WO1993011761A1 - Aryl-triflates and related compounds - Google Patents

Aryl-triflates and related compounds Download PDF

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WO1993011761A1
WO1993011761A1 PCT/DK1992/000389 DK9200389W WO9311761A1 WO 1993011761 A1 WO1993011761 A1 WO 1993011761A1 DK 9200389 W DK9200389 W DK 9200389W WO 9311761 A1 WO9311761 A1 WO 9311761A1
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PCT/DK1992/000389
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Håkan WIKSTRÖM
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H. Lundbeck A/S
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Publication of WO1993011761A1 publication Critical patent/WO1993011761A1/en
Priority to NO942296A priority patent/NO942296D0/en
Priority to FI942931A priority patent/FI942931A0/en

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    • C07D223/16—Benzazepines; Hydrogenated benzazepines
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
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    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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    • C07D221/28—Morphinans
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
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    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention is directed toward new aryltriflates, and their pharmaceuti ⁇ cally acceptable salts, to processes for preparing such compounds, pharmaceutical preparations of such compounds and the use of such compounds in manufacture of a pharmaceutical preparation.
  • Pharmaceutical preparations of these compounds are useful for peripheral and central nervous system disorders in mammals.
  • Aryl triflates are used as intermediates in organic syntheses. They can thus be removed via reduction (NEt 3 +HCOO-) or substituted by other groups like CN and COOR (Oda, R., Kagaku (Kyoto) 1987, 42, 710-11 ; Cacchi, S. et al., Tetrahedron Lett 1986, 27, 5541-4; Chambers, M. R. I. et al., J. Chem. Soc, Perkin Trans 1989, 1, 1365-6; Kotsuki, H. et al., Synthesis 1990; Martorell, G. et al., Tetrahedron Lett
  • Enzymatic deactivation of drugs is a well known phenomenon, in particular phenols and methoxylated aryls are in general easily oxidized in the liver and elsewhere where these enzyme systems are active (e. g. the gastric mucosa and the lungs). Inactivation of phenols can take place via direct conjugation (sulphation and glucoronidation) and/or via initial oxidation and then conjugation.
  • the inhibition of such enzymatic deactivation of drugs is highly desired, and the object of the present invention is to provide therapeutically effective drugs having a low liability for enzymatic deactivation.
  • drugs with better pharmacokinetic properties than the corresponding hydroxy and/or alkoxy substi ⁇ tuted analogues are particularly preferred.
  • triflate derivatives of drugs comprising a hydroxyaryl group or a similar group possess both good pharmacodynamic and good pharmaco ⁇ kinetic properties including a high resitance against enzymatic deactivation.
  • This invention relates to aryltriflates and related compounds having the general Formula 1 :
  • Formula 1 or pharmaceutically acceptable acid addition salts thereof wherein Ar is an aromatic or heteroaromatic system of a compound which has a therapeutic, biological activity when it, in the same position, carries a hydroxy, alkyloxy, halo, ester or cyano group; and Ri is CF 3 , (C Cs) alkyl, -CH 2 -(C 3 -C ⁇ ) cycloalkylalkyl, substituted phenyl, substi ⁇ tuted benzyl, substituted phenylethyl, substituted phenylpropyl, substituted 2-thio ⁇ phenylethyl or substituted 2-thiophenylpropyl; except the compounds wherein Ar is 2-(dipropylamino)-tetralin-8-yl or 4- acetamidophenyl.
  • the invention is directed to compounds of Formula 1 ; wherein Ri is CF 3 .
  • (C n -C m ) is inclusive such that a compound of (C C ⁇ ) would include compounds of one to 8 carbons and their isomeric forms.
  • Alkyl refers to an branched or unbranched aliphatic hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pen- tyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Compounds which has a therapeutic, biological activity when they, in the same position, carries a hydroxy, alkyloxy, halo, ester or cyano group may be any therapeutical effective compounds comprising an aryl group carrying such a substituent.
  • the compound is a drug acting in the central nervous system, in particular a dopamine agonist or antagonist, a dopamine autoreceptor agonist, a 5- HTIA ligand, 5-HTID ligand, a 5-HT 2 antagonist, an antipsychotic, a sigma ligand, or a melatonine analogue, beta blocker, analgesic, etc.
  • R_ is as defined above;
  • R2 designates C Cs alkyl, CH 2 -(C3-C8) cycloalkylalkyl, arylalkyl, phenylethyl or 2-thiophenylethyl;
  • R3 designates C Cs alkyl, CH2-(C3-Cs) cycloalkylalkyl, arylalkyl, phenylethyl or 2-thiophenylethyl;
  • X is CH 2 , O or S; and
  • Y is CH 2 , O or S.
  • R 2 and R 3 are not at the same time propyl
  • the pharmaceutically acceptable acid addition salts of the compounds may be for ⁇ med by reaction with non-toxic organic or inorganic acids in an aqueous miscible solvent, such as acetone or ethanol, and subsequent isolation of the salt by concen ⁇ tration and cooling or by reaction with an excess of the acid in aqueous immiscible 5 solvent, such as ethyl ether or chloroform, with the desired salt separating directly.
  • an aqueous miscible solvent such as acetone or ethanol
  • organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis methylene-salicylic, methanesulfonic, ethane- disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, o cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids as well as the 8- halotheophyllines, for example 8-bromo-theophylline.
  • inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
  • these salts may also be prepared by the classical method of 5 double decomposition of appropriate salts, which is well known to the art.
  • the compounds of the present invention will normally be adminis ⁇ tered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically 0 acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier.
  • a pharmaceutically 0 acceptable non-toxic, acid addition salt such as the hydrochloride, lactate, acetate, sulfamate salt
  • the suitable daily doses of the compounds of the invention are from about 1 mg to 2000 mg for oral application, preferentially 50-500 mg, and 0.1 to about 100 mg for parenteral application, preferentially 0.5-50 mg daily doses.
  • the daily dose will preferably be administered in individual dosages one to 4 times daily and the dosage amounts are based on an individual having a o weight of 70 kg.
  • the compounds of this invention have high oral potency and long duration of action, as compared to their hydroxy or alkoxy analogues. Both these pharmacokinetic features are beneficial to effective clinical treatment.
  • the triflating agent is conveniently triflic anhydride (Method A), N-phenyltrifluoro- methanesulfonimide (Method B) or triflic acid chloride (Method C).
  • trans-racemic 82172-01-8 trans-4aS,10bS: 131484-03-2 r trans-4aR,10bR: 131484-02-1 cis-racemic: 82172-00-7 cis-4aR,10bS: 109062-23-9 cis-4aS,10bR: 109062-21-7
  • the electronegativity of the OTf group is indicated by the downfield shift of the aromatic protons from 6.3-6.9 in the starting material (8-OH-2-(acetamido)tetralin) to 7.0-7.3 in the triflated product (with respect to the electronic effects of the triflate group, see also ref: Stang, P. and Anderson, A. G., J. Org. Chem. 1976, 41 , 781 ).
  • N-phenyltrifluoromethanesulfonimide [RN 37595-74-7; from Aldrich] (75 mg; 0.21 mmol) was added in one portion at room temperature.
  • the reaction mixture was monitored with GC and TLC, and after 20 h all starting material was consumed.
  • the solvent and the Et 3 N were evaporated and the remaining oil was dissolved in ether (10 mL) and washed 3 times with NaCI saturated water, separated and dried ( gS ⁇ 4 ).
