EP0896540A1 - Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression - Google Patents

Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression

Info

Publication number
EP0896540A1
EP0896540A1 EP97920431A EP97920431A EP0896540A1 EP 0896540 A1 EP0896540 A1 EP 0896540A1 EP 97920431 A EP97920431 A EP 97920431A EP 97920431 A EP97920431 A EP 97920431A EP 0896540 A1 EP0896540 A1 EP 0896540A1
Authority
EP
European Patent Office
Prior art keywords
dimethyl
phosphonate
trichloroethane
thiophosphonate
trifluoroethane
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Withdrawn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
EP97920431A
Other languages
German (de)
English (en)
French (fr)
Inventor
Fritz Maurer
Bernard Schmidt
Stephan Lensky
Franz-Josef Van Der Staay
Richard Joseph Fanelli
David Ross Britelli
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.)
Troponwerke GmbH
Bayer AG
Original Assignee
Troponwerke GmbH
Bayer AG
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 Troponwerke GmbH, Bayer AG filed Critical Troponwerke GmbH
Publication of EP0896540A1 publication Critical patent/EP0896540A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • 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
    • A61P25/24—Antidepressants
    • 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

Definitions

  • the invention relates to the use of phosphonic acid esters for the treatment and prevention of functional disorders of the brain and depression, and to new compounds and their production,
  • DE-1 078370 discloses phosphonic acid esters used for the control of insects.
  • metrifonate is suitable for the treatment of Alzheimer's disease (US 4,950,658) .
  • the assumed mode of action is that metrifonate is converted slowly into the organo- phosphoric acid ester dichlorvos and thereby induces a long-lasting inhibition of cholinesterase.
  • butonate was proposed as a suitable precursor for etrifonate/dichlorvos (B.R. Holmstedt and I. Nordgren, in Cholinergic Basis for Alzheimer Therapy (R.E. Becker and E. Giacobini, eds), Birkhauser, Boston, 155-161, 1S91) .
  • R represents straight-chain or branched alkyl which has up to 6 carbon atoms and is optionally substituted by one or more halogen atoms
  • R 1 represents hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms
  • R 2 represents hydrogen or represents straight-chain or branched alkyl, alkylcarbonyl, alkoxycarbonyl or alkylsulphonyl with in each case up to 6 carbon atoms in the alkyl group, or represents alkyl- or dialkylaminocarbcnyl with in each case up to 4 carbon atoms in the alkyl groups,
  • R 3 represents straight-chain or branched alkyl with up to 6 carbon atoms
  • X represents oxygen or sulphur, but does not denote oxygen where R represents trichloromethyl, R 1 represents hydrogen and R 2 represents hydrogen or propylcarbonyl,
  • the compounds of the formula (I) are suitable for the treatment and prevention of cognitive and affective diseases, and in particular for the treatment of senile and presenile dementia, dementia of the Alzheimer's type, AIDS-related dementia, cognitive deficits in Parkinson's and Huntington's disease or functional disorders of the brain as a result of infarction, multi-infarct dementia (MID), primary degenerative dementia (PDP) and other forms of dementia and for the treatment of depression.
  • MID multi-infarct dementia
  • PDP primary degenerative dementia
  • OBS organic brain syndrome
  • AAMI age-associated memory impairment
  • the compounds of the general formula (I) are extremely suitable for the treatment and prevention o senile and. presenile dementia and dementia of the Alzheimer's type.
  • R represents straight-chain or branched alkyl with up t o 4 c a r b o n a t o m s o r t r i f l u o r o e t h y 1 , trichloromethyi, difluoromethyl, 1, 1-dichloroethyl, dichloromethyl . f luoromethyl , chloro ethyl , dichlorofluoromethyl, difluorochloromethyl or represents the radical of the formula -CC1 2 CH 2 C1,( 1 > 1 . 2 - tri chl oroe thyl ) ,
  • R 1 represents hydrogen or straight-chain or branched alkyl with u to 4 carbon atoms ,
  • R 2 represents hydrogen or represent s straight-chain or branched alkyl , " alkylcarbonyl, alkoxycarbonyl or alkylsulphonyl with up to 4 carbon atoms in the alkyl group, or represents alkyl or dialkylaminocarbonyl with in each case up to 3 carbon atoms in the alkyl groups ,
  • R 3 represents straight-chain or branched alkyl with up to 3 carbon atoms
  • R represents oxygen or sulphur, but does not denote oxygen where R represents trichloromethyl, R 1 represents hydrogen and R 2 represents hydrogen or propylcarbonyl,
  • R represents methyl, tert. -butyl, 1, 1-dichloroethyl, chlorc erhyl, dichloro ethyl, trichloromethyl, trifluoro ethyl, dichlorofluormethyl, difluorochloromethyl or the radical -CC1-CH-C1, ( 1 , 1 , 2 - t r i chl oroe thy 1 )
  • R ⁇ represents hydrogen or methyl
  • R 2 represents hydrogen, -ethyl, ethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, t-butylcarbonyl, methoxycarbonyl, ethcxycarbonyl, propoxycarbonyl, tert . -butoxycarbonyl, rnethylsulphonyl , ethyl sulphonyl , propyls ulphonyl , methylaminocarbonyl, - ' dimethylaminocarbonyl or propylaminocarbonyl,
  • R 3 represents methyl, ethyl or propyl
  • X represents oxygen or sulphur, but does not denote oxygen where R represents trichloromethyl and R 1 represents hydrogen or propylcarbonyl, and their salts and isomers are particularly preferred.
  • the compounds according to the invention can exist in stereoisomeric forms which are either in the form of image and mirror image (enantiomers) or are not in the form of image and mirror image (diastereomers).
