CA2126242A1 - Aryl-triflates and related compounds - Google Patents
Aryl-triflates and related compoundsInfo
- Publication number
- CA2126242A1 CA2126242A1 CA002126242A CA2126242A CA2126242A1 CA 2126242 A1 CA2126242 A1 CA 2126242A1 CA 002126242 A CA002126242 A CA 002126242A CA 2126242 A CA2126242 A CA 2126242A CA 2126242 A1 CA2126242 A1 CA 2126242A1
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- phenylethyl
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- C07—ORGANIC CHEMISTRY
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- 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
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- 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
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- 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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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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
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- 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
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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
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
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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
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
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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
- C07D221/22—Bridged ring systems
- 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
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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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
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- 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
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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.
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
2 1 2 6 ~ PCl /DK92/00389 ARYL-TRIFLATES AND RELATED COMPOIJNDS.
Field o~ the Invention 5 The present invention is directed toward new aryltriflates, and their pharmaceuti-cally acceptable salts, to processes ~or 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.
Rackground of the Invention Aryl triflates are used as intermediates in organic syntheses. They can thus be removed via reduction tNEt3+HCOO-) or substituted by other groups like CN and 15 COOR (Oda, R., Kagaku (Kyoto) 1987, 42, 710-11; Cacchi, S. et al., Tetrahedron Lett 1986, 27, 5541-4; Cham~ers, 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 Lett198~7, 28, 1381-4; Roth, G. P. et al., J. Org. Chem. 1991, 56, 3493-6; Saa, J. M~ et al., J. Org. Chem. 1990, 20 55, 991-5; Subramanian, L. R. et al., Synthesis 1984; Chambers, M. R. I. et al., J.
Chem. Soc., Perkin Tra~s 1989, 1, 1365-6.; Takagi, K. et al., Bull. Chem. Soc. .~pn.
1991, 64, 1 1 18-21; FP-A1 399982; Liu, Y. et al., Bioorg. Med. Chem. Lett. 1991, 1, 257-62.
25 One aryltriflate with biological activity (5-HT1A affinity in a CNS preparation) is known ( EP-A1 399982, Liu, 1991 svpra). 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, svpra).
30 Enzymatic deactivation of drugs (the Cytochrome P450 .soenzyme system) is a well known phenomenon, in particular phenols and methoxylated aryls are in gerteral 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 con~ugation (sulphation and glucoronidation) and/or via initialoxidation and then conjugation.
Obviously, the inhibition of such enzymatic deactivati~n of drugs is highly desired, 5 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.
10 it has now bAen ~ound 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.
Summarv of the Invention This invention relates to aryltriflates and related compounds havirig the general Formula 1:
Ar--O--S- R
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 25 R1 iS CF3, (C~-C8) alkyl, -CH2-(C3-C8) 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.
WO 93/11761 PCr/DK92/00389 In a preferred embodiment, the invention is directed to compounds of Formula 1;
wherein R1 is CF3.
Processes for preparation of these compounds, their pharmaceutical use and 5 pharmaceutical preparations comprising such compounds constitute further aspects of the invention.
Detailed Descri~tion of the Invention 10 As used herein the term (Cn-Cm) is inclusive such that a compound of (C~-C8) would include compounds o~ one to 8 carbons and their isomeric forms. Alkyl refers to an branched or unbranched aliphatic hydrocarbon radical such as m~thyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-buty!, 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 20 diastereomeric forms of Formula 1 compounds either in pure ~orm or as mixtures of enantiomers or diastereomers. The therapeutic properties of the compounds may toa greater or lesser degree depend on the stereochemistry of a particular compound.
Pure ~nantiomers 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 pa~icular a dopamine agonist or antagonist, a dopamine autoreceptor agonist, a 5-HT,A ligand, 5-HT1D ligand, a 5-HT2 antagonist, an antipsychotic, a sigma ligand, or WO 93~11761 2 1 2 ~ 2 ~ 2 PCl/DK92/00389 a melatonine analogue, beta blocker, analgesic, e~c.
Specific examples of Ar appears from the following table showing examples of compounds of the invention.
In the table, R1 is as de~ined above; R2 designates C1-C8 alkyl, CH2-(C3-C8) cycloalkylalkyl, arylalkyl, phenylethyl or 2-thiophenylethyl; R3 designates C1-C8 alkyl, CH2-(C3-C8) cycloalkylalkyl, arylalkyl, phenylethyl or 2-thiophenylethyl; X is CH2, 0 or S; and Y is CH2, 0 or S.
Antiasthmatics oS2R1 oS2R1 HOJ~N ~1Z5J~ ,~t-Bu OH H OH H
Terbutalin analogues R,02SO~ -l~ ~t-Bu OH H: Salbutamol analogue ,'? 4 2 WO 93tll761 PCI/DK92/00389 Dopamine agonists OSO2R, ~N ' R2 R1O250J~J
CH2N~
R,02SO~ R3 R,02SO~CH2~4--N~
Roxindole analogues ~.~
,.
R,02SC~
HO~
W O 93tll761 2 12 6 ~ 4 2 PC~r/DK92/00389 Dopamine aaonists cont'd HO ~ Rl2S
~125~ R~02SO~
R2 R2 ., Dopamine autoreceptQr anta~Qnists oso2R1 ~N ~ R2 D1 agonists and/or ant~onists R,02SO~N_R2 R125~N_R2 R1O2SO~ ~
R,O2SO~N_R2 SK&F38393 analogues Cl~ ~ .
R,02SO~N--Me SCH23390 analogue 2.1262~2 WC) 93/11761 PCl/DK92tO0389 T1 A aponists ~?~N ~ RZ
~N,R2 Rz and R3 are not at the same time propyl R,02SO R3 (~N,R2 R1O250 R, trans ~
~N~R-Rl02SO R2 ~N~R3 R, 02SO R2 WO 93/11761 PCl`tDK92/00389 ~ 2 ~ 2 ~ 8 5-HT1 A liaands 5-HT1 D ligands OSO2R, ' ;
Me ~N~Me Sumatriptan analogue HN
.
Sigma iiçlands R1O250J~
he R1o2so~;e Pentazocine analogue CH2CHC(Me)2 Anti-Alzheimers R,02SO~l 7-Methoxytacrine analogue WO 93/11761 2 1 2 6 ~ 4 ~ PCI`/DK~2/00389 Neuroleptics ~ ~OSO2~1 Clozapine analogue ,_N
Me N~OSO2R
Chlorpromazine and levomepromazine analogue ` N
Me \~N--CH2-CH2-- N~,NH
(~1 Sertindole analogue Melatonine analogues ,~, ~_ H
H~ COR2 ~ ,COR2 WO 93/11761 PClJDK92/00389 212G!~ ~12 10 Anal~esiçs H OH
o~ morphine analogue 2SO~N
Me ~,ozso~e pentazocine analogue CH2CHC:(Nb)2 COOH ~
~OS02R1 W acetyl salicylic acid analogue OSO2R, Q
~-CH2CH3 Ketobemidone analogue ~N~
~eta-bl~ckers OCH2CHOHCH2NHlPr prenalterol analogue oSo2R1 OCH2CHOHCH2NHlPr ~,~oSo2R1 oxprenolol analogue Il I
~.,-i2~2 WO 93/11761 PCI`/DK92/00389 11 ..
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 misciblesolvent, 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, aceticl propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, 10 cinnamic, citraconic, aspartic, stearic, palmiticj 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 inorganicsalts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of 15 double decomposition of appropriate salts, which is well known to the art.
In clinical prac~tice the compounds of the present invention will normally be adminis-~-- tered orally, rectally~ or by injection, in the form of pharmaceuticai preparations comprising the ~active ingrédient either as a free base or as a pharmaceutically- ~ :20 acceptablé~non-toxic, acid~addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in~ association with~ a pharmæeutically 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.
,, -25 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 i i one to 4 times daily and the dosage amounts are based on an individual having a - 30 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 WO 93/11761 PC~/DK92/00389 ;:
21262~ 12 features are beneficial to effective clinical treatment.
The compounds of this invention may be obtained by the general general syntheticstrategy exemplified in Scheme 1: :
. .
Scheme 1 Triflating agent ¦ ¦ -Ar OH ~ Ar O S- CF3 Et3N in CH2CI2 O
The triflating agent is conveniently triflic anhydride (Method A), N-phenyltrifluoro- .
10 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:
WO93/11761 ?~ 4 2 PCI/DK92/00389 Dopamine aaonists: Startin~ mat~r~l~
OH CAS RN's: trans racemic: 110311-52-9 trans-4aS,1 ObS: 93601-83-3 trans-4aR,l~bP~: 93601-82-2 I I cis racemic: 82171-94~6 ,n-Pr cis-4aS,10bR: 93601-81-1 ¦~J cis-4aR,1 ObS: 93601-80-0 CAS RN's: tr~ns racemic: 110311-53-0 trans-4aS,1 ObS: 110311-50-7 trans-4aR,lObR: 103302-90-~
HO~N~n pr cis-racemic: 110311-5~2 cis-4aS,1 ObP~: 93601-81-1 cis-4aR,~ ObS: 93601-80-0 R See US Patent Nos. 4,946,862 CH2N~ and 4,847,254 HO~ R3 HO~CH,),--N~
N CAS RN: 112192-04-8 ~) 11-hydroxy aporphine Me HO ~ (-)-apomorphine:
CAS RN: 58-00-4 Me WO93/11761 ~125,~42 14 PCI/DK92/00389 Dopamine autore~tor antagonists: Star~n~ material$ ~;
CAS RN: cis-4aR,1 ObS: 9360~ -80-0 -,n-Pr D1 a~onists andlor anta~onists: Starting material~
HO~ SK&F75670 CAS RN: 62717-63-9 ~ ' c~
HOJ~ SCH23390 ~ CAS RN: 138584-32-4 ~ .. `.
