SE460517B - USE OF A COMPOSITION FOR THE PREPARATION OF A MEDICINE FOR THE TREATMENT OF INFECTIONS CAUSED BY TRYPANOSOMA BRUCEI - Google Patents

USE OF A COMPOSITION FOR THE PREPARATION OF A MEDICINE FOR THE TREATMENT OF INFECTIONS CAUSED BY TRYPANOSOMA BRUCEI

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Publication number
SE460517B
SE460517B SE8103678A SE8103678A SE460517B SE 460517 B SE460517 B SE 460517B SE 8103678 A SE8103678 A SE 8103678A SE 8103678 A SE8103678 A SE 8103678A SE 460517 B SE460517 B SE 460517B
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acid
compounds
group
treatment
infections caused
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SE8103678A
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Swedish (sv)
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SE8103678L (en
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A Sjoerdsma
P P Mccann
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Merrell Pharma Inc
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Publication of SE8103678L publication Critical patent/SE8103678L/en
Publication of SE460517B publication Critical patent/SE460517B/en

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/132—Heterocyclic compounds containing only one nitrogen as hetero atom
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Polymers & Plastics (AREA)
  • Epidemiology (AREA)
  • Zoology (AREA)
  • Food Science & Technology (AREA)
  • Animal Husbandry (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Feed For Specific Animals (AREA)
  • Fodder In General (AREA)

Description

460 517 S-adenosylmetioninsyntetas bildar S-adenosylmetionin, vilken sedan dekarboxyleras. Propylamindelen i det aktiverade metioni- net kan sedan överföras till putrescin under bildning av sper- midin. Alternativt kan propylamindelen överföras till spermidin under bildning av spermin. Följaktligen tjänar putrescin som fö- regångare till spermidin och spermin. Vidare har putrescin visat sig ha en klart reglerande effekt på biosyntesvägen till poly- amin. En ökad syntes av putrescin har också visat sig vara en tidig indikation på att en vävnad påverkas av en förnyad till- växtprocess. Kadaverin, vilket är en dekarboxyleringsprodukt av lysin, har visat sig stimulera aktiviteten hos S-adenosylmetionin- -dekarboxylas och är känt för att vara väsentligt vid tillväxtpro- cesserna för många mikroorganismer, exempelvis H. parainfluenza. 460,517 S-adenosylmethionine synthetase forms S-adenosylmethionine, which is then decarboxylated. The propylamine moiety in the activated methionine can then be converted to putrescine to form spermidine. Alternatively, the propylamine moiety can be transferred to spermidine to form spermine. Consequently, putrescine serves as a precursor to spermidine and spermine. Furthermore, putrescine has been shown to have a clear regulatory effect on the biosynthetic pathway to polyamine. An increased synthesis of putrescine has also been shown to be an early indication that a tissue is affected by a renewed growth process. Cadaverine, which is a decarboxylation product of lysine, has been shown to stimulate the activity of S-adenosylmethionine decarboxylase and is known to be essential in the growth processes of many microorganisms, for example H. parainfluenza.

Den logiska bakgrunden för polyaminmetabolismen har förslagits av Cohen, Science 205, 964 (1979). Den uppenbarligen unika rol- len i polyaminmetabolismen i trysanosomer och trysanosomernas beroende av ornitindekarboxylas som putrescinkälla stöder ytter- ligare våra observationer att vissa specifika ornitindekarboxylas- inhibitorer i polyaminsyntesen är klart effektiva för att förhind- ra tillväxt av protozoer.The logical background for polyamine metabolism has been suggested by Cohen, Science 205, 964 (1979). The apparently unique role of polyamine metabolism in trysanosomes and the dependence of trysanosomes on ornithine decarboxylase as a putrescine source further supports our observations that certain specific ornithine decarboxylase inhibitors in polyamine synthesis are clearly effective in preventing the growth of protozoa.

Det har nu visat sig att vissa föreningar som hör till en typ av irreversibla inhibitorer av ornitindekarboxylas är användbara för att inhibera tillväxt av protozoer. Vidare inträffar denna inhibition mot ett stort antal protozoer, såsom medlemmar av subphylum Sarcomastigophora och Sporozoa. Speciellt är nedan be- skrivna föreningar användbara för att förhindra tillväxt av ar- ter ur överklassen Mastigophora, speciellt Trypanosoma bnxnilnncei och organismer som orsakar koccidios på fjäderfä.It has now been found that certain compounds belonging to a type of irreversible inhibitors of ornithine decarboxylase are useful for inhibiting the growth of protozoa. Furthermore, this inhibition occurs against a large number of protozoa, such as members of the subcomyl Sarcomastigophora and Sporozoa. In particular, the compounds described below are useful in preventing the growth of species of the upper class Mastigophora, in particular Trypanosoma bnxnilnncei and organisms which cause coccidiosis in poultry.