  • the invention relates both to the enantiomers and the diastereomers and to respective mixtures thereof. Both the race ic forms and the diastereomers can be separated by the known methods into the stereoisomerically homogeneous components.
  • the invention also relates to the following compounds: dimethyl ( 1-tert. -butylcarbonyloxy-2 , 2,2-trichloroethane)- phosphonate dimethyl ( l-methanesulphonyloxy-2 ,2,2-trichloro ⁇ thane)- phosphonate, imethyl ( 1-ethanesulphonyloxy-2,2,2-trichloroethane)- phosphonate, dimethyl ( l-methoxycarbonyloxy-2, 2, 2-trichloroethane)- phosphonate, dimethyl ( l-acetyloxy-2, 2, 2-trifluoroethane)-phosphonate, dimethyl ( l-methoxycarbonyloxy-2, 2,2-trifluoroethane)- phosphonate , imethyl ( l-propylcarbonyloxy-2, 2 , 2-trifluoroethane)- phosphonate , dimethyl ( 1-methanesulphonyloxy-2, 2,2-tri
  • the present invention also relates to the use of the following compounds which are already known:
  • the starting compounds of the formulae (II), (III) and (IV) are known or can be prepared by known methods.
  • the process for the preparation of the compounds of the formula (I) by reaction with the halogen compounds of the formula (III) is preferably carried out using diluents. Suitable diluents are virtually all inert organic solvents.
  • These preferably include aliphatic and aromatic, optionally halogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, ethers such as diethyl and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxan, ketones such as acetone, .
  • aliphatic and aromatic, optionally halogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, xylene, methylene chloride
  • ethyl methyl ethyl, methyl isopropyl and methyl isobutyl ketone
  • -esters such as methyl and ethyl acetate
  • nitriles such as for example acetonitrile and propionitrile
  • amides such as for example dimethyl formamide, dimethyl acetamide and N-methylpyrrolidone as well as dimethyl sulphoxide, tetramethylene ⁇ ulphone and hexa ethylpho ⁇ phoric triamide.
  • Alkali metal and alkaline earth metal hydrides such as lithium, sodium, potassium and calcium hydride, alkali metal and alkaline earth metal hydroxides, such as lithium, sodium, potassium and calcium hydroxide, alkali metal and alkaline earth metal carbonates and hydrogen carbonates, such as sodium and potassium carbonate or sodium and potassium hydrogen carbonate as well as calcium carbonate, alkali metal acetates, such as sodium and potassium acetate, alkali metal alcoholates, such as sodium and potassium tert.-butylate, and furthermore basic nitrogen compounds such as trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, ethyldicyclohexylamine, N,N-dimethylbenzylamine, N,N-dimethyl- aniline, pyridine, 2-methyl-, 3-methyl-, 4-methyl-, 2,4
  • the reaction temperatures can be varied over a relatively large range. In general temperatures of between 0°C and 100°C, and preferably temperatures of between 10°C and 80°C are used.
  • the process is generally carried out under normal pressure. It is however also possible to use increased or reduced pressure.
  • the starting materials required in each case are generally used in approximately equi olar quantities. It is however also possible to use one of the two components employed in each case in a relatively large excess.
  • the reaction is generally carried out in a suitable diluent in the presence of an acid acceptor and the reaction mixture is stirred for several hours at the temperature required in each case.
  • the working up process is carried out in each case by the usual methods (cf. the preparation examples).
  • the process for the preparation of the compounds (I) by reaction with the carboxylic anhydrides of the formula (IV) can also be carried out without diluents.
  • All the usual mineral acids can be used as the catalyst.
  • Preferred acids are sulphuric acid, hydrochloric acid or phosphoric acid. They are used in a quantity of 0.001 to 10 mol % .
  • the compounds are usually obtained in the form of oils which in some cases cannot be distilled without decomposition, but which can be freed from the residual volatile constituents by so-called "incipient" distillation, i.e. by heating the compounds at moderately increased temperatures for relatively long periods under reduced pressure, as a result of which they are purified.
  • the compounds are characterised by means of their refractive index.
  • the crystalline compounds are characterised by their melting point.
  • test substances are administered once daily (60 mins. before the first training cycle) .
  • Control animals are administered a corresponding amount of the vehicle.
  • the platform is removed from the water and an additional swimming test is carried out in order to examine whether the test animals look for the platform within a defined small area surrounding the training position of the platform (retention test).
  • the activity of some compounds in relation to learning and remembrance processes were examined in the "Active Avoidance Test".
  • rats have to learn to move to the other side of a shuttle box consisting of two compartments (Coulbourn Instruments) as soon as a conditioned stimulus is actuated.
  • the conditioned stimulus consists of the simultaneous sounding of an acoustic signal and the flashing of a small light. If the rat does not leave the compartment of the shuttle box within 6 seconds after the onset of the stimulus it is given a slight electric shock (0.5 mA) via the base grid of the shuttle box.
  • the acquisition of the active avoidance behaviour is recorded over 20 conditioning tests on each of two successive days. The individual tests are separated from each other by variable breaks of 20 to 60 seconds. The increase in the correct avoidance reactions during the course of the training is used as a criterion for the learning activity of the animals.
