentioned have practically no structural relationship to the previously known serotonin antagonists such as methysergide, ondansetron or cyproheptadine.

Die neu entdeckte und unerwartete Wirkqualität der aufgezeigten Substanzklasse bedeutet die Möglichkeit der therapeutischen Beeinflussung von Krankheitszustanden, bei denen Serotonin als wesentlicher Mediator von Bedeutung ist. Zu nennen ist die Hemmung der Serotonin-Wirkung bei anaphylaktischen Reaktionen vom Sofort-Typ (Typ 1) nach Coombs und Gell, bei der es zu einer massiven Freisetzung von Serotonin aus Mastzellen kommt; die Behandlung von peripheren und zentralen serotoninbedingten Gefäßspasmen verbunden mit transitorischen ischämischen Attacken sowohl cerebraler als auch kardialer Lokalisation. Der Anwendungsbereich der beanspruchten Derivate als Serotonin- Antagonisten erstreckt sich sowohl auf den human- als auch den gesamten veterinärmedizinischen Bereich.The newly discovered and unexpected quality of action of the class of substances shown means the possibility of therapeutically influencing disease states in which serotonin is an important mediator. The inhibition of the serotonin effect in anaphylactic reactions of the immediate type (type 1) according to Coombs and Gell, in which there is a massive release of serotonin from mast cells; the treatment of peripheral and central serotonin-related vasospas associated with transient ischemic attacks of both cerebral and cardiac localization. The scope of the claimed derivatives as serotonin antagonists extends to both the human and the entire veterinary field.

Die experimentellen pharmakologischen Ergebnisse zeigen, daß die 1- Phenylalkylen-4-(azacyclohexyl)-diphenylmethanol-Derivate und Pheny1ethenyl-4-(azacyclohexyl)-diphenylmethanol-Derivate wirksame Serotonin-Antagonisten darstellen, die eine Therapie von Krankheitszustanden ermöglichen, deren Behandlung bis heute nicht befriedigend ist.The experimental pharmacological results show that the 1-phenylalkylene-4- (azacyclohexyl) -diphenylmethanol derivatives and phenylethenyl-4- (azacyclohexyl) -diphenylmethanol derivatives are effective serotonin antagonists which enable the treatment of disease states, the treatment of which to date is not satisfactory.

Die erfindungsgemäß verwendbaren l-Phenylalkylen-4-(azacyclohexyl)- diphenylmethanol-Derivate und Phenylethenyl-4-(azacyclohexyl)- diphenylmethanol-Derivate können beispielsweise oral, parenteral, z.B. intravenös, subcutan, intramuskulär, intranasal, intratracheal, intraoculär oder rektal appliziert sowie in Nebel- oder Pulverform verabreicht werden. Die Dosen der applizierten Substanz hängen von der Art der Anwendung und der individuellen Empfindlichkeit des zu Therapierenden ab. Der Dosisbereich erstreckt sich beispielsweise von 0,05 - 10 mg/kg/Tag zur Erzielung der gewünschten Wirkung. The l-phenylalkylene-4- (azacyclohexyl) diphenylmethanol derivatives and phenylethenyl 4- (azacyclohexyl) diphenylmethanol derivatives which can be used according to the invention can be administered, for example, orally, parenterally, e.g. administered intravenously, subcutaneously, intramuscularly, intranasally, intratracheally, intraocularly or rectally, and administered in mist or powder form. The doses of the applied substance depend on the type of application and the individual sensitivity of the person to be treated. The dose range extends, for example, from 0.05 to 10 mg / kg / day to achieve the desired effect.

