WO1995000478A1 - Aryltriflates and related compounds - Google Patents

Aryltriflates and related compounds Download PDF

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Publication number
WO1995000478A1
WO1995000478A1 PCT/DK1994/000244 DK9400244W WO9500478A1 WO 1995000478 A1 WO1995000478 A1 WO 1995000478A1 DK 9400244 W DK9400244 W DK 9400244W WO 9500478 A1 WO9500478 A1 WO 9500478A1
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alkyl
formula
triflate
phenyl
analogue
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PCT/DK1994/000244
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French (fr)
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Håkan WIKSTRÖM
Tjeerd Andries Barf
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Lundbeck & Co As H
Wikstroem Haakan
Tjeerd Andries Barf
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Priority to AU69955/94A priority Critical patent/AU6995594A/en
Publication of WO1995000478A1 publication Critical patent/WO1995000478A1/en

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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/80—[b, c]- or [b, d]-condensed
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D219/10—Nitrogen atoms attached in position 9
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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
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    • 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
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
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    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings

Definitions

  • OMe These compounds are D 2 and/or D 3 antagonists, which can be assayed in in vitro binding studies in human or rat membranes expressed e.g. in COS cells. Radio ligands for such studies are [3fH]-spiperone (antagonist binding) and [3H]-N-0437 (agonist binding).
  • the compounds are useful in the treatment of psychoses, in particular in schizophrenia.
  • R ⁇ is CF 3 , C-
  • (A, B, C, D) is : (Me, MeO, Me, CF 3 S0 2 0) (omeprazole); (H, CF 3 S0 2 0, Me, H) (lanzoprazole); or (H, MeO, MeO, CF 3 S0 0) (pantoprazole).
  • These compound are K+, H+ ATPase inhibitors useful in the treatment of e.g. duode- nal ulcer, reflux oesophagitis and the Zollinger-Ellison syndrome.
  • These compound belong to a class of class III anti-arrhythmic agents to be used in the treatment of heart arrhythmia ' s.
  • the effect can be assayed in both rats and pigs.
  • This compound is an estrogen with effects in breast and ovarian cancer treatment.
  • the compound may be in the ⁇ - or the ⁇ -form.
  • Rs is CF 3 C-i-Cs alkyl, C 3 -C ⁇ cycloalkylmethyl, phenyl, phenyl substituted with halogen or C 1 -C 4 alkyl, phenyl-CrC ⁇ alkyl, phenyl-CrCs alkyl substituted with halogen or C 1 -C 4 alkyl, thienyl, preferably 2-thienyl, thienyl-C Cs alkyl, preferably
  • R 3 is (C 1 -C 4 ) alkyl, preferably propyl.
  • inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
  • these salts may also be prepared by the classical method of double decomposition of appropriate salts, which is well known to the art.
  • the compounds of the present invention will normally be adminis ⁇ tered orally, rectaliy or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable non-toxic, acid addition salt such as the hydrochloride, lactate, acetate, sulfamate salt
  • 2-bromomethyl-3-methyl-4-(trifluotomethylsulfonyloxy)pyridine is first synthesized and then reacted with the commercially available 2-mercaptobenzimida zole (CAS RN: 583-39-1 , Aldrich) and subjected to oxidation of the sulfide group to the sulfoxide, in analogy with method of EP A1 233760.
  • Example 1 In the following the invention is further illustrated by way of examples which must not be construed as limiting of the invention.
  • Example 1
  • Phtalimido-5-HT 100 mg, 0.33 mmol
  • PhN(S0 2 CF 3 ) 2 (175 mg, 1.5 equiv.) were stirred in CH 2 CI 2 (5 mL), and thereafter Et 3 N (90 ⁇ L, 2 equiv.) was added.
  • the reaction mixture was stirred over night and was the diluted with CH 2 CI 2 (30 mL) and washed with 10% NaC0 3 (10 mL).
  • the aqueous layer was extracted with CH 2 CI 2 (30 mL) and the combined organic phases were dried (MgS ⁇ 4 ) and filtered, and the solvent was evaporated under reduced pressure yielding the raw product as a crystalline solid (180 mg).

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Abstract

Described are aryltriflates and related derivatives of raclopride, riluzole, cisapride, omeprazole, lanzoprazole, pantoprazole, paroxetine, fenfluramine, sotalol, estradiol, RU 486, tacrine, moclobemide, ifenprodil, brofaromine, melatonin, N-Acetyl-2[(7-trifluoromethylsulfonyloxy-1-naphtyl)ethyl]amine, prenalterol, sumatriptane, 6-substituted 3-amino-1,2,3,4-tetrahydrocarbazole, mianserin, trans-(4aS, 10bS)-7-hydroxy-4-n-Propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline and carbamazepine. The compounds are useful as drugs with, in particular for the treatment of disorders of the central nervous system.

Description

ARYL TRIFLATES AND RELATED COMPOUNDS
Field of the Invention
The present invention is directed towards certain new aryltriflates, and their pharmaceutically acceptable salts, and the use of such compounds in manufacture of a pharmaceutical preparation. Pharmaceutical preparations of these compounds are useful for peripheral and central nervous system disorders in mammals.
Background of the Invention
Aryl triflates are used as intermediates in organic syntheses. They can thus be removed via reduction (NEt3+HCOO-) or substituted by other groups like CN and COOR (Oda, R., Kagaku (Kyoto) 1987, 42, 710-11 ; Cacchi, S. et al., Tetrahedron Lett 1986, 27, 5541-4; Chambers, M. R. I. et al., J. Chem. Soc, Perkin Trans 1989, 1, 1365-6; Kotsuki, H. et al., Synthesis 1990; Martorell, G. et al., Tetrahedron Lett
1990, 31, 2357-60; Peterson, G. A. et al., Tetrahedron eft 1987, 28, 1381-4; R ot h , G. P. et al., J. Org. Chem. 1991, 56, 3493-6; Saa, J. M. et al., J. Org. Chem. 1990, 55, 991-5; Subramanian, L. R. et al., Synthesis 1984; Chambers, M. R. I. et al., J. Chem. Soc, Perkin Trans 1989, 1, 1365-6.; Takagi, K. et al., Bull. Chem. Soc Jpn.
1991 , 64, 1118-21 ; EP-A1 399982; Liu, Y. et al., Bioorg. Med. Chem. Lett. 1991 , 1, 257-62.
One aryltriflate with biological activity (5-HT-I A affinity in a CNS preparation) is known ( EP-A1 399982; Liu, 1991 supra). In addition, the triflate of the analgetic substance paracetamol has been used as an intermediate in the conversion of the phenol into its cyano analogue (Chambers, 1989, supra; Takagi, 1991 , supra).
Further aryltriflate compounds have been disclosed as being pharmacologecally active in US 4,618,622 (sulfonic acid esters of hydroxy cumarines), WO A1 9109853 (3-aminochroman or -thiochroman compounds having serotonergic properties), EP 0332064 (benzocyclohepten derivates), EP A1 259 782 (naphthalen and indan derivates having calcium-antagonistic effects) and EP A1 0470578 (tricyciic compounds having antibiotic activity). In the above patents the triflate group has only been used as one substituent among a number of substituents.
