DK171124B1 - Process for improving growth rate and improving meat-fat ratio in meat-producing animals - Google Patents
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- DK171124B1 DK171124B1 DK374381A DK374381A DK171124B1 DK 171124 B1 DK171124 B1 DK 171124B1 DK 374381 A DK374381 A DK 374381A DK 374381 A DK374381 A DK 374381A DK 171124 B1 DK171124 B1 DK 171124B1
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- A—HUMAN NECESSITIES
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- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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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Description
DK 171124 B1DK 171124 B1
Den foreliggende opfindelse angår en fremgangsmåde til forbedring af tilvæksthastigheden og til forbedring af forholdet mellem kød og fedt hos kødproducerende dyr.The present invention relates to a method for improving the rate of growth and for improving the meat-fat ratio of meat-producing animals.
Substitutionsprodukter af l-(amino-dihalogenphenyl)-5 -2-aminoethaner samt syreadditionssalte deraf er omtalt i US patentskrift nr. 3.536.712. Især er her omtalt fremgangsmåder til syntese af de nævnte forbindelser, der er nyttige til forøgelse af blodcirkulationen og som bronchodilatorer, analgetika, sedativer, antipyretika, antiflogistika og hoste-10 stillende midler til varmblodede dyr. Imidlertid er der kun anført eksempler på det analgetiske anvendelsesområde. Fremstillingen af andre beslægtede l-(amino-dihalogenphenyl)-2-aminoethanoler og disses derivater er omtalt i JP-A-77 83.619 (Chemical Abstracts £7, 201061r), DE offentliggørelsesskrif-15 ter nr. 2.804.625, 2.157.040 og 2.261.914, EP patentansøgning nr. 8.715 (1980) og NL patentansøgning nr. 73/03612. I disse ansøgninger omtales anvendelser såsom analgetika, broncholy-tisk, antiinflammatorisk, uterinspasmolytisk, j8-blokerende virkning, antispasmolytisk virkning på tværstribet muskula-20 tur, til tokologi, nedsættelse af blodtryk ved hjælp af perifer vasodilatering og mobilisering af kropsfedtstof og til behandling af allergier. Det er ikke anført eller antydet i nogle af disse publikationer, at forbindelserne er effektive vækstfremmende midler til kødproducerende dyr 25 såsom fjerkræ, kvæg og får, og der findes heller ingen angivelse af, at forbindelserne forbedrer foderudnyttelsen hos de nævnte kødproducerende dyr eller forholdet mellem kød (magert kød) og fedt.Substitution products of 1- (amino-dihalogenphenyl) -5-2-aminoethanes and their acid addition salts are disclosed in U.S. Patent No. 3,536,712. In particular, herein are disclosed methods of synthesis of said compounds useful for enhancing blood circulation and as bronchodilators, analgesics, sedatives, antipyretics, antiphlogistics, and coughing agents for warm blooded animals. However, only examples of the analgesic field of application are given. The preparation of other related 1- (amino-dihalogenphenyl) -2-aminoethanols and their derivatives is disclosed in JP-A-77 83,619 (Chemical Abstracts £ 7, 201061r), DE Publication No. 2,804,625, 2,157,040. and 2,261,914, EP Patent Application No. 8,715 (1980) and NL Patent Application No. 73/03612. These applications refer to applications such as analgesics, broncholytic, anti-inflammatory, uterine spasmolytic, β-blocking, antispasmolytic effect on cross-striated muscle, toxology, blood pressure reduction through peripheral vasodilatation and mobilization of body fat, and . It is not stated or suggested in any of these publications that the compounds are effective growth promoters for meat-producing animals such as poultry, cattle and sheep, nor is there any indication that the compounds improve feed utilization of said meat-producing animals or the ratio of meat (lean meat) and fat.
I US patentskrift nr. 3.818.101 er der beskrevet en 30 fremgangsmåde til forøgelse af foderindtagelsen hos kødproducerende dyr udover mæthed ved indgivelse af hydroxyphen-ethanolaminer med én eller to hydroxylgrupper knyttet til phenylgruppen. Indgivelsen af disse forbindelser fører til en forøget væksthastighed, men de bevirker ingen formindskel-35 se af forholdet mellem fedt og magert kød, og i nogle tilfælde fremkalder de endog et forøget forhold mellem fedt og 2 DK 171124 B1 kød.U.S. Patent No. 3,818,101 discloses a method of increasing feed intake in meat-producing animals in addition to satiety by administering hydroxyphene-ethanolamines with one or two hydroxyl groups attached to the phenyl group. The administration of these compounds leads to an increased rate of growth, but they do not diminish the ratio of fat to lean meat, and in some cases they even induce an increased ratio of fat to meat.
Formålet med opfindelsen er således at tilvejebringe en fremgangsmåde til forbedring af forholdet mellem kød og fedt hos kødproducerende dyr, idet dyrenes tilvæksthastighed 5 samtidig forøges.The object of the invention is thus to provide a method for improving the meat-fat ratio of meat-producing animals, while simultaneously increasing the rate of growth of the animals 5.
Ifølge opfindelsen har det vist sig, at man ved at gå frem på den måde, at man til dyrene i udvalgte indgivelsesmængder indgiver en forbindelse med den almene formel • *-O-'Ψ-Cf-®2"3 (I) Γ "i «4 i hvilken X er hydrogen eller halogen, 15 Y er hydrogen, NRgRg eller NHCOR5, Z er halogen, CN, CF3, COORlf CONH2, methyl, methoxy eller NO2, er hydrogen eller Ci_4-alkyl, R2 er hydrogen, C^-g-alkyl eller C3_4-alkenyl, 20 R3 er hydrogen, C^.g-alkyl, C3„6-cycloalkyl, C3_4-alkenyl, phenyl, 2-hydroxyethyl, α,α-dimethylphenethyl eller benzyl, R4 er OH, ORg eller SR]^, R5 er hydrogen, ¢3^.4-alkyl, C1_4-alkoxy eller 25 >> <g$>-CH2°. «10 «10 r6 er C^g-alkyl, C2_5-alkanoyl, 3° fio eller vl_y"CH2 eller C3_4-alkenyl, r8 er hydrogen, C1_4-alkyl eller C3_4-alkenyl, r9 er hydrogen, C^g-alkyl, C4_6-cycloalkyl eller 35 C3_4-alkenyl, r10 er chlor, dichlor, methyl, dimethyl, methoxy.In accordance with the invention, it has been found that by proceeding in a manner to provide to the animals in selected dosage amounts a compound of the general formula • * -O-'C-Cf-®2 "3 (I) Γ" in which 4 is hydrogen or halogen, Y is hydrogen, NRgRg or NHCOR5, Z is halogen, CN, CF3, COOR1f CONH2, methyl, methoxy or NO2, is hydrogen or C1-4 alkyl, R2 is hydrogen, C1 -g-alkyl or C3-4 alkenyl, R3 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C3-4 alkenyl, phenyl, 2-hydroxyethyl, α, α-dimethylphenethyl or benzyl, R4 is OH, ORg or SR] ^, R5 is hydrogen, 3³ ^ .4 alkyl, C1_4 alkoxy or 25 >> <g $> - CH₂ °. R 10 is C 1-6 alkyl, C 2- 5 alkanoyl, 3 ° fio or yl "Y 2 CH 2 or C 3-4 alkenyl, R 8 is hydrogen, C 1-4 alkyl or C 3-4 alkenyl, R 9 is hydrogen, C 1-6 alkyl, C4-6 cycloalkyl or C3-4 alkenyl, r10 is chloro, dichloro, methyl, dimethyl, methoxy.
3 DK 171124 B1 dimethoxy eller nitro, og Ru er Ci_6-alkyl, phenyl eller benzyl, forudsat, at når R3 er phenyl, 2-hydroxyethyl, α,α-dimethyl-phenethyl, C3_6-cycloalkyl eller benzyl, er R2 hydrogen, 5 og når R3 er 2-hydroxyethyl, er R4 hydroxyl, h° og når Rg er alkanoyl eller ^ΤΛ,-co, er R2 og R3 ikke hydrogen, undtagen når R3 er en alkyΙ-ΙΟ eller en substitueret alkylgruppe, der indeholder et tertiært carbonatom knyttet til nitrogen, og når Y er hydrogen, er X og Z halogen, og R2 er hydrogen, og R3 er isopropyl, 2-butyl eller tert.butyl, og når R8 er Ci_4-alkyl eller C3_4-alkenyl, er R9 hydrogen, Ci_4-alkyl eller C3_4-alkenyl, og mindst ét 15 af symbolerne X og Y er ikke hydrogen, og når Z ikke er halogen, er Y NRgRg eller NHCOR5, og når Y er hydrogen, NH2 eller NHCOR5, og Z er halogen, kan R4 ikke være OH eller 0R6, hvor Rg er C^.g-alkyl, eller racemiske blandinger, optiske aktive isomere eller ikke-toksiske farmakologisk 20 acceptable syreadditionssalte deraf, kan forbedre tilvæksthastigheden af kødproducerende dyr, f.eks. kyllinger, kalkuner, kaniner, får, svin, geder og kvæg, herunder kalve, idet foderudnyttelseseffektiviteten herved forbedres måleligt, og samtidig forbedre forholdet mellem magert kød og fedt.B1 is dimethoxy or nitro, and Ru is C1-6 alkyl, phenyl or benzyl, provided that when R3 is phenyl, 2-hydroxyethyl, α, α-dimethyl-phenethyl, C3-6 cycloalkyl or benzyl, R2 is hydrogen, and when R 3 is 2-hydroxyethyl, R 4 is hydroxyl, h ° and when R 9 is alkanoyl or ^--CO, R 2 and R 3 are not hydrogen except when R 3 is an alkyl Ι or a substituted alkyl group containing a tertiary carbon atom attached to nitrogen and when Y is hydrogen, X and Z are halogen and R 2 is hydrogen and R 3 is isopropyl, 2-butyl or tert-butyl and when R 8 is C 1-4 alkyl or C 3-4 alkenyl, R 9 is hydrogen , C1-4 alkyl or C3-4 alkenyl, and at least one of the symbols X and Y is not hydrogen and when Z is not halogen, Y is NRgRg or NHCOR5 and when Y is hydrogen, NH2 or NHCOR5, and Z is halogen, R 4 cannot be OH or OR 6 where R 9 is C 1-6 alkyl or racemic mixtures, optically active isomers or non-toxic pharmacologically acceptable acid addition salts thereof, improve the growth rate of meat-producing animals, e.g. chickens, turkeys, rabbits, sheep, pigs, goats and cattle, including calves, thereby improving feed utilization measurably while improving lean meat and fat ratios.
25 Indgivelsen kan ske oralt eller parenteralt.The administration may be orally or parenterally.
En foretrukken gruppe forbindelser til anvendelse ved fremgangsmåden ifølge opfindelsen har den ovenfor viste formel I, hvor X er hydrogen eller halogen, Y er hydrogen eller NRgRg, Z er chlor, brom, CN eller CF3, R^ er hydrogen 30 eller methyl, R4 er OH, ORg eller SR33, er Rg er Ci-C4-alkyl eller C2-C5-alkanoyl, eller ikke-toksiske, farmakologisk acceptable syreadditionssalte deraf.A preferred group of compounds for use in the process of the invention has the above formula I wherein X is hydrogen or halogen, Y is hydrogen or NRgRg, Z is chlorine, bromine, CN or CF3, R4 is hydrogen or methyl, R4 is OH, ORg or SR33, Rg is C1-C4 alkyl or C2-C5 alkanoyl, or non-toxic, pharmacologically acceptable acid addition salts thereof.