HT1A a~onists: Starting material~ :
CAS RN's: trans-racemic: ~82172-01-8 ~I trans-4aS,1 ObS: 131484-03-2 J~ ,~Pr trans-4aR,10bR: 131484-02-1 N cis-racemic: 82172-00-7 HO V cis-4aR,1 ObS: 109062-23-9 cis-4aS,1 ObR: 109062-2~ -7 ~ ,r~Pr CAS RN's: racemic: 127165-21-3 CH30 ~
5-HT1 A a~onists: Startin~ matçrials cont'~
CAS RN's: racemic: 127165-07~5 ~1 J~ , R enantiomer: 129568-16-7 ~ ~ N ~~ S enentiomer: 127253-43-4 CH30 ~
CAS RN's: trans-racemic: 110826-30-7 1~ 1S-trans: 110901-82-1 ,n-Pr 1 R-trans: 110901 -~1~0 H0 n~Pr CAS RN's: trans-racemic: 110826-37-4 ~ l S-trans: 110901 -84-3 HO~N,n Pr 1 R-trans: 110901-83~2 Pr CAS RN's: 6aS-enantiomer: 135529-45-2 6aR-enantiomer: 111635-19-9 Me O CAS RN's: racemic: 119755-88-3 and 109140-25-2 ,n-Pr (~)-form:- 117422-53-4 1' y (-)-form: 117422-55-6 H0 n-Pr Upjohn code name ,r~Pr CAS RN: 129301-34-4 HO n~Pr WO 93/11761 PC~JDK92/003~9 ~
21262'42 16 5-HT1 A liaands: Startina materials CAS RN: racemic: 127033-10-7 ~ R-enantiomer: 127126-18-5 I l S-enantiomer: 127126-21-0 ,n-Pr HO n-Pr 5-HT1 D~ands: Startinq materials OH
d~ M N, N-dimethyl-serotonin y~~N~ CAS RN: 487-93-4 HN.
Sigma liclands: Startin~ materials CAS RN's: trans racemic: 110311-53-0 ~ trans-4aS,1 ObS: 110311-50-7 ,l~ 1 ,n-Pr trans-4aR,10bR: 103302-90-5 HO ~ N t:is-racemic: 110311-55~2 cis-4aS,1 ObR: 93601-81-1 cis-4aR,1 ObS: 93601-80-0 CAS RN's: trans racemic: 110242-80-3 . . and 93503-t 1-8 ~ ~ ~ ,n-Bu trans-4aS,1 ObS: 119778-47-1 HO I ~ N cis-racemic: 110242-86-9 I~J cis-4aR,1 ObS: 119904-02-8 I.
Me pentazocine CAS RN: 359-83-1 CH?CHC(Me)2 WO 93/11761 ~ 1 ~ 6 ~ 4 2 PCT`/DK92/00389 Anti-Alzheimers: Startinç~ matçrials HO~o CAS RN: t36051-80-4 Neuroleetics: Starting material~
~OH
clozapine analogue N
Me 2-hydroxypromazine N OH CAS RN: 3926-64-5 Me~
Nb HO~N--CH2-CH2 -- N~f NH
Perregaard et al. J.Med.Chem.
r 11 1992 3~, 1092-1101.
Obtained from the corrssponding F 5-methoxy compound by treating with pyridine-hydrochloride WO 93/11761 ~ ~ 4 ~/~ PCl['/DK92/00389 Melatonine analo~ues: Startin~ mat rial~
OH
~_ H CAS RN: 1210-83-9 H COMe ,H AC2O ~N~ ,A~:
HO H AcO H
CAS R N ~
alkaline 94344-99~7 hydrolysis 85951-58~2 ~ ~ -, Ac HO I starting material ;Analgesics: Startina materials H OH
HO~ morph ne . Me e pentazocine CAS RN: 359-83-1 CH2CHC(Ubk ~1262~
WO 93/11761 , . PCr/DK92~0038g Analpesics: Startin~ materials con~
COOH Salicyli~ acid OH
OH
~C-CH2CH3 Ketobemidone Beta-bl~ers: Startin~ m~t~ls OCH2CHOHCH2NHiPr prenalterol CAS RN: 57526 81-5 ~ .
OH
An~iathmatics: Startin~ ma~erials OH
HO~ ~t Bu terbutalin OH H
salbutamol ~t-Bu WO 93/11761 2 1 2 ~i 2 ~ 2 PCrtDK92~00389 In the following the invention is further illustated by way of examples which must not be construed as limiting of the invention.
Example 1 5 8-Trifluoromethyl(sulfonyl)oxy-2-(acatamido)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 3~8-23-6; from Aldrich] ~2.0 mL; 23 mmol) and the reaction mixture was slirred 10 at this temperature for 0.5 h. The temperature was raised to room temperaturewithin 1.5 h and was stirred over night at this temperature. Water was added andthe product was extracted with CH2CI2 (10 mL). The organic layer was washed withsolutions of NH4CI, NaHCO3 and NaCI and then separated and dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The remaining oil 15 was chromatographed (SiO2) eluting with CH2CI2: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.
Example2 8-Trifluoromethyl(sulfonyl)oxy-2~(acetamido)te~ralin (Method E3).
8-OH-2-(acetamido~tetralin (see above) (0.49 9: 2.4 mmol) was disso~ved in CH2CI2 (25 mL) and Et3N (0.31 g: 3.1 mmol) was added. Then the mild, triflating agent 25 N-phenyltrifluoromethanesulfonimide [RN 37595-74-7; from Aldrich] (0.96 9; 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 30 washed once with NaCI saturated water, separated and dried (Na2SO4). The solvent was evaporated and the remaining oil (240 mg) was purified by flash chromatography (SiO2 60 mesh) eluting with GH2CI2:MeOH (10:1~. The fractions containing pure product were pooled and the solvent was evaporated under WO 93/11761 2 1 ~ 6 2 ~ ~ PCI/DK92/00389 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 mle=355. 1H-NMR (200 MHz, CDCI3, TMS) shows: ~ 7~0-7.3 (3H, ArH); 5.6-5.8 (1H, NH); 4.2-4.4 (lH, 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-(acetamldo)tetralin) to 7.0-7.3 in the triflated product (with respect to the electronic effects of the triflate 10 group, see also ref: Stang, P. and Anderson, A. G., J. Org. Chem. 1976, 41, 781).
Example 3.
5-Trifluoromethyl(sulfonyl)oxy-(N~cetyl)-tryptamine (Method B).
N-Acetyl-5-hydroxy tryptamine ~RN 1210-83-9] was triflated according to Method B15 and was isolated as an oil after chromatography and evaporation of th~ solvents in 60% yield. MS shows (chemical ionization with NH3) m/e - 351 (M~1).
H-NMR (200 MHz, CDCI3, TMS) shows: ~1.95 (s, 3H), 2.95 (t,2H), 3.55 (t, 2H), 6.0 (t, 1H, NHCO), 7.00-7.10 (m, 2H, aromatic) 7.30-7.5û (m, 2H, aromatic), 9.30 (s,20 1H, 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), 1276 (C:, aromatic), 135.2 (C, aromatic), 143.2 (CH, aromatic), 25 170.6 (CO); the CF3 signals apperar at ca 1 10, 1 16, 122 and 128.
Example 4.
8-Trifluoromethyl(sulfonyl)oxy-2-(N-methyl N~propargyl amino)tetralin (Method B).
30 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 WO 93/11761 PCl'/DK92/00389 2~,~6~4~ 22 mg, 0.20 mmol) was suspended in CH2CI2 (5 mL) ahd 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 Aldrieh~ (75 mg;
0.21mmol) was added in one portion at room temperature. The reaction mixture 5 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 (MgSO4). 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 10 and the solvent was evaporated. The remaining solid was recrystallized from i-propylacetate.
The mass spectrum (chemical ionlzation 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 extractlon and evaporation was purified by chromatography (SiO2), eluting with EtOAc:hexane (1:3). The base was converted to its HCI salt with HCI-sturated ether.
20 E3cample 5.
Trifluoromethyl(sulfonyl)oxy~Morphine (Method B).
Morphine:~ hydrochloride 1.1 9 (3.3 mmol) was~ stirred in CH2CI2 (50 mL) and Et3N
~(0.49 mL, 0.36 9: 3.6 mmol~ was added. Then the mild, triflating agent N-phenyltri-~iluoromethanesulfonimide [RN 37595-74-7; from Aldrich~ (1.3 g; 3.6 mmol) was 2s added in one portion at room temperature. The reaction mixture was monitored with -, GC and after 2 h all sta~ting 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% Na2CO3 and the organic layer was separated and washed once with NaCI saturated water, separated and dried (Na2SO4). The solvent was evaporated 30 and the remaining oil (1.9 9) was purified by chromatography (SiO2 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 9 (63%) of the pure triflated product as an oil. This oil (0.74 9, 1.8 mmol) was dissolved in .'~t~. ~?~2 WO 93/11761 PCl`/DK92/00389 warm EtOH (25 mL) and added to a warm solution of fumaric aoid (0.22 g, 1.9 mmol). Evaporation and recrystallization from refluxing EtOAc gave a gel, which was ~iltered 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.
H-NMR (200 MHz, CDCI3, TMS) shows: ~ 1.84 - 1.96 (m,1H), 2.10 (dt, 7 = 4.8 Hz, 1H), 2.22 - 2.43 (M, ~H), 2.58 -2.76 (M, 2H), 2.86 (br 5, 1 H) 3.08 (d. 7 = 19.2 Hz, 1H) 3.38 (dd. 7 = 6.1, 3.4 Hz, 1H), 4.17 - 4.24 (M, 1H), 5.01 (dd, 7 - 6.4, 1.2, 1H), 10 5.24 - 5.32 (M,1 H), ~.65 - ~.73 (M.1 H), 6.63 (d. 7 = 8.3 Hz,1 H) 6.88 (d. 7 = 8.5 Hz, 1H) 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 5 (CH), 121.0Z (GH), 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.