Our copending International Patent Application No PCT/DK92/00389 describes generically triflate and related derivatives of drugs comprising a hydroxyaryl group or a similar group and having the general Formula 1 :
Formula 1 O
A — O — S — R
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 R is CF3, (CrC8) alkyl, -CH2-(C3-C8) cycloalkylalkyl, substituted phenyl, benzyl, phenylethyl, phenylpropyl, 2-thiophenylethyl or 2-thiophenylpropyl; as possessing both good pharmacodynamic and good pharmacokinetic properties including a high resistance against enzymatic deactivation.
Is has now been found that certain triflate and related derivatives not specifically disclosed in International Patent Application No PCT/DK92/00389 have particular interesting therapeutical effects.
Summary of the Invention
Accordingly, this invention relates to aryltriflates and related compounds, in particu¬ lar triflate derivatives of the known drugs raclopride, riluzole, cisapride, omeprazole, lanzoprazole, pantoprazole, paroxetine, fenfluramine, sotalol, estradiol, RU 486, tacrine, moclobemide, ifenprodil, brofaromine, melatonin, N-Acetyl-2[(7-trifiuoromet hylsulfonyloxy-1-naphthyl)ethyl]amine, prenalterol, sumatriptane, 6-substituted 3- amino-1 ,2,3,4-tetrahydrocarbazole, mianserin, trans-(4aSJ 0bS)-7-hydroxy-4-n- Propyl-1 ,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline and carbamazepine which triflate derivatives have the formulas shown in Claim 1.
Pharmaceutically acceptable acid addition salts of the above triflate and related derivatives are also embraced by the invention.
It will be apparent to those skilled in the art that some compounds of this invention may contain chiral centres. The scope of this invention includes all enantiomeric or diastereomeric forms of the compounds either in pure form or as mixtures of enantiomers or diastereomers. The therapeutic properties of the compounds may to a greater or lesser degree depend on the stereochemistry of a particular compound. Pure enantiomers as well as enantiomeric or diastereomeric mixtures are within the scope of the invention.
The compounds of the invention have been found to show particularly advanta- geous effects with respect to pharmacology, pharmacokinetics, availability to the body, and metabolism.
Processes for preparation of these compounds, their pharmaceutical use and pharmaceutical preparations comprising such compounds constitute further aspects of the invention.
Detailed Description of the Invention
In the following the compounds of the invention are listed together with their advantages.
a) Triflate analogues of raclopride:
Formula A1 Formula A2
Figure imgf000005_0001
OMe These compounds are D2 and/or D3 antagonists, which can be assayed in in vitro binding studies in human or rat membranes expressed e.g. in COS cells. Radio ligands for such studies are [3fH]-spiperone (antagonist binding) and [3H]-N-0437 (agonist binding). The compounds are useful in the treatment of psychoses, in particular in schizophrenia.
b) Analogues of riluzole:
Formula B
Figure imgf000006_0001
wherein Rβ is CF3, C-|-C8 alkyl, C3-C8 cycloalkylmethyl, phenyl, phenyl substituted with halogen or C1-C4 alkyl, phenyl-CrC-β alkyl, phenyl-C-i-Ce alkyl substituted with halogen or C1-C4 alkyl, thienyl, preferably 2-thienyl, thienyl-CrCβ alkyl, preferably 2-thienylethyl or 2-thiophenylpropyl. These compounds are NMDA antagonists working through blockade of the sodium channels and are, accordingly, useful in the prevention or treatment of neurodegeneration ALS, MS, stroke and traffic accidents. They are also useful in the therapy of Alzheimers disease, ageing, heart infarction and in postoperative treatment, in particular in open heart surgery. Preferably, Rβ is CF3 or (C-i-Cβ) alkyl, in particular CF3, CH3 or iso-propyl.
c) Triflate analogues of cisapride:
Formula C1
Figure imgf000006_0002
Formula C2
Figure imgf000007_0001
These compounds are 5-HT4 antagonists, which can be assayed in radioiigand binding. The compounds are useful to prevent irritable bowel syndrome (IBS) and work by stimulating emptying of the stomach and intestinal motiiity, in particular in the colon.
d) Triflate analogues of omeprazole, lanzoprazole and pantoprazole:
Formula D
Figure imgf000007_0002
Wherein (A, B, C, D) is : (Me, MeO, Me, CF3S020) (omeprazole); (H, CF3S020, Me, H) (lanzoprazole); or (H, MeO, MeO, CF3S0 0) (pantoprazole). These compound are K+, H+ ATPase inhibitors useful in the treatment of e.g. duode- nal ulcer, reflux oesophagitis and the Zollinger-Ellison syndrome.
e) Triflate analogue of paroxetine: Formula E
Figure imgf000008_0001
This compound is a selective serotonin reuptake inhibitor and is useful in the treatment of panic disorders, anxiety and depression.
f) Triflate analogue of fenfluramine:
Formula F
Figure imgf000008_0002
This compound is an anoretic agent to be used in obesity. It is active upon the different serotonin receptors in the brain and can be used to prevent autism.
g) Triflate analogues of sotalol
Formula G1 Formula G2
Figure imgf000008_0003
These compound belong to a class of class III anti-arrhythmic agents to be used in the treatment of heart arrhythmia's. The effect can be assayed in both rats and pigs.
h) Triflate analogue of estradiol Formula H
Figure imgf000009_0001
This compound is an estrogen with effects in breast and ovarian cancer treatment. The compound may be in the α- or the β-form.
i) Triflate analogue of RU 486
Formula
Figure imgf000009_0002
This compound is a steroid with effects on the reproduction. It can be used to abort a foetus in the early phase of human pregnancy.
j) Triflate analogues of tacrine of Formula J
Formula J
Figure imgf000009_0003
wherein Rj is CF3, C-|-C8 alkyl, C3-Ce cycloalkylmethyl, phenyl, phenyl substituted with halogen or C1-C4 alkyl, phenyl-C-i-Ce alkyl, phenyl-Ci-Cs alkyl substituted with halogen or C1-C4 alkyl, thienyl, preferably 2-thienyl, thienyl-C-|-C8 alkyl, preferably 2-thienylethyl or 2-thiophenylpropyl. most preferably CF3. These compounds are acetylcholinesterase inhibitors useful in the treatment of Alzheimer's disease. They display better pharmacokinetic properties than their analogue Tacrine itself. Their effects can be shown by their induction of acetylcholine release in the rats using the microdialysis technique.
k) Triflate analogue of moclobemide
Formula K
Figure imgf000010_0001
This compound is a reversible MAO A inhibitor without the tyramine pressor effect. The effect can be shown by using microdialysis in freely moving animals.