  • the solvent was evaporated and the remaining oil was dissolved in EtOH (5 mL) and fumaric acid (0.23 g, 0.20 mmol) dissolved in EtOH (1 mL) was added and the solvent was evaporated.
  • the remaining solid was recrystaliized from i-propylacetate.
  • Example 6 11-Hydroxy-10-trifluoromethyl(sulfonyl)oxy-aporphine.
  • 3-Trifluoromethansulfonyloxy-morphine (fumarate salt) 100 mg; 0.19 mmol was stirred for 3 hrs at 105 °C in MeSOsH (5 mL) under N 2 -atmosphere.
  • the reaction mixture was allowed to cool to room temperature and was then diluted with H2O (10 mL).
  • the aquous layer was basified with NaHC03 (s) and then extracted with CH2CI2 (3x25 mL).
  • the organic layers were combined, dried over Na 2 S ⁇ 4 , filtered and evaporated in vacuo.
  • Dextrorphan tartaric acid salt (1 :1) (1.0 g; 2.46 mmol) was suspended in CH 2 CI 2 5 (100 mL) and Et 3 N (2 mL; 14 mmol) was added and the solution was stirred until all the starting material had dissolved. Then the mild, triflating agent N-phenyltrifluoro- methanesulfonimide [RN 37595-74-7; from Aldrich] (1.05 g; 2.94 mmol) was added in one portion. The reaction mixture was monitored with GC and after 4 h all dextrorphan was consumed. The solvent and the Et 3 N were evaporated and the
  • the base was converted to its hydrochloride salt with HCI saturated ether.
  • the IR spectrum shows strong absorption bands at: 3000, 1460, 1420, 1210 and 1140 cm -1.
  • This test is a test for the DA Di receptor antagonistic effect in vivo.
  • the experiments are performed as described by Arnt, J.et al., J. Neural. Transm. 1986, 67, 225-240.
  • the test is a test for 5-HT 2 -antagonistic effect testing the ability to inhibit quipazine induced head twitches.
  • the method and test results for some reference substances are published by Arnt et al. (Drug Development Research, 16, 59-70, 1989). Dopamine agonist studies

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Abstract

Aryltriflates and related compounds having general formula (1) wherein Ar is an aromatic or heteroaromatic system of a compound which has a therapeutic, biological activity when it, in the same position, carries a hydroxy, alkyloxy, halo, ester or cyano group; wherein R1 is CF3, (C1-C8)alkyl, -CH2-(C3-C8)cycloalkylalkyl, substituted phenyl, substituted benzyl, substituted phenylethyl, substituted phenylpropyl, substituted 2-thiophenylethyl or substituted 2-thiophenylpropyl; possess both good pharmacodynamic and good pharmacokinetic properties and are thus useful drugs.

Description

ARYL-TRIFLATES AND RELATED COMPOUNDS.
Field of the Invention
The present invention is directed toward new aryltriflates, and their pharmaceuti¬ cally acceptable salts, to processes for preparing such compounds, pharmaceutical preparations of such compounds and the use of such compounds in manufacture of a pharmaceutical preparation. Pharmaceutical preparations of these compounds are useful for peripheral and central nervous system disorders in mammals.
Background of the Invention
Aryl triflates are used as intermediates in organic syntheses. They can thus be removed via reduction (NEt3+HCOO-) or substituted by other groups like CN and COOR (Oda, R., Kagaku (Kyoto) 1987, 42, 710-11 ; Cacchi, S. et al., Tetrahedron Lett 1986, 27, 5541-4; Chambers, M. R. I. et al., J. Chem. Soc, Perkin Trans 1989, 1, 1365-6; Kotsuki, H. et al., Synthesis 1990; Martorell, G. et al., Tetrahedron Lett
1990, 31, 2357-60; Peterson, G. A. et al., Tetrahedron eft 1987, 28, 1381-4; Roth, G. P. et al., J. Org. Chem. 1991, 56, 3493-6; Saa, J. M. et al., J. Org. Chem. 1990, 55, 991-5; Subramanian, L R. et al., Synthesis 1984; Chambers, M. R. I. et al., J. Chem. Soc, Perkin Trans 1989, 1, 1365-6.; Takagi, K. et al., Bull. Chem. Soc. Jpn.
1991 , 64, 1118-21 ; EP-A1 399982; Liu, Y. et a!., Bioorg. Med. Chem. Lett. 1991 , 1, 257-62.
One aryltriflate with biological activity (5-HTTA affinity in a CNS preparation) is known ( EP-A1 399982; Liu, 1991 supra). In addition, the triflate of the analgetic substance paracetamol has been used as an intermediate in the conversion of the phenol into its cyano analogue (Chambers, 1989, supra; Takagi, 1991 , supra).
Enzymatic deactivation of drugs (the Cytochrome P450 isoenzyme system) is a well known phenomenon, in particular phenols and methoxylated aryls are in general easily oxidized in the liver and elsewhere where these enzyme systems are active (e. g. the gastric mucosa and the lungs). Inactivation of phenols can take place via direct conjugation (sulphation and glucoronidation) and/or via initial oxidation and then conjugation.
Obviously, the inhibition of such enzymatic deactivation of drugs is highly desired, and the object of the present invention is to provide therapeutically effective drugs having a low liability for enzymatic deactivation. in particular drugs with better pharmacokinetic properties than the corresponding hydroxy and/or alkoxy substi¬ tuted analogues.
It has now been found that triflate derivatives of drugs comprising a hydroxyaryl group or a similar group possess both good pharmacodynamic and good pharmaco¬ kinetic properties including a high resitance against enzymatic deactivation.
Summary of the invention
This invention relates to aryltriflates and related compounds having the general Formula 1 :
Figure imgf000004_0001
Formula 1 or pharmaceutically acceptable acid addition salts thereof, wherein Ar is an aromatic or heteroaromatic system of a compound which has a therapeutic, biological activity when it, in the same position, carries a hydroxy, alkyloxy, halo, ester or cyano group; and Ri is CF3, (C Cs) alkyl, -CH2-(C3-Cβ) cycloalkylalkyl, substituted phenyl, substi¬ tuted benzyl, substituted phenylethyl, substituted phenylpropyl, substituted 2-thio¬ phenylethyl or substituted 2-thiophenylpropyl; except the compounds wherein Ar is 2-(dipropylamino)-tetralin-8-yl or 4- acetamidophenyl. In a preferred embodiment, the invention is directed to compounds of Formula 1 ; wherein Ri is CF3.
Processes for preparation of these compounds, their pharmaceutical use and pharmaceutical preparations comprising such compounds constitute further aspects of the invention.
Detailed Description of the Invention
As used herein the term (Cn-Cm) is inclusive such that a compound of (C Cβ) would include compounds of one to 8 carbons and their isomeric forms. Alkyl refers to an branched or unbranched aliphatic hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pen- tyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl.
Halogen means fluoro, chloro, bromo or iodo.
It will be apparent to those skilled in the art that some compounds of this invention may contain chiral centers. The scope of this invention includes all enantiomeric or diastereomeric forms of Formula 1 compounds either in pure form or as mixtures of enantiomers or diastereomers. The therapeutic properties of the compounds may to a greater or lesser degree depend on the stereochemistry of a particular compound. Pure enantiomers as well as enantiomeric or diastereomeric mixtures are within the scope of the invention.
"Compounds which has a therapeutic, biological activity when they, in the same position, carries a hydroxy, alkyloxy, halo, ester or cyano group" may be any therapeutical effective compounds comprising an aryl group carrying such a substituent.