20 3-Trifluoromethansulfonyloxy-morphine (fumarate salt) (100 mg; 0.19 mmol) wasstirred for 3 hrs at 105 C in MeSO3H (5 mL) under N2-atmosphere. The re`action mix~ure was allowed to cool to room temperature and was then diluted with H2O (10 mL). The aquous layer was basified with NaHCO3 (s) and then extracted with CH2CI2 (3x25 mL). The organic layers were combined, dried over Na2SO4, ~iltered 25 and evaporated in vacuo. to give a greenish-white solid (72 mg; 96%~. The ~umarate salt was formed by mixing the product (36 mg; 0.09 mmol) in EtOH with ~umaric acid (10.5 mg) in EtOH and then evaporation of the solvent. MS (chemicalionization with NH3) showed M + 1 at m/e=400.
30 Example 7.
10~Hydroxy~ trifluoromethyl(sul~onyl)oxy~aporphine.
This compound was synthesized from apomorphine x HCI with Method B and gave a product with M+1 at m/e=400 (chemical ionization with NH3) according to GC/MS
W O 93/11761 PC~r/DK92/00389 f~ 6r? !~ 2 24 Example 8.
Trifluoromethanesulfonyl-Dextrorphan (Method A).
Dextrorphan tartaric acid salt (1:1) (1.0 g; 2.46 mmol) was suspended in CH2CI2 (100 mL) and Et3N (2 mL; 14 mmol) was added and the solution was stirred until all the starting material had dissolved. Then the miid, triflating agent N-phenyltrifluoro-methanesulfonimide [RN 37595-74-7; frorn 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 (Na2SO4). The solvent was evaporated and the remaining yellow oil was purified by flash chromatography (SiO2 60 mesh) eluting with CH2CI2:MeOH
(1:1). The 1ractions containing pure product were pooled and the solvent was evaporated under reduced pressure, yielding 630 mg (66%) of the pure triflated produc~t 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 recrystallized frorn 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.
Trifluoromethyl(sunonyl)oxy-2-(N-propyl-N-2-thienylethylamino)tetralin 25 (5-T~O~N-0437) (Method B).
General procedure: P. J. Stang, Synthesis, 1982, 115-118. To 5-hydroxy-2-(N-pro-pyl-N-2-thienylethylamino)tetralin (N-0437) (Horn, A. S.; Tepper, P.; Van derWeide, J.; Watanabe, M.; Grigoriades, D.; Seeman, P., Pharm. Weekbl. Sci. 7, 208-211, 19~5) (200 mg; 0.57 mmol) in dry pyridine (10 mL) was added triflic anhydride lRN
30 358-23-6; from Aldrich] (1.0 mL; 11 mmol) at -20 C. The temperature was raised to O 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-WO 93/11761 ~ 12 ~ 2 4 2 PCI/DK92/00389 rated, dried (Na2SO4), filtered and the solvent was evaporated under reducedpressure and the remaining oil was purified by column chromatography (SiO2 60 mesh) eluting with petroleum ether: EtOAc (1 :1). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure, 5 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 (CF3SO2) and m/e=149 (CF3SO~) 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 15 (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~
20 (*5-Trifluoromethyl(sulfonyl)oxy-2~(N-propyl-N-2-thienylethylamino)tetralin (R~ TfO-N~437; 5-TfO-N-0924) (Meihod 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, 25 W.; Wijnberg, H., J. Org. Chem. 50, 4508,1985).
, Example 12.
trifluoromethyl(sulfonyl)oxy)phenyl)indolizidine (Method B).
8-(3-Hydroxyphenyl)indolizidine (B0ges0 et al. J. Med. Chem. 30, 142-150, 1987) 30 (74 mg; 0.25 mmol) was dissolved in CH2CI2 (6 mL) and Et3N (68 IlL; 0.50 mmol) was added. Then the mild, triflating agent N-phenyltrifluoromethanesulfonimide lRN
37595-74-7; trom 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 WO 93/11761 PCl/DK92/00389 21262~2 26 starting material was consumed. The solvent and the Et3N were evaporated and theremaining oil was dissolved in CH2CI2 and washed 3 times with water and once with 5% Na2CO3 (25 mL) and the organic layer was separated and washed~ once with NaCI saturated water, separated and dried (Na2SO4). The solvent was evaporated 5 and the remaining oil (117 mg) was purified by flash chromatography (siO2 60 mesh) eluting with CH2CI2:MeOH (1:1). The fractions containing pure product werepooled and the solvent was evaporated under reduced pressure, yielding 73 mg - (84%) of the pure triflated product as an oil.
o The mass spectrum (chemical ionization with NH3) showed: M+1 at m/e=350.
H NMR (CDCI3, 200 MHz, TMS) shows: ~ 1.26 - 2.31 (m, 11 H), 2.44 - 2.62 (m, 1 H), 3.15 - 3.24 (m, 2H), 7.10 - 7.41 (m, 4H).
15 13C NMR (CDCI3,50 MHz); 20.15 (CH2), 25.41 (CH2), 28~.94 (CH2), 32.59 (CH2), 48.6~1 (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 (G), 149.62 (C).
Example 13. 1-(3-Trltluoromethyl(sulfonyl)oxy)phenyl)-3,4,6,7,8,9-hexa-20 hydro-9aH-quinolizine (Method B~.
1-(3-Hydroxyphenyl~-3,4,6j7,8,9-hexahydro-9aH-quinolizine (B0ges0 et al. J. Med.~Chem. 30, 142-150, 1987) (130 mg; 0.57 ~mmol)~ was dissoived in CH2CI2 (20 mL) and Et3N~ ~158~11L; 1.14 mmol) was added. Then the mild, triflating agent N-phenyltrifluoromethanesulfonimide lRN 37595-74-7; from Aldrichl (300 mg; 0.85 2s 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 Na2CO3 (50 mL), the water layer was washed with CH2CI2 (30 mL) and the combined organio~ phases were dried (Na2SO4). The solvent was evaporated and the remaining oil was purified by chromatography 30 (siO2 60 mesh) eluting with CH2CI2: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.
WO 93111761 21 ~ 6 ,'J ll 2 PCI`/DK92/00389 The mass spectrum (chemical ionization with NH3) showed: M~1 at m/e=362.
.
1H NMR (CDCI3, 200 MHz, TMS) shows: ~1.1 (dp, J=11.7 and 3.0,1H), 1.2 - 1.5 5 (m, 1H), 1.5 - 1.8 (m, 4H), 2.1-2.3 (m, 1H), 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 signais).
Examples 14 1-Methyl~-propionyl~-[3-1(trifluoromethyl)sulfonyloxy]phenyl]pip~ridine, 15 ~umarate (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 trifluoromethansulfonylchioride (1.0 ml) at 0-5 C. The mixture was stirred for additionally 1 hour at room temperature. Brine20 (200 ml) was added and extractsd with dichloromethane (3x 50 ml). The combined organic extracts were dried (anh. MgSO4) and dic~hloromethane evaporated leavingths crude title compound as a visceous oil. The tnflate derivative crystallked as the acidic fumarate satt from ethanol. Yield 2.0 9, mp: 164.6-165.4 C. 1H-NMR (250 MHz, DMSO-d6): ~ 0.75 (t, 3H); 2.15 (broad t,2H); 2.30 (q, 2H); 2.40 (s, 3H); 2.5-2.7 (m, 4H); 2.85 (broad s, 2H); 6.55 (s, 2H); 6.95 (s, 1H); 7.0 (m, 2H); 7.10 (t, 1H). `
In a corresponding way the following triflate derivatives were prepared: -(+)-7-Chloro-3-methyl-1 -phenyl-8-~(trifluoromethyl~sulfonyloxy]-2,3,4,5~ -~o tetrahydro-1H-3-benzazepine, oxalate (compound C2). Mp: 167-169 C (from ac~tone). 1H-NMR (250 MHz, DMSO-d6): ~ 2.75 (s, 3H); 2.95 (t, 1H); 3.10 (dd, 1H); 2.85-3.10 (m, 3H); 4.5-5.2 (m, 4H); 6.45 (s, 1H); 7.25 (d, 2H); 7.35-7.50 (m, WO 93/11761 ~ PCI /DK92/00389 , 3H); 7.75 (s, 1H). Prepared ~rom the selective dopamine D1 antagonist SCH 23390 (racemate used) (CAS RN: 138584-32-4).
(-)-N,N-diethyl-N-16-1(trifluormethyl)sulfonyloxy]indan-1-yl]methylamine, :~' 5 oxalate (Compound C3). Mp: 120-122 C (from acetone). 1H-NMR (250 MHz, DMSC)-d6~: ~ 1.15 (t, 6H); 1.9-2.0 (m,1H); 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, 1H); 7.40 (d, 1H); 7.55 td, 1H). Prepared from the corresponding dopamine D2 agonist (US patent no 4,946,863).
10 (+)-N,N-dipropyl-N-15-[(trifluormethyl)sulfonyloxy]-2,3-dihydrnbenzofuran-3-yl]methylamine, oxalate (Compound C4). Mp: 125-126 C (from acetone). 1H-NMR (250 MHz, DMSO-d6): ~ 0.90 (t, 6H); 1.~ (dq, 4H); 2.80 (t, 4H); 3.05 (t, 1 H);
Field o~ the Invention 5 The present invention is directed toward new aryltriflates, and their pharmaceuti-cally acceptable salts, to processes ~or 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.
Rackground of the Invention Aryl triflates are used as intermediates in organic syntheses. They can thus be removed via reduction tNEt3+HCOO-) or substituted by other groups like CN and 15 COOR (Oda, R., Kagaku (Kyoto) 1987, 42, 710-11; Cacchi, S. et al., Tetrahedron Lett 1986, 27, 5541-4; Cham~ers, 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 Lett198~7, 28, 1381-4; Roth, G. P. et al., J. Org. Chem. 1991, 56, 3493-6; Saa, J. M~ et al., J. Org. Chem. 1990, 20 55, 991-5; Subramanian, L. R. et al., Synthesis 1984; Chambers, M. R. I. et al., J.
Chem. Soc., Perkin Tra~s 1989, 1, 1365-6.; Takagi, K. et al., Bull. Chem. Soc. .~pn.
1991, 64, 1 1 18-21; FP-A1 399982; Liu, Y. et al., Bioorg. Med. Chem. Lett. 1991, 1, 257-62.