I) Triflate analogue of ifenprodil of the Formula L
Formula L
Figure imgf000010_0002
wherein Rι_ is CF3, C-i-Cβ alkyl, C3-C8 cycloalkylmethyl, phenyl, phenyl substituted with halogen or C1-C4 alkyl, phenyl-d-Cβ alkyl, phenyl-C-i-Ce alkyl substituted with halogen or C1-C4 alkyl, thienyl, preferably 2-thienyl, thienyl-C-i-Cβ alkyl, preferably 2-thienylethyl or 2-thiophenylpropyl. The compounds are NMDA antagonists acting through the polymine site. They are useful to prevent neurodegeneration in ALS, MS, stroke and traffic accidents and are also useful in the therapy of Alzheimer's disease, ageing and hart infarction. They are also useful in postoperative treatment, in particular at open heart surgery.
m) Triflate analogues of brofaromine
Formula M1
Figure imgf000010_0003
Formula M2
Figure imgf000011_0001
These compound are serotonin reuptake inhibitors and at the same time MAO inhibitors, useful in the treatment of panic disorders, anxiety and depression, also in the elderly.
n) Triflate analogue of melatonin of Formula N
Formula N
Figure imgf000011_0002
This compound acts on the CNS and has a highly selective affinity for melatonin receptors. It has sedative, anxiolytic, antipsychotic and analgesic properties. Used in treatment of stress, sleep disorders, epilepsy, Parkinson's disease, senile dementia, disorder due to pathological or normal ageing, migraine, memory loss, Alzheimer's disease, cerebral circulatory disorders and for appetite regulation.
o) N-Acetyl-2[(7-trifiuoromethylsulfonyloxy-1-naphthyl)ethyl]amine
Formula O HCOCH3
Figure imgf000011_0003
This compound has a high central affinity for melatonin receptors and, accordingly it is useful in the treatment of the conditions listed in n) above.
p) Triflate analogue of prenalterol Formula P
Figure imgf000012_0001
q) Triflate and related analogues of sumatriptane having Formula Q
Formula Q
Figure imgf000012_0002
wherein R1 and R2 are the same or different and selected from the group consisting of H, Ci-Cβ alkyl, C2-C-8 alkenyl, C-2-Cβ alkynyl, cycloalkyl, cycloalkyl-C-i-Cβ alkyl, C-i-Cβ haloalkyl, phenyl-d-Cβ alkyl and heteroaryl-CrCβ alkyl; and RQ is C-i-Ce alkyl, C1-C-8 haloalkyl, phenyl, phenyl substituted with halogen or C1-C4 alkyl, phenyl-C-i-Cβ alkyl, phenyl-CrCβ alkyl substituted with halogen or C1-C4 alkyl, heteroaryl or heteroaryl-C-i-Cβ alkyl.
Halogen means fluoro, chloro, bromo or iodo and haloalkyl designates an alkyl group comprising one or more halogen atoms, such as trifluoromethyl. The term cycloalkyl designates a carbocyclic ring having 3-8 carbon atoms, inclusive, such as cyclopropyl, cyclopentyl, cyclohexyl, etc, especially cyclopropyl The term heteroaryl refers to a monocyciic heteroaromatic group, such as thienyl, pyrimidyl, pyridyl and furanyl, in particular 2-thienyl.
Preferred compounds of Formula Q are those wherein R1 and R2 are independently selected from the group consiting of H and C1-C4 alkyl C2-C4 alkenyl and C2-C4 alkynyl, most preferably H, methyl, ethyl and propyl. Furthermore, RQ is preferably CF3, CH3l phenyl, p-methylphenyl or thienyl.
These compounds act on the CNS and have affinity for one or several of the serotonin receptors. It has sedative, anxiolytic, antipsychotic and analgesic properties. Used in treatment of stress, sleep disorders, anxiety, seasonal depres¬ sion, insomnia and fatigue, schizophrenia, panic attacks, melancholy, psychotic disorders, epilepsy, Parkinson's disease, senile dementia, disorder due to patholog¬ ical or normal ageing, migraine, memory loss, Alzheimer's disease, cerebral circulatory disorders and for appetite regulation.
r) Triflate analogues of 6-substituted 3-amino-1 ,2,3,4-tetrahydrocarbazole deriva¬ tives of Formula R
Formula R
Figure imgf000013_0001
This compound is a 5-HT-ID agonist useful in the treatment of migraine (cf. above),
s) Triflate analogue of mianserin
Formula S
Figure imgf000013_0002
This compound is believed to show antidepressant effects which is metabolically stable.
t) Triflate analogues of the compounds of Formula T Formula T
Figure imgf000014_0001
wherein Rs is CF3) C-i-Cs alkyl, C3-Cβ cycloalkylmethyl, phenyl, phenyl substituted with halogen or C1-C4 alkyl, phenyl-CrCβ alkyl, phenyl-CrCs alkyl substituted with halogen or C1-C4 alkyl, thienyl, preferably 2-thienyl, thienyl-C Cs alkyl, preferably
2-thienylethyl or 2-thiophenylpropyl, preferably CF3, CH3, phenyl, p-methylphenyl or
2-thienyl; and
R3 is (C1-C4) alkyl, preferably propyl.
These compounds show dopaminergic activities.
u) Triflate analogue of carbamazepine
Formel U
Figure imgf000014_0002
This compound is believed to be an anticonvulsant and or neuroprtectant.
The pharmaceutically acceptable acid addition salts of the compounds may be for¬ med by reaction with non-toxic organic or inorganic acids in an aqueous miscible solvent, such as acetone or ethanol, and subsequent isolation of the salt by concen- tration and cooling or by reaction with an excess of the acid in aqueous immiscible 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, ethanedisul- fonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids as well as the 8-halotheop hyllines, for example 8-bromo-theophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts, which is well known to the art.
In clinical practice the compounds of the present invention will normally be adminis¬ tered orally, rectaliy or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier. The use and administration to a patient to be treated in the clinic would be readily apparent to a person of ordinary skill in the art.
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 0J to about 100 mg for parenteral application, preferentially 0.5-50 mg daily doses. The daily dose will preferably be administered in individual dosages one to 4 times daily and the dosage amounts are based on an individual having a weight of 70 kg.
The compounds of this invention have high oral potency and long duration of action, as compared to their hydroxy or alkoxy analogues. Both these pharmacokinetic features are beneficial to effective clinical treatment.
The compounds of this invention may be obtained by the general synthetic strategy exemplified in Scheme 1 :
Scheme 1
Figure imgf000015_0001
The t flating agent is conveniently triflic anhydride (Method A), N-phenyltrifluoro- methanesulfonimide (Method B) or triflic acid chloride (Method C).
Method C is conveniently performed by dissolving the Ar-OH compound in CH2CI2 and the adding the same volume of e.g. a 10% solution of NaOH in water (important to have reasonably concentrated solutions), adding an ion pair ammonium salt (e.g. BU4NHSO4) dissolved in CH2CI2 and then dropwise adding the sulfonating agent (RS02CI or PhN(S02CF3)2) dissolved in CH2CI2 followed by extraction and evaporation.
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.
The triflate analogues of omeprazole and pantoprazole, respectively, may conve¬ niently be synthezisedfrom 6-hydroxy-2-mercaptobenzimidazole via triflation (se above) and coupling with theproperly substituted 2-bromomethylpyridine derivatives in analogy with the methods of EP A1 5129 and EP A1 166287. The triflate analogue of lanzoprazole may be prepared from its benzyloxy analogue via debenzylation and then triflation under phase transfer conditions (see above). Alternatively, 2-bromomethyl-3-methyl-4-(trifluotomethylsulfonyloxy)pyridine is first synthesized and then reacted with the commercially available 2-mercaptobenzimida zole (CAS RN: 583-39-1 , Aldrich) and subjected to oxidation of the sulfide group to the sulfoxide, in analogy with method of EP A1 233760.