Föreningarna, som kan användas för ovan angivna ändamål enligt föreliggande uppfinning, är Mrsubstituerade aminer eller K-sub- stituerade dèaminosyror med den allmänna formeln I Y I Z-ç-R1 NH2 där R1 betecknar väte eller en karboxylgruPP7 där Y betecknar CHZF eller CHF2; där Z betecknar H2N*(CH2\3, H2N-ÉH-(CH2)2 och CH3 HZN-CH2CH=CH; med det villkoret att när R1 betecknar väte Z be- tecknar HZN-çH-(CH2)2 och salter och individuella optiska isome- CH3 rer därav.The compounds which can be used for the above purposes of the present invention are Mrs-substituted amines or K-substituted diamino acids of the general formula I Y I Z-ç-R1 NH2 where R1 represents hydrogen or a carboxyl group PP7 where Y represents CH2F or CHF2; where Z represents H2N * (CH2 \ 3, H2N-ÉH- (CH2) 2 and CH3 HZN-CH2CH = CH; provided that when R1 represents hydrogen Z represents HZN- optical isomers CH3 thereof.

Administrerade in vivo till djur utsatta för aktiva protozoala infektioner, kan föreningarna med formeln (I) användas för att behandla djuren genom inhiberande av ytterligare tillväxt av de protozoala infektionerna. Alternativt kan de beskrivna föreningar- na administreras profylaktiskt för att förhindra sådana protozoala irfektioner från att uppstå.Administered in vivo to animals exposed to active protozoal infections, the compounds of formula (I) may be used to treat the animals by inhibiting further growth of the protozoal infections. Alternatively, the described compounds may be administered prophylactically to prevent such protozoal infections from occurring.

I den allmänna formeln (I) ovan betecknar symbolen R1 antingen väte eller en karboxylgrupp. När symbolen R1 betecknar väte, in- nefattas en typ avlX-substituerade aminer. När symbolen R1 be- tecknar en karboxylgrupp erhålles üksubstituerade üèaminosyror.In the general formula (I) above, the symbol R 1 represents either hydrogen or a carboxyl group. When the symbol R1 denotes hydrogen, a type of avlX-substituted amines is included. When the symbol R1 represents a carboxyl group, unsubstituted amino acids are obtained.

Symbolen Z betecknar antingen 3-aminopropylgruppen, 3-amino-3- -metylpropylgruppen eller 3-amino-1-propylengruppen. De mättade grupperna, nämligen 3-amino-propylgruppen och 3-amino-3-metylpro- pylgruppen representerar de föredragna sidokedjorna.The symbol Z represents either the 3-aminopropyl group, the 3-amino-3-methylpropyl group or the 3-amino-1-propylene group. The saturated groups, namely the 3-amino-propyl group and the 3-amino-3-methyl-propyl group represent the preferred side chains.

Det är avsett att utesluta en viss typ av diaminer från den all- männa definitionen av föreningarna enligt föreliggande uppfinning.It is intended to exclude a particular type of diamine from the general definition of the compounds of the present invention.

Uteslutna från uppfinningen genom denna avgränsning är sålunda Vksubstituerade diaminer där symbolen Z betecknar 3-aminopropyl- gruppen eller 3-amino-1-propylengruppen, dvs sådana föreningar som har de allmänna formlerna Y I 112m- (C112) 3-cH-NH2 (II) och _ Y I HZN-cnzcnæn-cn-NHZ (III) där Y tidigare definierats. 46Û 517 4 Inom ramen för den grupp av föreningar som innefattas ärIÅ-sub- stituerade aminosyror med formeln Y I H2N-(CH2)3-o-COOH (V) NH2 Y I H N- - - - 2 çH (CH2)2 ç COOH (V1) CH3 NH2 och I 4 I HZN-CH2CH=CH-C-COOH (VII) I NH2 I formlerna (V), (VI) och (VII) ovan har symbolen Y tidigare de- finierats.Excluded from the invention by this delimitation are thus Vx-substituted diamines where the symbol Z represents the 3-aminopropyl group or the 3-amino-1-propylene group, i.e. such compounds having the general formulas YI 112m- (C112) 3-cH-NH2 (II) and Y1 HZN-cnzcnæn-cn-NHZ (III) where Y has been previously defined. 46Û 517 4 Within the group of compounds included are IÅ-substituted amino acids of the formula YI H2N- (CH2) 3-o-COOH (V) NH2 YIH N- - - - 2 çH (CH2) 2 ç COOH ( V1) CH3 NH2 and I 4 I HZN-CH2CH = CH-C-COOH (VII) In NH2 In formulas (V), (VI) and (VII) above, the symbol Y has been previously defined.