De mest foretrukne forbindelser til anvendelse ved ved fremgangsmåden ifølge opfindelsen er: 35 N-tert. -butyl-3,5-dichlor-/?-methoxy-4-methylaminophenethyl-amin, a- [ (tert.-butylamino)methyl]-3,5-dichlor-4-isopropyl- 4 DK 171124 B1 aminobenzylalkohol, 5-[2-(tert.-butylamino)-1-hydroxyethyl]--3-chloranthranilonitril, 5-[2-(tert.-butylamino)-1-hydroxy-ethyl]anthranilonitril, methyl-5-[2-(tert.-butylamino)-1-hy-droxyethyl]-3-chloranthranilat, 4-amino-N-tert.-butyl-3,5-di-5 chlor-0-(methylthio)phenethylamin, a-[(tert.-butylamino)- methyl]-3,5-dichlor-4-methylaminobenzylalkohol, a-[(tert.-butylamino) -methyl) -3,5-dichlor-4-dimethylaminobenzylalkohol, methyl-4-[2-(tert.-butylamino)-l-hydroxyethyl]-2,6-dichlor-carbanilat samt de ikke-toksiske, farmaceutisk acceptable 10 syreadditionssalte deraf.The most preferred compounds for use in the process of the invention are: 35 N-tert. -butyl-3,5-dichloro-methoxy-4-methylaminophenethyl-amine, α- [(tert-butylamino) methyl] -3,5-dichloro-4-isopropyl-4-aminobenzyl alcohol, 5- [2- (tert.-butylamino) -1-hydroxyethyl] -3-chloroanthranilonitrile, 5- [2- (tert.-butylamino) -1-hydroxyethyl] anthranilonitrile, methyl-5- [2- (tert. -butylamino) -1-hydroxyethyl] -3-chloroanthranilate, 4-amino-N-tert-butyl-3,5-dichloro-O- (methylthio) phenethylamine, α - [(tert-butylamino) ) - methyl] -3,5-dichloro-4-methylaminobenzyl alcohol, α - [(tert-butylamino) methyl) -3,5-dichloro-4-dimethylaminobenzyl alcohol, methyl 4- [2- (tert.-butylamino) ) -1-hydroxyethyl] -2,6-dichloro-carbanilate and the non-toxic, pharmaceutically acceptable acid addition salts thereof.
Det har vist sig, at forbindelserne med formlen I nedenfor (hvor Y er hydrogen) kan fremstilles ved kondensation af et passende substitueret styrenoxid med en passende substitueret amin i nærværelse af et inaktivt opløsningsmid-15 del, såsom en lavere alkohol, ved eller i nærheden af dettes kogepunkt som vist nedenfor:It has been found that the compounds of formula I below (where Y is hydrogen) can be prepared by condensing an appropriately substituted styrene oxide with an appropriately substituted amine in the presence of an inactive solvent, such as a lower alcohol, at or in the vicinity. of its boiling point as shown below:
XX
_ _ * 2 ethanol ^ ^R3 -a-^ z_ _ * 2 ethanol ^^ R3 -a- ^ z
XX
™ <0^ΓΟΗ2<«3 1 2 3 4 5 6 hvor X og Z er halogen, og R3 har de ovenfor anførte be 2 tydninger, og Y er hydrogen. Således kan 3,5-dichlorstyrenoxid 3 omsættes med en ækvimolær mængde eller med molært overskud af 4 tert.-butylamin i ethanol ved tilbagesvaling i fra ca. 1 til 8 5 timer, eller indtil reaktionen er i det væsentlige afsluttet, 6 og den ønskede a-[(tert,-butylamino)methyl]-3,5-dichlorbenzyl-alkohol fås som vist nedenfor: DK 171124 Bl 5 0 Cl C1 + H2HC4H9-t EtOH </j^-CH-CarKH-C4S9-t 5 Cl C1™ <0 ^ ΓΟΗ2 <«3 1 2 3 4 5 6 where X and Z are halogen and R3 has the above two meanings and Y is hydrogen. Thus, 3,5-dichlorostyrene oxide 3 can be reacted with an equimolar amount or with a molar excess of 4 tert.-butylamine in ethanol at reflux for from ca. 1 to 8 for 5 hours or until the reaction is substantially complete, 6 and the desired α - [(tert, -butylamino) methyl] -3,5-dichlorobenzyl alcohol is obtained as shown below: DK 171124 B1 5 Cl C1 + H2HC4H9-t EtOH </ j ^ -CH-CarKH-C4S9-t 5 Cl C1
Det således opnåede produkt kan renses ved kendte metoder såsom chromatografi eller omkrystallisation af dets salte.The product thus obtained can be purified by known methods such as chromatography or recrystallization of its salts.
Det ovennævnte styrenoxid fremstilles ved at reducere det tilsvarende phenacylbromid med NaBH^ ved eller under 5°C 10 i nærværelse af en vandfri lavere alkohol såsom ethanol.The above styrene oxide is prepared by reducing the corresponding phenacyl bromide with NaBH 3 at or below 5 ° C in the presence of anhydrous lower alcohol such as ethanol.
Phenacylbromid-mellemproduktet fremstilles ved bromering af en passede substitueret acetophenon med CuBr2 i nærværelse af chloroform og ethylacetat. Den ovennævnte reaktionsrække kan illustreres som vist nedenfor: 15The phenacyl bromide intermediate is prepared by bromination of a suitably substituted acetophenone with CuBr2 in the presence of chloroform and ethyl acetate. The above reaction sequence can be illustrated as shown below:
Cl Cl U V-C-CH,. CuBr 2_^ V-C-CH-Br \_J I J ~CHC1 ,/EtOAc ~ \-/ Il 20 V 0 Γ 0Cl Cl U V-C-CH,. CuBr 2_ ^ V-C-CH-Br \ _J I J ~ CHCl, / EtOAc ~ \ - / Il 20 V 0 Γ 0
NaBH. Π—\ 26 EtOH >NaBH. Π— \ 26 EtOH>
ClCl
Alternativt kan en forbindelse med formlen I, hvor Y er hydrogen, fremstilles ud fra den tilsvarende forbindelse 30 med formlen I, hvor Y er amino, via en deamineringsreaktion ved at opløse aminen i 50-52% vandig hypophosphorsyre (H3P02). Opløsningen afkøles til under 10°C, og der sættes i løbet af et vist tidsrum en ækvimolær mængde eller et overskud af natriumnitrit til den vandige opløsning. Efter at tilsætningen 3g er afsluttet, opvarmes reaktionsblandingen til stuetemperatur og omrøres i yderligere et stykke tid. Derefter udvindes produktet fra reaktionsblandingen ved standardlaboratoriemetoder og renses om ønsket.Alternatively, a compound of formula I wherein Y is hydrogen can be prepared from the corresponding compound 30 of formula I, where Y is amino, via a deamination reaction by dissolving the amine in 50-52% aqueous hypophosphoric acid (H3 PO2). The solution is cooled to below 10 ° C and an equimolar amount or excess sodium nitrite is added to the aqueous solution over a period of time. After the addition 3g is complete, the reaction mixture is warmed to room temperature and stirred for a further time. The product is then recovered from the reaction mixture by standard laboratory methods and purified if desired.
OISLAND
DK 171124 B1 6DK 171124 B1 6
Fremstillingen af 4-substituerede aminoacetophenoner, der er nødvendige til fremstillingen af 4-substituerede phenyl-ethanderivater, der nu har vist sig nyttige til opdræt af kød- producerende dyr, kan f.eks. foregå på nedenstående måde; 5 F—CO—CH3 + RgRgNH —=► R8R9N~C0"" CH3 (overskud) 10 Fluorudskiftningen udføres med overskud af amin i nærvær eller fravær af et opløsningsmiddel, og dersom et opløsningsmiddel er påkrævet, synes vand at være det bedst egnede. Med flygtige aminer udføres reaktionen i en lukket beholder, og i reglen er temperaturer på 50-100°C tilstrækkelige til fuldførelse af reak-1 tionen.The preparation of 4-substituted aminoacetophenones necessary for the preparation of 4-substituted phenyl-ether derivatives which have now been found useful for breeding meat-producing animals may be e.g. proceed as follows; 5 F-CO-CH3 + RgRgNH - = ► R8R9N ~ C0 "" CH3 (excess) 10 Fluorine exchange is carried out with excess amine in the presence or absence of a solvent, and if a solvent is required, water seems to be the most suitable. With volatile amines, the reaction is carried out in a sealed container and, as a rule, temperatures of 50-100 ° C are sufficient to complete the reaction.
Chlorering og bromering af disse aminoacetophenoner kan ske med N-chlorsuccinimid og N-bramsucciniroid i toluen, chlorbenzen eller dichlorbenzen ved 90-100°C. Io-20 dering kan foretages med NaI/N,N-dichlorbenzensulfonamid eller iodmonochlorid i eddikesyre.Chlorination and bromination of these aminoacetophenones can occur with N-chlorosuccinimide and N-bramsucciniroid in toluene, chlorobenzene or dichlorobenzene at 90-100 ° C. Eoding can be done with NaI / N, N-dichlorobenzenesulfonamide or iodine monochloride in acetic acid.
Ved omsætning af disse acetophenoner med brom i chloroform eller methylenchlorid kan der fremstilles de tilsvarende phenacylbromider. Disse phenacylbromider kan derefter 25 omsættes med I^R^N-aminer, og aminoketonerne reduceres medBy reacting these acetophenones with bromine in chloroform or methylene chloride, the corresponding phenacyl bromides can be prepared. These phenacyl bromides can then be reacted with 1 R 2 N amines and the amino ketones reduced by
NaBH^ eller NaCNBH^ ved gængs teknik som beskrevet i de ovenfor omtalte publikationer. Naturligvis kræver forbindelser, der indeholder grupper, der er reaktionsdygtige med halogen, såsom når Rg er alkenyl, andre metoder, der omtales 30 nedenfor.NaBH3 or NaCNBH3 by conventional techniques as described in the publications mentioned above. Of course, compounds containing halogen-responsive groups, such as when R 9 is alkenyl, require other methods discussed below.
35 7 DK 171124 B135 7 DK 171124 B1
OISLAND
x xx x
RgRgN-^^-COCH3 -RgRgN—COCH2Br Z~ 2'RgRgN - ^^ - COCH3 -RgRgN — COCH2Br Z ~ 2 '
LL
R2R3NI^ RgRgN—COCH2NR2R3R2R3N1 ^ RgRgN-COCH2NR2R3
ZZ
10 X,10 X,
NaBH4^ I4R9N-^^-|H—CH2'"NR2R3NaBH4 ^ I4R9N - ^^ - | H-CH2
Z OHZ OH
15 hvor X og Z er hydrogen, chlor eller brom, og R2 og R3 er hydrogen, C^_^-alkyl eller C2_3-alkenyl.Wherein X and Z are hydrogen, chlorine or bromine and R2 and R3 are hydrogen, C1-6 alkyl or C2-3 alkenyl.