The triflate analogue of RU 486 is conveniently prepared by sulfonation of the corresponding hydroxy derivative (CAS RN: 88257-21-0) with the respective activated sulphonic acid (acid chloride, anhydride or diimide).
In the following the invention is further illustrated by way of examples which must not be construed as limiting of the invention. Example 1
Triflate analogue of riluzoie (Formula B).
Figure imgf000017_0001
p-Nitrophenol (3.2 g, 23 mmol) and Et3N (3. 9 mL, 2.81 g, 28 mmol) were dissolved in dry CH2CI2 (150 mL). The reaction mixture was cooled to -30 °C and a solution of triflic anhydride (9.8 g, 35 mmol) in CH2CI2 (50 mL) was added dropwise over 20 min. After 18 h the reaction mixture turned red and the solvent was evaporated. The product was purified by chromatography (Siθ2, eluting with p-ether:EtOAc (9:1)). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure leaving the pure product (5.41 g, 87%). This product (1.0 g, 3.7 mmol) was put in a 25 mL flask together with Sn(s) powder and cone. HCI (10 mL) was added. The reaction mixture was warmed and stirred for 1 h on a water bath. The reaction mixture was cooled and water (25 mL) was added and the water phase was washed with ether (3x25 mL). The acidic water phase was basified (30% NaOH) and the product was extracted with ether (3x25 mL). The collected ether phases were pooled, washed with brine, dried (Na2Sθ4), filtered and the solvent was evaporated, yielding 970 mg of the raw product, which was purified by chroma- tography (Siθ2). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure leaving the pure product (830 mg, 93%).
This product (1.2 g, 5.0 mmol) was dissolved in HOAc (10 mL). KSCN (1.0 g, 10.3 mmol) was added in one poriton to the solution prepared. Then a solution of Br2 (800 mg, 5.0 mmol) in HOAc (6.5 mL) was added dropwise over 20 min to the reaction mixture. The mixture was stirred vigofously overnight at foom temperature and a precipitate formed. The reaction mixture was poured onto water (100 mL) and the pH was adjusted to 10 (27 mL 25% NaOH). The stirring was continued for another h. The precipitated product was collected by filtration and was then dissolved in acetone and the remains were removed by filtration. The filtrate was concentrated to dryness and the residual product was purified by chromatography (S.O2, eluting with CH2CI2:MeOH (9:1)). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure leaving the pure product as yellow crystals, which were recrystallized (toluene), filtered and washed with hexane yielding yellow crystals (710 mg, 48%) melting at 144.2-144.7 °C. MS (chemical ionization with NH3) shows m/e + 299 (M + 1). The base was dissolved in ether (50 mL) and converted to the HCI salt with ethereal HCI, yielding 730 mg (44%) of light-yellow crystals melting at 218.5-219.5 °C.
Example 2
Triflate analogue of sotalol (Formula G1)
OctopaminexHCI [770-05-8] (1.0 g, 5.3 mmol) was dissolved in MeOH (50 mL) and acetone (10 mL) was added. To this mixture was added NBH3CN (2.0 g, 31.8 mmol) and HOAc (1 mL). After 2h in room temperature the starting material was consumed and 10% HCI was added until no more HCN (caution!) evolved. The mixture was extracted once with ether and then the water phase was basified with 10% N2C03 and extracted with (3x100 mL). The organic phase was washed once with brine, dried, filtered and the solvent was evaporated under reduced pressure, leaving the product, N-i-Pr-octopamine, as a white solid (0.55 g, 53%), which was used in the next reaction step without further purification.
N-i-Pr-Octopamine (0.5 g, 2.6 mmol) was dissolved in CH2CI2 (50 mL). To this mixture was added Et3N (2 mL) and the triflating agent N-phenyltrifluoromethanesulf onimide [37595-74-7] (1.0 g, 2.8 mmol) and the mixture was stirred for 48 h in room temperature. The solvent and excess CH2CI2 were removed under reduced pressure and the residue was chromatographed on Siθ2, eluting with CH2CI2 :MeOH (10:1). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure yielding a colourless oil (263 mg). GC/MS (chemical ionization with NH3 shows m/e=328 (M+1). Example 3.
Triflate analogue of the N,N-diethyl derivative of sotalol (Formula G2).
Oc paminexHCI [770-05-8] (1.0 g, 5.3 mmol) was dissolved in MeOH (50 mL) and acetaldehyde (10 mL) was added. To this mixture was added NBH3CN (2.0 g, 31.8 mmol) and HOAc (1 mL). After one night in room temperature the starting material was consumed and 10% HCI was added until no more HCN (caution!) evolved. The mixture waε iracted once with ether and then the water phase was basified with 10% N2C03 and extracted with (3x100 mL). The organic phase was washed once with brine, dried, filtered and the solvent was evaporated under reduced pressure, leaving a mixture of N,N-di-Et-octopamine and N-Et-octopamine, as a light-yellow oil (1.21 g, 100%). This mixture (0.63 g) was subjected to another synthesis with the same reagents (25 mL MeOH, 6 mL acetaldehyde, 1.2 g NaBH3CN and 0.6 mL HOAc). The mixture was stirred overnight and worked up as described above, yielding a light-brown oil (0.52 g), which was used in the next reaction step without further purification.
(Triflation Method C) N,N-di-Et-octopaminexHCI (0.26 g, 1 J mmol) was dissolved in CH2CI2 (3 mL) and the phase-transfer catalyst BsBu3N+Br- (80 mg, 0.22 mmol) and NaOH (0.3 g, 7.5 mmol) in water (1.5 mL) was added. This mixture was vigorously stirred for 10 min before the addition of CF3S02CI (0J8 mL, 1.6 mmol).
The reaction was worked up after 2h, when no more starting material was present.
The organic layer was extracted twice with 2N NaOH and washed with brine, dried, filtered and the solvent was evaporated under reduced pressure, leaving an oil, which was purified on Siθ2, eluting with CH2Cl2:MeOH (10:1). The fractions containing pure product were pooled and the solvent was evaporated under reduced pressure yielding the pure product as an oil (47 mg).
Example 4.
Triflate analogues of estradiol
3-Trifluoromethanesulfonate-β-estradiol. β-Estradiol (CAS RN: 50-28-2) (50 mg, 0J8 mmol) was suspended in CH2CI2 (1 mL) and 2N NaOH was added (10 mL). Dioxane (1 mL) was added and the mixture was stirred and NBu4+l- (10 mg) and PhN(S02CF3)2 (79 mg) was added. The reaction mixture was stirred for 24 h in room temperature. 2N NaOH was added (10 mL) and the product was extracted with EtOAc (2x5 mL). The organic layer was separated, dried (Na2Sθ4) and filtered and the solvent was eveporated under reduced pressure yielding 58 mg (80%) of the pure product as an oil. GC/MS (EI-PI) shows: M+ at m/e=404, base peak at m/e=386 (M-H2O) and other prominent peaks at m/e=253 (M-H20-CF3S02).
3-Trifluoromethanesulfonate-α-estradiol
3-Trifluoromethanesulfonate-α-estradiol was synthesised from α-Estradiol (CAS
RN: 57-91-0) in analogy with the synthesis of 3-Trifluoromethanesulfonate-β- estradiol, as described. GC/MS (EI-PI) shows: M+ at m/e=404, base peak at m/e=69 (M-H2O) and other prominent peaks at m/e=253 (M-H2O-CF3SO2), 345, 292 and 159.