25 One aryltriflate with biological activity (5-HT1A affinity in a CNS preparation) is known ( EP-A1 399982, Liu, 1991 svpra). 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, svpra).
30 Enzymatic deactivation of drugs (the Cytochrome P450 .soenzyme system) is a well known phenomenon, in particular phenols and methoxylated aryls are in gerteral 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 con~ugation (sulphation and glucoronidation) and/or via initialoxidation and then conjugation.
Obviously, the inhibition of such enzymatic deactivati~n of drugs is highly desired, 5 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.
10 it has now bAen ~ound 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.
Summarv of the Invention This invention relates to aryltriflates and related compounds havirig the general Formula 1:
Ar--O--S- R
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 25 R1 iS CF3, (C~-C8) alkyl, -CH2-(C3-C8) 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.
WO 93/11761 PCr/DK92/00389 In a preferred embodiment, the invention is directed to compounds of Formula 1;
wherein R1 is CF3.
Processes for preparation of these compounds, their pharmaceutical use and 5 pharmaceutical preparations comprising such compounds constitute further aspects of the invention.
Detailed Descri~tion of the Invention 10 As used herein the term (Cn-Cm) is inclusive such that a compound of (C~-C8) would include compounds o~ one to 8 carbons and their isomeric forms. Alkyl refers to an branched or unbranched aliphatic hydrocarbon radical such as m~thyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-buty!, 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 20 diastereomeric forms of Formula 1 compounds either in pure ~orm or as mixtures of enantiomers or diastereomers. The therapeutic properties of the compounds may toa greater or lesser degree depend on the stereochemistry of a particular compound.
Pure ~nantiomers 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 pa~icular a dopamine agonist or antagonist, a dopamine autoreceptor agonist, a 5-HT,A ligand, 5-HT1D ligand, a 5-HT2 antagonist, an antipsychotic, a sigma ligand, or WO 93~11761 2 1 2 ~ 2 ~ 2 PCl/DK92/00389 a melatonine analogue, beta blocker, analgesic, e~c.
Specific examples of Ar appears from the following table showing examples of compounds of the invention.
In the table, R1 is as de~ined above; R2 designates C1-C8 alkyl, CH2-(C3-C8) cycloalkylalkyl, arylalkyl, phenylethyl or 2-thiophenylethyl; R3 designates C1-C8 alkyl, CH2-(C3-C8) cycloalkylalkyl, arylalkyl, phenylethyl or 2-thiophenylethyl; X is CH2, 0 or S; and Y is CH2, 0 or S.
Antiasthmatics oS2R1 oS2R1 HOJ~N ~1Z5J~ ,~t-Bu OH H OH H
Terbutalin analogues R,02SO~ -l~ ~t-Bu OH H: Salbutamol analogue ,'? 4 2 WO 93tll761 PCI/DK92/00389 Dopamine agonists OSO2R, ~N ' R2 R1O250J~J
CH2N~
R,02SO~ R3 R,02SO~CH2~4--N~
Roxindole analogues ~.~
,.
R,02SC~
HO~
W O 93tll761 2 12 6 ~ 4 2 PC~r/DK92/00389 Dopamine aaonists cont'd HO ~ Rl2S
~125~ R~02SO~
R2 R2 ., Dopamine autoreceptQr anta~Qnists oso2R1 ~N ~ R2 D1 agonists and/or ant~onists R,02SO~N_R2 R125~N_R2 R1O2SO~ ~
R,O2SO~N_R2 SK&F38393 analogues Cl~ ~ .
R,02SO~N--Me SCH23390 analogue 2.1262~2 WC) 93/11761 PCl/DK92tO0389 T1 A aponists ~?~N ~ RZ
~N,R2 Rz and R3 are not at the same time propyl R,02SO R3 (~N,R2 R1O250 R, trans ~
~N~R-Rl02SO R2 ~N~R3 R, 02SO R2 WO 93/11761 PCl`tDK92/00389 ~ 2 ~ 2 ~ 8 5-HT1 A liaands 5-HT1 D ligands OSO2R, ' ;
Me ~N~Me Sumatriptan analogue HN
.
Sigma iiçlands R1O250J~
he R1o2so~;e Pentazocine analogue CH2CHC(Me)2 Anti-Alzheimers R,02SO~l 7-Methoxytacrine analogue WO 93/11761 2 1 2 6 ~ 4 ~ PCI`/DK~2/00389 Neuroleptics ~ ~OSO2~1 Clozapine analogue ,_N
Me N~OSO2R
Chlorpromazine and levomepromazine analogue ` N
Me \~N--CH2-CH2-- N~,NH
(~1 Sertindole analogue Melatonine analogues ,~, ~_ H
H~ COR2 ~ ,COR2 WO 93/11761 PClJDK92/00389 212G!~ ~12 10 Anal~esiçs H OH
o~ morphine analogue 2SO~N
Me ~,ozso~e pentazocine analogue CH2CHC:(Nb)2 COOH ~
~OS02R1 W acetyl salicylic acid analogue OSO2R, Q
~-CH2CH3 Ketobemidone analogue ~N~
~eta-bl~ckers OCH2CHOHCH2NHlPr prenalterol analogue oSo2R1 OCH2CHOHCH2NHlPr ~,~oSo2R1 oxprenolol analogue Il I
~.,-i2~2 WO 93/11761 PCI`/DK92/00389 11 ..
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 misciblesolvent, 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, aceticl propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, 10 cinnamic, citraconic, aspartic, stearic, palmiticj 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 inorganicsalts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of 15 double decomposition of appropriate salts, which is well known to the art.
In clinical prac~tice the compounds of the present invention will normally be adminis-~-- tered orally, rectally~ or by injection, in the form of pharmaceuticai preparations comprising the ~active ingrédient either as a free base or as a pharmaceutically- ~ :20 acceptablé~non-toxic, acid~addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in~ association with~ a pharmæeutically 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.
,, -25 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 i i one to 4 times daily and the dosage amounts are based on an individual having a - 30 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 WO 93/11761 PC~/DK92/00389 ;:
21262~ 12 features are beneficial to effective clinical treatment.
The compounds of this invention may be obtained by the general general syntheticstrategy exemplified in Scheme 1: :
. .
Scheme 1 Triflating agent ¦ ¦ -Ar OH ~ Ar O S- CF3 Et3N in CH2CI2 O
The triflating agent is conveniently triflic anhydride (Method A), N-phenyltrifluoro- .
10 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:
WO93/11761 ?~ 4 2 PCI/DK92/00389 Dopamine aaonists: Startin~ mat~r~l~
OH CAS RN's: trans racemic: 110311-52-9 trans-4aS,1 ObS: 93601-83-3 trans-4aR,l~bP~: 93601-82-2 I I cis racemic: 82171-94~6 ,n-Pr cis-4aS,10bR: 93601-81-1 ¦~J cis-4aR,1 ObS: 93601-80-0 CAS RN's: tr~ns racemic: 110311-53-0 trans-4aS,1 ObS: 110311-50-7 trans-4aR,lObR: 103302-90-~
HO~N~n pr cis-racemic: 110311-5~2 cis-4aS,1 ObP~: 93601-81-1 cis-4aR,~ ObS: 93601-80-0 R See US Patent Nos. 4,946,862 CH2N~ and 4,847,254 HO~ R3 HO~CH,),--N~
N CAS RN: 112192-04-8 ~) 11-hydroxy aporphine Me HO ~ (-)-apomorphine:
CAS RN: 58-00-4 Me WO93/11761 ~125,~42 14 PCI/DK92/00389 Dopamine autore~tor antagonists: Star~n~ material$ ~;
CAS RN: cis-4aR,1 ObS: 9360~ -80-0 -,n-Pr D1 a~onists andlor anta~onists: Starting material~
HO~ SK&F75670 CAS RN: 62717-63-9 ~ ' c~
HOJ~ SCH23390 ~ CAS RN: 138584-32-4 ~ .. `.
HT1A a~onists: Starting material~ :
CAS RN's: trans-racemic: ~82172-01-8 ~I trans-4aS,1 ObS: 131484-03-2 J~ ,~Pr trans-4aR,10bR: 131484-02-1 N cis-racemic: 82172-00-7 HO V cis-4aR,1 ObS: 109062-23-9 cis-4aS,1 ObR: 109062-2~ -7 ~ ,r~Pr CAS RN's: racemic: 127165-21-3 CH30 ~
5-HT1 A a~onists: Startin~ matçrials cont'~
CAS RN's: racemic: 127165-07~5 ~1 J~ , R enantiomer: 129568-16-7 ~ ~ N ~~ S enentiomer: 127253-43-4 CH30 ~
CAS RN's: trans-racemic: 110826-30-7 1~ 1S-trans: 110901-82-1 ,n-Pr 1 R-trans: 110901 -~1~0 H0 n~Pr CAS RN's: trans-racemic: 110826-37-4 ~ l S-trans: 110901 -84-3 HO~N,n Pr 1 R-trans: 110901-83~2 Pr CAS RN's: 6aS-enantiomer: 135529-45-2 6aR-enantiomer: 111635-19-9 Me O CAS RN's: racemic: 119755-88-3 and 109140-25-2 ,n-Pr (~)-form:- 117422-53-4 1' y (-)-form: 117422-55-6 H0 n-Pr Upjohn code name ,r~Pr CAS RN: 129301-34-4 HO n~Pr WO 93/11761 PC~JDK92/003~9 ~
21262'42 16 5-HT1 A liaands: Startina materials CAS RN: racemic: 127033-10-7 ~ R-enantiomer: 127126-18-5 I l S-enantiomer: 127126-21-0 ,n-Pr HO n-Pr 5-HT1 D~ands: Startinq materials OH
d~ M N, N-dimethyl-serotonin y~~N~ CAS RN: 487-93-4 HN.
Sigma liclands: Startin~ materials CAS RN's: trans racemic: 110311-53-0 ~ trans-4aS,1 ObS: 110311-50-7 ,l~ 1 ,n-Pr trans-4aR,10bR: 103302-90-5 HO ~ N t:is-racemic: 110311-55~2 cis-4aS,1 ObR: 93601-81-1 cis-4aR,1 ObS: 93601-80-0 CAS RN's: trans racemic: 110242-80-3 . . and 93503-t 1-8 ~ ~ ~ ,n-Bu trans-4aS,1 ObS: 119778-47-1 HO I ~ N cis-racemic: 110242-86-9 I~J cis-4aR,1 ObS: 119904-02-8 I.