Forbindelserne med formlen I, hvor Rg og Rg begge er forskellige fra hydrogen, kan også fremstilles som vist i neden-20 stående reaktionsskema: 25 1 35The compounds of formula I wherein R 9 and R 9 are both different from hydrogen can also be prepared as shown in the reaction scheme below:
OISLAND
DK 171124 B1 8DK 171124 B1 8
LL
NHj—^ \-COCH3 + (R'CO)2o pyridins ^ 5 1 x R’-C-NH—— coch3NH 2 - + - COCH 3 + (R'CO) 20 pyridine 1 x R'-C-NH
(RI,C0)2° . 1 BH3/THF(RI, CO) 2 °. 1 BH3 / THF
10 pyridip- s' jC10 pyridip- s' jC
χ fχ f
R’CO^. jU-v 2 OHR'CO ^. jU-v 2 OH
—V ')-COCH_ | R"CO-^ W 3 I [O] Γ t B8„h_<Q_c-ce3-V ') -COCH_ | R "CO- ^ W 3 I [O] Γ t B8" h_ <Q_c-ce3
BH3/THF p OBH3 / THF p O
20 X * R8R9N-Q—9>-«3 I 1) se02 I iu 42) R2R3NH/NaBH4 25 i103 RgNH—W—CH-CH2-NR2R3X * R8R9N-Q-9> - «3 I 1) seO2 I iu 42) R2R3NH / NaBH4 I103 RgNH-W-CH-CH2-NR2R3
X Γ *HX Γ * H
R8R9N —-Q-1*^3 ZR8R9N —-Q-1 * 3 Z
Z 0 30 I 1) Se02 4 2) R2R3NH/NaBH4Z 0 30 I 1) Se02 4 2) R2R3NH / NaBH4
XX
R8R9N-0- ch-ch2-nk2r3R8R9N-0- ch-ch2-nk2r3
35 V OH35 V OH
9 DK 171124 B19 DK 171124 B1
De metoder, der benyttes i det ovenfor viste skema, er enten, omtalt i de ovennævnte publikationer eller er gængse metoder. Oxidation af alkoholen kan foretages med chromsyre (Jones' reagens), Mn02, pyridiniumchlorchromat 5 eller andre oxidationsmidler. Når X og Z er de BH3-reducer-bare grupper CN, COOR eller CONH2, fremstilles de egnede acetophenoner ved omdannelse af X og Z repræsenteret ved brom med CuCN/DMF ved 100-160“C ved en gængs metode efter reduktion af de acylerede aminoacetophenoner i det første 10 trin, efterfulgt af genoxidation i det andet trin af ovennævnte metode. De cyano-substituerede amino-acetophenoner omdannes derefter til deres tilsvarende ethanolaminer, som derefter omdannes til de ønskede estere, syrer og amider ved gængse metoder såsom R^OH/syre -+ estere, hydrolyse -♦ 15 syrer og delvis hydrolyse -* amider.The methods used in the scheme shown above are either, discussed in the above publications or are common methods. Oxidation of the alcohol can be carried out with chromic acid (Jones' reagent), MnO 2, pyridinium chlorochromate 5 or other oxidizing agents. When X and Z are the BH3 reducible groups CN, COOR or CONH2, the appropriate acetophenones are prepared by conversion of X and Z represented by bromine with CuCN / DMF at 100-160 ° C by a conventional method after reduction of the acylated aminoacetophenones in the first step, followed by re-oxidation in the second step of the above method. The cyano-substituted amino-acetophenones are then converted to their corresponding ethanolamines which are then converted to the desired esters, acids and amides by conventional methods such as R 2 OH / acid + esters, hydrolysis - 15 acids and partial hydrolysis - * amides.
Desuden fremstilles forbindelser med nedenstående formel ved at lade de tilsvarende ethanolaminer reagere med en ækvivalent mængde eller et lille overskud af syreanhydri-derne med eller uden organiske baser såsom tertiære aminer 20 eller pyridin. Disse reaktioner udføres i inaktive opløsningsmidler 0 X <Rl2C->2° i \ t-^W-ch-ns2r3 ^ ΓI ^ 25 Γ fe °-C-R12In addition, compounds of the formula below are prepared by reacting the corresponding ethanolamines with an equivalent amount or a small excess of the acid anhydrides with or without organic bases such as tertiary amines 20 or pyridine. These reactions are carried out in inactive solvents 0 X <R12 C-> 2 ° i \ t- ^ W-ch-ns2r3 ^ ΓI ^ 25 Γ fe ° -C-R12
z Oz O
(hvor R12 er C1-c4-alkyl eller u /)- ) y 30 10 såsom chlorerede carbonhydrider eller aromatiske opløsningsmidler ved 0-25°C. Omsætning af anhydridet ved hydroxylgrup-pen forløber godt, forudsat at R2 og R^ ikke er hydrogen, og 35 når R2 er hydrogen, er R^ en substituent indeholdende et tertiært carbonatom knyttet til nitrogen.(where R 12 is C 1 -C 4 alkyl or ω) -yl γ 10 such as chlorinated hydrocarbons or aromatic solvents at 0-25 ° C. Reaction of the anhydride at the hydroxyl group proceeds well, provided that R 2 and R 2 are not hydrogen, and when R 2 is hydrogen, R 2 is a substituent containing a tertiary carbon atom attached to nitrogen.
DK 171124 ΒΊ 10 oDK 171124 ΒΊ 10 o
Yderligere fremstilles forbindelser med formlen I, hvor Rg og R^ er hydrogen eller Cg_4-alkenyl, ved alkenyle-ring af 4-amino-3,5-disubstituerede phenacylbromider i dime-thylformamid (DMF) i nærværelse af en syreacceptor, såsom tri- 5 ethylamin eller natriumcarbonat, ved 70-100°C, hvilket giver mono- og dialkenylerede produkter, der fraskilles og omdannes til forbindelser med formlen I ved gængse metoder. Det følgende skema viser den ovennævnte almene metode: 10Further, compounds of formula I wherein R 9 and R 5 are hydrogen or C 1-4 alkenyl are prepared by alkenylation of 4-amino-3,5-disubstituted phenacyl bromides in dimethylformamide (DMF) in the presence of an acid acceptor such as 5 ethylamine or sodium carbonate, at 70-100 ° C to give mono- and dialkenylated products which are separated and converted into compounds of formula I by conventional methods. The following diagram shows the above general method:
Cl H2N~V-^““COCH2Br + CH2*CH“CH2Br C2H5^ 3^ > (overskud) ^MF ' C1 15Cl H2N ~ V - ^ "" COCH2Br + CH2 * CH "CH2Br C2H5 ^ 3 ^> (excess) ^ MF 'C1 15
Cl Cl CH2*CH—CI^-NH-^^-COCH2Br + (CH2»CH=CH2) 2 N—\Γ\~-C0CH2Br ^ . Cl.Cl Cl CH2 * CH-Cl2 -NH - ^^ - COCH2Br + (CH2 »CH = CH2) 2 N— \ \ \ ~ -COCH2Br ^. Cl.
20 t—BuNH2/NaBH4 \l· Cl 25 CH2=CH—CH2-NH— \__)—CH·—CH2^-NH—C (CH3) 3 ώ 0H 1 2 3 4 5 6T-BuNH2 / NaBH4 \ l · Cl 25 CH2 = CH-CH2-NH- \ __) - CH · -CH2 -NH-C (CH3) 3 ώ OH 1 2 3 4 5 6
Forbindelser med formlen I, hvor R4 er 0Rg og SR^, 2 hvor Rg og R^ har de ovenfor anførte betydninger, kan frem 3 stilles ved at omdanne alkoholen (R4-OH) med thionylchlorid 4 under et tæppe af inaktiv gas såsom nitrogen ved en temperatur 5 fra ca. 0 til 10°C og fortrinsvis fra 0 til 5°C i en reak- 6 tionstid, der er tilstrækkelig til i det væsentlige af fuldføre reaktionen. Den således fremstillede halogenforbindel- 11 DK 171124 B1 o se isoleres ved gængse metoder og omsættes derefter med en passende alkohol eller mercaptan under et tæppe af inaktiv gas, såsom nitrogen, ved en temperatur fra ca. 0 til 50°C.Compounds of formula I wherein R4 is ORg and SR2, wherein Rg and R4 have the above meanings, can be prepared 3 by converting the alcohol (R4-OH) with thionyl chloride 4 under a blanket of inert gas such as nitrogen at a temperature of 5 from approx. 0 to 10 ° C and preferably from 0 to 5 ° C for a reaction time sufficient to substantially complete the reaction. The halogen compound thus prepared is isolated by conventional methods and is then reacted with a suitable alcohol or mercaptan under a blanket of inert gas such as nitrogen at a temperature of ca. 0 to 50 ° C.
Det således fremstillede produkt med formlen I isoleres der-5 efter ved standard-laboratoriemetoder og renses om ønsket.The product of formula I thus prepared is then isolated by standard laboratory methods and purified if desired.
Den ovennævnte reaktionsrækkefølge kan gengives som følger: V* 10 Y"W*]:H"CH2""SR2R3 S0C12 ^The above reaction sequence can be represented as follows: V * 10 Y "W *]: H" CH2 "" SR2R3 SO212
Z 0HZ 0H
•(HC1)o,1,2• (HC1) O, 1.2
X XX X
15 i-0-CH-CH2-HRjR3 R6°\ VI-O-CH-CH2-HRjR3 R6 ° \ V
, 6 ·(Η01,1,2, 6 · (Η01,1,2
20 X20 X
X-O-ra-CHj-NRjRj Γ k, 25 '(HCl)^ hvor X, Y, Z, R2, / Rg og R^ har de ovenfor anførte betyd ninger.X-O-ra-CH₂-NR₂R₂ Γ k, 25 '(HCl) +, where X, Y, Z, R2, / Rg and R R have the above meanings.
3Q Disse ombytningsreaktioner kan også udføres ved hjælp af et overskud af alkoxid (RO ) eller mercaptid _ 6 (R11S ^ ^ et ^nalctivt opløsningsmiddel, såsom tetrahydrofu-ran, hvilket giver de ovennævnte estere og thioestere på lignende måde.These exchange reactions can also be carried out by an excess of alkoxide (RO) or mercaptide - 6 (R11S4) an inert solvent such as tetrahydrofuran to give the above esters and thioesters in a similar manner.