Example 5.
Triflate analogues of 6-OH-tacrine and 8-OH-tacrine (Formula J).
6-OH-Tacrine x HBr (50 mg, 0J7 mmol) was triflated with the triflating agent N- phenyltrifluoromethansulfonimide according to Method C (the phase transfer catalysis method), yielding after 3 days a brown insoluble compound. Extractive workup with CH2CI2 yielded a small amount of the product 6-TfO-tacrine. MS (chemical ionization with NH3) shows m/e = 346 (M + 1).
8-OH-Tacrine x HBr (50 mg, 0J7 mmol) was triflated in the same way as the 6-OH analogue above (Method C), yielding 10 mg (17%) of the free base of 8-TfO-tacrine. MS (chemical ionization with NH3) shows m/e = 346 (M + 1).
Example 6
Triflate analogues of ifenprodil (Formula L). The triflate analogue of ifenprodil was prepared similarly to the above examples. M+1 at m/e=458 (Cl, NH3).
Example 7.
4-(7-Bromo-5-trifluoromethanesulfonate-2-benzofuranyl)piperidine.
O-Desmethylbrofaromine.
Brofaromine x HCI (CAS RN: 63638-90-4, 15 mg, 0.04 mmol) was dissolved in dry CH2CI2 (2 mL) and the solution was chilled to -78 oC. 1 M BBr3 in CH2CI (0.5 mL) was added and the mixture was stirred under N2(g) over night and had then reached room temperature. A solid had formed. MeOH (5 mL) was added and the mixture was refluxed for 1 h. The solvents were evaporated and 10% Na2C03 and EtOAc were added and the product was extracted to the organic layer, which was separated, dried (Na Sθ4) and filtered. The solvent of the filtrate was evaporated under reduced pressure, leaving the product as an oil. GC/MS (EI-PI) showed: M+ and M+2 at m/e=295 and 297, respectively. Base peak at m/e=82. Another prominent peak was found at m/e=56.
4-(7-Bromo-5-trifluoromethanesulfonate-2-benzofuranyl)piperidine.
O-DesmethylbrofarominexHBr (CAS RN: 120465-04-5, 2.6 mg, 7 umol), a catalytic amount of the phase transfer catalyst BU4N+I-, 10% NaOH (0.5 mL) and CH2CI2 (0.5 mL) were mixed and vigorously stirred in room temperature. PhN(Sθ2CF3)2 (1.97 mg, 7 umol) was added and the mixture was stirred in room temperature for 6h. The reaction mixture was acidified with 1 N HCI and extra CH2CI2 (0.5 mL) was added. The acidic water layer was separated and basified with NaHC03 (s) and then extracted with CH2CI2. The organic layer was separated, dried (Na2S04) and filtered. The solvent of the filtrate was evaporated under reduced pressure, leaving the product as an oil. GC/MS (EI-PI) showed: M+ and M+2 at m/e=427 and 429, respectively. Base peak at m/e=56.
Example 8 6-Trifluoromethansulfonate-5-methoxy-N-acetyl tryptamine 1,6-Di-Trifluoromethansulfonyioxy-5-methoxy-N-acetyl tryptamine.
6-Hydroxy-melatonine (CAS RN: 2208-41-5, 10 mg, 0.04 mmol) and Ph(S02CF3)2 (21 mg, 1.5 equiv.) and Bu4N+l- were added to a mixture of CH CI (0.25 mL) and 10% NaOH (0.5 mL). The reaction was stirred vigorously in room temperature for 5 h. The basic water layer was extracted with ether (3x2 mL). The organic layer was separated, dried (MgS04) and filtered, and the solvent was evaporated under reduced pressure yielding an oil (17 mg), which was chromatographed (Si02). The fractions containing the pure product were pooled and the solvent was evaporated. GC/MS (EI-PI) shows: M+ at m/e=512 and the base peak at m/e=72. Other prominent peaks are: m/e=453 (M-59), m/e=379 (M-S02CF3), m/e=320 (M-59- S02CF3) and m/e=187.
6-Trifluoromethansulfonate-5-methoxy-N-acetyl tryptamine. 1 ,6-Di-Trifluoromethansulfonate-5-methoxy-N-acetyl tryptamine (5 mg) was hydrolyzed in MeOH containing NaOMe (synthesized by adding a small piece of Na to dry MeOH). THF (0.25 mL) was added and the mixture was refluxed for 4 h. The reaction mixture was allowed to cool to room temperature and water was added. The product was extracted with ether and the organic layer was separated, dried (MgS04) and filtered, and the solvent was evaporated under reduced pressure yielding the raw product as an oil. GC/MS (EI-PI) shows: M+ at m/e=380 and the base peak at m/e=188 M-59-S02CF3). Another prominent peaks is: m/e=321 (M- 59) and m/e=160.
Example 9.
N-Acetyl-2[(7-trif luoromethylsuif onyloxy-1 -naphthyl)ethyl]amine (Formula O)
The corresponding methoxy analogue was synthesized according to L. Andrieux et al. EP-447285 A (910918, DW9138)) and then dissolved in CH2CI2. The mixture is chilled to - 70 °C and BBr3 is added and the reaction mixture is allowed to reach room temperature overnight. Water is added and the hydroxyl product 2 is extracted to the organic layer, which is separated, dried (Na2S04), filtered and the solvent is evaporated under reduced pressure, yielding the product (2). This product is triflated with either of Methods A, B or C to give the product 3. Alternatively, the methoxy compound 1 can be cleaved into the hydroxy analogue 2 by reluxing in 48% HBr under N2(g) for 2-3 h.
Example 10.
Triflate analogues of prenalterol (Formula P).
A mixture of prenalterol (100 mg, 0.44 mmol of the base), benzyltributylammonium bromide (16 mg, 0.044 mmol) (a phase transfer catalyst) CH CI2 (2.3 mL) and 20% NaOH (0.5 mL) was vigorously stirred for 1 h at room temperature. To the reaction mixture was added dropwise CF3Sθ2CI (50 μL, 0.47 mmol) over 20 min via a syringe. After 2 h the reaction mixture was worked up by extracting with CH2CI2. The collected organic layers were washed once with water and once with brine. The organic phase was separated, dried (Na2Sθ4), filtered and the solvent was evaporated under reduced pressure, yielding the product as an oil. The base was converted to the HCI salt with ethereal HCI giving white crystals, which were filtered and recrystallized in EtOH/ether, yielding white crystals (63 mg, 53%) melting at
107.9-108.6 °C.
Example 11.
5-Trifuoromethylsulfonyloxy-3-(N,N-diethylaminoethyl)-indole (Formula Q) Sumatriptane analogues.