Preferably, the compound is a drug acting in the central nervous system, in particular a dopamine agonist or antagonist, a dopamine autoreceptor agonist, a 5- HTIA ligand, 5-HTID ligand, a 5-HT2 antagonist, an antipsychotic, a sigma ligand, or a melatonine analogue, beta blocker, analgesic, etc.
Specific examples of Ar appears from the following table showing examples of compounds of the invention.
In the table, R_ is as defined above; R2 designates C Cs alkyl, CH2-(C3-C8) cycloalkylalkyl, arylalkyl, phenylethyl or 2-thiophenylethyl; R3 designates C Cs alkyl, CH2-(C3-Cs) cycloalkylalkyl, arylalkyl, phenylethyl or 2-thiophenylethyl; X is CH2, O or S; and Y is CH2, O or S.
AntigsthrngtiPS
Figure imgf000006_0001
Terbutalin analogues
Salbutamol analogue
Figure imgf000006_0002
Dopamine agonists
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000007_0003
Roxindole analogues
Figure imgf000007_0004
Dopamine agonists cont'd
Figure imgf000008_0001
Dopamine autoreceptor antagonists
Figure imgf000008_0002
D1 agonists and/or antagonists
Figure imgf000008_0003
SK&F38393 analogues
SCH23390 analogue
Figure imgf000008_0004
-HT1 A agonists
Figure imgf000009_0001
R2 and R3 are not at the same time propyl
Figure imgf000009_0002
Figure imgf000009_0003
trans
Figure imgf000009_0004
Figure imgf000009_0005
Figure imgf000009_0006
5-HT1A lioands
Figure imgf000010_0001
5-HT1D liαands
Sumatriptan analogue
Figure imgf000010_0002
Sigma ligands
analogue
Figure imgf000010_0003
Anti-Alzheimers
7-Methoxytacrine analogue
Figure imgf000010_0004
Neuroleptics
Clozapine analogue
Chlorpromazine and levomepromazine analogue
Figure imgf000011_0001
Figure imgf000011_0002
Melatonine analogues
Figure imgf000011_0003
Analgesics
morphine analogue
Figure imgf000012_0001
analogue
Figure imgf000012_0002
acetyl salicylic acid analogue
Ketobemidone analogue
Figure imgf000012_0003
Beta-blockers
prenalterol analogue
oxprenolol analogue
Figure imgf000012_0004
The pharmaceutically acceptable acid addition salts of the compounds may be for¬ med by reaction with non-toxic organic or inorganic acids in an aqueous miscible solvent, such as acetone or ethanol, and subsequent isolation of the salt by concen¬ tration and cooling or by reaction with an excess of the acid in aqueous immiscible 5 solvent, such as ethyl ether or chloroform, with the desired salt separating directly.
Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis methylene-salicylic, methanesulfonic, ethane- disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, o cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids as well as the 8- halotheophyllines, for example 8-bromo-theophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of 5 double decomposition of appropriate salts, which is well known to the art.
In clinical practice the compounds of the present invention will normally be adminis¬ tered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically 0 acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier. The use and administration to a patient to be treated in the clinic would be readily apparent to a person of ordinary skill in the art.
5 In therapeutical treatment the suitable daily doses of the compounds of the invention are from about 1 mg to 2000 mg for oral application, preferentially 50-500 mg, and 0.1 to about 100 mg for parenteral application, preferentially 0.5-50 mg daily doses. The daily dose will preferably be administered in individual dosages one to 4 times daily and the dosage amounts are based on an individual having a o weight of 70 kg.
The compounds of this invention have high oral potency and long duration of action, as compared to their hydroxy or alkoxy analogues. Both these pharmacokinetic features are beneficial to effective clinical treatment.
The compounds of this invention may be obtained by the general general synthetic strategy exemplified in Scheme 1 :
Scheme 1
Figure imgf000014_0001
The triflating agent is conveniently triflic anhydride (Method A), N-phenyltrifluoro- methanesulfonimide (Method B) or triflic acid chloride (Method C).
Starting materials for the preparation of the compounds of the invention are commercially available, or they can be obtained by the methods described below or by methods known in the art.
Specific examples of starting materials for their preparation are shown below. In the formulas X and Y are as defined above:
Dopamine agonists: Starting materials
CAS RN's: trans racemic: 110311-52-9 trans-4aS,10bS: 93601-83-3 trans-4aR,10bR : 93601 -82-2 cis racemic: 82171-94-6 cis-4aS,10bR: 93601 -81-1 cis-4aR,10bS: 93601-80-0
Figure imgf000015_0001
CAS RN's: trans racemic: 110311-53-0 trans-4aS,10bS: 110311-50-7 trans-4aR,10bR : 103302-90-5 cis-racemic: 110311 -55-2 cis-4aS,10bR: 93601 -81 -1
Figure imgf000015_0002
cis-4aR,10bS: 93601 -80-0
11-hydroxy aporphine
(-)-apomorphine: CAS RN: 58-00-4
Figure imgf000015_0004
Dopamine autoreceptor antagonists: Starting materials
CAS RN: cis-4aR,10bS: 93601-80-0
Figure imgf000016_0001
D1 agonists and/or antagonists: Starting materials
Figure imgf000016_0002
Figure imgf000016_0003
-HT1A agonists: Starting materials
CAS RN's: trans-racemic: 82172-01-8 trans-4aS,10bS: 131484-03-2 r trans-4aR,10bR: 131484-02-1 cis-racemic: 82172-00-7 cis-4aR,10bS: 109062-23-9 cis-4aS,10bR: 109062-21-7
CAS RN's: racemic: 127165-21-3
Figure imgf000016_0004
-HT1A agonists: Starting materials cont'd
CAS RN's: racemic: 127165-07-5
R enantiomer: 129568-16-7 S enentiomer: 127253-43-4
CAS RN's: trans-racemic: 110826-30-7 1S-trans: 110901-82-1 1 R-trans: 110901-81-0
Figure imgf000017_0001
CAS RN's: trans-racemic: 110826-37-4 1S-trans: 110901-84-3 1 R-trans: 110901-83-2
CAS RN's: 6aS-enantiomer: 135529-45-2 6aR-enantiomer: 111635-19-9
Figure imgf000017_0002
Figure imgf000017_0003
de name
129301-34-4
Figure imgf000017_0004
5-HT1A ligands: Starting materials
CAS RN: racemic: 127033-10-7
R-enantiomer: 127126-18-5 S-enantiomer: 127126-21-0
Figure imgf000018_0001
5-HT1 D ligands: Starting materials
in
Figure imgf000018_0002
Sigma ligands; starting materials
CAS RN's: trans racemic: 110311-53-0 trans-4aS,10bS: 110311-50-7 trans-4aR,10bR : 103302-90-5 cis-racemic: 110311-55-2 cis-4aS,10bR: 93601-81-1
Figure imgf000018_0003
cis-4aR,10bS: 93601-80-0
-
Figure imgf000018_0004
Figure imgf000018_0005
Anti-Alzheimers: Starting materials
Figure imgf000019_0001
Neuroleptics: Starting materials
clozapine analogue
Figure imgf000019_0002
m.
Figure imgf000019_0003
Melatonine analogues: Starting materials
Figure imgf000020_0001
Figure imgf000020_0002
alkaline hydrolysis
Figure imgf000020_0003
Figure imgf000020_0004
material
Analgesics: Starting materials
morphine
Figure imgf000020_0005
Figure imgf000020_0006
Analgesics: Starting materials cont'd
Salicylic acid
Figure imgf000021_0001
Ketobemidone
Figure imgf000021_0002
Beta-blockers: Starting materials
Figure imgf000021_0003
Antiathmatics: Starting materials
terbutalin
Figure imgf000021_0004
salbutamol
Figure imgf000021_0005
In the following the invention is further illustated by way of examples which must not be construed as limiting of the invention.