35 Alternativt kan en forbindelse med formlen I, hvor R4 er ORg, fremstilles ved at opløse den tilsvarende forbin- 12Alternatively, a compound of formula I wherein R4 is ORg may be prepared by dissolving the corresponding compound 12
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DK 171124 B1 delse med formlen I, hvor R er OH, i den tilsvarende R-OH- 4 o -alkohol og mætte den således opnåede opløsning med tør HC1-gas. Derefter omrøres reaktionsblandingen ved stuetemperatur i tilstrækkelig tid til, at reaktionen er i det væsent-5 lige afsluttet, og derefter isoleres produktet ved hjælp af standard-laboratoriemetoder og renses, om ønsket. Denne reaktionsrækkefølge kan gengives som følger:The compound of formula I, wherein R is OH, in the corresponding R-OH-4O-alcohol and saturates the solution thus obtained with dry HCl gas. Then, the reaction mixture is stirred at room temperature for a sufficient time for the reaction to be substantially complete and then the product is isolated by standard laboratory methods and purified, if desired. This sequence of reactions can be reproduced as follows:
X XX X
° HJrW· -hc°W-> y-^_y~cs-cs2m2n3.hci \ 0H I °*x z * (i) 15 hvor X, Y, Z, R£, R^ og Rg har de ovenfor anførte betydninger.° HJrW · -hc ° W-> y - ^ _ y ~ cs-cs2m2n3.hci \ 0H I ° * x z * (i) 15 where X, Y, Z, R £, R ^ and Rg have the meanings given above.
I nærværende beskrivelse med krav betyder udtrykket α,α-dimethylphenethyl en struktur med følgende konfiguration: _- 9?3 20 CH-C- Når det ovennævnte phenylethanderivat eller dets syreadditionssalt indgives oralt i foderet, i reglen ca. 0,01-25 300 g pr. ton foder, er det i stand til at forøge vækstraten og forbedre den effektive foderudnyttelse hos de ovennævnte kødproducerende dyr.As used herein, the term α, α-dimethylphenethyl means a structure having the following configuration: CH-C- When the aforementioned phenylethane derivative or its acid addition salt is orally administered in the feed, usually about 0.01-25 300 g per per ton of feed, it is capable of increasing the growth rate and improving the efficient feed utilization of the above-mentioned meat-producing animals.
Eftersom de effektive og foretrukne mængder i foderet af det aktive stof varierer noget fra dyreart til dyre-30 art, er mængderne for hver enkelt dyreart anført i tabel I nedenfor som mængde i gram pr. ton foder: 35Since the effective and preferred amounts in the feed of the active substance vary somewhat from animal species to animal species, the amounts for each animal species are listed in Table I below as the quantity in grams per gram. tonnes of feed: 35
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DK 171124 B1 13DK 171124 B1 13
Tabel ITable I
Effektiv Foretrukken mængde i mængde iEffective Preferred quantity in quantity i
Forbindelse foder q/t_foder, q/t_Dyr_ 5 Formlen I 0,1-200 1-100 Får, geder 0,01-50 0,1-10 Kyllinger, kaniner 0,01-50 0,1-10 Kalkuner _0,1-300_1-100_Kvæg, svin_ 10 Dyrefodersammensætninger, der giver den ønskede vækst forøgelse og foderudnyttelse hos de ovennævnte dyr, kan fremstilles ved at blande phenylethanderivatet eller et syreadditionssalt deraf eller et dyrefodertilskud, der indeholder den nævnte forbindelse, med en tilstrækkelig mængde af et pas-15 sende dyrefoder, så at der fås den Ønskede mængde aktiv forbindelse i foderet.Compound feed q / t_ feed, q / t_Animal_ 5 Formula I 0.1-200 1-100 Sheep, goats 0.01-50 0.1-10 Chickens, rabbits 0.01-50 0.1-10 Turkeys _ 0.1 Animal feed compositions which provide the desired growth enhancement and feed utilization of the above animals may be prepared by mixing the phenylethane derivative or an acid addition salt thereof or an animal feed supplement containing said compound with a sufficient amount of a passport. 15 send animal feed so that the desired amount of active compound is obtained in the feed.
Dyrefodertilskud kan fremstilles ved at blande ca. 10-75 vægtprocent af phenylethanderivatet eller et syreadditionssalt deraf med ca. 90-25 vægtprocent af et passende bære-20 stof eller fortyndingsmiddel. Bærestoffer, der er egnede til af komplettere fodertilskudssammensætningerne, omfatter følgende: lucernemel, sojabønnemel, bomuldsfrøoliemel, hørfrøo liemel/natriumchlorid, majsmel, sukkerrørmelasse, urinstof, benmel, majskolbemel og lignende. Bærestoffet fremmer 25 en homogen fordeling af det aktive stof i det endelige foder, hvori tilskudet blandes. Det har således en vigtig funktion ved at sørge for en rigtig fordeling af aktivt stof i hele foderet.Animal feed supplements can be prepared by mixing approx. 10-75% by weight of the phenylethane derivative or an acid addition salt thereof, with approx. 90-25% by weight of a suitable carrier or diluent. Carriers suitable for complementary feed supplement compositions include the following: lucerne flour, soybean meal, cotton seed oil, flax seed lime / sodium chloride, corn flour, sugarcane molasses, urea, bone meal, corn cob flour and the like. The carrier promotes a homogeneous distribution of the active substance in the final feed in which the supplement is mixed. It thus has an important function in ensuring a proper distribution of active substance throughout the feed.
Hvis tilskudet anvendes som overfladetilsætning til 30 foderet, hjælper det med til at sikre en homogen fordeling af det aktive materiale i hele det øverste lag af det tilberedte foder.If the supplement is used as a surface additive to the feed, it helps to ensure a homogeneous distribution of the active material throughout the top layer of the prepared feed.
Til parenteral indgivelse kan phenylethanderivatet fremstilles i form af en pasta eller pellet og indgives som 35 implantat, i reglen under hovedhuden eller øret på dyret, hvis vækstrate eller effektive foderudnyttelse man søger at forbedre.For parenteral administration, the phenylethane derivative can be prepared in the form of a paste or pellet and administered as an implant, usually under the scalp or ear of the animal, whose growth rate or effective feed utilization is sought to improve.
14 DK 171124 B1 I praksis indebærer parenteral indgivelse i reglen injektion af en tilstrækkelig mængde af ovennævnte phe-nylethanderivat til at dyret får 0,001-50 mg/kg legemsvægt aktivt stof. Det foretrukne dosisinterval for kvæg ligger mel-5 lem 0,001 og 25 mg/kg legemsvægt af det aktive phenylethande-rivat. Det foretrukne dosisinterval for phenylethanderivat til fjerkræ er ca. 0,001-35 mg/kg legemsvægt af dyret, og det foretrukne dosisinterval for phenylethanderivat til får og geder er 0,001 til 40 mg/kg legemsvægt af dyret. Det foretrukne dosis-10 interval for kaniner er 0,001 til 35 mg/kg legemsvægt af dyret.In practice, parenteral administration usually involves injection of a sufficient amount of the above phenylethane derivative to give the animal 0.001-50 mg / kg body weight of active substance. The preferred dose range for cattle is between 0.001 and 25 mg / kg body weight of the active phenylethane derivative. The preferred dose range for phenylethane derivative for poultry is approx. 0.001 to 35 mg / kg body weight of the animal and the preferred dose range for phenylethane derivative for sheep and goats is 0.001 to 40 mg / kg body weight of the animal. The preferred dose-range for rabbits is 0.001 to 35 mg / kg body weight of the animal.
Pastapræparater kan fremstilles ved at dispergere det aktive phenylethanderivat i en farmaceutisk acceptabel olie såsom jordnøddeolie, sesamolie, majsolie eller lignende.Pasta preparations can be prepared by dispersing the active phenylethane derivative in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.
Pellets med et effektivt indhold af phenylethanderi-15 vat kan fremstilles ved at blande ovennævnte aktive stof med et fortyndingsmiddel såsom carbowax, bionedbrydelige polymere, carnaubavoks eller lignende. Et smøremiddel såsom magnesium-stearat eller calciumstearat kan om ønsket tilsættes for at lette pelletteringsprocessen.Pellets with an effective content of phenylethane derivative can be prepared by mixing the above active ingredient with a diluent such as carbowax, biodegradable polymers, carnauba wax or the like. A lubricant such as magnesium stearate or calcium stearate may, if desired, be added to facilitate the pelletizing process.
20 Det er indlysende, at der kan indgives mere end én pellet til et dyr for at opnå den ønskede dosis, der kan give en forøget vækstrate og/eller forbedret effektiv foderudnyttelse hos dyret. Det har desuden vist sig, at implantater derudover også kan indføres med mellemrum i behandlings-25 perioden for at opretholde en korrekt præparatfrigivelseshastighed i dyrets krop.It is obvious that more than one pellet can be administered to an animal to obtain the desired dose that can provide an increased growth rate and / or improved effective feed utilization in the animal. In addition, it has been found that implants may additionally be inserted at intervals during the treatment period to maintain a correct preparation release rate in the animal's body.
Ud over forbedret vækstforøgelse og effektiv foderudnyttelse hos kødproducerende dyr har forbindelserne anvendt ved fremgangsmåden ifølge den foreliggende opfindelse den 30 yderligere fordel, at de ved udvalgte indgivelsesniveauer forøger afsætningen af magert kød (dvs. muskler eller protein) i de nævnte dyr og forbedrer kødkroppens kvalitet ved at forøge forholdet mellem magert kød og fedt hos dyr, der får disse forbindelser. Denne biologiske reaktion er en 35 væsentlig fordel for opdrættere af fjerkræ, kvæg og svin, får og geder, eftersom indgivelse af forbindelserne i ud- 15 DK 171124 B1 valgte mængder giver magrere dyr, der berettiger til bonuspriser hos kødindustrien.In addition to improved growth enhancement and efficient feed utilization in meat-producing animals, the compounds used in the method of the present invention have the additional advantage that, at selected levels of administration, they increase the deposition of lean meat (i.e., muscle or protein) in said animals and improve the quality of the meat body by to increase the lean meat-fat ratio in animals receiving these compounds. This biological reaction is a major benefit for breeders of poultry, cattle and pigs, sheep and goats, since the administration of the compounds in selected quantities gives leaner animals that are eligible for bonus prices in the meat industry.
Disse og andre fordele ved den foreliggende opfindelse vil fremgå af de nedenfor anførte eksempler.These and other advantages of the present invention will become apparent from the examples set forth below.
55
Eksempel 1Example 1
Bedømmelse af prøveforbindelser som vækstfremmende midler til dyr CFI hunmus fra Carworth Farms modtages, når de er 10 6 uger gamle. De opbevares 10 i et bur i luftconditionerede rum (22-24°C) med automatisk reguleret lys, 14 timer tændt og 10 timer slukket. Grundkosten, der anvendes til disse undersøgelser, er "Purina Laboratory Chow" (se beskrivelsen nedenfor), hvilket gives ad libitum. Vand gives ad libitum.Assessment of test compounds as growth promoters for animal CFI female mice from Carworth Farms is received when they are 10 6 weeks old. They are stored 10 in a cage in air-conditioned rooms (22-24 ° C) with automatically controlled light, 14 hours on and 10 hours off. The basic diet used for these studies is the "Purina Laboratory Chow" (see description below), which is given ad libitum. Water is given ad libitum.