Me pentazocine CAS RN: 359-83-1 CH?CHC(Me)2 WO 93/11761 ~ 1 ~ 6 ~ 4 2 PCT`/DK92/00389 Anti-Alzheimers: Startinç~ matçrials HO~o CAS RN: t36051-80-4 Neuroleetics: Starting material~
~OH
clozapine analogue N
Me 2-hydroxypromazine N OH CAS RN: 3926-64-5 Me~
Nb HO~N--CH2-CH2 -- N~f NH
Perregaard et al. J.Med.Chem.
r 11 1992 3~, 1092-1101.
Obtained from the corrssponding F 5-methoxy compound by treating with pyridine-hydrochloride WO 93/11761 ~ ~ 4 ~/~ PCl['/DK92/00389 Melatonine analo~ues: Startin~ mat rial~
OH
~_ H CAS RN: 1210-83-9 H COMe ,H AC2O ~N~ ,A~:
HO H AcO H
CAS R N ~
alkaline 94344-99~7 hydrolysis 85951-58~2 ~ ~ -, Ac HO I starting material ;Analgesics: Startina materials H OH
HO~ morph ne . Me e pentazocine CAS RN: 359-83-1 CH2CHC(Ubk ~1262~
WO 93/11761 , . PCr/DK92~0038g Analpesics: Startin~ materials con~
COOH Salicyli~ acid OH
OH
~C-CH2CH3 Ketobemidone Beta-bl~ers: Startin~ m~t~ls OCH2CHOHCH2NHiPr prenalterol CAS RN: 57526 81-5 ~ .
OH
An~iathmatics: Startin~ ma~erials OH
HO~ ~t Bu terbutalin OH H
salbutamol ~t-Bu WO 93/11761 2 1 2 ~i 2 ~ 2 PCrtDK92~00389 In the following the invention is further illustated by way of examples which must not be construed as limiting of the invention.
Example 1 5 8-Trifluoromethyl(sulfonyl)oxy-2-(acatamido)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 3~8-23-6; from Aldrich] ~2.0 mL; 23 mmol) and the reaction mixture was slirred 10 at this temperature for 0.5 h. The temperature was raised to room temperaturewithin 1.5 h and was stirred over night at this temperature. Water was added andthe product was extracted with CH2CI2 (10 mL). The organic layer was washed withsolutions of NH4CI, NaHCO3 and NaCI and then separated and dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The remaining oil 15 was chromatographed (SiO2) eluting with CH2CI2: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.
Example2 8-Trifluoromethyl(sulfonyl)oxy-2~(acetamido)te~ralin (Method E3).
8-OH-2-(acetamido~tetralin (see above) (0.49 9: 2.4 mmol) was disso~ved in CH2CI2 (25 mL) and Et3N (0.31 g: 3.1 mmol) was added. Then the mild, triflating agent 25 N-phenyltrifluoromethanesulfonimide [RN 37595-74-7; from Aldrich] (0.96 9; 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 30 washed once with NaCI saturated water, separated and dried (Na2SO4). The solvent was evaporated and the remaining oil (240 mg) was purified by flash chromatography (SiO2 60 mesh) eluting with GH2CI2:MeOH (10:1~. The fractions containing pure product were pooled and the solvent was evaporated under WO 93/11761 2 1 ~ 6 2 ~ ~ PCI/DK92/00389 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 mle=355. 1H-NMR (200 MHz, CDCI3, TMS) shows: ~ 7~0-7.3 (3H, ArH); 5.6-5.8 (1H, NH); 4.2-4.4 (lH, 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-(acetamldo)tetralin) to 7.0-7.3 in the triflated product (with respect to the electronic effects of the triflate 10 group, see also ref: Stang, P. and Anderson, A. G., J. Org. Chem. 1976, 41, 781).
Example 3.
5-Trifluoromethyl(sulfonyl)oxy-(N~cetyl)-tryptamine (Method B).
N-Acetyl-5-hydroxy tryptamine ~RN 1210-83-9] was triflated according to Method B15 and was isolated as an oil after chromatography and evaporation of th~ solvents in 60% yield. MS shows (chemical ionization with NH3) m/e - 351 (M~1).
H-NMR (200 MHz, CDCI3, TMS) shows: ~1.95 (s, 3H), 2.95 (t,2H), 3.55 (t, 2H), 6.0 (t, 1H, NHCO), 7.00-7.10 (m, 2H, aromatic) 7.30-7.5û (m, 2H, aromatic), 9.30 (s,20 1H, 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), 1276 (C:, aromatic), 135.2 (C, aromatic), 143.2 (CH, aromatic), 25 170.6 (CO); the CF3 signals apperar at ca 1 10, 1 16, 122 and 128.
Example 4.
8-Trifluoromethyl(sulfonyl)oxy-2-(N-methyl N~propargyl amino)tetralin (Method B).
30 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 WO 93/11761 PCl'/DK92/00389 2~,~6~4~ 22 mg, 0.20 mmol) was suspended in CH2CI2 (5 mL) ahd 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 Aldrieh~ (75 mg;
0.21mmol) was added in one portion at room temperature. The reaction mixture 5 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 (MgSO4). 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 10 and the solvent was evaporated. The remaining solid was recrystallized from i-propylacetate.
The mass spectrum (chemical ionlzation 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 extractlon and evaporation was purified by chromatography (SiO2), eluting with EtOAc:hexane (1:3). The base was converted to its HCI salt with HCI-sturated ether.
20 E3cample 5.
Trifluoromethyl(sulfonyl)oxy~Morphine (Method B).
Morphine:~ hydrochloride 1.1 9 (3.3 mmol) was~ stirred in CH2CI2 (50 mL) and Et3N
~(0.49 mL, 0.36 9: 3.6 mmol~ was added. Then the mild, triflating agent N-phenyltri-~iluoromethanesulfonimide [RN 37595-74-7; from Aldrich~ (1.3 g; 3.6 mmol) was 2s added in one portion at room temperature. The reaction mixture was monitored with -, GC and after 2 h all sta~ting 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% Na2CO3 and the organic layer was separated and washed once with NaCI saturated water, separated and dried (Na2SO4). The solvent was evaporated 30 and the remaining oil (1.9 9) was purified by chromatography (SiO2 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 9 (63%) of the pure triflated product as an oil. This oil (0.74 9, 1.8 mmol) was dissolved in .'~t~. ~?~2 WO 93/11761 PCl`/DK92/00389 warm EtOH (25 mL) and added to a warm solution of fumaric aoid (0.22 g, 1.9 mmol). Evaporation and recrystallization from refluxing EtOAc gave a gel, which was ~iltered 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.
H-NMR (200 MHz, CDCI3, TMS) shows: ~ 1.84 - 1.96 (m,1H), 2.10 (dt, 7 = 4.8 Hz, 1H), 2.22 - 2.43 (M, ~H), 2.58 -2.76 (M, 2H), 2.86 (br 5, 1 H) 3.08 (d. 7 = 19.2 Hz, 1H) 3.38 (dd. 7 = 6.1, 3.4 Hz, 1H), 4.17 - 4.24 (M, 1H), 5.01 (dd, 7 - 6.4, 1.2, 1H), 10 5.24 - 5.32 (M,1 H), ~.65 - ~.73 (M.1 H), 6.63 (d. 7 = 8.3 Hz,1 H) 6.88 (d. 7 = 8.5 Hz, 1H) 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 5 (CH), 121.0Z (GH), 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.
20 3-Trifluoromethansulfonyloxy-morphine (fumarate salt) (100 mg; 0.19 mmol) wasstirred for 3 hrs at 105 C in MeSO3H (5 mL) under N2-atmosphere. The re`action mix~ure was allowed to cool to room temperature and was then diluted with H2O (10 mL). The aquous layer was basified with NaHCO3 (s) and then extracted with CH2CI2 (3x25 mL). The organic layers were combined, dried over Na2SO4, ~iltered 25 and evaporated in vacuo. to give a greenish-white solid (72 mg; 96%~. The ~umarate salt was formed by mixing the product (36 mg; 0.09 mmol) in EtOH with ~umaric acid (10.5 mg) in EtOH and then evaporation of the solvent. MS (chemicalionization with NH3) showed M + 1 at m/e=400.
30 Example 7.
10~Hydroxy~ trifluoromethyl(sul~onyl)oxy~aporphine.
This compound was synthesized from apomorphine x HCI with Method B and gave a product with M+1 at m/e=400 (chemical ionization with NH3) according to GC/MS
W O 93/11761 PC~r/DK92/00389 f~ 6r? !~ 2 24 Example 8.
Trifluoromethanesulfonyl-Dextrorphan (Method A).
Dextrorphan tartaric acid salt (1:1) (1.0 g; 2.46 mmol) was suspended in CH2CI2 (100 mL) and Et3N (2 mL; 14 mmol) was added and the solution was stirred until all the starting material had dissolved. Then the miid, triflating agent N-phenyltrifluoro-methanesulfonimide [RN 37595-74-7; frorn 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 (Na2SO4). The solvent was evaporated and the remaining yellow oil was purified by flash chromatography (SiO2 60 mesh) eluting with CH2CI2:MeOH
(1:1). The 1ractions containing pure product were pooled and the solvent was evaporated under reduced pressure, yielding 630 mg (66%) of the pure triflated produc~t 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 recrystallized frorn 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.
Trifluoromethyl(sunonyl)oxy-2-(N-propyl-N-2-thienylethylamino)tetralin 25 (5-T~O~N-0437) (Method B).