Example 1 8-Trifluoromethyl(sulfonyl)oxy-2-(acetamido)tetralin (Method A).
8-OH-2-(acetamido)tetralin (ref: Swier Copinga et al. oral presentation at the Xllth Int. Symposium on Med. Chem. in Basel, September 13-17, 1992) (0.22 g: 1.1 mmol) was dissolved in pyridine (10 mL) and at - 20 °C was added triflic anhydride [RN 358-23-6; from Aldrich] (2.0 mL; 23 mmol) and the reaction mixture was stirred at this temperature for 0.5 h. The temperature was raised to room temperature within 1.5 h and was stirred over night at this temperature. Water was added and the product was extracted with CH2CI2 (10 mL). The organic layer was washed with solutions of NH CI, NaHC03 and NaCI and then separated and dried (MgS04), filtered and the solvent was evaporated under reduced pressure. The remaining oil was chromatographed (Si02) eluting with CH2C-2-MeOH (10:1). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure, yielding a brown solid as the product, which was recrystallized yielding white crystals (100 mg; 28%). MS with chemical ionization (NH3) detection shows M + 1 at m/e=338 and M + 18 at m/e=355.
Example 2 8-Trifluoromethyl(sulfonyl)oxy-2-(acetamido)tetralin (Method B).
8-OH-2-(acetamido)tetralin (see above) (0.49 g: 2.4 mmol) was dissolved in CH2CI2 (25 mL) and Et3N (0.31 g: 3.1 mmol) was added. Then the mild, triflating agent N-phenyltrif luoromethanesulfonim.de [RN 37595-74-7; from Aldrich] (0.96 g; 2.69 mmol) was added in one portion at room temperature. The reaction mixture was monitored with GC and after one night all starting material was consumed. The solvent and the Et3N were evaporated and the remaining oil was dissolved in CH2CI2 and washed 3 times with water and the organic layer was separated and washed once with NaCI saturated water, separated and dried (Na2Sθ4). The solvent was evaporated and the remaining oil (240 mg) was purified by flash chro atography (Si02 60 mesh) eluting with CH2CI2:MeOH (10:1). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure, yielding 40 mg (6%) of the pure triflated product as a colourless oil. The mass spectrum (chemical ionization with NH3) showed: M+1 at m/e=338 and M+18 at m/e=355. 1H-NMR (200 MHz, CDCI3, TMS) shows: δ 7.0-7.3 (3H, ArH); 5.6-5.8 (1 H, NH); 4.2-4.4 (1 H, C2); 1.5-3.3 (6H, C1 , C3, C4); 2.0 (3H, COCH3).
The electronegativity of the OTf group is indicated by the downfield shift of the aromatic protons from 6.3-6.9 in the starting material (8-OH-2-(acetamido)tetralin) to 7.0-7.3 in the triflated product (with respect to the electronic effects of the triflate group, see also ref: Stang, P. and Anderson, A. G., J. Org. Chem. 1976, 41 , 781 ).
Example 3. 5-Trifluoromethyl(sulfonyl)oxy-(N-acetyl)-tryptamine (Method B).
N-Acetyl-5-hydroxy tryptamine [RN 1210-83-9] was triflated according to Method B and was isolated as an oil after chromatography and evaporation of the solvents in 60% yield. MS shows (chemical ionization with NH3) m/e = 351 (M+1).
1H-NMR (200 MHz, CDCI3, TMS) shows: δ 1.95 (s, 3H), 2.95 (t,2H), 3.55 (t, 2H), 6.0
(t, 1 H, NHCO), 7.00-7.10 (m, 2H, aromatic) 7.30-7.50 (m, 2H, aromatic), 9.30 (s, 1 H, NH-indole)
13C-NMR (CDCI3, 50 MHz); 23.2 (CH3), 25.0 (CH2), 39.9 (CH2), 111.0 (CH, aromatic), 112.4 (CH, aromatic), 113.4 (C, aromatic), 114.9 (CH, aromatic), 124.7 (CH, aromatic), 127.6 (C, aromatic), 135.2 (C, aromatic), 143.2 (CH, aromatic), 170.6 (CO); the CF3 signals apperar at ca 110, 116, 122 and 128.
Example 4.
8-Trifluoromethyl(sulfonyl)oxy-2-(N-methyl-N-propargyl-amino)tetralin (Method B). The hydrochloride of 8-hydroxy-2-(N-methyl-N-propargyl-amino)tetralin (Presented in Durk Dijkstra's Thesis 1992 from the Department of Med. Chem., Univ. Centre of Pharmacy, Antonius Deusinglaan 2, NL-9713 AW Groningen, The Netherlands) (50 mg, 0.20 mmol) was suspended in CH2CI2 (5 mL) and Et3N (0.1 mL) was added. The mixture was stirred until all crystals were dissolved. Then the mild, triflating agent N-phenyltrifluoromethanesulfonimide [RN 37595-74-7; from Aldrich] (75 mg; 0.21 mmol) was added in one portion at room temperature. The reaction mixture was monitored with GC and TLC, and after 20 h all starting material was consumed. The solvent and the Et3N were evaporated and the remaining oil was dissolved in ether (10 mL) and washed 3 times with NaCI saturated water, separated and dried ( gSθ4). The solvent was evaporated and the remaining oil was dissolved in EtOH (5 mL) and fumaric acid (0.23 g, 0.20 mmol) dissolved in EtOH (1 mL) was added and the solvent was evaporated. The remaining solid was recrystaliized from i-propylacetate.
The mass spectrum (chemical ionization with NH3) showed: M+1 at m/e=348.
A second synthesis was performed as described above with a change in workup. The raw oil after extraction and evaporation was purified by chromatography (S1O2), eluting with EtOAc:hexane (1 :3). The base was converted to its HCI salt with HCI-sturated ether.
Example 5.
3-TrifluoromethyI(sulfonyl)oxy-Morphine (Method B).
Morphine hydrochloride 1.1 g (3.3 mmol) was stirred in CH2CI2 (50 mL) and EtβN (0.49 mL, 0.36 g: 3.6 mmol) was added. Then the mild, triflating agent N-phenyltri- fluoromethanesulfonimide [RN 37595-74-7; from Aldrich] (1.3 g; 3.6 mmol) was added in one portion at room temperature. The reaction mixture was monitored with GC and after 2 h all starting material was consumed. The solvent and the Et3N were evaporated and the remaining oil was dissolved in CH2CI2 (50 mL) and washed 3 times with 5% Na2C03 and the organic layer was separated and washed once with NaCI saturated water, separated and dried (Na2S04). The solvent was evaporated and the remaining oil (1.9 g) was purified by chromatography (Siθ2 60 mesh) eluting with CH2CI2:MeOH (1:1). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure, yielding 0.86 g (63%) of the pure triflated product as an oil. This oil (0.74 g, 1.8 mmol) was dissolved in warm EtOH (25 mL) and added to a warm solution of fumaric acid (0.22 g, 1.9 mmol). Evaporation and recrystallization from refluxing EtOAc gave a gel, which was filtered and dried, yielding 600 mg of white crystals melting at 111-116 °C.
The mass spectrum (chemical ionization with NH3) showed: M+1 at m/e=418.