De fiësubstiturade aminer som innefattas inom ramen för förelig- gande uppfinning som kan med fördel utnyttjas har den allmänna formeln Y I HZN-çfl-(CH2)2-CH-NH2 (VIII) där symbolen Y betecknar CHZF eller CHF2.The fi-unsubstituted amines included within the scope of the present invention which can be advantageously used have the general formula Y 1 HZN-ç fl- (CH 2) 2 -CH-NH 2 (VIII) where the symbol Y represents CH 2 F or CHF 2.

Belysande exempel på salter av föreningar enligt föreliggande upp- I finning innefattar icke toxiska syraadditionssalter bildade med oorganiska syror, såsom saltsyra, bromvätesyra, svavelsyra och fosforsyra och organiska syror, såsom metansulfonsyra, salicyl-~ syra, maleinsyra, malonsyra, vinsyra, citronsyra, n-cyklohexyl- sulfaminsyra och askorbinsyra.Illustrative examples of salts of compounds of the present invention include non-toxic acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and organic acids such as methanesulfonic acid, salicylic acid, maleic acid, malonic acid, tartaric acid, citric acid, n -cyclohexyl- sulfamic acid and ascorbic acid.

En föredragen grupp föreningar enligt föreliggande uppfinning är sådana föreningar, i vilka symbolen Y betecknar difluormetyl- gruppen. En annan föredragen grupp föreningar är sådana där sym- u i, 460 517 bolen Z betecknar 3-aminopropylgruppen eller 3-amino-3-metyl- propylgruppen.A preferred group of compounds of the present invention are those compounds in which the symbol Y represents the difluoromethyl group. Another preferred group of compounds are those in which the symbol Z represents the 3-aminopropyl group or the 3-amino-3-methylpropyl group.

Förutom ovan angivna salter innefattar uttrycket även inre sal- ter eller zwitterjoner av dessa föreningar med formeln (I) ovan, vilka har amfoter natur. Vidare, medan den optiska konfiguratio- nen för de här beskrivna föreningarna inte speciellt anges, bör hågkommas attifl-kolatomen har ett asymmetriskt centrum och att individuella optiska isomerer av dessa föreningar existerar.In addition to the salts indicated above, the term also includes internal salts or zwitterions of these compounds of formula (I) above, which are amphoteric in nature. Furthermore, while the optical configuration of the compounds described herein is not specifically stated, it should be remembered that the fl-carbon atom has an asymmetric center and that individual optical isomers of these compounds exist.

Följaktligen innefattas inom ramen för uppfinningen såväl d- som l-optiska isomerer och racemiska blandningar av nämnda föreningar.- Laktambildning kan ske i de fall när symbolen R1 betecknar en karboxylgrupp och symbolen Z betecknar 3-aminopropylgruppen el- ler 3-amino-3-metylpropylgruppen och representeras av följande allmänna formel (IX) av Y-c-c=o (Ix) r (cH2)3 Nu I ovanstående allmänna formel har symbolen Y tidigare definie- rats. Där symbolen Z betecknar 3-amino-3-metylpropylgruppen, kan (CH2)3-gruppen i formeln (IX) dessutom vara substituerad med en 3-metylgrupp.Accordingly, within the scope of the invention, both d- and 1-optical isomers and racemic mixtures of said compounds are included. Lactam formation can take place in the cases where the symbol R1 represents a carboxyl group and the symbol Z represents the 3-aminopropyl group or 3-amino-3- methylpropyl group and is represented by the following general formula (IX) of Ycc = o (Ix) r (cH2) 3 Now in the above general formula, the symbol Y has been previously defined. Where the symbol Z represents the 3-amino-3-methylpropyl group, the (CH 2) 3 group of formula (IX) may also be substituted by a 3-methyl group.