General procedure: P. J. Stang, Synthesis, 1982, 115-118. To 5-hydroxy-2-(N-pro-pyl-N-2-thienylethylamino)tetralin (N-0437) (Horn, A. S.; Tepper, P.; Van derWeide, J.; Watanabe, M.; Grigoriades, D.; Seeman, P., Pharm. Weekbl. Sci. 7, 208-211, 19~5) (200 mg; 0.57 mmol) in dry pyridine (10 mL) was added triflic anhydride lRN
30 358-23-6; from Aldrich] (1.0 mL; 11 mmol) at -20 C. The temperature was raised to O 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-WO 93/11761 ~ 12 ~ 2 4 2 PCI/DK92/00389 rated, dried (Na2SO4), filtered and the solvent was evaporated under reducedpressure and the remaining oil was purified by column chromatography (SiO2 60 mesh) eluting with petroleum ether: EtOAc (1 :1). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure, 5 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 (CF3SO2) and m/e=149 (CF3SO~) 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 15 (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~
20 (*5-Trifluoromethyl(sulfonyl)oxy-2~(N-propyl-N-2-thienylethylamino)tetralin (R~ TfO-N~437; 5-TfO-N-0924) (Meihod 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, 25 W.; Wijnberg, H., J. Org. Chem. 50, 4508,1985).
, Example 12.
trifluoromethyl(sulfonyl)oxy)phenyl)indolizidine (Method B).
8-(3-Hydroxyphenyl)indolizidine (B0ges0 et al. J. Med. Chem. 30, 142-150, 1987) 30 (74 mg; 0.25 mmol) was dissolved in CH2CI2 (6 mL) and Et3N (68 IlL; 0.50 mmol) was added. Then the mild, triflating agent N-phenyltrifluoromethanesulfonimide lRN
37595-74-7; trom 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 WO 93/11761 PCl/DK92/00389 21262~2 26 starting material was consumed. The solvent and the Et3N were evaporated and theremaining oil was dissolved in CH2CI2 and washed 3 times with water and once with 5% Na2CO3 (25 mL) and the organic layer was separated and washed~ once with NaCI saturated water, separated and dried (Na2SO4). The solvent was evaporated 5 and the remaining oil (117 mg) was purified by flash chromatography (siO2 60 mesh) eluting with CH2CI2:MeOH (1:1). The fractions containing pure product werepooled and the solvent was evaporated under reduced pressure, yielding 73 mg - (84%) of the pure triflated product as an oil.
o The mass spectrum (chemical ionization with NH3) showed: M+1 at m/e=350.
H NMR (CDCI3, 200 MHz, TMS) shows: ~ 1.26 - 2.31 (m, 11 H), 2.44 - 2.62 (m, 1 H), 3.15 - 3.24 (m, 2H), 7.10 - 7.41 (m, 4H).
15 13C NMR (CDCI3,50 MHz); 20.15 (CH2), 25.41 (CH2), 28~.94 (CH2), 32.59 (CH2), 48.6~1 (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 (G), 149.62 (C).
Example 13. 1-(3-Trltluoromethyl(sulfonyl)oxy)phenyl)-3,4,6,7,8,9-hexa-20 hydro-9aH-quinolizine (Method B~.
1-(3-Hydroxyphenyl~-3,4,6j7,8,9-hexahydro-9aH-quinolizine (B0ges0 et al. J. Med.~Chem. 30, 142-150, 1987) (130 mg; 0.57 ~mmol)~ was dissoived in CH2CI2 (20 mL) and Et3N~ ~158~11L; 1.14 mmol) was added. Then the mild, triflating agent N-phenyltrifluoromethanesulfonimide lRN 37595-74-7; from Aldrichl (300 mg; 0.85 2s 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 Na2CO3 (50 mL), the water layer was washed with CH2CI2 (30 mL) and the combined organio~ phases were dried (Na2SO4). The solvent was evaporated and the remaining oil was purified by chromatography 30 (siO2 60 mesh) eluting with CH2CI2: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.
WO 93111761 21 ~ 6 ,'J ll 2 PCI`/DK92/00389 The mass spectrum (chemical ionization with NH3) showed: M~1 at m/e=362.
.
1H NMR (CDCI3, 200 MHz, TMS) shows: ~1.1 (dp, J=11.7 and 3.0,1H), 1.2 - 1.5 5 (m, 1H), 1.5 - 1.8 (m, 4H), 2.1-2.3 (m, 1H), 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 signais).
Examples 14 1-Methyl~-propionyl~-[3-1(trifluoromethyl)sulfonyloxy]phenyl]pip~ridine, 15 ~umarate (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 trifluoromethansulfonylchioride (1.0 ml) at 0-5 C. The mixture was stirred for additionally 1 hour at room temperature. Brine20 (200 ml) was added and extractsd with dichloromethane (3x 50 ml). The combined organic extracts were dried (anh. MgSO4) and dic~hloromethane evaporated leavingths crude title compound as a visceous oil. The tnflate derivative crystallked as the acidic fumarate satt from ethanol. Yield 2.0 9, mp: 164.6-165.4 C. 1H-NMR (250 MHz, DMSO-d6): ~ 0.75 (t, 3H); 2.15 (broad t,2H); 2.30 (q, 2H); 2.40 (s, 3H); 2.5-2.7 (m, 4H); 2.85 (broad s, 2H); 6.55 (s, 2H); 6.95 (s, 1H); 7.0 (m, 2H); 7.10 (t, 1H). `
In a corresponding way the following triflate derivatives were prepared: -(+)-7-Chloro-3-methyl-1 -phenyl-8-~(trifluoromethyl~sulfonyloxy]-2,3,4,5~ -~o tetrahydro-1H-3-benzazepine, oxalate (compound C2). Mp: 167-169 C (from ac~tone). 1H-NMR (250 MHz, DMSO-d6): ~ 2.75 (s, 3H); 2.95 (t, 1H); 3.10 (dd, 1H); 2.85-3.10 (m, 3H); 4.5-5.2 (m, 4H); 6.45 (s, 1H); 7.25 (d, 2H); 7.35-7.50 (m, WO 93/11761 ~ PCI /DK92/00389 , 3H); 7.75 (s, 1H). Prepared ~rom the selective dopamine D1 antagonist SCH 23390 (racemate used) (CAS RN: 138584-32-4).
(-)-N,N-diethyl-N-16-1(trifluormethyl)sulfonyloxy]indan-1-yl]methylamine, :~' 5 oxalate (Compound C3). Mp: 120-122 C (from acetone). 1H-NMR (250 MHz, DMSC)-d6~: ~ 1.15 (t, 6H); 1.9-2.0 (m,1H); 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, 1H); 7.40 (d, 1H); 7.55 td, 1H). Prepared from the corresponding dopamine D2 agonist (US patent no 4,946,863).
10 (+)-N,N-dipropyl-N-15-[(trifluormethyl)sulfonyloxy]-2,3-dihydrnbenzofuran-3-yl]methylamine, oxalate (Compound C4). Mp: 125-126 C (from acetone). 1H-NMR (250 MHz, DMSO-d6): ~ 0.90 (t, 6H); 1.~ (dq, 4H); 2.80 (t, 4H); 3.05 (t, 1 H);
3.15 (dd, 1H); 3.9-4.0 ~m, 1H); 4.45 (dd, 1H); 4.75 (t, 1H); 6.95 (d, 1H); 7.25 (dd, 1H); 7.55 (d, 1H). Prepared from the corresponding dopamine D2 agonist ~US ~:
15 patent no 4,B47,254).
(+)-N-me~hyl^N~propyl-N-[~[(trifluormethyl)sulfonyloxy]-2,3 clihydrobenzofu- :~:
ran-3-yllmethylamine, oxalate (Compound C5). Mp: 138-141 C (from acetone).
1H-NMR (250 MHz, DMSO-d6): ~ 0.90 (t, 3H); t.65 (dq~ 2H); 2.70 (s, 3H); 2.95 (dt, 20 2H); 3.20 (t,1H); 3.30 (dd, 1H); 4.0-4.1 (m, 1H); 4.55 (dd,1H); 4.80 (t, 1H); 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 (+j-3-methyl-1-phenyl-7,8-dil(trlfluorome-25 thyl~sulfonyloxy]-2,3,4,5-tetrahydro~ 3-benzazepine, (~)-8-hydroxy-3-m~thyl-1-phenyl-7-l(trifluoromethyl)sultonyloxyl-2"3,4,5-tetrahydro- 1~3-benzazepine, (+)-7-hydroxy-3-methyl-1 -phenyl~l(trifluoromethyl)sulfonyloxy]-2,3,4,5-tetrahydro-1~3-benzazepine, oxalat~s (mixtures C6 and C7).
The ~ree catechole base (1.6 g) liberated ~rom (+)-7,8-dihydroxy-3-methyl-1-phenyl-30 2,3,4,5-tetrahydro-1H-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 9). The mixture was cooled to C and a WO 93/11761 2 1 2 l~ r? ~1 ~ PCI`/DK92/00389 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-- 5 pounds, which were subjected to column chromatography on silica gel (eluted with diisopropyl ether/tetrahydro~uran/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 - 10 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 molucùlar ratio.
i~xample 15.
Com~ound Method MS(chem. ioniz~i~n NH~) Roxindole-OTf B M + 1 at m/e=479 6,7~ OTf-DPAT B ~ M + 1 at m/e=~28 2-OTf-N-Pr-Ph-pip B M + 1 at m/e=380 OT~-N-Pr-Ph-pip B M + 1 at m/e=380 3-0}f-N-PhEth-Ph-pip B M + 1 at m/e=442 5 CI~OTf-N-Pr-N-thienylethyl-2-AT B ~ M + 1 at m/e=482 M + 3 at m/e=484 trans-9-OTf-PHNO B M + 1 at m/e=379 c is-9-OTf-PHNO B M + 1 at m/e=379 Triflat~d nor-Remoxipride B M + 1 at m/e=489 - M + 3 at m/e=491 30 Ditrlflated isoprenaline B M + 1 at m/e=476 DUrltlatedterbutalin B M + 1 at m/e=490 Tritriflatedfenoterol B M + 1 at m/e=700 WO 93/11761 PCr/DK92/00389 21262~2 30 ~ :
Triflated R-(+)-8-OH-DPAT B M + 1 at m/e=380 la~D25= +18.2 at c=0.35 in MeOH tbase); +52.0 at c=1.00 in MeOH (base) Triflated $(-)-8-OH-DPAT B M + 1 at mte=380 [a3D25= -24.~ at c=0.44 in MeOH (base); -~.9 at c=1.00 in MeOH (base) Tri~lated 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 0 Triflated ~(-)-N~437 B M + 1 at m/e=448 a]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 D1 receptors. Inhibition of 3H-SCH 23390 binding to DA D1 receptors in rat 20 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 25 described by Hyttel, J. Acta. 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. Act~. Pharm Suec. 24, 145.