1H-NMR (200 MHz, CDCI3, TMS) shows: δ 1.84 - 1.96 (m, 1 H), 2.10 (dt, 7 = 4.8 Hz,
1 H), 2.22 - 2.43 (M, 5H), 2.58 -2.76 (M, 2H), 2.86 (br 5, 1 H) 3.08 (d. 7 = 19.2 Hz, 1 H) 3.38 (dd. 7 = 6.1 , 3.4 Hz, 1 H), 4.17 - 4.24 (M, 1 H), 5.01 (dd, 7 = 6.4, 1.2, 1 H), 5.24 - 5.32 (M, 1 H), 5.65 - 5.73 (M. 1 H), 6.63 (d. 7 = 8.3 Hz, 1 H) 6.88 (d. 7 = 8.5 Hz, 1 H)
13C-NMR (CDCI3, 50 MHz); 20.91 (CH2), 35.20 (CH2), 40.42 (CH), 42.95 (CH), 43.33 (C), 46.02 (CH2), 58.43 (CH), 66.48 (CH), 93.57 (CH), 115.42 (C), 120.24 (CH), 121.02 (CH), 121.80 (C), 128.26 (CH), 130.55 (C), 133.58 (CH), 133.76 (C), 135.70 (C).
Example 6. 11-Hydroxy-10-trifluoromethyl(sulfonyl)oxy-aporphine. 3-Trifluoromethansulfonyloxy-morphine (fumarate salt) (100 mg; 0.19 mmol) was stirred for 3 hrs at 105 °C in MeSOsH (5 mL) under N2-atmosphere. The reaction mixture was allowed to cool to room temperature and was then diluted with H2O (10 mL). The aquous layer was basified with NaHC03 (s) and then extracted with CH2CI2 (3x25 mL). The organic layers were combined, dried over Na2Sθ4, filtered and evaporated in vacuo. to give a greenish-white solid (72 mg; 96%). The fumarate salt was formed by mixing the product (36 mg; 0.09 mmol) in EtOH with fumaric acid (10.5 mg) in EtOH and then evaporation of the solvent. MS (chemical ionization with NH3) showed M + 1 at m/e=400.
Example 7.
10-Hydroxy-11-trifluoromethyl(sulfonyl)oxy-aporphine.
This compound was synthesized from apomorphine x HCl with Method B and gave a product with M+1 at m/e=400 (chemical ionization with NH3) according to GC/MS. Example 8. Trifluoromethanesulfonyl-Dextrorphan (Method A).
Dextrorphan tartaric acid salt (1 :1) (1.0 g; 2.46 mmol) was suspended in CH2CI2 5 (100 mL) and Et3N (2 mL; 14 mmol) was added and the solution was stirred until all the starting material had dissolved. Then the mild, triflating agent N-phenyltrifluoro- methanesulfonimide [RN 37595-74-7; from Aldrich] (1.05 g; 2.94 mmol) was added in one portion. The reaction mixture was monitored with GC and after 4 h all dextrorphan was consumed. The solvent and the Et3N were evaporated and the
10 remaining oil was dissolved in CH2CI2 and washed 3 times with water and the organic layer was separated and washed once with NaCI saturated water, separa¬ ted and dried (Na2S04). The solvent was evaporated and the remaining yellow oil was purified by flash chromatography (Siθ2 60 mesh) eluting with CH2Cl2-MeOH (1 :1). The fractions containing pure product were pooled and the solvent was
15 evaporated under reduced pressure, yielding 630 mg (66%) of the pure triflated product as a light yellow oil. This oil was dissolved in EtOH (10 mL) and fumaric acid (190 mg; 1.65 mmol) was dissolved in EtOH (10 mL) and added. The EtOH was evaporated off and the remaining solid was recrystaliized from warm EtOH with cooling to room temperature and scraping with a glass rod. The first crop of crystals
20 were filtered and dried and they weighed 360 mg and melted at 85-90 °C. The mass spectrum (chemical ionization with NH3) showed: M+ + 1 at m/e=390.
Example 9. (±)-5-Trifluoromethyl(sulfonyl)oxy-2-(N-propyl-N-2-thienylethylamino)tetralin
25 (5-TfO-N-0437) CMethod B).
General procedure: P. J. Stang , Synthesis, 1982, 115-118. To 5-hydroxy-2-(N-pro- pyl-N-2-thienylethylamino)tetraiin (N-0437) (Horn, A. S.; Tepper, P.; Van der Weide, J.; Watanabe, M.; Grigoriadesr D.; Seeman, P., Pharm. Weekbi. Sci. 7, 208-211, 1985) (200 mg; 0.57 mmol) in dry pyridine (10 mL) was added triflic anhydride [RN
30 358-23-6; from Aldrich] (1.0 mL; 11 mmol) at -20 °C. The temperature was raised to 0 °C and was maintained there for 48 h, when the solvent was evaporated under reduced pressure. To the residue was added CH2CI2 (50 mL) and the solution was extracted twice with brine (check how this is done). The organic layer was sepa- rated, dried (Na2S0 ), filtered and the solvent was evaporated under reduced pressure and the remaining oil was purified by column chromatography (Siθ2 60 mesh) eluting with petroleum ether : EtOAc (1 :1 ). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure, yielding the pure product an oil. The base was converted to its hydrochloride salt with HCI saturated ether. The IR spectrum shows strong absorption bands at: 3000, 1460, 1420, 1210 and 1140 cm -1. MS with EC detection shows: m/e=133 (CF3S02) and m/e=149 (CF3SO3) but no M+ could be seen. MS with chemical ionization (NH3) detection shows M + 1 at m/e=448 (M + H+).
Example 10.
(-)-5-Trifluoromethyl(sulfonyl)oxy-2-(N-propyl-N-2-thienylethylamino)tetralin
(S-(-)-5-TfO-N-0437; 5-TfO-N-0923) (Method B).
Starting material: S-(-)-5-Hydroxy-2-(N-propyl-N-2-thienylethylamino)tetralin (S-(-)-N-0437; N-0923) (Horn, A. S.; Tepper, P.; Van der Weide, J.; Watanabe, M.; Grigoriades, D.; Seeman, P., Pharm. Weekbl. Sci. 7, 208-211 , 1985; Ten Hoeve, W.; Wijnberg, H., J. Org. Chem. 50, 4508, 1985).
Example 11. (+)-5-Trifluoromethyl(sulfonyl)oxy-2-(N-propyl-N-2-thienylethylamino)tetralin (R-(+)-5-TfO-N-0437; 5-TfO-N-0924) (Method B).
Starting material: R-(+)-5-Hydroxy-2-(N-propyl-N-2-thienylethylamino)tetralin (R-(+)-N-0437; N-0924) (Horn, A. S.; Tepper, P.; Van der Weide, J.; Watanabe, M.; Grigoriades, D.; Seeman, P., Pharm. Weekbl. Sci. 7, 208-211 , 1985; Ten Hoeve, W.; Wijnberg, H., J. Org. Chem. 50, 4508, 1985).
Example 12. 8-(3-trifluoromethyl(sulfonyl)oxy)phenyl)indolizidine (Method B).