  • the test results show that the abovementioned compounds have a positive effect on the learning behaviour of the animals and the retention of what has been learned.
  • the special advantage of the abovementioned compounds is that they do not induce any inhibition of cholinesterase activity in the brain within their active dosage range. This results in improved tolerance compared with procholinergic reference substances; such as for example tetrahydroaminoacridine, physostigmine or metrifonate.
  • the abovementioned phosphonic ": acid esters can therefore be used both for the therapeutic and the preventive treatment of cognitive disorders in general, and in particular dementias of the Alzheimer's type.
  • the abovementioned phosphonic acid esters shorten the duration of immobility and result in behavioural activation.
  • the abovementioned compounds are also suitable for the treatment of affective disorders, and in particular depression.
  • this antidepressive component can also not be explained by the inhibition of cholinesterase.
  • mice 6-8-week old ICR mice (weighing approx. 22-28 g) from Harlan-Sprague-Dawley, Inc. (Indianapolis Indiana, USA) were used for this test. 8 animals at a time were placed together in a cage; they had free access to feed and water.
  • the Morris Maze consisted of a circular, galvanised steel tank which was painted white (and was open at the top) and had a diameter of 76 cm; at the base of the tank a plastic holding device for the attachment of the exit platform was arranged in each of 4 identically sized circular segments. Prior to the behavioural test the tank was filled with water to such a level that the 25 cm high platform was 1 cm below the surface of the water; the water had been preheated to 22°C and rendered opaque by adding 0.9 kg of dried milk powder. Numerous firmly fixed optical "cues" were present in the test chamber. The data were obtained using a "Multiple Zone Distance Traveled" programme from the Video-A Analytical System (Columbus Instruments International Corp., Columbus Ohio, USA).
  • mice After one week's acclimatisation in animal housing the mice had the opportunity to swim freely in the abovementioned stee l tank (no platform present) for 90 seconds.
  • acquisition training began which consisted of 4 cycles on each of three successive days (a total of 12 cycles). No test substances were administered.
  • the allocation of the mice to the target quadrants, in each of which the platforms were arranged was based on random selection.
  • the mice were placed in the water facing the wall of the tank at one of 4 points uniformly distributed around the circumference of the Morris Maze; the starting position varied per mouse from one cycle to the next in such a manner that each mouse started from each of the four starting points once a day.
  • the mice In each of the training cycles the mice had a period of 120 seconds to reach the target platform. If they did not do so within this period they were placed on the target platform by hand. There was an interval of 30 seconds, in which the mouse remained on the target platform, between each cycle.
  • mice On the fourth day the behaviour of the animals was examined for 30 seconds in a trial cycle in which no platform was present; the period of time which the mice spent in each of the four quadrants was determined. The mice had been administered the substance to be tested or the vehicle 30 minutes or one hour before the test cycle; the selection of mice for the vehicle and test substance groups was carried out at random. Dimethyl(l-hydroxy-2,2,2-trimethylethane)-phosphonate showed an ED-JQ of 0.1-4 mg/kg after oral administration.
  • the present invention also relates to pharmaceutical agents containing the abovementioned compounds in an effective quantity as well as their production and use for the treatment and prevention of the abovementioned diseases.
  • the new active compounds can be converted into the usual formulations such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions by known methods using inert, non-toxic pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should be used in each case in a concentration of approximately 0.5 to 90% by weight of the total mixture, i.e. in quantities which are sufficient to obtain the indicated dosage range.
  • the formulations are for example prepared by extending the active compounds with solvents and/or excipients, optionally using emulsifiers and/or disp ⁇ rsants, it being possible optionally to use organic solvents as auxiliary solvents where water is for example used as a diluent.
  • Administration is carried out in the usual manner, preferably orally or parenterally , and in particular perlingually or intravenously. Administration can also be carried out transdermally, such as for example by means of plasters.
  • intravenous administration it has in general proven advantageous to administer quantities of approximately 0.001 to 1 mg/kg, preferably approximately 0.01 to 0.5 mg/kg of body weight for the obtainment of effective results and in the case of oral administration the dosage is approximately 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP97920431A 1996-04-25 1997-04-17 Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression Withdrawn EP0896540A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19616471 1996-04-25
DE19616471A DE19616471A1 (de) 1996-04-25 1996-04-25 Phosponsäureester zur Behandlung von Hirnleistungsstörungen und Depressionen
PCT/US1997/006469 WO1997039756A1 (en) 1996-04-25 1997-04-17 Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression

