EP0859757A1 - Derivates of n,n-dimethyl-2-(arylthio)benzylamine, their salts, methods of preparation and their use in pharmaceutical medicaments - Google Patents

Derivates of n,n-dimethyl-2-(arylthio)benzylamine, their salts, methods of preparation and their use in pharmaceutical medicaments

Info

Publication number
EP0859757A1
EP0859757A1 EP96934332A EP96934332A EP0859757A1 EP 0859757 A1 EP0859757 A1 EP 0859757A1 EP 96934332 A EP96934332 A EP 96934332A EP 96934332 A EP96934332 A EP 96934332A EP 0859757 A1 EP0859757 A1 EP 0859757A1
Authority
EP
European Patent Office
Prior art keywords
dimethyl
substituents
formula
phenylthio
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96934332A
Other languages
German (de)
English (en)
French (fr)
Inventor
Zdenek Polivka
Karel Dobrovsky
Alexandra Silhankova
Karel Sindelar
Ruzena Mickova
Vladimir Valenta
Ivan Krejci
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Farmak AS
Original Assignee
Farmak AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Farmak AS filed Critical Farmak AS
Publication of EP0859757A1 publication Critical patent/EP0859757A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/27—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/65—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfone or sulfoxide groups bound to the carbon skeleton

Definitions

  • the invention relates to the derivatives of N ,N-dime ⁇ hyl -2- (arylthio) benzylamine and their salts, which selectively inhibit serotonin re-uptake in the brain structures It is also concerned with the methods of preparation and pharma ⁇ ceutical medicaments on their basis suitable for treatment of depression and other diseases of the central nervous sys ⁇ tem, based on serotonin transport defects and serotonin me ⁇ tabolism imbalance in the brain.
  • N,N-dimethyl-2- (2-hydroxymethyl)phenyl ⁇ thio)benzylamine (VO 93/12080, and particularly N,N-dimethyl- 2- (4- (trifluoromethyl) -2- (hydroxymethyl) phenylthio) benzyl ⁇ amine .
  • the aim of the invention is to find the modification of the compound on the basis of N,N-dimethyl -2- (pheny1 thi o) benzy1 - amine, which would show higher selectivity and better ef ⁇ fects than compounds having been applied up to the present.
  • substituents R or R in the A ring in 4 and 5 positions is an hydrogen atom
  • the other substituent R or R in the A ring is either a fluorine atom or chlorine atom
  • two to three among the substituents R to R in the B ring in the 2 to 5 positions are hydrogen atoms
  • the substituents in the D ring are either three hydrogen atoms and one substituent formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulf nyl , or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxy- carbonyl, or methylthio, or nitro, or amino group, or are two hydrogen atoms, one fluorine or chlorine atom and one substituent
  • the advantageous compound is N,N-dimethyl-2- (2-am no-4- (trif1uoromethyI ) pheny1 thi o) benzy1 - amine, and among its salts particularly oxalate, dihydro- chloride and maleate.
  • This compound shows the highest selec ⁇ tivity regarding the comparison of inhibition of serotonin re-uptake and noradrenaline re-uptake in the brain structu ⁇ res, which is apparent from the Table of biological activity (see bel ow) .
  • subst i tuents R to R are identical to tliosc in formula (I) , and besides that, in the B ring can also he a formyl or dimethylaminocarbonyl group.
  • these amides are reduced by e.g. complex hydrides of the lithium aluminium hydride type, or by diborane, which is advantageously used "in situ", so that in the reaction mixture it is generated by the reaction of so ium boro- hydride with boron trifluoride etherate.
  • any of the sub ⁇ stituents R 3 to R in the B ring is a formyl , dimethylamino ⁇ carbonyl or carboxyl group, according to the invention also such a group is reduced at the same time and provide the de ⁇ rivative of the compound of general formula (I) with a hydroxyl or dimethylaminomethyl group.
  • Another method of preparation of the derivatives of the com ⁇ pound (I) according to the invention uses benzylhalogenides of general formula (III) as an intermediate product in the last step
  • Hal is an chlorine or bromine atom and the substitu ⁇ ents R to R are identical to the substituents in formula (I) .