8-(3-Hydroxyphenyl)indolizidine (Bøgesø et al. J. Med. Chem. 30, 142-150, 1987) (74 mg; 0.25 mmol) was dissolved in CH2CI2 (6 mL) and Et3N (68 μL; 0.50 mmol) was added. Then the mild, triflating agent N-phenyltrifluoromethanesulfonimide [RN 37595-74-7; from Aldrich] (89 mg; 0.25 mmol) was added in one portion at room temperature. The reaction mixture was monitored with GC and after one night all starting material was consumed. The solvent and the Et3N were evaporated and the remaining oil was dissolved in CH2CI2 and washed 3 times with water and once with 5% Na2Cθ3 (25 mL) and the organic layer was separated and washed once with NaCI saturated water, separated and dried (Na2S04). The solvent was evaporated and the remaining oil (117 mg) was purified by flash chromatography (Siθ2 60 mesh) eluting with CH2C.2:MeOH (1 :1). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure, yielding 73 mg (84%) of the pure triflated product as an oil.
The mass spectrum (chemical ionization with NH3) showed: M+1 at m/e=350.
1H NMR (CDCI3, 200 MHz, TMS) shows: δ 1.26 - 2.31 (m, 11 H), 2.44 - 2.62 (m, 1H), 3.15 - 3.24 (m, 2H), 7.10 - 7.41 (m, 4H).
13C NMR (CDCIs, 50 MHz); 20.15 (CH2), 25.41 (CH2), 28.94 (CH2), 32.59 (CH2), 48.61 (CH), 52.49 (CH2), 54.30 (CH2), 69.05 (CH), 119.14 (CH), 120.10 (CH), 121.89 (C), 127.60 (CH), 130.04 (CH), 146.97 (C), 149.62 (C).
Example 13. 1-(3-Trifluoromethyl(sulfonyl)oxy)phenyl)-3,4,6,7,8,9-hexa- hydro-9aH-quinolizine (Method B).
1-(3-HydroxyphenyI)-3,4,6,7.8,9-hexahydro-9aH-quinolizine (Bøgesø et al. J. Med. Chem. 30, 142-150, 1987) (130 mg; 0.57 mmol) was dissolved in CH2CI2 (20 mL) and Et3N (158 μL; 1.14 mmol) was added. Then the mild, triflating agent N-phenyltrifluoromethanesulfonimide [RN 37595-74-7; from Aldrich] (300 mg; 0.85 mmol) was added in one portion at room temperature. The reaction mixture was monitored with GC and after 5 h all starting material was consumed. The CH2CI2 phase was washed with saturated Na2Cθ3 (50 mL), the water layer was washed with CH2CI2 (30 mL) and the combined organic phases were dried (Na2S04). The solvent was evaporated and the remaining oil was purified by chromatography (S1O2 60 mesh) eluting with CH2Cl2:MeOH (1 :1). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure, yielding 197 mg (82%) of the pure triflated product as a yellow oil. The mass spectrum (chemical ionization with NH3) showed: M+1 at m/e=362.
1H NMR (CDCI3, 200 MHz, TMS) shows: δ 1.1 (dp, J=11.7 and 3.0,1 H), 1.2 - 1.5 5 (m, 1 H), 1.5 - 1.8 (m, 4H), 2.1-2.3 (m, 1 H), 2.3-2.6 (m, 3H), 2.8-3.1 (m, 3H), 5.9 (dd, J=5.4 and 2.0, 1 H), 7.1 - 7.4 (m, 4H).
13C NMR (CDCI3, 50 MHz); 25.10 (CH2), 26.15 (CH2), 29.82 (CH2), 51.06 (CH2), 56.46 (CH2), 62.71 (CH), 119.07 (CH), 119.73 (CH), 126.55 (CH), 126.89 (CH), 10 130.04 (CH), 129.73 (CH), 139.60 (C), 144.10 (C) (note: one quaternary C and CF3 are not listed due to a too weak signals).
Examples 14
1-Methyl-4-propionyl-4-[3-[(trifluoromethyl)sulfonyloxy]phenyl]piperidine, 15 fumarate (ketobemidone triflate) (Method C) (compound C1)
To a solution of 1-methyl-4-propionyl-4-(3-hydroxyphenyl)piperidine (ketobemidone, CAS RN : 83544-10-9) (2 g) and triethylamine (1.2 ml) in dichloromethane (25 ml) was added dropwise during 10 minutes trifluoromethansulfonylchloride (1.0 ml) at 0- 5 °C. The mixture was stirred for additionally 1 hour at room temperature. Brine 0 (200 ml) was added and extracted with dichloromethane (3x 50 ml). The combined organic extracts were dried (anh. MgS04) and dichloromethane evaporated leaving the crude title compound as a visceous oil. The triflate derivative crystallized as the acidic fumarate salt from ethanol. Yield 2.0 g, mp : 164.6-165.4 °C. "iH-NMR (250
MHz, DMSO-de) : δ 0.75 (t, 3H); 2.15 (broad t,2H); 2.30 (q, 2H); 2.40 (s, 3H); 2.5- 5 2.7 (m, 4H); 2.85 (broad s, 2H); 6.55 (s, 2H); 6.95 (s, 1 H); 7.0 (m, 2H); 7.10 (t, 1 H).
In a corresponding way the following triflate derivatives were prepared:
(±)-7-Chloro-3-methyl-1-phenyl-8-[(trifluoromethyl)sulfonyloxy]-2,3,4,5- 0 tetrahydro-rH-3-benzazepine, oxalate (compound C2). Mp: 167-169 °C (from acetone). 1H-NMR (250 MHz, DMSO-d6) : δ 2.75 (s, 3H); 2.95 (t, 1 H); 3.10 (dd, 1 H); 2.85-3.10 (m, 3H); 4.5-5.2 (m, 4H); 6.45 (s, 1 H); 7.25 (d, 2H); 7.35-7.50 (m, 3H); 7.75 (s, 1H). Prepared from the selective dopamine D_ antagonist SCH 23390 (racemate used) (CAS RN : 138584-32-4).
(-J-N.N-diethyl-N-fe-Ktrifluormethy sulfonyloxyJindan-l-yllmethylamine, oxalate (Compound C3). Mp: 120-122 °C (from acetone). 1H-NMR (250 MHz,
DMSO-de) : δ 1.15 (t, 6H); 1.9-2.0 (m, 1 H); 2.3-2.4 (m, 1H); 2.8-3.2 (m, 7H); 3.3-3.4 (m, 1H); 3.5-3.6 (m, 1H); 7.30 (dd, 1 H); 7.40 (d, 1 H); 7.55 (d, 1H). Prepared from the corresponding dopamine D2 agonist (US patent no 4,946,863).
(±)-N,N-dipropyl-N-[5-[(trifluormethyl)sulfonyloxy]-2,3-dihydrobenzofuran-3- yl]methylamine, oxalate (Compound C4). Mp: 125-126 °C (from acetone). 1H- NMR (250 MHz, DMSO-d6) : δ 0.90 (t, 6H); 1.55 (dq, 4H); 2.80 (t, 4H); 3.05 (t, 1H);
3.15 (dd, 1 H); 3.9-4.0 (m, 1H); 4.45 (dd, 1 H); 4.75 (t, 1 H); 6.95 (d, 1H); 7.25 (dd, 1 H); 7.55 (d, 1H). Prepared from the corresponding dopamine D2 agonist (US patent no 4,847,254).
(±)-N-methyl-N-propyl-N-[5-[(trifluormethyl)sulfonyloxy]-2,3-dihydrobenzofu- ran-3-yl]methylamine, oxalate (Compound C5). Mp: 138-141 °C (from acetone). 1H-NMR (250 MHz, DMSO-d6) : δ 0.90 (t, 3H); 1.65 (dq, 2H); 2.70 (s, 3H); 2.95 (dt, 2H); 3.20 (t, 1 H); 3.30 (dd, 1 H); 4.0-4.1 (m, 1 H); 4.55 (dd, 1 H); 4.80 (t, 1 H); 6.95 (d, 1H); 7.30 (dd, 1H); 7.55 (d, 1H). Prepared from the corresponding dopamine D2 agonist (US patent no. 4,847,254).