15 13 dage efter ankomsten vejes musene i grupper på 10 og udpeges vilkårligt til forskellige behandlinger. Koncentrationen af de forskellige forbindelser i kosten er anført i de følgende tabeller. 12 dage senere vejes musene i-gen, og eksperimentet afsluttes. Prøvedata findes i tabel II 20 nedenfor, hvor dataene er anført som procentvis mervækst i forhold til kontroldyrene. Der anvendes nye kontroldyr til hver prøve. Nedenstående findes sammensætningen af den kost, hvortil de vækstfremmende forbindelser sættes. 1 2 3 4 5 6 7 8 9 10 1115 13 days after arrival, the mice are weighed in groups of 10 and randomly selected for different treatments. The concentration of the various compounds in the diet is given in the following tables. Twelve days later, the mice are weighed again and the experiment is terminated. Sample data can be found in Table II 20 below, where the data is given as percentage added growth relative to the control animals. New control animals are used for each sample. Below is the composition of the diet to which the growth-promoting compounds are added. 1 2 3 4 5 6 7 8 9 10 11
Kost 2Cost 2
Garanteret analyse 3 Råprotein ikke under 23,0% 4 Råfedtstof ikke under 4,5% 5 Råfiber ikke over 6,0% 6Guaranteed analysis 3 Crude protein not less than 23.0% 4 Crude fat not less than 4.5% 5 Crude fiber not less than 6.0% 6
Aske ikke mere end 9,0% 7Ash no more than 9.0% 7
Bestanddele 8 Kød- og benmel, tørret skummetmælk, hvedekimmel, 9 fiskemel, dyrelevermel, tørret roeaffald, malet ekstruderet 10 majs, malet havregrut, sojabønnemel, dehydratiseret lucerne- 11 mel, sukkerrørmelasse, dyrefedt konserveret med BHA, tilskud af vitamin calciumpantothenat, cholinchlorid, folinsyre, riboflavintilskud, tørret bryggerigær, thiamin, niacin, til-Ingredients 8 Meat and bone meal, dried skimmed milk, wheat flour, 9 fish meal, animal liver meal, dried beet waste, ground extruded 10 corn, ground oatmeal, soybean meal, dehydrated alfalfa 11 flour, sugar cane molasses, animal fat preserved with BHA supplement, supplement folic acid, riboflavin supplement, dried brewer's yeast, thiamine, niacin,
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DK 171124 B1 16 skud af Z-vitamin, D-aktiveret plantesterol, tilskud af E-vi-tamin, calciumcarbonat, cicalciumphosphat, ioderet salt, fer-riammoniumcitrat, jernoxid, manganoxid, koboltcarbonat, kobberoxid og zinkoxid.DK 171124 B1 16 shots of vitamin Z, D-activated plant cholesterol, supplementation of E-vitamin, calcium carbonate, cicalcium phosphate, iodinated salt, ferric ammonium citrate, iron oxide, manganese oxide, cobalt carbonate, copper oxide and zinc oxide.
55
Tabel IITable II
Bedømmelse af prøveforbindelser som vækstfremmende midler til dyr % mervækstAssessment of test compounds as growth promoters for animals% added growth
Dosering Tilvækst i.f.t. kon- 10 Forbindelse_(ppm)_(gram) troldyr_ a- ((Tertr-butylamino) methyl] -3,5-dichlor-4- 200 16,0 0 -diiiethylaminobenzylalkohol 50 21,9 + 36,9 et- [ (Tert-butylamino) methyl] -3,5-dichlor-4- 200 19,4 +21,3 -methylaminobenzylalkohol 50 24,4 + 52,5 15 Methyl-4- [2- (tert-butylamino)-1-hydroxye- 50 27,9 + 40,8 thyl]-2,6-dichlarcarbanilat 5- [ 2- (Tertr-butylamino) - 1-hydroxyethy 1] -3- 200 27,3 +90,9 -chlor anthrani lonitr i1 50 26,2 +83,2 20 a- [ (Tert-butylamino) methyl] -3,5-dichlor-4- 200 24,6 +72,0 -iscprqpylamincbenzylalkohol 50 24,3 +69,9 12 28,0 + 95,8 3 27,3 + 90,8 5- [2- (Tert-butylamino) -1-hydroxyethyl] an- 200 29,6 +79,4 25 thranilonitril 50 29,9 + 81,2Dosage Increase i.f.t. Compound Compound (ppm) (Gram) Troll-α- ((Tertr-butylamino) methyl] -3,5-dichloro-4,200 16,0 O-diethylaminobenzyl alcohol 50 21.9 + 36.9 Et- [( Tert-Butylamino) methyl] -3,5-dichloro-4,200 19,4 + 21,3-methylaminobenzyl alcohol 24,4 + 52,5 Methyl 4- [2- (tert -butylamino) -1-hydroxy - 50 27.9 + 40.8 thyl] -2,6-dichlorocarbanilate 5- [2- (Tertr-butylamino) -1-hydroxyethyl] -3,200 27,3 + 90,9 -chloroethranilonitrone 26.2 ± 83.2 α- [(Tert-Butylamino) methyl] -3,5-dichloro-4,200 24,6 +72,0-isopropylpyramine benzyl alcohol 24.3 +69.9 12 28.0 + 95.8 3 27.3 + 90.8 5- [2- (Tert-Butylamino) -1-hydroxyethyl] anthrax 29.6 +79.4 Thranilonitrile 50 29.9 ± 81.2
Methyl-5- [2- (tert-butylamino) -1-hydroxye- 200 24,4 +47,9 thyl] -3-chloranthranilat-hydrochlorid 50 20,1 +21,8 4-AninD-N-tert-butylamino-3,5-dichlar-8- 200 25,4 +55,8 - (methylthio) phenetbylamin-hydrochlorid 50 25,3 + 55,2 30 3-Brom- 5- [ 2- (tert-butylamino) -1-hydroxy- 200 16,1 + 50,5 ethyl] -anthrani loni tri1 50 24,2 +126,2 4-Amino-a- [ (tert-butylamino)methyl]-3-me- 100 20,8 +94,5 thylbenzylalkohol 4-(Butylamino)-a-[(tert-butylamino)methyl]- 200 19,3 +80,4 35 -3,5-dichlorbenzylalkohol 50 19,4 +81,3Methyl 5- [2- (tert-butylamino) -1-hydroxy-200 24.4 + 47.9-methyl] -3-chloranthranilate hydrochloride 20.1 + 21.8 4-Anin -3,5-dichloro-8,200 25,4 + 55,8 - (methylthio) phenethbylamine hydrochloride 50,3,3,5,5,2 3-Bromo-5- [2- (tert-butylamino) -1- hydroxy-200 16.1 + 50.5 ethyl] -anthranilonitrile 24.2 + 126.2 4-Amino-α- [(tert-butylamino) methyl] -3-meth-100 20.8 +94, Thylbenzyl alcohol 4- (Butylamino) -α - [(tert-butylamino) methyl] - 200 19.3 + 80.4 -3,5-Dichlorobenzyl alcohol 50 19.4 +81.3
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DK 171124 B1 17DK 171124 B1 17
Tabel II (forts.) % mervækstTable II (cont.)% Added growth
Dosering Tilvækst i.f.t. kon-Dosage Increase i.f.t. sex-
For bindel se_(ppm)_(gram) troldyr_ 5 2-Amino-3-brcin-5- [2- (ter tbuty lamino)-1- 200 17,4 +62,6 -hydroxyethyl] benzamid 50 19,8 + 85,0 4-Amino-a- [ (ter t-butylanino)ne thyl] -3,5- 200 14,6 +36,4 -di chlorbenzylalkchol-acetat(ester) 50 19,1 +78,5 3-Brcm-Er- [2- (tert-butylamLnoJ-l-hydroxye- 200 18,2 +70,1 10 thyl] anthranilinsyre 50 13,6 + 27,1 N-tert-butyl-3,5-dichloi>-8-inethoxy-4-ine- 200 18,0 + 68,2 thylatmjxi^enethylamin-hydrochlorid 50 23,1 +115,9 a- [ (Tert-butylamino) methyl] -3,5-dichlor-4- 200 19,6 +83,2 - (hexylaitiino)benzylalkchol 50 20,7 + 93,5 15 4-åmino-a-[(tert-buty lamino)methyl]-3,5-di- 200 14,4 + 34,6 chlorbenzylalkoholacetat(ester), acetat 50 18,7 + 74,8 (Allyloxy) -4-amino-N-tert-buty 1-3,5-di- 200 21,5 +100,9 chlorphenethylamin 50 19,6 + 83,2 20 4- (Ally lamino) -a- [ (tert-bu ty lamino) methyl] - 200 20,2 + 88,8 -3,5-dichlorbenzy lalkohol 50 21,9 +104,7 4[3— (Tert-buty lamino) -1-hydroxyethyl] - 200 25,8 +141,1 -2' ,6 '-dichloraætanilidacetat(ester)-hy- 50 16,2 + 51,4 drochlorid 25 a- [ (Tert-buty lamino) methyl] -3,5-dichlor-4- 100 23,0 +115,0 -cyclohexylaminobenzylalkohol a- [ (Tert-butylamino)methyl] -4-amino-3- 2 00 16,5 + 54,2 -chlor- 5^methy Ibenzy lalkchol-hydrochlorld 5 0_19,7_+ 84,1 1 2 3 4 5 6For binding se (ppm) (gram) sorcery 5 2-Amino-3-brcine-5- [2- (terbuty lamino) -1,200 17,4 + 62,6-hydroxyethyl] benzamide 50 19.8 + 85.0 4-Amino-α- [(ter t-butylanino) neethyl] -3,5- 200 14,6 + 36,4-di chlorobenzyl alcoholchol acetate (ester) 19.1 +78.5 3- Brcm-Er- [2- (tert-butylamino] -1-hydroxy-200 18.2 + 70.1-thyl] anthranilic acid 50 13.6 + 27.1 N-tert-butyl-3,5-dichloro-8 -ethethoxy-4-indene-200 18.0 + 68.2 thylate methyleneethylamine hydrochloride 50 23.1 + 115.9 a - [(Tert-butylamino) methyl] -3,5-dichloro-4,200 19, 6 + 83,2 - (Hexyl) amino benzyl alcohol 50 20.7 + 93.5 4-Amino-α - [(tert-butylamino) methyl] -3,5-di-200 14.4 + 34.6 Chlorobenzyl alcohol acetate (ester), acetate 50 18.7 + 74.8 (Allyloxy) -4-amino-N-tert-buty 1-3,5-di-21,2,5 + 100,9 chlorophenethylamine 50 19,6 + 83, 4- (Ally lamino) -a- [(tert-butylamino) methyl] - 200 20.2 + 88.8 -3,5-dichlorobenzyl alcohol 50 21.9 + 104.7 4 [3- Tert-butylamino] -1-hydroxyethyl] - 200 25.8 +141.1 -2 ', 6' -dichloroethanilide acetate (ester) -hydro 16.2 + 51.4 Chloride a - [(Tert-butylamino) methyl] -3,5-dichloro-4- 100 23.0 + 1155-cyclohexylaminobenzyl alcohol a- [(Tert-butylamino) methyl] - 4-Amino-3- 200 00 16.5 + 54.2-Chloro-5-methylbenzylalkalkol hydrochloride 5__19.7_ + 84.1 1 2 3 4 5 6
Eksempel 2 2Example 2 2
Antilipogen bedømmelse af prøveforbindelser - undersøgelse af 3 mus 4 CFI hunmus, 55 dage gamle, vejes i grupper på 10 og 5 indsættes i bure, så at vægtfofskellen mellem burene bliver så 6 lille som muligt. Burene udpeges vilkårligt til behandlingerne.Antilipogenic assessment of test compounds - examination of 3 mice 4 CFI female mice, 55 days old, are weighed in groups of 10 and 5 inserted into cages so that the weight difference between the cages becomes as small as possible. The cages are arbitrarily designated for the treatments.