  • These benzylhalogenides are brought into reaction with dimethylamine in an organic solvent - advantageously in toluene at room temperature.
  • one of the substituents on the B ring of the compound of general formula (I) according to the invention shall be methylsulfinyl
  • the corresponding methylthioderivative is oxidised by hydrogen peroxide in acetic acid at room tempe ⁇ rature.
  • one of the substituents on the B ring of the compound of general formula (I) according to the invention shall be esterified carbonyl , i.e. methoxycarbonyl or ethoxycarbonyl
  • the corresponding carboxyderivative is esterified by metha- nol or ethanol - advantageously in the presence of hydrogen chloride, or the corresponding trifluoromethylderivative is used, which is hydrolysed with sulfuric acid at 90 to 110 C and then is esterified with the corresponding alcohol.
  • salts of compounds of general formula (I) according to the invention can anvantageously be prepared via neutralisation of bases with phar acodynamically harm ⁇ less inorganic or organic acids.
  • All derivatives of the compound of general formula (I) ac ⁇ cording to the invention are of an alkaline nature and their bases are insoluble in water, and mostly are of oily appea ⁇ rance. Neutralisation of all of them with suitable acids yields their crystalline salts, usually also badly soluble in water; their examples can be hydrochlorides , oxalates or maleates . Providing one substituent on the B ring is carb ⁇ oxyl, the final products are amphoteric, but, however, they also provide the crystalline salts due to the presence of a strong basic amino group.
  • the benzene phase was dried with magnesium sulfate and evaporated i n va ⁇ cuo , to obtain 13.7 g of N,N-dimethyl-2- (2 , 4-dichloropheny1 - thio) benzamide , which after crystallisation from a mixture of benzene and petroleum ether melted at 120-122 C.
  • 3.0 g of sodium borohydride was added to a solution of 11.83 g of N,N-dimethyl-2- (2, 4-dichlorophenylthio) benzamide in 60 ml of tetrahydrofuran and then 10 ml of boron tri ⁇ fluoride etherate was added dropwise over a period of 40 min.
  • the reaction mixture was processed in analogy to example pie 1/d.
  • the crude base was dissolved in chloroform and purified by filtration on a 150 g silica gel column. After evapora ⁇ ting the chloroform, the obtained crude base was neutralised using 5.0 g of oxalic acid dihydrate in 50 ml of ethanol, which yielded 10.6 g of crystalline N, N-dimethyl-2- (2 , 4-di - chlorophenylthio)benzylamine hydrogen oxalate, melting at 208-211°C.
  • a suspension of 3 , 5-dichloroaniline hydrochloride obtained from 29.0 g of 3 , 5-dichloroaniline and 75 ml of diluted hydrochloric acid (1:1) was diazotized under stirring at 0-5 C with a solution of 13.7 g of sodium nitrite in 30 ml of water.
  • 0.2 g of nickel sulfate was added to a solution of the diazonium salt and the cooled mixture was added in small amounts to a solution of 35 g of potassium xantha ⁇ e in 45 ml of water kept between 40-45 C. After having added every ⁇ thing, this temperature was kept for a further 1 h.
  • N,N-Dimethy1-4-fluoro-2- (4-isopropylphenylthio)benzylamine One drop of dimethylformamide was added to a suspension of 22.0 g of 4-fluoro-2- (4-isopropylphenylthio)benzoic acid (Protiva M. et al . : Collect. Czech. Chem. Commun.
  • the water phase was acidified with hydrochloric acid, the preci ⁇ pitated crude 2- (4- (fluoro-3-methoxyphenylthio)benzoic acid (20.6 g) was filtered by suction and after crystallisation from ethanol melted at 222-224°C.
  • N,N-Dimethyl-2- (4-fluoro-3-hydroxyphenylthio)benzylamine A solution of 7.0 g of N,N-dimethy -2- (4-fluoro-3-methoxy- phenylthio)benzylamine hydrochloride (see example 27) in 50 ml of 46% hydrobromic acid was heated up to 120 C under stirring for 8 h. After cooling, the mixture was diluted with 100 ml of water, its pH was adjusted up to 8 using 20% solution of sodium hydroxide, and the mixture was extracted with chloroform. The extract was filtered over a 100 g sili ⁇ ca gel column, which was eluted with chloroform.