Claims

Patentansprüche: Claims: 1. Verwendung von l-Phenylalkylen-4-(azacyc1ohexyl)-diphenylmethanol- Derivaten oder Phenyletheny1-4-(azacyclohexyl)-diphenylmethanol- Derivaten der allgemeinen Formel1. Use of l-phenylalkylene-4- (azacyc1ohexyl) diphenylmethanol derivatives or phenyletheny1-4- (azacyclohexyl) diphenylmethanol derivatives of the general formula
Figure imgf000012_0001
in der Rl, R2, R3, R4 und R5, die gleich oder verschieden sind, für
Figure imgf000012_0001
in the R1, R2, R3, R4 and R5, which are the same or different, for Wasserstoff, d - C-.-Alkyl, C3-Cβ-Cycloalky1, d - C4-Hydrogen, d - C -.- alkyl, C 3 -C β -cycloalky1, d - C 4 - Hydroxyalkyl, Ci - C4-Alkoxy, Hydroxy, die Gruppe -COOH, die inHydroxyalkyl, Ci - C 4 alkoxy, hydroxy, the group -COOH, which in Form eines physiologisch verträglichen Salzes vorliegen kann,May be in the form of a physiologically acceptable salt, -C00R6, -C0R7, oder -CONXY stehen, A für die Gruppe
Figure imgf000012_0002
oder -C2H2- steht,-C00R6, -C0R7, or -CONXY stand, A for the group
Figure imgf000012_0002
or -C 2 H 2 - stands, R6 Cx - C4-Alkyl bedeutet,R6 is C x - C 4 alkyl, R7 für einen von Piperidin, Morpholin oder Pyrrolidin abgeleiteten heterocyclischen Rest steht,R7 represents a heterocyclic radical derived from piperidine, morpholine or pyrrolidine, X und Y, die gleich oder verschieden sind, für Wasserstoff oder C-_ - Cβ-Alkyl stehen, und n eine ganze Zahl von 1 oder 2 bedeutet, sowie von deren Salzen, als Serotonin-Antagonisten, bzw. bei der Behandlung vonX and Y, which are the same or different, represent hydrogen or C-_ - C β- alkyl, and n represents an integer of 1 or 2, and their salts, as serotonin antagonists, or in the treatment of Krankheitszustanden, bei denen Serotonin als Mediator wirkt, sowie zur Herstellung von Arzneimitteln, die als Serotonin-Antagonisten wirken, bzw. zur Herstellung von Arzneimitteln zur Behandlung vonConditions in which serotonin acts as a mediator, as well as for the manufacture of medicinal products that act as serotonin antagonists or for the manufacture of medicinal products for the treatment of Krankheitszustanden, bei denen Serotonin als Mediator wirkt. Conditions in which serotonin acts as a mediator. 2. Verwendung nach Anspruch 1, wobei höchstens zwei der Reste Rl, R2, R3, R4 und R5 von Wasserstoff verschieden sind.2. Use according to claim 1, wherein at most two of the radicals Rl, R2, R3, R4 and R5 are different from hydrogen. 3. Verwendung nach Anspruch 1 und 2 zur Behandlung von, bzw. zur Herstellung von Arzneimitteln zur Behandlung von serotoninbedingten pressorischen sowie diktatorischen Gefäßwirkungen.3. Use according to claim 1 and 2 for the treatment of, or for the manufacture of medicaments for the treatment of serotonin-related pressor and dictatorial vascular effects. Verwendung nach Anspruch 1 und 2 zur Behandlung von, bzw. zur Herstellung von Arzneimitteln zur Behandlung von serotoninbedingten Bronchialspasmen.Use according to claims 1 and 2 for the treatment of or for the manufacture of medicaments for the treatment of serotonin-related bronchial spasms. 5. Verwendung nach Anspruch 1 und 2 zur Behandlung von, bzw. zur Herstellung von Arzneimitteln zur Behandlung von serotoninbedingten Gefäßspasmen.5. Use according to claim 1 and 2 for the treatment of, or for the manufacture of medicaments for the treatment of serotonin-related vascular spasms. 6. Verwendung nach Anspruch 1 und 2 zur Behandlung von, bzw. zur Herstellung von Arzneimitteln zur Behandlung von serotoninbedingten ischämischen Attacken.6. Use according to claim 1 and 2 for the treatment of, or for the manufacture of medicaments for the treatment of serotonin-related ischemic attacks. 7. 1-Phenylalkylen-4-(azacyclohexyl)-diphenylmethanol-Derivate oder Pheny1etheny1-4-(azacyclohexyl)-diphenylmethanol-Derivate der allgemeinen Formel7. 1-phenylalkylene-4- (azacyclohexyl) diphenylmethanol derivatives or phenyletheny1-4- (azacyclohexyl) diphenylmethanol derivatives of the general formula
Figure imgf000013_0001
Figure imgf000013_0001