Belysande exempel på föreningar enligt föreliggande uppfinning är: 2,5-diamino-2-(fluorometyl)pentansyra 2,5-diamino-2-(difluorometyl)pentansyra 2,5-diamino-2-fluorometyl-5-metylpentansyra 2,5-diamino-2-difluorometyl-5-metylpentansyra 2,5-diamino-2-fluorometyl-3-pentensyra 2,5-diamino-2-difluorometyl-3-pentensyra 1-fluorometyl-4-metyl-1,4-butandiarln och 2-difluorometyl-4-metyl-1,4-butandiamin.Illustrative examples of compounds of the present invention are: 2,5-diamino-2- (fluoromethyl) pentanoic acid 2,5-diamino-2- (difluoromethyl) pentanoic acid 2,5-diamino-2-fluoromethyl-5-methylpentanoic acid 2,5- diamino-2-difluoromethyl-5-methylpentanoic acid 2,5-diamino-2-fluoromethyl-3-pentenoic acid 2,5-diamino-2-difluoromethyl-3-pentenoic acid 1-fluoromethyl-4-methyl-1,4-butanediaryl and 2 -difluoromethyl-4-methyl-1,4-butanediamine.

Föreningarna med den allmänna formeln (I) där Z betecknar HZN-(CH2)3; där Y betecknar CHZF eller CHF2 och där R1 beteck- nar en karboxylgrupp framställes genom behandling av motsvaran- de esterderivat av ornitin, varvid aminogrupperna på lämpligt sätt skyddas, med en stark bas under bildning av en karbanjon- mellanprodukt. Denna får reagera med ett lämpligt halogenmetyl- -halogenalkylerande reagens i ett aprotiskt lösningsmedel, såsom dimetylsulfoxid, dimetylformamid, dimetylacetamid, bensen, tolu- en, etrar, såsom tetrahydrofuran, dietyleter eller dioxan, och i närvaro av hexametylfosfortriamid när Y har annan betydelse än FZCH-, vid en temperatur från omkring -120 till 120°C, företrä- desvis omkring 25 till 50°C för omkring Q timme till 48 timmar, följt av sur eller basisk hydrolys. Detta kan ske enligt följan- de reaktionsschema. |“'" _'1 Zl-?H-COORZ :Zl-Y COOR2 ß N=ï-R3 stark bas ; | N=ç-R3 | I | Ru L, _ __ J Förening 1 alkylerande reagens Y ¥ utspädd vatten- I Z2-C-COOR2 lösning av Zl-C-COORZ NH syra/hydrazín | 2The compounds of general formula (I) wherein Z represents HZN- (CH 2) 3; where Y represents CH 2 F or CHF 2 and where R 1 represents a carboxyl group is prepared by treating the corresponding ester derivatives of ornithine, the amino groups being suitably protected, with a strong base to form a carbonate intermediate. This is reacted with a suitable halomethyl-haloalkylating reagent in an aprotic solvent such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, benzene, toluene, ethers such as tetrahydrofuran, diethyl ether or dioxane, and in the presence of hexamethylphosphorus triamide when Y , at a temperature of from about -120 to 120 ° C, preferably about 25 to 50 ° C for about Q hour to 48 hours, followed by acidic or basic hydrolysis. This can be done according to the following reaction scheme. Z1-Y COOR2: Z1-Y COOR2 ß N = ï-R3 strong base; | N = ç-R3 | I | - In Z2-C-COOR2 solution of Z1-C-COORZ NH acid / hydrazine | 2

Claims (3)

10 15 20 PatentkravClaims 10 1. Användning av en.förening för framställning av ett läkemedel för behandling av infektioner orsakade av Trypanosoma brucei. k ä n n e t e c k n a d av att föreningen har formeln där 81 betecknar väte eller en karboxylgrupp. Y betecknar CHZP. eller CHF2: Z betecknar HZN-(CH H N-$H-(CH2)2- eller 2 CH3 2)3_0 -H2N-CH2-CH-CH- och att där RI betecknar väte Z betecknar H N-CH(CH3)-(CH2)2- eller salter eller individuellaUse of a compound for the manufacture of a medicament for the treatment of infections caused by Trypanosoma brucei. characterized in that the compound has the formula wherein 81 represents hydrogen or a carboxyl group. Y represents CHZP. or CHF2: Z represents HZN- (CH H N- $ H- (CH2) 2- or 2 CH3 2) 3-0 -H2N-CH2-CH-CH- and that where RI represents hydrogen Z represents H N-CH (CH3) - (CH2) 2- or salts or individual 2. Optiska isomerer därav i kombination med en lämplig bärare. É. Användning enligt krav ll k ä n n e t e c k n a d av att föreningen utgöres av 2.5-diamino-2-difluorometylpentansyra. k ä n n e t e c k n a d av att2. Optical isomers thereof in combination with a suitable carrier. Use according to claim 1, characterized in that the compound consists of 2,5-diamino-2-difluoromethylpentanoic acid. k ä n n e t e c k n a d of att 3. Användning enigt krav 1. föreningen utgöres av monofluorometylornitin.Use according to claim 1. The compound is monofluoromethylornitine.
SE8103678A 1980-06-16 1981-06-11 USE OF A COMPOSITION FOR THE PREPARATION OF A MEDICINE FOR THE TREATMENT OF INFECTIONS CAUSED BY TRYPANOSOMA BRUCEI SE460517B (en)