  • the reduction of the acid into alcohol is more suitably carried out in the follo ⁇ wing way: 323 g of 70% solution (toluen) of sodium dihydridobis(2-methoxyethoxo)aluminate (NaAlH 2 (OCH2CH2OCH3) 2 in 300 ml of toluene was under stirring over a period of 75 min added dropwise to a solution of 125 g of 2- (2-amino-4- (trifluoromethyl)phenylthio)benzoic acid in 2 1 of toluene and the mixture was stirred at room temperature for 4 h.
  • the residue was 41 g of crude 2- (2-amino-4- (trifluoromethyl)phenylthio) -5-fluorobenzy1alcohol to which 40 ml of thionylchloride was added dropwise under cooling with ice and under stirring. The mixture was stirred at room temperature for 2 h and left standing for 16 h The excess thionylchloride evaporated off i n vacuo The residue was crude 2- (2-amino-4- (trifluoromethyl)phenyl thio) -5-fluoro- benzyl chloride hydrochloride.
  • N,N-Dimethyl-2- (4-amino-2- (trifluoromethyl) phenylthio) - benzylamine 0.93 g of thiosalicylic acid and 1.6 g of 2-bromo-5-nitro- benzotrifluoride (Filler R. , Novar H. : J. Org. Chem. 26, 2707 (1961)) were added to a solution of 0.48 g of sodium hydroxide in 25 ml of ethanol and the mixture was refluxed under stirring for 2.5 h. The ethanol evaporated off i n va ⁇ cuo and the residue was dissolved in 25 ml of hot water. After cooling, the mixture was acidified under stirring with 2.5 ml of 3M hydrochloric acid.
  • the residue was 4.42 g (90%) of the crude base, which was purified by crystallisation on a sili ⁇ ca gel column gradually eluted with a mixture of chloroform and ethylacetate, chloroform and a mixture of methanol and chloroform saturated with ammonium at last.
  • the residue of the chloroform eluate was an oily base whose neutralisation with oxalic acid dihydrate in acetone yielded crystalline N,N-dimethyl-2- (4- (hydroxymethyl) heny1thio) benzylamine hydrogen oxalate, which after crystallisation from a mixture of acetone, ethanol and ether melted at 96-98 C.
  • this aldehyde can be converted to crystalline 2, 4-dinitrophenylhydrazon in a familiar way, which after crystallisation from a mixture of ethylacetate and ethanol melted at 216-222°C.
  • the following Table contains the values of serotonin re-uptake inhibition (5HT) , noradrenaline re-uptake inhibi ⁇ tion (NA) and paroxetine binding inhibition (PA) for some compounds prepared via the methods described in Examples hereinbefore in relation to the known compounds mentioned in the Background of the Invention hereinbefore.
  • 5HT serotonin re-uptake inhibition
  • NA noradrenaline re-uptake inhibi ⁇ tion
  • PA paroxetine binding inhibition
  • -ICCQ is the concentration causing 50% inhibition of [ H]paroxetine binding
  • a and B mean the known compounds;
  • A-compound 1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) - phthalato-5-carbonitrile) and
  • B-compound N,N-dimethyl-2- (4- (trifluoromethyl) -2- (hydroxy ⁇ methyl)phenylthio)benzylamine.
  • this compound does not show the affinity towards alpha-adrenergic muskarine and benzo- diazepine receptors, so that it does not inhibit binding of [ H] preparatives (prazosin, quinuclidinnyl benzilate and flunitrazepam) onto the receptors in the corresponding brain structures. This suggests a low probability of occurrence of some cardiovascular anticholinergic and central neurotropic effects of the benzodiazepine type compounds .
  • Derivatives of general formula (I) and their pharmaceuti ⁇ cally acceptable salts are suitable for the production of pharmaceutical medicaments designed primarily for treatment and prophylaxis of depression, anxious states, migraine and other diseases of the central nervous system, in which the brain serotonin plays an important role.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP96934332A 1995-11-09 1996-11-07 Derivates of n,n-dimethyl-2-(arylthio)benzylamine, their salts, methods of preparation and their use in pharmaceutical medicaments Withdrawn EP0859757A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CZ952935A CZ293595A3 (cs) 1995-11-09 1995-11-09 Deriváty N,N-dimethyl-2-(arylthio)benzylaminu, jejich soli, způsoby jejich přípravy a jejich použití v léčivých přípravcích
CZ293595 1995-11-09
PCT/CZ1996/000022 WO1997017325A1 (en) 1995-11-09 1996-11-07 Derivates of n,n-dimethyl-2-(arylthio)benzylamine, their salts, methods of preparation and their use in pharmaceutical medicaments