3~ 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.
WO 93/11761 2 1 2 6 ,~ 4 2 PCI /DK92/00389 5-HT2 receptors.
Inhibition of 3H-ketanserin binding to 5-HT2 receptors in membranes from rat cortex was determined as described by Hyttel, J. Acta. Pharmacol. Toxicol. 1987, 61, 126.
5 5-HT1A receptors.
Inhibition of 3H-8-OH-DPAT Binding to Serotonin 5-HT1A Receptors in Rat Brain invitro as described by Gozlan H. et al. Nature 1983, 305, 140, and Pazos A et al,Eur. J. Ph~rmacol. 1985, 106, 539.
10 Sigma Receptors Inhibition by drugs of the binding of 3H-DTG (1,3,di-o-tolyl guanidine) to sigmareceptors in homogenates cr membranes from rat brain without cerebellum as modified from Weberet 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 D1 receptor antagonistic effect in vivo. The experiments 20 are performed as described by Arnt, J.et al., J. Neural. Transm. 19S6, 67, 225-240.
.
Antagonism of Pergolide-induced circling behavior in rats with unilateral 6- -OltDA lesions.
ThiS test model is used to determine dopamine (DA) D2 antagonistic effect. (Arnt,J.
25 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 30 induced head twitches. The method and test results for some reference substances are published by Arnt et al. (Drvg DeYelopment Research, 16, 59-70, 1989).
WO 93/11761 PCI/DK92/003~9 ~12~2~2 32 Dopamine agonist studies Dopamine agonist effects are studied as described in US patent no. 4~946,863.
~. .
8-OH-DPAT Cue Antagonism in Rats.
5 This test model is used to determine the antagonist effects of a test compound on 5-HTlA receptors in viYo. A related method is described by Tricklebank, M. D., et al, Eur. J. Pharmacol., 1987, 133, 47-56; Arnt, J. Pharmacology & Toxicology, 1989, 64, 1 65.
10 8-OH-DPAT Cue Agonism in Rats This test rnodel is used to determine the agonist effects of a test compound on 5-HT1~ receptors in vivo. A related rnethod 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-TfC)-N-0437) showed an IC50 value of 69 nM in the [3H~-spiperone 20 binding assay according to the method of Krotowska A. et al.(sup~a).
Furthermore the compounds of Example 14 showed binding affinities in the above 3H-SCH 23390 binding assay as follows:
25 Compound no IC50 value in nM
15 patent no 4,B47,254).
(+)-N-me~hyl^N~propyl-N-[~[(trifluormethyl)sulfonyloxy]-2,3 clihydrobenzofu- :~:
ran-3-yllmethylamine, oxalate (Compound C5). Mp: 138-141 C (from acetone).
1H-NMR (250 MHz, DMSO-d6): ~ 0.90 (t, 3H); t.65 (dq~ 2H); 2.70 (s, 3H); 2.95 (dt, 20 2H); 3.20 (t,1H); 3.30 (dd, 1H); 4.0-4.1 (m, 1H); 4.55 (dd,1H); 4.80 (t, 1H); 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 (+j-3-methyl-1-phenyl-7,8-dil(trlfluorome-25 thyl~sulfonyloxy]-2,3,4,5-tetrahydro~ 3-benzazepine, (~)-8-hydroxy-3-m~thyl-1-phenyl-7-l(trifluoromethyl)sultonyloxyl-2"3,4,5-tetrahydro- 1~3-benzazepine, (+)-7-hydroxy-3-methyl-1 -phenyl~l(trifluoromethyl)sulfonyloxy]-2,3,4,5-tetrahydro-1~3-benzazepine, oxalat~s (mixtures C6 and C7).
The ~ree catechole base (1.6 g) liberated ~rom (+)-7,8-dihydroxy-3-methyl-1-phenyl-30 2,3,4,5-tetrahydro-1H-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 9). The mixture was cooled to C and a WO 93/11761 2 1 2 l~ r? ~1 ~ PCI`/DK92/00389 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-- 5 pounds, which were subjected to column chromatography on silica gel (eluted with diisopropyl ether/tetrahydro~uran/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 - 10 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 molucùlar ratio.
i~xample 15.
Com~ound Method MS(chem. ioniz~i~n NH~) Roxindole-OTf B M + 1 at m/e=479 6,7~ OTf-DPAT B ~ M + 1 at m/e=~28 2-OTf-N-Pr-Ph-pip B M + 1 at m/e=380 OT~-N-Pr-Ph-pip B M + 1 at m/e=380 3-0}f-N-PhEth-Ph-pip B M + 1 at m/e=442 5 CI~OTf-N-Pr-N-thienylethyl-2-AT B ~ M + 1 at m/e=482 M + 3 at m/e=484 trans-9-OTf-PHNO B M + 1 at m/e=379 c is-9-OTf-PHNO B M + 1 at m/e=379 Triflat~d nor-Remoxipride B M + 1 at m/e=489 - M + 3 at m/e=491 30 Ditrlflated isoprenaline B M + 1 at m/e=476 DUrltlatedterbutalin B M + 1 at m/e=490 Tritriflatedfenoterol B M + 1 at m/e=700 WO 93/11761 PCr/DK92/00389 21262~2 30 ~ :
Triflated R-(+)-8-OH-DPAT B M + 1 at m/e=380 la~D25= +18.2 at c=0.35 in MeOH tbase); +52.0 at c=1.00 in MeOH (base) Triflated $(-)-8-OH-DPAT B M + 1 at mte=380 [a3D25= -24.~ at c=0.44 in MeOH (base); -~.9 at c=1.00 in MeOH (base) Tri~lated 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 0 Triflated ~(-)-N~437 B M + 1 at m/e=448 a]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 D1 receptors. Inhibition of 3H-SCH 23390 binding to DA D1 receptors in rat 20 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 25 described by Hyttel, J. Acta. 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. Act~. Pharm Suec. 24, 145.
3~ 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.
WO 93/11761 2 1 2 6 ,~ 4 2 PCI /DK92/00389 5-HT2 receptors.
Inhibition of 3H-ketanserin binding to 5-HT2 receptors in membranes from rat cortex was determined as described by Hyttel, J. Acta. Pharmacol. Toxicol. 1987, 61, 126.
5 5-HT1A receptors.
Inhibition of 3H-8-OH-DPAT Binding to Serotonin 5-HT1A Receptors in Rat Brain invitro as described by Gozlan H. et al. Nature 1983, 305, 140, and Pazos A et al,Eur. J. Ph~rmacol. 1985, 106, 539.
10 Sigma Receptors Inhibition by drugs of the binding of 3H-DTG (1,3,di-o-tolyl guanidine) to sigmareceptors in homogenates cr membranes from rat brain without cerebellum as modified from Weberet 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 D1 receptor antagonistic effect in vivo. The experiments 20 are performed as described by Arnt, J.et al., J. Neural. Transm. 19S6, 67, 225-240.
.
Antagonism of Pergolide-induced circling behavior in rats with unilateral 6- -OltDA lesions.
ThiS test model is used to determine dopamine (DA) D2 antagonistic effect. (Arnt,J.
25 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 30 induced head twitches. The method and test results for some reference substances are published by Arnt et al. (Drvg DeYelopment Research, 16, 59-70, 1989).
WO 93/11761 PCI/DK92/003~9 ~12~2~2 32 Dopamine agonist studies Dopamine agonist effects are studied as described in US patent no. 4~946,863.
~. .
8-OH-DPAT Cue Antagonism in Rats.
5 This test model is used to determine the antagonist effects of a test compound on 5-HTlA receptors in viYo. A related method is described by Tricklebank, M. D., et al, Eur. J. Pharmacol., 1987, 133, 47-56; Arnt, J. Pharmacology & Toxicology, 1989, 64, 1 65.
10 8-OH-DPAT Cue Agonism in Rats This test rnodel is used to determine the agonist effects of a test compound on 5-HT1~ receptors in vivo. A related rnethod 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-TfC)-N-0437) showed an IC50 value of 69 nM in the [3H~-spiperone 20 binding assay according to the method of Krotowska A. et al.(sup~a).
Furthermore the compounds of Example 14 showed binding affinities in the above 3H-SCH 23390 binding assay as follows:
25 Compound no IC50 value in nM
Claims (7)
1, An aryltriflate or a related compound having the general Formula 1:
Formula 1 or pharmaceutically acceptable acid addition salts thereof, wherein Ar is an aromatic or hetroaromatic system of a compound which has a thera-peutic, biological activity when it, in the same position, carries a hydroxy, alkyloxy, halo, ester or cyano group; and R1 is CF3, (C1-C8) alkyl, (C3-C8) cycloalkylmethyl, substituted phenyl, substituted 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-acetamido-phenyl.
Formula 1 or pharmaceutically acceptable acid addition salts thereof, wherein Ar is an aromatic or hetroaromatic system of a compound which has a thera-peutic, biological activity when it, in the same position, carries a hydroxy, alkyloxy, halo, ester or cyano group; and R1 is CF3, (C1-C8) alkyl, (C3-C8) cycloalkylmethyl, substituted phenyl, substituted 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-acetamido-phenyl.
