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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/16—Benzazepines; Hydrogenated benzazepines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—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
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
  • C07C309/63—Esters of sulfonic acids
  • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
  • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
  • C07D209/16—Tryptamines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—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
  • C07D213/46—Oxygen atoms
  • C07D213/50—Ketonic radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D221/04—Ortho- or peri-condensed ring systems
  • C07D221/18—Ring systems of four or more rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D221/22—Bridged ring systems
  • C07D221/28—Morphinans
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—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
  • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
  • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
  • C09D11/00—Inks
  • C09D11/30—Inkjet printing inks
  • C09D11/32—Inkjet printing inks characterised by colouring agents
  • C09D11/324—Inkjet printing inks characterised by colouring agents containing carbon black
  • C09D11/326—Inkjet printing inks characterised by colouring agents containing carbon black characterised by the pigment dispersant

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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