Publications (1)

Publication Number Publication Date
EP0859757A1 true EP0859757A1 (en) 1998-08-26

Family

ID=5465870

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96934332A Withdrawn EP0859757A1 (en) 1995-11-09 1996-11-07 Derivates of n,n-dimethyl-2-(arylthio)benzylamine, their salts, methods of preparation and their use in pharmaceutical medicaments

Country Status (5)

Country Link
EP (1) EP0859757A1 (cs)
CZ (1) CZ293595A3 (cs)
HU (1) HUP9901136A2 (cs)
SK (1) SK46798A3 (cs)
WO (1) WO1997017325A1 (cs)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000056707A1 (en) * 1999-03-24 2000-09-28 Sepracor, Inc. Diaryl thioethers, compositions and uses thereof
US6921840B1 (en) 1999-04-30 2005-07-26 The Trustees Of The University Of Pennsylvania SPECT imaging agents for serotonin transporters
US6410736B1 (en) 1999-11-29 2002-06-25 Pfizer Inc. Biaryl ether derivatives useful as monoamine reuptake inhibitors
SK4732002A3 (en) * 1999-10-13 2002-12-03 Pfizer Prod Inc Biaryl ether derivatives useful as monoamine reuptake inhibitors
US6448293B1 (en) 2000-03-31 2002-09-10 Pfizer Inc. Diphenyl ether compounds useful in therapy
US6610747B2 (en) 2000-08-31 2003-08-26 Pfizer Inc. Phenoxybenzylamine derivatives as SSRIs
PL360743A1 (en) * 2000-08-31 2004-09-20 Pfizer Inc. Phenoxybenzylamine derivatives as selective serotonin re-uptake inhibitors
US6630504B2 (en) 2000-08-31 2003-10-07 Pfizer Inc. Phenoxyphenylheterocyclyl derivatives as SSRIs
UA81749C2 (uk) 2001-10-04 2008-02-11 Х. Луннбек А/С Фенілпіперазинові похідні як інгібітори зворотного захоплення серотоніну
SE0103325D0 (sv) 2001-10-04 2001-10-04 Astrazeneca Ab Novel compounds
US7041851B2 (en) 2002-03-14 2006-05-09 The Trustees Of The University Of Pennsylvania Fluorinated phenyl thiophenyl derivatives and their use for imaging serotonin transporters
US20110097274A1 (en) * 2002-05-17 2011-04-28 Yiyun Huang Carbon-11 and fluorine-18 labeled radioligands for positron emission tomography (PET) imaging for the brain serotonin transporters
US6800652B2 (en) 2002-08-16 2004-10-05 Pfizer Inc. Diaryl compounds
GB0219154D0 (en) * 2002-08-16 2002-09-25 Pfizer Ltd Diaryl compounds
JP2006511606A (ja) 2002-12-13 2006-04-06 ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー 下部尿路症状を治療するα−２−δリガンド
SI1626720T1 (sl) 2003-04-04 2008-12-31 Lundbeck & Co As H Derivati 4-(2-fenilsulfanil-fenil)-piperidina kotzaviralci ponovnega vnosa serotonina
TWI347183B (en) 2003-12-23 2011-08-21 Lundbeck & Co As H 2-(1h-indolylsulfanyl)-benzyl amine derivatives
AU2004303461B2 (en) 2003-12-23 2011-04-28 H. Lundbeck A/S 2-(1H-indolylsulfanyl)-benzyl amine derivatives as SSRI
AR052308A1 (es) 2004-07-16 2007-03-14 Lundbeck & Co As H Derivados de 2-(1h-indolilsulfanil)-arilamina y una composicion farmaceutica que contiene al compuesto
EP1793829A1 (en) * 2004-10-01 2007-06-13 Neurocure Ltd. Use of pharmaceutical compositions of lofepramine for the treatment of adhd, cfs, fm and depression
US7629473B2 (en) 2005-06-17 2009-12-08 H. Lundbeck A/S 2-(1H-indolylsulfanyl)-aryl amine derivatives
AR054393A1 (es) 2005-06-17 2007-06-20 Lundbeck & Co As H Derivados de benzo(b)furano y benzo(b)tiofeno, composiciones farmaceuticas que los contienen y su uso en la fabricacion de un medicamento para el tratamiento de enfermedades mediadas por la inhibicion de la reabsorcion de neurotransmisores de amina biogenicos.
KR20090092307A (ko) 2006-12-22 2009-08-31 레코르다티 아일랜드 리미티드 하요도 장애에 대한 α2δ 리간드 및 ＮＳＡＩＤｓ의 복합 치료