Preparation of mixtures of (±)-3-methyI-1-phenyI-7,8-di[(trifluorome- thyl)sulf ony loxy]-2,3,4,5-tetrahydro- 7 -benzazepine, (±)-8-hydroxy-3-methyl«
1-phenyl-7-[(trifluoromethyl)sulfonyloxy]-2,3,4,5-tetrahydro-rH-3-benzazepine,
(±)-7-hydroxy-3-methyl-1-phenyl-8-[(trifluoromethyl)sulfonyloxy]-2,3,4,5- tetrahydro-7H-3-benzazepine, oxalates (mixtures C6 and C7).
The free catechole base (1.6 g) liberated from (±)-7,8-dihydroxy-3-methyl-1-phenyI- 2,3,4,5-tetrahydro-7tf-3-benzazepine, HBr (2.0 g) (SK&F 75670, see Arnt and
Perregaard : Eur. J. Pharmacol. 1987, 143 , 45-53) was dissolved in dichlomethane
(100 ml) containing triethylamine (0.7 g). The mixture was cooled to °C and a solution of trifluoromethansulfonylchloride (1.1 g) in dichloromethane (5 ml) was added dropwise during 10 minutes. After stirring for another hour at room tempera¬ ture water (100 ml) was added. Extraction with dichloromethane (3x 25 ml) and subsequent work-up of the combined organic phases afforded a mixture of com- pounds, which were subjected to column chromatography on silica gel (eluted with diisopropyl ether/tetrahydrofuran/triethylamine 70:20:10). Two fractions were eluted. To the first fraction collected was added oxalic acid in an attempt to crystallize the oxalate salt, however without success. The mass spectrum (chemical ionization with NH3) of this mixture (mixture C6) showed: M+1 at m/e 534 (ditriflate) and M+1 at m/e 402 (mono triflate isomer(s)). Similarly attempts to crystallize oxalic acid salts from the second fraction were unsuccessful. The mass spectrum (chemical ionization with NH3) of the second mixture (mixture C7) also showed: M+1 at m/e
534 (ditriflate) and M+1 at m/e 402 (mono triflate isomer(s)), however in another molucular ratio.
Example 15.
Compound Roxindole-OTf 6,7-di-OTf-DPAT 2-OTf-N-Pr-Ph-pip 3-OTf-N-Pr-Ph-pip 3-OTf-N-PhEth-Ph-pip 5-CI-8-OTf-N-Pr-N-thienylethyl-2-A
trans-9-OTf-PHNO cis-9-OTf-PHNO Triflated nor-Remoxipride
Ditriflated isoprenaline Ditriflated terbutalin Tritriflated fenoterol
Figure imgf000031_0001
Triflated R-(+)-8-OH-DPAT B M + 1 at m/e=380
[ ]D 25= +18.2 at c=0.35 in MeOH (base); +52.0 at c=1.00 in MeOH (base) Triflated S-(-)-8-OH-DPAT B M + 1 at m/e=380
[α]D 25= -24.5 at c=0.44 in MeOH (base); -55.9 at c=1.00 in MeOH (base) Triflated Apocodeine B M + 1 at m/e=414
Triflated 8-OH-2-[N-n-Pr,N-(2-thienyl)ethylamino)tetralin
B M + 1 at m/e=448
Triflated 8-OH-2-[N-n-Pr,N-phenylethylamino)tetralin
B M + 1 at m/e=442 Triflated S-(-)-N-0437 B M + 1 at m/e=448
[α]25= -40.7 at c=62.5 mg/5 mL in MeOH
PHARMACHOLOGY
The following reliable and well recognised test methods are used to establish the effects of the compounds of the invention:
Receptor binding studies.
DA Di receptors. Inhibition of 3H-SCH 23390 binding to DA Di receptors in rat striatal membranes was determined as described by Hyttel, J. and Arnt, J. J. Neural. Transm. 1987, 68, 171.
DA D2 receptors.
Inhibition of 3H-spiperone binding to DA D2 receptors in rat striatal membranes as described by Hyttel, J. Ada. Pharmacol. Toxicol. 1986, 59, 387; or
Inhibition of 3H-spiperone binding to DA D2 receptors in calf striatal membranes as described by Krotowska A. et al. Acta. Pharm Suec. 24, 145.
Inhibition of 3H-N-0437 binding in calf striatal membranes as described by Van der Weide J et al, Eur. J. Pharmacol. 1986, 134, 211. 5-HT2 receptors.
Inhibition of 3H-ketanserin binding to 5-HT2 receptors in membranes from rat cortex was determined as described by Hyttel, J. Ada. Pharmacol. Toxicol. 1987, 61, 126.
5-HT1A receptors.
Inhibition of 3H-8-OH-DPAT Binding to Serotonin 5-HT1A Receptors in Rat Brain in vitro as described by Gozlan H. et al. Nature 1983, 305, 140, and Pazos A et al, Eur. J. Pharmacol. 1985, 106, 539.
Sigma Receptors
Inhibition by drugs of the binding of 3H-DTG (1 ,3,di-o-tolyl guanidine) to sigma receptors in homogenates or membranes from rat brain without cerebellum as modified from Weberef al. Proc. Natl. Acad. Sci. 1986, 83, 8784.
In Vivo Tests
Antagonism of SK&F 38393-induced circling behavior in rats with unilateral 6- OHDA lesions.
This test is a test for the DA Di receptor antagonistic effect in vivo. The experiments are performed as described by Arnt, J.et al., J. Neural. Transm. 1986, 67, 225-240.
Antagonism of Pergolide-induced circling behavior in rats with unilateral 6- OHDA lesions.
This test model is used to determine dopamine (DA) D2 antagonistic effect. (Arnt.J. and J.Hyttel, Eur. J. Pharmacol. 102, 349-354, 1984; Arnt, J. and J. Hyttel, J. Neural. Transm. 67, 225-240, 1986).
Quipazine inhibition
The test is a test for 5-HT2-antagonistic effect testing the ability to inhibit quipazine induced head twitches. The method and test results for some reference substances are published by Arnt et al. (Drug Development Research, 16, 59-70, 1989). Dopamine agonist studies
Dopamine agonist effects are studied as described in US patent no. 4,946,863.
8-OH-DPAT Cue Antagonism in Rats. This test model is used to determine the antagonist effects of a test compound on 5- HT-iA receptors in vivo. A related method is described by Tricklebank, M. D., etal, Eur. J. Pharmacol., 1987, 133, 47-56; Arnt, J. Pharmacology & Toxicology, 1989, 54, 165.
8-OH-DPAT Cue Agonism in Rats
This test model is used to determine the agonist effects of a test compound on 5- HTIA receptors in vivo. A related method is described by Tricklebank, M. D et al, Eur. J. Pharmacol., 1987, 133, 47-56; Arnt, J. Pharmacology & Toxicology, 1989, 64, 165.
The following results have been obtained:
The compound (±)-5-Trifluoromethyl(sulfonyl)oxy-2-(N-propyl-N-2-thienylethylami- no)tetralin (5-TfO-N-0437) showed an IC50 value of 69 nM in the [3H]-spiperone binding assay according to the method of Krotowska A. et al(supra).