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18 DK 171124 B118 DK 171124 B1
Hver behandling afprøves i 3 gentagne forsøg, dvs. i 3 bure med 10 mus i hvert. Der er lo bure med 10 kontrolmus i hvert. Præparaterne blandes i kosten i den anførte dosis.Each treatment is tested in 3 repeated experiments, ie. in 3 cages with 10 mice in each. There are lo cages with 10 control mice in each. The preparations are mixed in the diet at the indicated dose.
Føde og vand tilbydes ad libitum i en prøveperiode på 12 5 dage. Fødespildet opsamles under prøveperioden. Ved slutningen af prøveperioden vejes den opsamlede føde, og det gennemsnitlige fødeforbrug pr. bur med 10 mus bestemmes for hver behandling. Musene vejes som en gruppe på 10, og vægtforøgelsen bestemmes. Musene aflives ved at få drejet halsen 10 om. Den højre uterine fedtpude på hver mus fjernes. Fedtpuderne for hvert bur på 10 mus vejes som en enhed.Food and water are offered ad libitum for a trial period of 12 5 days. The food waste is collected during the trial period. At the end of the trial period, the food collected and the average food consumption per day are weighed. Cage with 10 mice is determined for each treatment. The mice are weighed as a group of 10 and the weight gain determined. The mice are killed by rotating the neck 10. The right uterine fat pad on each mouse is removed. The fat pads for each cage of 10 mice are weighed as one unit.
De opnåede data er anført i tabel III. Dataene er angivet som procent reduktion af fedtpudevægten. Reduktion af fedtpudevægten hos dyrene er i reglen tegn på reduk-15 tion af de behandlede dyrs totale kropsfedt.The data obtained are listed in Table III. The data is given as percent reduction of fat pad weight. Reduction of the fat pad weight in the animals is usually indicative of reduction of the total body fat of the treated animals.
Tabel IIITable III
Antilipogen bedømmelse af prøveforbindelser - undersøgelse af mus 20 % redukt. afAntilipogenic evaluation of test compounds - study of mice 20% reduced. of
Dosering fedtpudevægtDosage fat pad weight
Forbindelse_(ppm) vs. kontroldyr a-[(Tert-butylamino)methyl]-3,5-dichlor-4- 200 -46,1 -dimethylaminobenzylalkohol 50 -14,8 25 Methyl-4-[2-(tert-butylamino)-l-hydroxye- 50 -23,5 thyl]-2,6-dichlorcarbanilat a[(Tert-butylamino)-methyl]-3,5-dichlor- 200 -51,0 4- methylaminobenzylalkohol ^0 -41,9 30 5- [2-Tert-butylamino-l-hydroxyethyl]-3-chlor- 200 -45,9 anthranilonitril 50 -10,4 a-[(Tert-butylamino)methyl]-3,5-dichlor-4-i- 200 -52,5 sopropylaminobenzylalkohol 50 -22,6 35 12-6,3 3 -25,5 DK 171124 B1 19Compound_ (ppm) vs. Control Animals α - [(Tert-Butylamino) Methyl] -3,5-Dichloro-4- 200 -46,1-Dimethylaminobenzyl Alcohol 50 -14.8 Methyl 4- [2- (Tert-Butylamino) -1-Hydroxy 50 -23.5 thyl] -2,6-dichlorocarbanilate a [(Tert-butylamino) methyl] -3,5-dichloro-200.0-4-methylaminobenzyl alcohol Tert-butylamino-1-hydroxyethyl] -3-chloro-200 -45.9 anthranilonitrile 50 -10.4 a - [(Tert-butylamino) methyl] -3,5-dichloro-4-i-200 -52,5 sopropylaminobenzyl alcohol 50 -22.6 12-6.3 3 -25.5 DK 171124 B1 19
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Tabel III (forts.) % redukt. af Dosering fedtpudevægtTable III (cont.)% Reduced. of Dosage fat pad weight
Forbindelse_(ppm) vs kontroldyr 5 Methyl-5-[2-(tert-butylamino)-1-hydroxyethyl]- 200 - 5,9 -3-chloranthranilat-hydrochlorid 50 - 5,8 5- [2- (Tert-butylamino)-1-hydroxyethyl] anthra- 200 -41,5 nilonitril 50 -10,3 4- [Amino-N-tert-buty 1-3,5-dichlor-f3- (methyl- 200 -28,9 10 thio)-phenethylamin-hydrochlorid 50 -16,2Compound (ppm) vs Control Animals 5 Methyl 5- [2- (tert -butylamino) -1-hydroxyethyl] - 200 - 5,9 -3-chloroanthranilate hydrochloride 50 - 5.8 5- [2- (Tert-butylamino) ) -1-hydroxyethyl] anthra 200 -41,5 nilonitrile 50 -10,3 4- [Amino-N-tert-buty 1-3,5-dichloro-3- (methyl-200 -28,9-thio) -phenethylamine hydrochloride 50 -16.2
Eksempel 3 N-Tert-buty 1-3,5-dichlor-3-methoxy-3-methylaminophenethylamin-15 -hydrochloridExample 3 N-Tert-buty 1-3,5-dichloro-3-methoxy-3-methylaminophenethylamine-15 hydrochloride
En prøve på 7 g a-[(tert-butylamino)methyl]-3,5--dichlor-4-methylaminobenzylalkohol sættes til 70 ml thionyl-chlorid under N2~atmosfære, og blandingen omrøres i to timer. Overskydende thionylchlorid fjernes i vakuum, og den glasag-20 tige remanens opløses i 50 ml methanol. Opløsningen omrøres i 1,5 time og inddampes til tørhed. Remanensen opløses i 100 ml H20 og ekstraheres med 2 x 50 ml CH2C12· Det vandige lag neutraliseres med fast NaHCO^ og ekstraheres med CH2C12.A sample of 7 g of α - [(tert-butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol is added to 70 ml of thionyl chloride under N 2 atmosphere and the mixture is stirred for two hours. Excess thionyl chloride is removed in vacuo and the glassy residue is dissolved in 50 ml of methanol. The solution is stirred for 1.5 hours and evaporated to dryness. The residue is dissolved in 100 ml H 2 O and extracted with 2 x 50 ml CH 2 Cl 2 · The aqueous layer is neutralized with solid NaHCO 3 and extracted with CH 2 Cl 2.
Ekstrakten tørres (MgSO.) og inddampes til tørhed i vakuum, 25 ^ hvilket giver 4,1 g halvfast stof, som efter triturering med ethylether giver 1,07 g af den i overskriften nævnte forbindelse, smeltepunkt 220-221°C. På lignende måde fremstilles de følgende ethere. 1 35 0 DK 171124 B1 20 CH-NH—(f V—CH—CH- —NH—*Bu—t 3 W I 2 5 ClThe extract is dried (MgSO 4) and evaporated to dryness in vacuo to give 4.1 g of semi-solid which after trituration with ethyl ether gives 1.07 g of the title compound, mp 220-221 ° C. Similarly, the following ethers are prepared. 1 17 0 DK 171124 B1 20 CH-NH- (f V-CH-CH- -NH- * Bu-t 3 W I 2 5 Cl
Alkohol______ R__Alcohol______ R__
Ethanol ^2** 5 1- Propanol l-C^H^ 2- Propanol 10 1-Butanol 1-C^Hg 2-Butanol 2-C^Hg 1- Hexanol n-CgH^Ethanol ^ 2 ** 5 1- Propanol l-C ^ H ^ 2- Propanol 10 1-Butanol 1-C ^ Hg 2-Butanol 2-C ^ Hg 1- Hexanol n-CgH ^
Allylalkohol Allyl 4-Methoxybenzylalkohol 4-Methoxybenzyl 15 4-Chlorbenzylalkohol 4-Chlorbenzyl 4-Nitrobenzylalkohol 4-Nitrobenzyl 4-Methylbenzylalkohol 4-Methylbenzyl 3.4- Dimethylbenzylalkohol 3,4-Dimethylbenzy1 3.4- Dimethoxybenzylalkohol 3,4-Dimethoxybenzyl 20 3,4-Dichlorbenzylalkohol 3,4-D.ichlorbenzen 2- Chlorbenzylalkohol 2-Chlorbenzyl 2-Me thylbenzylalkoho1 2-Methylbenzy1Allyl alcohol Allyl 4-Methoxybenzyl alcohol 4-Methoxybenzyl 15 4-Chlorobenzyl alcohol 4-Chlorobenzyl 4-Nitrobenzyl alcohol 4-Nitrobenzyl 4-Methylbenzyl alcohol 4-Methylbenzyl 3.4 , 4-D.ichlorobenzene 2- Chlorobenzyl alcohol 2-Chlorobenzyl 2-Me thylbenzyl alcohol 2-Methylbenzyl
Eksempel 4 25 På den i eksempel 3 beskrevne måde fremstilles de følgende ethere ved at anvende de tilsvarende alkoholer i stedet for methanol.Example 4 In the manner described in Example 3, the following ethers are prepared using the corresponding alcohols instead of methanol.