5-Benzyloxyindole (5.98 g, 26.8 mmol) was dissolved in dry ether (120 mL). Oxalyichloride (2.6 mL, 29.5 mmol) dissolved in dry ether (20 mL) was added dropwise and the mixture was then stirred in room temperature overnight. The precipitated orange solid was collected and dried, leaving a raw product (7.29 g, 87%), melting at 186-189 °C (starting to melt at 147-148 °C). This product (2.01 g, 6.4 mmol) was added to a stirred solution of Et3N (30 mL, 50%). After 30 min stirring the reaction mixture was poured into 10% HCI. The reaction mixture was extracted with CH2CI2 (3x50 mL) and a yellow solid remained in the water phase. The organic phases were pooled, dried (Na2S0 ), filtered and the solvent was evaporated under reduced pressure yielding the crude product as a yellow solid (2.02 g, 91%). This product (1.93 g, 5.5 mmol) was dissolved in dry ether (80 mL) and dry THF (20 mL). Under inert atmosphere (N2(g)), L.AIH4 (1.9 g, 50J mmol) was added. The reaction mixture was refluxed for 6 h and was then cooled to room temperature before adding water (1.9 mL), 4 N NaOH (1.9 mL) and water (5.7 mL). The precipitated salts were filtered and the filtrate was dried (Na2S04), filtered and the solvent was evaporated under reduced pressure, yielding the crude product as a brown oil (1.70 g, 96%). The amine was converted to the oxalate and the salt was crystallized and recrystallized from acetone, yielding greenish crystals (1.75 g, 77%). This product (1.0 g, 2.43 mmol) was dissolved in 96% EtOH (50 mL) and NH4+COO- (1.73 g, 26.7 mmol) and Pd/C (10%) (500 mg) was added. The reaction mixture was stirred in room temperature for 2 days and was then filtered through Celite and the filtrate was evaporated, yielding a colourless oil (0.6 g), which crystallized upon cooling. This solid was taken up in 10% Na2C03 and extracted with EtOAc (3x30 mL). The organic phases were pooled and dried (Na2Sθ4) and filtered and the solvent was evaporated under reduced pressure, yielding a colourless oil (386 mg), which solidified into white crystals upon cooling.
[1H]-NMR (CD3OD): 3 1.09 (t, 6H, J=7J7), 2.64 (q, 4H, J=7.27), 2.72-2.79 (m, 4H), 6.67 (dd, 1 H, J=8.65, J=2.38), 6.92 (d, 1 H, J=2.23), 6.96 (s, 1 H), 7J5 (d, 1 H, J=8.68)
This product (200 mg, 0.86 mmol) was dissolved in CH2CI2 (10 mL) and Et3N (240 μL) and the triflating agent N-phenyltrifluoromethanesulfonimide [37595-74-7] (461 mg, 1.29 mmol) were added and the mixture was stirred for 3 h in room tempera- ture. The reaction mixture was diluted with CH2CI2 (20 mL) and the organic phase was washed with 10% Na2C03 (2x30 mL). The water phase was extracted with CH2CI2 (2x20 mL) and the combined organic phases were dried (Na2S04), filtered and the solvent was removed under reduced pressure. The residue was chromatographed on Si02, eluting with CH2CI :MeOH (5:1). The fractions contain- ing pure product were pooled and the solvent was evaporated under reduced pressure yielding a colourless oil (317 mg, 97%).
[1H]-NMR (CD3OD): 3 1.16 (t, 6H, J=7.27), 2.84 (q, 4H, J=7.26), 2.93 (s, 4H), 6.87 (br s, 1 H), 6.96 (dd, 1 H, J=8.97, J=2.56), 7.05 (s, 1 H), 7.31 (d, 1 H, J=8.97, 7.43 (d, 1H, J=2J3), 9.80 (br s, 1H).
The following sumatriptane analogues were prepared in a similar way using the appropriate starting materials:
5-Trifuoromethylsulfonyloxy-3-(N,N-dimethylaminoethyl)-indole
MS (direct inlet, pos ionization with NH3) shows M+1 at m/e=337.
5-Trifuoromethylsuifonyloxy-3-(N,N-dipropylaminoethyl)-indole MS (direct inlet, pos ionization with NH3) shows M+1 at m/e=393.
5-Phenylsulfonyloxy-3-(N,N-diethylaminoethyl)-indole
MS (direct inlet, El) shows M+ at m/e=372.
5-(4-Methylphenyl)sulfonyloxy-3-(N,N-diethylaminoethyl)-indole
MS (direct inlet, El) shows M+ at m/e=386. 5-(2-Thienyl)sulfonyloxy-3-(N,N-diethylaminoethyl)-indole
The raw product showed a GC/MS (El - PI) with M+ at m/e=378 and base peak at m/e=86.
5-Methylsulfonyloxy-3-(N,N-diethylaminoethyl)-indole
MS (direct inlet, El) shows M+ at m/e=310.
Example 12
5-Trifluoromethanesuifonate tryptamine (Formel Q)
N-Phtalimido-5-hydroxy tryptamine. 5-Hydroxy tryptamine creatininesulfat monohydrate (CAS RN:61-47-2, 245 mg, 0.604 mmol) was stirred in water (1 mL) and basified with 10% NaHC03 until pH=8. N-Carbethoxyphtalimide (133 mg, 0.607 mmol) was added and the solution turned yellow. Upon the addition of THF (1 mL) the reaction mixture became unclear. A bright yellow solid had formed after one night stirring in room temperature. The organic solvent was evaporated and the solid was filtered on a sintered glass funnel. After drying in the air the raw product wheighed 149 mg (81%). GC/MS (EI- PI) shows: M+ at m/e=306 and the base peak at m/e=146 (phtalimide - H). N-Phtalimido-5-trifluoromethanesulfonate tryptamine
Phtalimido-5-HT (100 mg, 0.33 mmol) and PhN(S02CF3)2 (175 mg, 1.5 equiv.) were stirred in CH2CI2 (5 mL), and thereafter Et3N (90 μL, 2 equiv.) was added. The reaction mixture was stirred over night and was the diluted with CH2CI2 (30 mL) and washed with 10% NaC03 (10 mL). The aqueous layer was extracted with CH2CI2 (30 mL) and the combined organic phases were dried (MgSθ4) and filtered, and the solvent was evaporated under reduced pressure yielding the raw product as a crystalline solid (180 mg). This raw product was chromatographed (Si02) eluting with CH2CI2. The pure fraction were pooled and the solvent was evaporated yielding a white crystalline solid (144 mg, 100%) . GC/MS (EI-PI) shows: M+ at m/e=438 and the base peak at m/e=291.
5-Trifluoromethanesulfonate tryptamine.
N-Phtalimido-5-trifluoromethanesulfonate tryptamine (51 mg, 0J 16 mmol) was dissolved in abs. EtOH (3 mL) and hydrazine hydrate (0.6 mL) was added and the reaction mixture was stirred in room temperature over night. The EtOH was evaporated under reduced pressure and the product was extracted with ether. The ether layer was dried (MgS04) and filtered, and the solvent was evaporated under reduced pressure yielding the raw product as an oil. GC/MS (EI-PI) shows: M+ at m/e=308 and the base peak at m/e=279 (M-29). Another prominent peak appears at m/e=146 (M-29-S02CF3).
Example 13.
3-amino-6-trif luoromethylsulfonyl-1 ,2,3,4-tetrahydrocarbazole (Formula R) The title compound was prepared according to the following reaction scheme according to the method of WO 93/00086. GC/MS (EI-PI) of the raw product showed M+ at m/e=334.
Figure imgf000027_0001
Example 14.
8-Triflate analogue of mianserin (Formula S).
8-Formyl-mianserine (ref. Adamczyk et al. Org. Prep. Proced. Int., 23(3), 365-72, 1991).