Furthermore the compounds of Example 14 showed binding affinities in the above 3H-SCH 23390 binding assay as follows:
Compound no IC50 value in nM
C2 50
C6 28
C7 85

Claims

WHAT IS CLAIMED:
1. An aryltriflate or a related compound having the general Formula 1 :
Figure imgf000035_0001
Formula 1 or pharmaceutically acceptable acid addition salts thereof, wherein
Ar is an aromatic or heteroaromatic system of a compound which has a therapeutic, biological activity when it, in the same position, carries a hydroxy, alkyloxy, halo, ester or cyano group; and
Ri is CF3, (CrCs) alkyl, -CH2-(C3-Cβ) cycloalkylalkyl, substituted phenyl, substi¬ tuted benzyl, substituted phenylethyl, substituted phenylpropyl, substituted 2-thio¬ phenylethyl or substituted 2-thiophenylpropyl; except the compounds wherein Ar is 2-(dipropylamino)-tetralin-8-yl or 4- acetamidophenyl.
2. A compound of claim 1 , Formula 1 , wherein Ri is CF3.
3. Compounds of claim 1 which are given in Enclosure 1 (at the end of this docu- ment).
4. A method for treating human disorders comprising the administration to a mammal of a therapeutic amount of a compound of Claim 1 or a pharmaceutically acceptable acid addition salt thereof to a patient in need thereof.
5. The method of claim 4, wherein said compound is administered in an amount of from about 1 to about 2000 mg oral daily dose, or from 0.1 to about 100 mg parenteral daily dose.
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Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3725451A (en) * 1970-04-13 1973-04-03 Riker Laboratories Inc Substituted benzoylhaloalkanesulfonanilides
EP0072532A1 (en) * 1981-08-14 1983-02-23 Hoechst Aktiengesellschaft 5(6)-Phenyl-sulfonyloxy-benzimidazole derivatives, process for their production, pharmaceutical compositions containing them and their use against liver disorders
US4470991A (en) * 1983-04-22 1984-09-11 Merck & Co., Inc. Benzothiazolesulfonamide derivatives for the topical treatment of elevated intraocular pressure
US4504490A (en) * 1982-09-04 1985-03-12 Hoechst Aktiengesellschaft Substituted benzenesulfonic esters and their use as medicaments for combatting helminths
EP0148167A2 (en) * 1984-01-04 1985-07-10 Adir Quinoline derivatives, process for their preparation and pharmaceutical compositions containing them
US4618622A (en) * 1982-11-23 1986-10-21 Basf Aktiengesellschaft Sulfonates of hydroxycoumarins
EP0198208A1 (en) * 1985-03-15 1986-10-22 Hoechst Aktiengesellschaft Substituted benzimidazole derivatives, process for their preparation, pharmaceutical compositions containing them and their use as inhibitors of gastric-acid secretion
US4639463A (en) * 1982-12-23 1987-01-27 Hoechst Aktiengesellschaft Substituted phenylsulfonyloxybenzimidazolecarbamates and anthelmintic compositions
EP0259782A1 (en) * 1986-09-11 1988-03-16 Dr. Karl Thomae GmbH Naphthalene and indane derivatives, medicaments containing these compounds and processes for their preparation
US4772612A (en) * 1985-06-19 1988-09-20 Bayer Aktiengesellschaft Circulation-active 1,4-dihydropyridines
EP0332064A2 (en) * 1988-03-10 1989-09-13 Dr. Karl Thomae GmbH Benzocycloheptene derivatives, pharmaceutical preparations containing these compounds and process for their preparation
EP0399982A1 (en) * 1989-05-26 1990-11-28 Astra Aktiebolag Novel 8-substituted-2-amino-tetralines
US4997840A (en) * 1988-02-22 1991-03-05 The Boots Company, Plc Quinolone sulphonates having antihypertensive activity
WO1991009853A1 (en) * 1989-12-22 1991-07-11 Aktiebolaget Astra New chroman and thiochroman derivatives
EP0470578A1 (en) * 1990-08-09 1992-02-12 Wakunaga Seiyaku Kabushiki Kaisha Novel tricyclic compound or salts thereof, method for producing the same and antimicrobial agent containing the same

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3725451A (en) * 1970-04-13 1973-04-03 Riker Laboratories Inc Substituted benzoylhaloalkanesulfonanilides
EP0072532A1 (en) * 1981-08-14 1983-02-23 Hoechst Aktiengesellschaft 5(6)-Phenyl-sulfonyloxy-benzimidazole derivatives, process for their production, pharmaceutical compositions containing them and their use against liver disorders
US4504490A (en) * 1982-09-04 1985-03-12 Hoechst Aktiengesellschaft Substituted benzenesulfonic esters and their use as medicaments for combatting helminths
US4618622A (en) * 1982-11-23 1986-10-21 Basf Aktiengesellschaft Sulfonates of hydroxycoumarins
US4639463A (en) * 1982-12-23 1987-01-27 Hoechst Aktiengesellschaft Substituted phenylsulfonyloxybenzimidazolecarbamates and anthelmintic compositions
US4470991A (en) * 1983-04-22 1984-09-11 Merck & Co., Inc. Benzothiazolesulfonamide derivatives for the topical treatment of elevated intraocular pressure
EP0148167A2 (en) * 1984-01-04 1985-07-10 Adir Quinoline derivatives, process for their preparation and pharmaceutical compositions containing them
EP0198208A1 (en) * 1985-03-15 1986-10-22 Hoechst Aktiengesellschaft Substituted benzimidazole derivatives, process for their preparation, pharmaceutical compositions containing them and their use as inhibitors of gastric-acid secretion
US4772612A (en) * 1985-06-19 1988-09-20 Bayer Aktiengesellschaft Circulation-active 1,4-dihydropyridines
EP0259782A1 (en) * 1986-09-11 1988-03-16 Dr. Karl Thomae GmbH Naphthalene and indane derivatives, medicaments containing these compounds and processes for their preparation
US4997840A (en) * 1988-02-22 1991-03-05 The Boots Company, Plc Quinolone sulphonates having antihypertensive activity
EP0332064A2 (en) * 1988-03-10 1989-09-13 Dr. Karl Thomae GmbH Benzocycloheptene derivatives, pharmaceutical preparations containing these compounds and process for their preparation
EP0399982A1 (en) * 1989-05-26 1990-11-28 Astra Aktiebolag Novel 8-substituted-2-amino-tetralines
WO1991009853A1 (en) * 1989-12-22 1991-07-11 Aktiebolaget Astra New chroman and thiochroman derivatives
EP0470578A1 (en) * 1990-08-09 1992-02-12 Wakunaga Seiyaku Kabushiki Kaisha Novel tricyclic compound or salts thereof, method for producing the same and antimicrobial agent containing the same

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US7956187B2 (en) 2000-10-31 2011-06-07 Rensselaer Polytechnic Institute Method for decreasing opioid metabolism
US9932349B2 (en) 2000-10-31 2018-04-03 Rensselaer Polytechnic Institute 8-carboxamido-2,6-methano-3-benzazocines
EP1944292A1 (en) * 2000-10-31 2008-07-16 Rensselaer Polytechnic Institute 8-substituted-2,6-methano-3-benzazocines and 3-substituted morphinanes as opioid receptor binding agents
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US8044090B2 (en) 2001-03-29 2011-10-25 Eli Lilly N-(2-arylethyl)benzylamines as antagonists of the 5-HT6 receptor
US7157488B2 (en) 2001-03-29 2007-01-02 Eli Lilly And Company N-(2-Arylethyl) benzylamines as antagonists of the 5-HT6 receptor
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