Publications (1)

Publication Number Publication Date
EP0896540A1 true EP0896540A1 (en) 1999-02-17

Family

ID=7792381

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97920431A Withdrawn EP0896540A1 (en) 1996-04-25 1997-04-17 Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression

Country Status (19)

Country Link
EP (1) EP0896540A1 (cs)
JP (1) JP2000510455A (cs)
KR (1) KR20000010611A (cs)
AR (1) AR006870A1 (cs)
AU (1) AU2462397A (cs)
BG (1) BG102864A (cs)
BR (1) BR9709300A (cs)
CA (1) CA2252567A1 (cs)
CZ (1) CZ343498A3 (cs)
DE (1) DE19616471A1 (cs)
HU (1) HUP9903366A3 (cs)
ID (1) ID16678A (cs)
IL (1) IL126698A0 (cs)
NO (1) NO984964L (cs)
PL (1) PL333464A1 (cs)
SK (1) SK146398A3 (cs)
TR (1) TR199802137T2 (cs)
WO (1) WO1997039756A1 (cs)
ZA (1) ZA973538B (cs)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1078370B (de) * 1958-09-16 1960-03-24 Norddeutsche Affinerie Schaedlingsbekaempfungsmittel
US3069312A (en) * 1960-09-28 1962-12-18 California Research Corp N-substituted dimethyl 1-carbamoyloxy-2, 2, 2-trichloroethyl phosphonates as insecticidal compositions
BE632366A (cs) * 1962-05-16 1900-01-01
DE1193044B (de) * 1963-08-05 1965-05-20 Bayer Ag Verfahren zur Herstellung phosphorylierter Urethane
DE2512375A1 (de) * 1975-03-21 1976-09-30 Bayer Ag 1-hydroxy-2,2,2-trichloraethan- thionophosphonsaeuredialkylester, verfahren zu ihrer herstellung sowie ihre verwendung als insektizide
US4950658A (en) * 1988-12-06 1990-08-21 Board Of Trustees Of Southern Illinois Univ. Method of medical treatment of Alzheimer's disease