Phosphorus oxachloride (0.4 mL, 4.2 mmol) was added dropwise to dry DMF (0.64 mL, 8.4 mmol) at 0 °C. The mixture was stirred and warmed to rt over 10 min. To the resulting colorless viscous solution was added mianserine hydrochloride (410 mg, 1.55 mmol). The reaction mixture was heated at 100 °C for 4 h with stirring and quenched with 15 mL of ice-water, following the adjustment of pH to be 12 with 2N NaOH. The resulting solution was extracted with chloroform (4 x 20 mL). The combined organic layers were concentrated and the dark brown oily residue was purified by flash chromatography (60 mesh silica-gel, ethylacetate then tetrahydrofuran as eluent) to afford 400 mg (88 %) of the desired product as a light yellow oil, which partially solidified at rt. GC/MS (PICI-CH4) shows M+1 at m/e = 293 and M+28 at m/e = 321.
8-Hydroxy-mianserine (ref. Adamczyk et al. Org. Prep. Proced. Int., 23(3), 365-72, 1991). To a solution of 8-formyl-mianserine (400 mg, 1.37 mmol) in 10 mL of dichloro¬ methane (precooled to 0°C) was added dropwise trifluoroacetic acid (TFA) (0.4 mL, 5.0 mmol) and then a solution of m-chloroperbenzoid acid (m-CPBA) (330 mg, 1.5 mmol) in 6 mL of dichloromethane over 5 min. After the removal of the ice-cooling bath, the reaction mixture was stirred at rt for 2 h, quenched with 20 mL of 1 N NaHS03) following the adjustment of PH to be 8 with 2N NaOH. The organic layer was separated and the aqueous layer was extracted with CHCI3 (3 x 20 mL). The combined organic layers were concentrated by evaporator to afford the crude formate as a yellow oil which was hydrolyzed in next step without further purifica¬ tion.
The above crude formate was mixed with 10 mL of methanol and 10 mL of cone. HCI (aq). The mixture was stirred at rt for 2 h and quenched with 20 mL of ice- water, following the adjustment of PH to be 8 with 4 N NaOH and the extraction with CHCI3 (4 x 25 mL) and ethylacetate (2 x 25 mL). The combined organic layers were concentrated by evaporator and the brown solid residue was purified by flash chromatography (Si02, ethylacetate then THF as eluents) to afford 280 mg (73 %) of the desired compound as a yellow solid: mp 139-140 °C (dec).
8-Trifluoromethanesulfonate-mianserine.
To a suspension of 8-hydroxymianserine (50 mg, 0J8 mmol) in 2 mL of dry CH2CI2 at -78 °C under nitrogen was added slowly triflic anhydride. After removal of the cooling bath, the recation mixture was stirred 2 h and quenched with 2 mL of ice- water, following the adjustment of PH of the aqueous layer to be 12 with 2 N NaOH and the extraction with CHCI3 (3 x 5 mL). The combined organic layers were concentrated and the residue was purified by flash chromatography (Si02, 10:1 CH2CI2/MeOH as eluents) to afford 47 mg (63 %) of the desired product as a colorless oil. GC/MS (EI-PI) shows M+ at m/e=412. Other prominent peaks are m/e=279 (M-S02CF3), m/e=208 and the base peak at m/e=71.
Example 15 trans-(4aS,10bS)-7-trif luoromethansulf onate-4-n-Propyl-1 ,2,3,4,4a,5,6,1 Ob-oc tahydrobenzo[f]quinoline.
trans-(4aS,10bS)-7-hydroxy-4-n-Propyl-1 ,2,3,4,4a,5,6J0b-octahydrobenzo[f]quino- line (prepared as described by Wikstrom et al. in J. Med. Chem., 1985, 28, 215) (10 mg, 30 umol) was dissolved in CH2CI2 (0.5 mL) and 2N NaOH (0.5 mL) was added together with Bu4N+S04- (catalytic amount) and PhN(S02CF3)2 (16 mL, 46 umol). Water (1 mL) and CH2CI2 (0.5 mL) were added and the product was extracted to the organic phase, which was separated, dried (MgS04) and filtered. The solvent of the filtrate was evaporated under reduced pressure, yielding the raw product as an oil. GC/MS (EI-PI) shows: M+ at m/e=377 and the base peak at m/e=348 (M- CH2CH3). Other prominent peaks were seen at: m/e=244 (M-S02CF3) and m/e=215 (M-CH2CH3-S02CF3).
The following compounds were synthesized with the same phase transfer reaction, however, using the corresponding sulfonyl chlorides (commercially available, Aldrich) instead.
Trans-(4aS,10bS)-7-methansulfonate-4-n-Propyl-1 ,2,3,4,4a,5,6,10b-octahydrob- enzo[f]quinoline. GC/MS (EI-PI) shows: M+ at m/e=323 and the base peak at m/e=294 (M-CH2CH3). Other prominent peaks were seen at: m/e=244 (M-S02CH3) and m/e=215 (M- CH2CH3-S02CH3).
Trans-(4aS,10bS)-7-phenylsulfonate-4-n-Propyl-1 ,2,3,4,4a,5,6,1 Ob-octahydrobe- nzo[f]quinoline.
GC/MS (EI-PI) shows: M+ at m/e=385 and the base peak at m/e=77 (C6H5). Other prominent peaks were seen at: m/e=356 (M-CH2CH3), M/E=244 (M-S02C6H5) and m/e=215 (M-CH2CH3-S02C6H5).
Trans-(4aS,10bS)-7-p-toluensulfonate-4-n-Propyl-1 ,2,3,4,4a,5,6,10b-octahydro- benzo[f]quinoline.
GC/MS (EI-PI) shows: M+ at m/e=399 and the base peak at m/e=91 (CH3C6H4). Other prominent peaks were seen at: m/e=370 (M-CH2CH3), M/E=244 (M-S02C6H4CH3) and m/e=215 (M-CH2CH3-S02C6H4CH3).
Trans-(4aS,10bS)-7-(2-thiophensulfonate)-4-n-Propyl-1 ,2,3,4,4a,5,6,10b-octa- hydrobenzo[f]quinoline.
GC/MS (EI-PI) shows: M+ at m/e=399 and the base peak at m/e=362 (M-CH2CH3). Other prominent peaks were seen at: m/e=244 (M-[S02-2-thienyl]) and m/e=215 (M-CH2CH3-[S02-2-thienyl]).
Eksempel 16
Triflate analogue of carbamazepine
The title compound was prepared from 2-hydroxycarbamazepine as deseibed by Chang in Jour. Heterocycl. Chem., 1983, 20, p 2,3 and 7.
The raw product showed on GC/MS (EI-PI): M+ at m/e=384. Pharmacology
Compounds of the invention were subjected to well recognized and reliable standard pharmacological tests.
The sumatriptane analogues were tested in binding assays for determination of the affinity for 5-HT-IA 5-HT1 B and 5-HTID receptors according to the methods of Guan X. "Miscellaneous Receptors"; and Peroutka S.J. "5-Hydroxytryptamine Receptors." both in Peroutka S.J.: Handbook of Receptors and Channels., 1994a, CRC Press, Inc. p. 209-236 The results were as shown in Table 1.
Table 1 : Binding affinity of the test compounds for different subtypes of 5-HT receptors.