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0396827A1 (en) * 1989-05-09 1990-11-14 SPOFA Spojené Podniky Pro Zdravotnickou Vyrobu 2-Phenylthiobenzylamine dervivatives and acid addition salts thereof
GB8912971D0 (en) * 1989-06-06 1989-07-26 Wellcome Found Halogen substituted diphenylsulfides
GB9126311D0 (en) * 1991-12-11 1992-02-12 Wellcome Found Substituted diphenylsulfides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9717325A1 *

Also Published As

Publication number Publication date
HUP9901136A2 (hu) 1999-08-30
CZ293595A3 (cs) 1999-12-15
SK46798A3 (en) 1998-09-09
WO1997017325A1 (en) 1997-05-15

Similar Documents

Publication Publication Date Title
EP0859757A1 (en) Derivates of n,n-dimethyl-2-(arylthio)benzylamine, their salts, methods of preparation and their use in pharmaceutical medicaments
CA1073925A (en) Sulphur-containing arylamine derivatives
US6043284A (en) Anti-atherosclerotic diaryl compounds
CA1116611A (en) Imidazole derivatives exhibiting anticonvulsant activity
HU185799B (en) Process for producing acil-anilides
CZ281137B6 (cs) V jádru substituovaný 2-amino-1,2,3,4-tetrahydronaftalen-3-aminochroman a 3-aminothiochroman, způsob jejich přípravy a farmaceutické prostředky je obsahující
US4207343A (en) 1-Phenyl-3-(substituted phenoxy)propylamines
SK123993A3 (en) N,n-disubstituted arylcycloalkylamides, their salts, process for their preparation and their pharmaceutical agents
FI101791B (fi) Menetelmä valmistaa terapeuttisesti aktiivista substituoitua 1-(1H-imi datsol-4-yyli)alkyylibentsamidia
WO1996020936A1 (en) Novel thiazolidin-4-one derivatives
US4985585A (en) Phenoxyalkylcarboxylic acid derivatives and process for their preparations
HUT57717A (en) Process for producing halogen-substituted diphenyl sulfides and pharmaceutical compositions comprising such compounds
EP0292202B1 (en) 2-(3,4-dihydroxyphenyl ethyl amines, their preparation and use as pharmaceutical compounds
FR2621038A1 (fr) Derives d'alcadienes, leurs preparations, les medicaments les contenant et produits intermediaires
Machin et al. . beta. 1-Selective adrenoceptor antagonists. 2. 4-Ether-linked phenoxypropanolamines
US4970238A (en) 3-aminopropoxyphenyl derivatives, their preparation and pharmaceutical compositions containing them
US5436244A (en) Indane derivatives and analgesic and diuretic compositions thereof
GB2053897A (en) Piperazine derivatives
AU633923B2 (en) Substituted aminoalkylbenzene derivatives
US4992459A (en) Dopamine-β-hydroxylase inhibitors
US5736568A (en) 2-(aminoalkoxy) phenylalkylamines with antiinflammatory activity
IE61277B1 (en) Improvements in or relating to leukotriene antagonists
US5739334A (en) Alkyl derivatives of trazodone with CNS activity
US4061655A (en) 3,6-Dicarboximidamidecarbazoles
US4017543A (en) α,α-Dialkyl-4-phenethyl-benzylamines and the salts thereof

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19980528

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: RO PAYMENT 980528;SI PAYMENT 980528

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19990601