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9739756A1 *

Also Published As

Publication number Publication date
TR199802137T2 (xx) 1999-02-22
PL333464A1 (en) 1999-12-20
CZ343498A3 (cs) 1999-02-17
NO984964D0 (no) 1998-10-23
SK146398A3 (en) 1999-06-11
WO1997039756A1 (en) 1997-10-30
AU2462397A (en) 1997-11-12
HUP9903366A3 (en) 2000-08-28
ZA973538B (en) 1997-11-18
BR9709300A (pt) 1999-08-10
KR20000010611A (ko) 2000-02-25
HUP9903366A2 (en) 2000-07-28
JP2000510455A (ja) 2000-08-15
BG102864A (en) 1999-09-30
CA2252567A1 (en) 1997-10-30
ID16678A (id) 1997-10-30
NO984964L (no) 1998-12-22
DE19616471A1 (de) 1997-10-30
AR006870A1 (es) 1999-09-29
IL126698A0 (en) 1999-08-17

Similar Documents

Publication Publication Date Title
Nugent et al. Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents
SI9111099A (sl) Postopek za pripravo aralifatsko N-substituiranih aminoalkanfosfinskih kislin
JPH08508245A (ja) ホスホン酸誘導体
EP1000015A1 (en) Bicyclic metabotropic glutamate receptor ligands
HU200465B (en) Process for producing substituted alphaamino acids, derivatives thereof and pharmaceutical compositions comprising such compounds
JPH0649083A (ja) 置換アミノホスホネート誘導体、その製造方法及びそれを含む製薬組成物
HUT64079A (en) Process for producing new n-aralkyl and n-heteroaralkyl amino alakanephosphinic acids and pharmaceutical compositions comprising same as active ingredient
Nugent et al. Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents
EP2240500A1 (fr) Procede de synthese de derives d'acide hydroxy-bisphosphonique
EP0896540A1 (en) Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression
CA1328113C (en) Process for the manufacture of novel unsaturated amino acid compounds
MXPA98008643A (en) Use of phosphonic acid esters for the treatment of functional transtornes of the brain and the depression
US20050234021A1 (en) Amino phosphonate and amino bis-phosphonate derivatives
FI97231B (fi) Menetelmä 4-substituoitujen 2-aminoalk-3-eenihappojen valmistamiseksi
US5489717A (en) Glutamate (NMDA) receptor antagonists
CA2138331A1 (en) Use of phosphoric acid esters and phosphonic acid esters for treating disorders of cognitive function and depressions
US7687540B2 (en) Substituted propane phosphinic acid esters
HU214628B (hu) Eljárás amidinvegyületek és hatóanyagként ezeket tartalmazó gyógyszerkészítmények előállítására
US5620990A (en) Alpha-(4-chlorophenyl)-4-[(4-fluorphenyl)-methyl]piperidine-1-ethanol esters, their preparation and their therapeutic application
DE69323070T2 (de) Methandiphosphonsäure-derivat, verfahren zu ihrer herstellung und pharmazeutische verwendung davon
WO1989004821A1 (en) N-(biphenylmethyl)-3-hydroxyglutaramic acid and derivatives as hypocholesterolemic agents
EP0654035B1 (en) Phosphonoacetic esters and acids as anti-inflammatories
JP2784921B2 (ja) カルバメート化合物
JPH06247965A (ja) ピペラジン−及びピペリジンイソオキサゾール誘導体
CN1222853A (zh) 应用膦酸酯治疗脑功能紊乱和抑郁症

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: 19981125

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 NL PT SE

AX Request for extension of the european patent

Free format text: RO PAYMENT 981125;SI PAYMENT 981125

RIN1 Information on inventor provided before grant (corrected)

Inventor name: BRITELLI, DAVID, ROSS

Inventor name: FANELLI, RICHARD, JOSEPH

Inventor name: VAN DER STAAY, FRANZ-JOSEF

Inventor name: LENSKY, STEPHAN

Inventor name: SCHMIDT, BERNARD

Inventor name: MAURER, FRITZ

17Q First examination report despatched

Effective date: 20010427

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: 20010509