Cl 1 35 H2”-Q—Y8—”2—C <Cg3> 3Cl 1 35 H2 "-Q — Y8—" 2 — C <Cg3> 3
Cl 011 DK 171124 B1 21 oCl 011 DK 171124 B1 21 o
R_Smeltepunkt °CR melting point ° C
Allyl 57- 59 4-Methoxybenzyl 5 4-Chlorbenzyl 4-Nitrobenzyl 4-Methylbenzyl 3.4- Dimethylbenzyl 3.4- Dimethoxybenzyl 10 3,4-DAchlorbenzy] 4-Chlorphenyl 4-Methoxyphenyl 4-Methylphenyl 2-Chlorphenyl 15 4-NitrophenylAllyl 57-59 4-Methoxybenzyl 5 4-Chlorobenzyl 4-Nitrobenzyl 4-Methylbenzyl 3,4-Dimethylbenzyl 3,4-Dimethoxybenzyl 3,4-DAchlorobenzyl] 4-Chlorophenyl 4-Methoxyphenyl 4-Methylphenyl 2-Chlorophenyl 4-Nitrophenyl
Eksempel 5 N-tert-Butyl-3-chlor-5-cyano-b-methoxy-4-aminophenethylamin- -hydrochlorid 20 På den i eksempel 3 beskrevne måde omdannes oc-[(tert- butylamino)methyl]-4-amino-3-chlor-5-cyanobenzylalkohol til den i overskriften nævnte forbindelse, og på lignende måde fremstilles tillige: 25 Ar-CH-CH~-NH-R-HClExample 5 N-tert-Butyl-3-chloro-5-cyano-b-methoxy-4-aminophenethylamine hydrochloride In the manner described in Example 3, o - [(tert -butylamino) methyl] -4-amino 3-chloro-5-cyanobenzyl alcohol to the title compound, and similarly prepared also: Ar-CH-CH--NH-R-HCl
Ar_R_ 4-Amino-3-chlor-5-trifluormethyl- t-butyl 30 phenyl 4-Ami no-3-chlor-5-tr i fluormethyl- i-propy1 phenyl 35 DK 171124 B1 22Ar_R_ 4-Amino-3-chloro-5-trifluoromethyl-t-butyl phenyl 4-amino-3-chloro-5-tr in fluoromethyl-i-propylphenyl
Ar_R__ 4-Amino-3-chlor-5-H2N-CO-phenyl t-butyl 4-Amino-3-chlor-5-HO-CO-phenyl t-butyl 4-Amino-3-chlor-5-methylphenyl t-butyl 5 4-Amino-3-chlor-5-methoxyphenyl t-butyl 4-Amino-3-chlor-5-nitrophenyl t-butyl 4-Amino-3-chlor-5-CH2C)-CO-phenyl t-butyl 4-Amino-3-cyanophenyl t-butyl 10Ar_R__ 4-Amino-3-chloro-5-H2N-CO-phenyl t-butyl 4-Amino-3-chloro-5-HO-CO-phenyl t-butyl 4-Amino-3-chloro-5-methylphenyl t-butyl butyl 5 4-Amino-3-chloro-5-methoxyphenyl t-butyl 4-Amino-3-chloro-5-nitrophenyl t-butyl 4-Amino-3-chloro-5-CH 2 C) -CO-phenyl t-butyl 4 -Amino-3-cyanophenyl t-butyl 10
Eksempel 6 4-Amino-a-[(tert-butylamino)methyl]-3,5-dichlorbenzylalkohol- -acetatExample 6 4-Amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol acetate
En blanding indeholdende 1 g 4-amino-a-[(tert-bu-15 tylamino)methyl]-3,5-dichlorbenzylalkohol i 35 ml CH2C12 omrøres ved 10-15°C, og der tilsættes dråbevis 0,37 g Ac20 og 0,5 ml Et.jN. Derefter får reaktionsblandingen lov at varme op til stuetemperatur, og reaktionen følges ved tyndtlags-chromatografi til afslutningen. Blandingen inddampes til 20 tørhed i vakuum, og den gule viskose væske (1,5 g) omrøres med 50 ml ethylether, hvilket giver 0,84 g gult fast stof, smeltepunkt 128-131°C. Dette materiale viser sig ved kernemagnetisk resonansspektroskopi og ved neutralisering med alkali at være eddikesyresaltet. Ved at behandle 100 mg af 25 dette salt i 30 ml CH2C12 med 30 ml 10%'s vandig NaOH neutraliseres saltet. CH2Cl2-Opløsningen tørres (MgSC>4) og inddampes til tørhed i vakuum, hvilket giver den i overskriften nævnte viskose forbindelse.A mixture containing 1 g of 4-amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol in 35 ml of CH 2 Cl 2 is stirred at 10-15 ° C and 0.37 g Ac 2 O is added dropwise. 0.5 ml Et.jN. Then, the reaction mixture is allowed to warm to room temperature and the reaction is followed by thin layer chromatography to complete. The mixture is evaporated to dryness in vacuo and the yellow viscous liquid (1.5 g) is stirred with 50 ml of ethyl ether to give 0.84 g of yellow solid, mp 128-131 ° C. This material turns out to be the acetic acid salt by nuclear magnetic resonance spectroscopy and by neutralization with alkali. By treating 100 mg of this salt in 30 ml of CH 2 Cl 2 with 30 ml of 10% aqueous NaOH, the salt is neutralized. The CH 2 Cl 2 solution is dried (MgSC> 4) and evaporated to dryness in vacuo to give the title viscous compound.
Analyse: 30 Beregnet for C^4H2q02N2C12: C 52,67, H 6,32, N 8,78 Fundet: C 52,38, H 6,51, N 8,88.Calcd. For C ^ 4H₂qO₂N₂Cl₂: C 52.67, H 6.32, N 8.78 Found: C 52.38, H 6.51, N 8.88.
På samme måde får propionsyreanhydrid og smørsyrean-hydrid lov at reagere med henholdsvis 4-amino-a-[(tert.-bu-tylamino)methyl]-3,5-dichlorbenzylalkohol (A) og a-[(tert.-3 5 -butylamino)methyl]-3,5-dichlor-4-methylaminobenzylalkohol (B), hvilket giver propionatet og butyratet af A og B.Similarly, propionic anhydride and butyric anhydride are allowed to react with 4-amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol (A) and α - [(tert-3 -butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol (B) to give the propionate and butyrate of A and B.
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Eksempel 7Example 7
De følgende estere fremstilles ved hjælp af den i eksempel 6 beskrevne metode ved anvendelse af det passende syreanhydrid. Cl 5 R8RgN-^~A-CH-CH2-NH-C(CH3)3 , O-C-R,The following esters are prepared by the method described in Example 6 using the appropriate acid anhydride. Cl 5 R8 RgN- ^ A-CH-CH2-NH-C (CH3) 3, O-C-R,
Cl " x ^χ o 10 Rg Rg Ri2 Ή CH3 ch3 H C2H5 CH3 H n-C3H7 CH3 15 H 2-C3H7 CH3 H allyl CH3 ch3 ch3 ch3 H CH3 C2H5 H CH30-C0- CH3 20 H CH3 n-C4Hg C2H5 C2H5 CH3 n-C4Hg n-C4Hg CH3 25 1 35Cl "x ^ χ o 10 Rg Rg Ri2 Ή CH3 ch3 H C2H5 CH3 H n-C3H7 CH3 15 H 2-C3H7 CH3 H allyl CH3 ch3 ch3 ch3 H CH3 C2H5 H CH30-C0-CH3 20 H CH3 n-C4Hg C2H5 C2H5 CH3 n-C4Hg n-C4Hg CH3 25 1 35
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Ar-CB—CH2—NH—C (CH3) 3Ar-CB-CH2-NH-C (CH3) 3
o—CO Io — CO I
R12 5R12 5
Ar_R12 3,5-Dichlorphenyl 2-C-jH.j 4-Amino-3-chlor-5-cyanophenyl CH3 10 4-Amimo-3-chlor-5-trifluormethylphenyl CH3 4-Amino-3-chlor-5-H2NCO-phenyl CH3 4-Amino-3-chlor-5-HOOC-phenyl CH^ 4-Amino-3-chlor-5-methylpheny1 CH^ 4-Amino-3-brom-5-cyanopheny1 CH^ 15 4-Amino-3-chlor-5-CH3OCO-phenyl CH3 4-Amino-3-cyanophenyl t-C^HgAr_R12 3,5-Dichlorophenyl 2-C-1H 4-Amino-3-chloro-5-cyanophenyl CH 3 4-Amimo-3-chloro-5-trifluoromethylphenyl CH 3 4-Amino-3-chloro-5-H2NCO phenyl CH 3 4-Amino-3-chloro-5-HOOC-phenyl CH 2 -4-Amino-3-chloro-5-methylphenyl CH 2 4-Amino-3-bromo-5-cyanophenyl CH 4 4-Amino-3 chloro-5-CH 3 OCO-phenyl CH 3 4-Amino-3-cyanophenyl tC
Eksempel 8 20 4-Acetamido-a-[(tert-butylamino)methyl]-3-5-dlchlorbenzylalko- holacetat I 15 ml CH2CI2 suspenderes 1,57 g 4-acetamido-3" -[(tert-butylamino)methyl]-3,5-dichlorbenzylalkohol og omrøres, medens der tilsættes 1,2 g triethylamin i 30 ml CHjC^ 25 efterfulgt af 0,7 g eddikesyreanhydrid i 15 ml CI^C^. Blandingen omrøres i 20 timer og vaskes derefter med 100 ml 10%'s NaOH-opløsning. Den organiske fase fraskilles, tørres, (Na2SO^) og inddampes til tørhed i vakuum. Remanensen opløses i 30 ml ethanol, og der tilsættes spor af I^O, efterfulgt af 10%'s HCl 30 til syrning. Blandingen inddampes til tørhed i vakuum, og remanensen krystalliseres ud fra acetone/hexan (30 ml/5 ml).Example 8 4-Acetamido-α - [(tert-butylamino) methyl] -3-5-dichlorobenzyl alcohol acetate In 15 ml of CH 2 Cl 2, 1.57 g of 4-acetamido-3 "- [(tert-butylamino) methyl] are suspended. 3,5-dichlorobenzyl alcohol and stirring while adding 1.2 g of triethylamine in 30 ml of CH₂Cl₂ followed by 0.7 g of acetic anhydride in 15 ml of C CI₂. The mixture is stirred for 20 hours and then washed with 100 ml of 10% NaOH solution. The organic phase is separated, dried (Na 2 SO 4) and evaporated to dryness in vacuo. The residue is dissolved in 30 ml of ethanol and traces of 1 O are added, followed by 10% HCl 30 for acidification. The mixture is evaporated to dryness in vacuo and the residue is crystallized from acetone / hexane (30 ml / 5 ml).
Dette giver 1,35 g af den i overskriften nævnte forbindelse, smeltepunkt 254-257°C, under sønderdeling.This gives 1.35 g of the title compound, mp 254-257 ° C, with decomposition.
På lignende måde fremstilles ved at erstatte eddi-35 kesyreanhydrid med propionsyreanhydrid, smørsyreanhydrid og pivalinsyreanhydrid,det tilsvarende propionat, butyrat og pivalat.Similarly, by replacing acetic anhydride with propionic anhydride, butyric anhydride and pivalic anhydride, the corresponding propionate, butyrate and pivalate are prepared.