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AT (1) AT377180B (en)
AU (1) AU544990B2 (en)
BE (1) BE889230A (en)
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FR (1) FR2484255A1 (en)
GB (1) GB2078735B (en)
IE (1) IE51300B1 (en)
IL (1) IL63087A (en)
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JPS58123555U (en) * 1982-02-17 1983-08-23 三菱電機株式会社 In-line electron gun assembly equipment
NL8400927A (en) * 1984-03-23 1985-10-16 Philips Nv DEVICE AND METHOD FOR MOUNTING AN INTEGRATED ELECTRON CANNON SYSTEM.
DE3421384A1 (en) * 1984-06-08 1985-12-12 Standard Elektrik Lorenz Ag, 7000 Stuttgart DEVICE FOR ASSEMBLING ELECTRONIC RADIATOR GENERATORS
JPS62148462A (en) * 1985-12-19 1987-07-02 メレルダウフア−マス−テイカルズ　インコ−ポレ−テツド Novel method of controlling growth of protozoa
ATE77367T1 (en) * 1988-02-05 1992-07-15 Merrell Dow Pharma 5-SUBSTITUTED ORNITHINE DERIVATIVES.
US5455234A (en) * 1994-03-16 1995-10-03 Ahluwalia; Gurpreet S. Inhibition of hair growth

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FR2392958A1 (en) * 1977-06-01 1978-12-29 Merck & Co Inc NEW FLUORINE AMINO ACIDS USEFUL AS A MEDICINAL PRODUCT
US4139563A (en) * 1977-07-01 1979-02-13 Merrell Toraude Et Compagnie α-ACETYLENIC DERIVATIVES OF AMINES
CA1121375A (en) * 1977-07-01 1982-04-06 Brian W. Metcalf Derivatives of amines and amino acids
US4088667A (en) * 1977-07-01 1978-05-09 Merrell Toraude Et Compagnie Lower alkyl 2-tri-(lower)alkylsilylacetylene-N-carbethoxyglycinates and process for using same
US4182891A (en) * 1977-07-01 1980-01-08 Merrell Toraude Et Compagnie α-Acetylenic derivatives of α-amino acids
CA1091661A (en) * 1977-07-11 1980-12-16 Philippe Bey .alpha.-HALOMETHYL DERIVATIVES OF .alpha.-AMINO ACIDS
US4134918A (en) * 1977-09-06 1979-01-16 Merrell Toraude Et Compagnie Alpha-halomethyl derivatives of amines

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GB2078735A (en) 1982-01-13
DE3153623C2 (en) 1991-06-27
DE3123295C2 (en) 1990-07-12
NZ197394A (en) 1984-09-28
FR2484255B1 (en) 1984-12-14
JPS5731613A (en) 1982-02-20
IE811308L (en) 1981-12-16
AU7165481A (en) 1981-12-24
JPH0432052B2 (en) 1992-05-28
ATA266581A (en) 1984-07-15
FR2484255A1 (en) 1981-12-18
IT8148684A0 (en) 1981-06-15
SE8103678L (en) 1981-12-17
CA1174603A (en) 1984-09-18
AU544990B2 (en) 1985-06-27
CH651206A5 (en) 1985-09-13
IL63087A (en) 1984-10-31
BE889230A (en) 1981-12-15
NL194153C (en) 2001-08-03
NL8102863A (en) 1982-01-18
NL194153B (en) 2001-04-02
AT377180B (en) 1985-02-25
IT1171380B (en) 1987-06-10
DE3123295A1 (en) 1982-04-29
ZA813953B (en) 1982-06-30
GB2078735B (en) 1985-05-15
PH16634A (en) 1983-12-05
IE51300B1 (en) 1986-11-26

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