Figure imgf000031_0001
5-HT1A 5-HT1 B 5-HT1D
Me Me CF3 nt 98 8.4 Et Et CF3 120 530 21 n-Pr n-Pr CF3 nt 660 170
*: nt = = not tested
Further testing of anti-migraine effects is performed by the methods of: Perren et al., The selective closure of feline carotid arteriovenous anastomoses by GR(43175). Cephalalgia, 1989:9 (suppl. 9):41-6; and
Den Boer et al., Role of 5-HTHike receptors in the reduction of porcine cranial arteriovenous anastomotic shunting by Sumatriptan. Br. J. Pharmacol., 1991 , 102, 323-30. The riluzole analogues were tested in the Hypoxia Model: ref. Rice, J.E., Vannucci, R.C., Brierly, J.B., The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann. Neurol., 9, 121-141 , 1981 and the Electroconvulsive Chock Model: ref. Krall, R.L., Penry, J.K., White, B.G., Kupferberg, H.J. and Swinyard, E.A., Antiepileptic drug development: II. Anticonvulsant drug screening, Epiiepsia, 19, 409-428, 1978.
Results from the hypoxia model showed that the riluzole triflate (Formula B: RB CF3) gave significant neuroprotective in a dose of 30 mg/kg calculated as the free base. Accordingly the triflate analogue is slightly less potent but equally efficacious as riluzole (which was protective in a dose of 10 mg/kg) whereas it is believed to be safer, since higher doses may be administered (30mg/kg riluzole is expected to be toxic).

Claims

1. An aryltriflate or a related compound characterized in that is selected from
a) Triflate analogues of raclopride:
Formula A1 Formula A2
Figure imgf000033_0001
b) triflate analogues of riluzole:
Formula B
Figure imgf000033_0002
wherein RB is CF3, C-|-C8 alkyl, C3-Cβ cycloalkylmethyl, phenyl, phenyl substituted with halogen or C1-C4 alkyl, phenyl-Ci-Cβ alkyl, phenyl-CrCβ alkyl substituted with halogen or C1-C4 alkyl, thienyl or thienyl-C-i-Cs alkyl, Rβ preferably being CF3 or (C-i-Cs) alkyl, in particular CF3, CH3 or iso-propyl.
c) Triflate analogues of cisapride:
Formula C1
Figure imgf000033_0003
Formula C2
Figure imgf000034_0001
d) Triflate analogues of omeprazole, lanzoprazole and pantoprazole:
Formula D
Figure imgf000034_0002
Wherein (A, B, C, D) is : (Me, MeO, Me, CF3S020) (omeprazole); (H, CF3S020, Me, H) (lanzoprazole); or (H, MeO, MeO, CF3S0 0) (pantoprazole);
e) Triflate analogue of paroxetine:
Formula E
Figure imgf000034_0003
f) Triflate analogue of fenfluramine: Formula F
Figure imgf000035_0001
g) Triflate analogues of sotalol
Formula G1 Formula G2
Figure imgf000035_0002
h) Triflate analogue of estradiol
Formula H
Figure imgf000035_0003
in the α- or the β-form;
i) Triflate analogue of RU 486
Formula
Figure imgf000035_0004
j) Triflate analogues of tacrine of Formula J Formula J
Figure imgf000036_0001
wherein Rj is CF3, CrCβ alkyl, C3-Cβ cycloalkylmethyl, phenyl, phenyl substituted with halogen or C1-C4 alkyl, phenyl-C-i-Cβ alkyl, phenyl-C-i-Cβ alkyl substituted with halogen or C1-C4 alkyl, thienyl or thienyl-C-i-Cβ alkyl, preferably CF3;
k) Triflate analogue of moclobemide
Formula K
Figure imgf000036_0002
I) Triflate analogue of ifenprodil of the Formula L
Formula L
Figure imgf000036_0003
wherein R ΪS CF3, C Cβ alkyl, C3-Cβ cycloalkylmethyl, phenyl, phenyl substituted with halogen or C1-C4 alkyl, phenyl-C-i-Cβ alkyl, phenyl-C-i-Cβ alkyl substituted with halogen or C1-C4 alkyl, thienyl or thienyl-C-pCβ alkyl;
m) Triflate analogues of brofaromine
Formula M1
Figure imgf000036_0004
Formula M2
Figure imgf000037_0001
n) Triflate analogue of melatonin of Formula N
Formula N
Figure imgf000037_0002
0) N-Acetyl-2[(7-trifluoromethylsulfonyloxy-1 -naphthyl)ethyl]amine
Formula O HCOCH3
Figure imgf000037_0003
p) Triflate analogue of prenalterol
Formula P
Figure imgf000037_0004
q) Triflate and related analogues of sumatriptane having Formula Q Formula Q
Figure imgf000038_0001
wherein Ri and R2 are the same or different and selected from the group consisting of H, Ci-Cβ alkyl, C2-Cβ alkenyl, C2-Cβ alkynyl, cycloalkyl, cycloalkyl-C-i-Cβ alkyl, C Cβ haloalkyl, phenyl-C-i-Cβ alkyl and heteroaryl-CrCβ alkyl, preferably from H, methyl, ethyl or propyl; and
RQ is C Cβ alkyl, CrCβ haloalkyl, phenyl, phenyl substituted with halogen or C1-C4 alkyl, phenyl-CrCβ alkyl, phenyl-CrCβ alkyl substituted with halogen or C1-C4 alkyl, heteroaryl or heteroaryl-CrCβ alkyl, preferably CF3, CH3, phenyl, p-methylphenyl or thienyl;
r) Triflate analogues of 6-substituted 3-amino-1 ,2,3,4-tetrahydrocarbazole deriva¬ tives of Formula R
Formula R
Figure imgf000038_0002
s) Triflate analogue of mianserin
Formula S
Figure imgf000038_0003
t) Triflate analogues of the compounds of Formula T Formula T
Figure imgf000039_0001
wherein Rs is CF3, CrCβ alkyl, C3-Cβ cycloalkylmethyl, phenyl, phenyl substituted with halogen or C1-C4 alkyl, phenyl-CrCβ alkyl, phenyl-CrCβ alkyl substituted with halogen or C1-C4 alkyl, thienyl or thienyl-CrCβ alkyl, preferably CF3, CH3, phenyl, p-methylphenyl or 2-thienyl; and R3 is (C1-C4) alkyl, preferably propyl;
u) Triflate analogue of carbamazepine
Formel U
Figure imgf000039_0002
or a pharmaceutically acceptable acid addition salt thereof.
2. 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.
3. The method of Claim 2, wherein said compound is administered in an amount of from about 1 to about 2000 mg oral daily dose, or from 0J to about 100 mg parenteral daily dose.
4. Pharmaceutical composition characterized in that it comprises a therapeutically effective amount of a compound of Claim 1 together with a pharmaceutically acceptable carrier or diluent.
PCT/DK1994/000244 1993-06-18 1994-06-20 Aryltriflates and related compounds WO1995000478A1 (en)

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WO1997015306A1 (en) * 1995-10-25 1997-05-01 Janssen Pharmaceutica N.V. Infusions of neuroprotectants and perfluorochemicals
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US10774064B2 (en) 2016-06-02 2020-09-15 Cadent Therapeutics, Inc. Potassium channel modulators
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