2. A compound of claim 1, Formula 1, wherein R1 is CF3.
3. A compounds of claim 1 which is selected from the group consisting of the following compounds:
Antiasthmatics of formulas:
, , analogues of dopamine agonists having formulas , dopamine autoreceptor antagonists of formula:
dopamine D1 receptor antagonists of formulas:
5-HT1A ligands of formulas;
in which R2 and R3 are not both propyl, , , , , 5-HT1D ligands of formula:
Sigma ligands of formulas:
, Anti-Aizheimers drugs of formula:
Neuroleptics of formulas:
, , melatonine analogues of formulas:
, analgesics of formulas:
, , , , and Beta-blockers of formulas:
, in which formulas R1 is as defined in Claim 1; R2 designates C1-C8 alkyl, C3-C8 cycloalkylmethyl, arlalkyl, phenylethyl or 2-thiophenylethyl; R3 designates C1-C8 alkyl, (C3-C8) cycloalkylmethyl, arylalkyl, phenylethyl or 2-thiophenylethyl; X is CH2, O or S; and Y is CH2, O or S.
Antiasthmatics of formulas:
, , analogues of dopamine agonists having formulas , dopamine autoreceptor antagonists of formula:
dopamine D1 receptor antagonists of formulas:
5-HT1A ligands of formulas;
in which R2 and R3 are not both propyl, , , , , 5-HT1D ligands of formula:
Sigma ligands of formulas:
, Anti-Aizheimers drugs of formula:
Neuroleptics of formulas:
, , melatonine analogues of formulas:
, analgesics of formulas:
, , , , and Beta-blockers of formulas:
, in which formulas R1 is as defined in Claim 1; R2 designates C1-C8 alkyl, C3-C8 cycloalkylmethyl, arlalkyl, phenylethyl or 2-thiophenylethyl; R3 designates C1-C8 alkyl, (C3-C8) cycloalkylmethyl, arylalkyl, phenylethyl or 2-thiophenylethyl; X is CH2, O or S; and Y is CH2, O or S.
4. A compound of Claim 3 wherein R1 is CF3.
5. A method of improving the pharmacodinetic and/or pharmacodynamic preper-ties of a therapeutically active compound comprising an aromatic or heteroaroma-tic ring system carrying a substituent selected from the group consisting of hydroxy, alkyloxy, halo, ester and cyano, comprising preparing a therapeutically active derivatized compound by replacing said substituent in said compound with a substituent of formula herein R1 is CFS, (C1-C8) alkyl, (C3-C8) cycloalkylmethyl, substituted phenyl, substituted benzyl, substituted phenylethyl, substituted phenylpropyl, substituted 2-thiophenylethyl or substitutad 2-thiophenylpropyl.
6. A therapeutically active derivatized compound which is obtained by the methodof Claim 6.
7. 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9103745A SE9103745D0 (en) | 1991-12-18 | 1991-12-18 | ARYL-TRIFLATES AND RELATED COMPOUNDS |
| SE9103745-7 | 1991-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2126242A1 true CA2126242A1 (en) | 1993-06-24 |
Family
ID=20384643
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002126242A Abandoned CA2126242A1 (en) | 1991-12-18 | 1992-12-18 | Aryl-triflates and related compounds |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0617618A1 (en) |
| JP (1) | JPH08504744A (en) |
| AU (1) | AU3255993A (en) |
| CA (1) | CA2126242A1 (en) |
| FI (1) | FI942931A (en) |
| NO (1) | NO942296L (en) |
| SE (1) | SE9103745D0 (en) |
| WO (1) | WO1993011761A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008009125A1 (en) * | 2006-07-20 | 2008-01-24 | Cascade Therapeutics Inc. | Tetrahydro-5h-pyrido[2,3-d]azepines as 5-ht2c ligands |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1353909B1 (en) | 2000-10-31 | 2005-04-06 | Rensselaer Polytechnic Institute | 8-substituted-2,6-methano-3-benzazocines and 3-substituted morphinanes as opioidreceptor binding agents |
| DK1379239T3 (en) | 2001-03-29 | 2008-01-07 | Lilly Co Eli | N (2-aryl-ethyl) -benzylamines as antagonists of the HT6 receptor |
| EP1490324A4 (en) * | 2002-02-27 | 2007-10-10 | Teva Pharma | Propargylamino indan derivatives and propargylamino tetralin derivatives as brain-selective mao inhibitors |
| TW200744576A (en) | 2006-02-24 | 2007-12-16 | Teva Pharma | Propargylated aminoindans, processes for preparation, and uses thereof |
| HUE043963T2 (en) | 2009-12-04 | 2019-09-30 | Alkermes Pharma Ireland Ltd | Morphinan derivatives for the treatment of drug overdose |
| AU2011232628B2 (en) | 2010-03-22 | 2015-04-09 | Rensselaer Polytechnic Institute | Morphinane derivatives containing a carboxamide group as opioid receptor ligands |
| AU2011293502B2 (en) | 2010-08-23 | 2015-03-19 | Alkermes Pharma Ireland Limited | Methods for treating antipsychotic-induced weight gain |
| WO2012138888A1 (en) | 2011-04-05 | 2012-10-11 | Alkermes, Inc. | Process for the synthesis of quaternary amine compounds |
| SI2725908T1 (en) | 2011-06-29 | 2017-10-30 | Alkermes, Inc. | Peripherally acting opioid compounds |
| US9211293B2 (en) | 2011-12-15 | 2015-12-15 | Alkermes Pharma Ireland Limited | Opioid agonist antagonist combinations |
| EA030609B8 (en) | 2011-12-15 | 2018-10-31 | Алкермес Фарма Айэленд Лимитед | Compositions of buprenorphine and mu-opioid receptor antagonists |
| JO3459B1 (en) | 2012-09-09 | 2020-07-05 | H Lundbeck As | Pharmaceutical compositions for treating alzheimer's disease |
| EP3004114B1 (en) | 2013-05-24 | 2019-12-25 | Alkermes Pharma Ireland Limited | Morphan and morphinan analogues, and methods of use |
| EP3003311A2 (en) | 2013-05-24 | 2016-04-13 | Alkermes Pharma Ireland Limited | Methods for treating depressive symptoms |
| EP4243768A1 (en) | 2020-11-12 | 2023-09-20 | Alkermes Pharma Ireland Limited | Immediate release multilayer tablet |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3725451A (en) * | 1970-04-13 | 1973-04-03 | Riker Laboratories Inc | Substituted benzoylhaloalkanesulfonanilides |
| DE3132167A1 (en) * | 1981-08-14 | 1983-03-03 | Hoechst Ag, 6000 Frankfurt | "5 (6) -PHENYLSULFONYLOXY-BENZIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING IT AND THEIR USE AGAINST LIVER RULES" |
| DE3232959A1 (en) * | 1982-09-04 | 1984-03-08 | Hoechst Ag, 6230 Frankfurt | SUBSTITUTED Benzenesulfonic Acid Ester, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DE3243158A1 (en) * | 1982-11-23 | 1984-05-24 | Basf Ag, 6700 Ludwigshafen | NEW SULPHONIC ACID ESTERS OF HYDROXYCUMARINES, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM |
| DE3247615A1 (en) * | 1982-12-23 | 1984-07-05 | Hoechst Ag, 6230 Frankfurt | SUBSTITUTED PHENYLSULFONYLOXYBENZIMIDAZOLE CARBAMINATES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
| US4470991A (en) * | 1983-04-22 | 1984-09-11 | Merck & Co., Inc. | Benzothiazolesulfonamide derivatives for the topical treatment of elevated intraocular pressure |
| FR2557570B1 (en) * | 1984-01-04 | 1986-04-18 | Adir | NEW QUINOLEIN DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| DE3509333A1 (en) * | 1985-03-15 | 1986-09-18 | Hoechst Ag, 6230 Frankfurt | SUBSTITUTED BENZIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND THEIR USE AS AN INGESTIC ACID INHIBITOR |
| DE3521761A1 (en) * | 1985-06-19 | 1987-01-02 | Bayer Ag | NEW 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION AND THEIR USE IN MEDICINAL PRODUCTS |
| DE3630903A1 (en) * | 1986-09-11 | 1988-03-24 | Thomae Gmbh Dr K | NEW TETRAHYDRONAPHTHALINE AND INDANDERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| GB8804016D0 (en) * | 1988-02-22 | 1988-03-23 | Boots Co Plc | Therapeutic agents |
| DE3807813A1 (en) * | 1988-03-10 | 1989-09-21 | Thomae Gmbh Dr K | NEW BENZOCYCLOHEPEN DERIVATIVES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| SE8901889D0 (en) * | 1989-05-26 | 1989-05-26 | Astra Ab | NOVEL 8-SUBSTITUTED-2-AMINOTETRALINES |
| SE8904361D0 (en) * | 1989-12-22 | 1989-12-22 | Astra Ab | NEW CHROMAN AND THIOCHROMAN DERIVATIVES |
| KR920004385A (en) * | 1990-08-09 | 1992-03-27 | 와꾸나가 기스께 | New tricyclic compounds or salts thereof, preparation method thereof and antimicrobial agent containing same |
-
1991
- 1991-12-18 SE SE9103745A patent/SE9103745D0/en unknown
-
1992
- 1992-12-18 JP JP5510538A patent/JPH08504744A/en active Pending
- 1992-12-18 AU AU32559/93A patent/AU3255993A/en not_active Abandoned
- 1992-12-18 WO PCT/DK1992/000389 patent/WO1993011761A1/en not_active Application Discontinuation
- 1992-12-18 EP EP93901666A patent/EP0617618A1/en not_active Withdrawn
- 1992-12-18 CA CA002126242A patent/CA2126242A1/en not_active Abandoned
-
1994
- 1994-06-17 NO NO942296A patent/NO942296L/en unknown
- 1994-06-17 FI FI942931A patent/FI942931A/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008009125A1 (en) * | 2006-07-20 | 2008-01-24 | Cascade Therapeutics Inc. | Tetrahydro-5h-pyrido[2,3-d]azepines as 5-ht2c ligands |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993011761A1 (en) | 1993-06-24 |
| NO942296D0 (en) | 1994-06-17 |
| FI942931A0 (en) | 1994-06-17 |
| EP0617618A1 (en) | 1994-10-05 |
| FI942931A (en) | 1994-06-17 |
| JPH08504744A (en) | 1996-05-21 |
| NO942296L (en) | 1994-06-17 |
| SE9103745D0 (en) | 1991-12-18 |
| AU3255993A (en) | 1993-07-19 |
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