 in derin the Rl, R2, R3, R4 und R5, die gleich oder verschieden sind, für Wasserstoff oder die Gruppe -COOH, die in Form eines physiologisch verträglichen Salzes vorliegen kann, -C00R6, -C0R7 oder -CONXY stehen, wobei mindestens ein Rest Rl, R2, R3, R4 oder R5 von Wasserstoff verschieden ist,Rl, R2, R3, R4 and R5, which are the same or different, represent hydrogen or the group -COOH, which may be in the form of a physiologically acceptable salt, -C00R6, -C0R7 or -CONXY, where at least one radical Rl, R2, R3, R4 or R5 from Hydrogen is different A für die Gruppe 4CH2-K- oder -C2H2- stehtA represents the group 4CH 2 -K- or -C 2 H 2 - R6 Ci - C4-Alkyl bedeutet,R6 means Ci - C 4 alkyl, R7 für einen von Piperidin, Morpholin oder Pyrrolidin abgeleiteten heterocyclischen Rest steht,R7 represents a heterocyclic radical derived from piperidine, morpholine or pyrrolidine, X und Y, die gleich oder verschieden sind, für Wasserstoff oderX and Y, which are the same or different, represent hydrogen or Cx - Cβ-Alkyl stehen, und n die ganze Zahl von 1 oder 2 bedeutet, sowie deren Salze.C x - C β alkyl, and n is the integer of 1 or 2, and their salts. 1010 8. Derivate nach Anspruch 7, wobei höchstens zwei der Reste Rl , R2, R3, R4 oder R5 von Wasserstoff verschieden sind.8. Derivatives according to claim 7, wherein at most two of the radicals Rl, R2, R3, R4 or R5 are different from hydrogen. 9. Derivate nach Anspruch 7, worin vier der Reste Rl, R2, R3, R4 und 15 R5 Wasserstoff bedeuten, sowie deren Salze.9. Derivatives according to claim 7, wherein four of the radicals Rl, R2, R3, R4 and 15 R5 are hydrogen, and their salts. 10. Derivate nach Anspruch 7 , worin Rl, R2, R4 und R5 Wasserstoff und R3 -COOH, ein physiologisch verträgliches Salz davon, -C00R6, -C00R7 oder -CONXY bedeutet, worin X, Y, R6 und R7 wie in Anspruch10. Derivatives according to claim 7, wherein Rl, R2, R4 and R5 are hydrogen and R3 is -COOH, a physiologically acceptable salt thereof, -C00R6, -C00R7 or -CONXY, wherein X, Y, R6 and R7 are as in claim 20 7 definiert sind, sowie deren Salze.20 7 are defined, and their salts. 11. Verwendung nach Ansprüchen 1 bis 6, wobei das l-Phenylalkylen-4- (azacyclohexyl)-diphenylmethanolderivat11. Use according to claims 1 to 6, wherein the l-phenylalkylene-4- (azacyclohexyl) diphenylmethanol derivative
Figure imgf000014_0001
^ i
Figure imgf000014_0001
^ i (l - ( 4-Methylphenyl )methyl -4- ( azacyclohexyl ) -di pheny lmethanol ) i st . i0(l - (4-Methylphenyl) methyl -4- (azacyclohexyl) -di phenylmethanol) i st. i0 12. Verwendung oder Derivat nach Ansprüchen 1 bis 6 bzw. 7 b i s 10 , wobe i das 1 -Pheny lalkylen-4- (azacyc lohexyl ) -di pheny lmethanolderi vat 9
Figure imgf000015_0001
12. Use or derivative according to claims 1 to 6 or 7 to 10, where the 1-phenylalkylene-4- (azacyc lohexyl) -di pheny lmethanolderi vat 9
Figure imgf000015_0001
 ((4-Azacyclohexyl-di pheny lmethanol )-l-methy 1-4' -benzoesäure) ist. ((4-Azacyclohexyldiphenylmethanol) -l-methyl 1-4 '-benzoic acid).
PCT/EP1996/005626 1995-12-20 1996-12-14 Novel 1-phenylalkyl/alkylene-4-(.alpha.-hydroxydiphenylmethyl)-piperidine derivatives and their use as serotonin antagonists Ceased WO1997022583A1 (en)

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AU13014/97A AU1301497A (en) 1995-12-20 1996-12-14 Novel 1-phenylalkyl/alkylene-4-(.alpha.-hydroxydiphenylmethyl)-pip eridine derivatives and their use as serotonin antagonists

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WO2000031034A1 (en) * 1998-11-20 2000-06-02 Fmc Corporation Insecticidal photostable acid salt derivatives of n-benzyl-4-benzhydrolpiperidines
WO2001014332A1 (en) * 1999-08-21 2001-03-01 Merck Patent Gmbh Piperidine alcohols

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WO2000031034A1 (en) * 1998-11-20 2000-06-02 Fmc Corporation Insecticidal photostable acid salt derivatives of n-benzyl-4-benzhydrolpiperidines
WO2001014332A1 (en) * 1999-08-21 2001-03-01 Merck Patent Gmbh Piperidine alcohols
US6756370B1 (en) * 1999-08-21 2004-06-29 Merck Patent Gmbh Piperidine alcohols

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