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Eksempel 9 g-[(tert-Butylamino)methyl]-3,5-dichlor-4-dimethylaminobenzyl- alkoholExample 9 g - [(tert-Butylamino) methyl] -3,5-dichloro-4-dimethylaminobenzyl alcohol
En blanding indeholdende 50 g p-fluoracetophenon og 5 150 ml 40%'s vandig dimethylamin opvarmes i en trykflaske ved 90-100°C. Efter to timers forløb dannes der en bleggul olie. Blandingen afkøles, og olien størkner. Det faste stof opsamles og vaskes godt med H20, hvilket giver 54,93 g p-dimethyl-aminoacetophenon, smeltepunkt 101-103°C efter heptanomkrystal-10 lisation. En prøve på 72 g af denne acetophenon opvarmes med 129 g N-chlorsuccinimid i 700 ml toluen ved tilbagesvalingstemperatur og holdes ved denne temperatur i 35 minutter. Blandingen afkøles og filtreres. Filterkagen vaskes med 200 ml toluen, og filtratet og vaskeopløsningen inddampes til tør-15 hed i vakuum, hvilket giver 66 g olie. Denne olie chromato-graferes på Si02 med 4 0%'s hexan/CH2Cl2, hvilket giver 38,9 g 3,5-dichlor-4-dimethylaminoacetophenon som en gul olie. 5,22g af denne olie tilsættes portionsvis til 2,75 g Se02 i 20 ml dioxan og 0,7 ml H20 ved 55-60°C. Denne blanding opvarmes 20 ved tilbagesvaling i 4,5 timer, afkøles og filtreres gennem kiseljord. Filterkagen vaskes med 20 ml dioxan. Dioxanop-løsningen afkøles til 15°C, og der tilsættes dråbevis 2,77 g t-butylamin, hvilket giver et gyldenbrunt bundfald. Efter omrøring i 15 minutter ved stuetemperatur fortyndes blandin-25 gen med 200 ml ethanol, afkøles til 5°C, hvorefter der tilsættes 7 g NaBH^ portionsvis. Efter 15 timers forløb behandles blandingen med 300-400 g is og 200 ml H20 på under 10°C. Blandingen omrøres for at opløse alle faste stoffer og ekstra-heres med 300 ml CH2C12. CH2Cl2-laget vaskes med 100 ml H20, 30 tørres (MgSO^) og inddampes til tørhed i vakuum, hvilket giver 5,6 g orangefarvet olie. Denne olie opløses i ethylether, affarves med aktiveret kul og inddampes til 15 ml. Ved afkøling fås der krystaller. Den i overskriften nævnte forbindelse opsamles som hvide krystaller, smeltepunkt 96-99°C.A mixture containing 50 g of p-fluoroacetophenone and 5 150 ml of 40% aqueous dimethylamine is heated in a pressure flask at 90-100 ° C. After two hours, a pale yellow oil is formed. The mixture is cooled and the oil solidifies. The solid is collected and washed well with H 2 O to give 54.93 g of p-dimethylaminoacetophenone, mp 101-103 ° C after heptanoma crystallization. A sample of 72 g of this acetophenone is heated with 129 g of N-chlorosuccinimide in 700 ml of toluene at reflux temperature and maintained at this temperature for 35 minutes. The mixture is cooled and filtered. The filter cake is washed with 200 ml of toluene and the filtrate and wash solution are evaporated to dryness in vacuo to give 66 g of oil. This oil is chromatographed on SiO 2 with 40% hexane / CH 2 Cl 2 to give 38.9 g of 3,5-dichloro-4-dimethylaminoacetophenone as a yellow oil. 5.22g of this oil are added portionwise to 2.75g of SeO2 in 20ml of dioxane and 0.7ml of H2O at 55-60 ° C. This mixture is heated at reflux for 4.5 hours, cooled and filtered through silica. The filter cake is washed with 20 ml of dioxane. The dioxane solution is cooled to 15 ° C and 2.77 g of t-butylamine are added dropwise to give a golden brown precipitate. After stirring for 15 minutes at room temperature, the mixture is diluted with 200 ml of ethanol, cooled to 5 ° C and then 7 g of NaBH 3 added portionwise. After 15 hours, the mixture is treated with 300-400 g of ice and 200 ml of H 2 O below 10 ° C. The mixture is stirred to dissolve all solids and extracted with 300 ml of CH 2 Cl 2. The CH 2 Cl 2 layer is washed with 100 ml H 2 O, dried (MgSO 4) and evaporated to dryness in vacuo to give 5.6 g of orange oil. This oil is dissolved in ethyl ether, decolorized with activated charcoal and evaporated to 15 ml. On cooling, crystals are obtained. The title compound is collected as white crystals, mp 96-99 ° C.
3535
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De følgende forbindelser fremstilles ved den samme fremgangsmåde:The following compounds are prepared by the same procedure:
Cl 5 RgRgN-V CH-CBj-NH-C (CHj) jCl 5 RgRgN-V CH-CBj-NH-C (CHj) j
Cl 08Cl 08
Rg Rg smp. °CRg Rg m.p. ° C
10 H 1_C4H9 olie H l-CgH13 62-64 H C2H5 209 (HCl-salt) H cyclopentyl olie 15 H cyclohexyl 194-198 (HCl-salt)H 1 -C 4 H 9 oil H 1-Cg H 13 62-64 H C 2 H 5 209 (HCl salt) H cyclopentyl oil 15 H cyclohexyl 194-198 (HCl salt)
Eksempel 10 q-[(tert-butylamino)methyl]-3 ,5-dichlor-4-methylaminobenzyl— 20 alkohol p-Methylaminoacetophenon fremstilles og chloreres som beskrevet i eksempel 19/ hvilket giver 3,5-dichlor-4-me-thylaminoacetophenon. Denne keton (18 g) i 200 ml CHCl^ omrøres , og der tilsættes dråbevis 4,65 ml Br2 i 50 ml CHCl^-25 Efter at tilsætningen er afsluttet, omrøres blandingen i y-derligere 20 minutter og opvarmes ved tiIbagesvali'ngstemperatur i 25 minutter. Blandingen afkøles, der tilsættes 100 ml H20, og mættet Na2C03-opløsning forsigtigt, indtil blandingen er neutral. CHCl^-laget skilles fra, og det vandige 30 lag ekstraheres yderligere med 100 ml CH2C19. De kombinerede ekstrakter tørres (MgSO^) og inddampes til tørhed, hvilket giver 16,3 g af phenacylbromidet. Dette materiale (16 g) i 80 ml EtOH omrøres ved 12-15°C, og der tilsættes dråbevis 40 ml t-butylamin. Efter at tilsætningen er afsluttet, omrøres bian- . 35 dingen i 10 minutter ved 12-15°C og afkøles derefter til 5°C, og der tilsættes forsigtigt 4 g NaBH^. Efter omrøring i 0,5Example 10 q - [(tert-Butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol p-Methylaminoacetophenone is prepared and chlorinated as described in Example 19 to give 3,5-dichloro-4-methylaminoacetophenone . This ketone (18 g) in 200 ml of CHCl4 is stirred and 4.65 ml of Br2 is added dropwise in 50 ml of CHCl4 -25. After the addition is complete, the mixture is stirred for another 20 minutes and heated at reflux temperature for 25 minutes. Cool the mixture, add 100 ml of H2 O and gently saturate Na 2 CO 3 solution until the mixture is neutral. The CHCl ^ layer is separated and the aqueous layer is further extracted with 100 ml of CH₂Cl₂. The combined extracts are dried (MgSO4) and evaporated to dryness to give 16.3 g of the phenacyl bromide. This material (16 g) in 80 ml of EtOH is stirred at 12-15 ° C and 40 ml of t-butylamine are added dropwise. After the addition is complete, stir the mixture. The mixture is cooled for 10 minutes at 12-15 ° C and then cooled to 5 ° C and 4 g of NaBH After stirring for 0.5
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DK 171124 B1 27 time får.blandingen lov til at varme op til stuetemperatur, og omrøringen fortsættes i 0,75 time. Blandingen hældes på 300 ml is under omrøring, og den fremkomne blanding ekstrahe-res med 300 ml CI^C^· Cl^C^-ekstrakten tørres (MgSO^) og 5 inddampes til tørhed i vakuum, hvilket giver en gul olie.The mixture is allowed to warm to room temperature and stirring is continued for 0.75 hours. The mixture is poured onto 300 ml of ice with stirring, and the resulting mixture is extracted with 300 ml of C ^ ^C Cl · Cl₂C₂ extract dried (MgSO ^) and evaporated to dryness in vacuo to give a yellow oil.
Triturering af denne remanens med ethylether giver 7,45 g af den i overskriften nævnte forbindelse, der smelter ved 98-100°C efter omkrystallisation ud fra ethylether.Trituration of this residue with ethyl ether gives 7.45 g of the title compound, which melts at 98-100 ° C after recrystallization from ethyl ether.
10 Eksempel 11 5-[2-(Tert-butylamino)-1-hydroxyethyl]anthanilonitrilExample 11 5- [2- (Tert-Butylamino) -1-hydroxyethyl] anthanilonitrile
En blanding indeholdende 48,86 g p-aminoacetophenon i 490 ml toluen omrøres, medens der portionsvis i løbet af 0,5 time tilsættes 64,5 g N-bromsuccinimid ved en temperatur 15 under 40°C. Efter 15 minutters forløb vaskes blandingen med 4 x 100 ml H2O. Opløsningen tørres (MgSO^) og inddampes til tørhed, hvilket giver 70,53 g 4-amino-3-bromacetophenon, smeltepunkt 59-62°C. 35 g af dette materiale i 180 ml tør dime- thulformamid omrøres og opvarmes ved tilbagesvaling med 17,57 — 20A mixture containing 48.86 g of p-aminoacetophenone in 490 ml of toluene is stirred while 64.5 g of N-bromosuccinimide are added portionwise over a period of 0.5 hours at a temperature below 40 ° C. After 15 minutes, the mixture is washed with 4 x 100 ml H 2 O. The solution is dried (MgSO4) and evaporated to dryness to give 70.53 g of 4-amino-3-bromoacetophenone, mp 59-62 ° C. 35 g of this material in 180 ml of dry dimethylformamide is stirred and heated at reflux with 17.57-20
Cu2(CN>2 i 6 timer under ^-atmosfære. Derefter tilsættes 180 ml FeCl3/HCl-opløsning (40 g FeCl^.6H2O/10 ml koncentreret HC1/60 ml H2o)og blandingen opvarmes i 20 minutter ved 60-70°C og hældes i 350 ml H20. Den vandige blanding ekstra-heres med CH-C1-, og ekstrakterne vaskes med H^O, mættet 25 Δ Δ iCu2 (CN> 2 for 6 hours under an atmosphere. Then 180 ml FeCl3 / HCl solution (40 g FeCl3 .6H2O / 10 ml concentrated HCl / 60 ml H2o) is added and the mixture is heated at 60-70 ° for 20 minutes. C and poured into 350 ml of H2 O. The aqueous mixture is extracted with CH-C1- and the extracts are washed with H 2 O, saturated 25 Δ Δ in
NaHCO^-opløsning og H20. CH2Cl2-opløsningen inddampes til tørhed i vakuum, og remanensen omkrystalliseres ud fra 95%'s EtOH, hvilket giver 14,25 g 4-amino-3-cyanoacetophenon, smeltepunkt 155-159°C. 4,8 g af dette produkt i 100 ml EtOAc og 30 100 ml CHCl^ indeholdende 13,32 g CuBr2 opvarmes ved tilbage svalingstemperatur i 20 minutter. Blandingen opvarmes yderligere, efter at der er tilsat 20 ml EtOH, og filtreres, medens den endnu er varm. Filterkagen vaskes med 50 ml varm 20%'s MeOH/CH2Cl2, og de forenede organiske opløsninger inddampes 35 til tørhed i vakuum. Remanensen omrøres i 25 ml CH2C12, og det faste stof opsamles og vaskes med CH^^/ hvilket giverNaHCO 3 solution and H2 O. The CH 2 Cl 2 solution is evaporated to dryness in vacuo and the residue is recrystallized from 95% EtOH to give 14.25 g of 4-amino-3-cyanoacetophenone, mp 155-159 ° C. 4.8 g of this product in 100 ml of EtOAc and 100 ml of CHCl ^ containing 13.32 g of CuBr2 are heated at reflux temperature for 20 minutes. The mixture is further heated after adding 20 mL of EtOH and filtered while still warm. The filter cake is washed with 50 ml of warm 20% MeOH / CH 2 Cl 2 and the combined organic solutions are evaporated to dryness in vacuo. The residue is stirred in 25 ml of CH 2 Cl 2 and the solid is collected and washed with CH
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DK 171124 B1 28 8,08 g phenacylbromid. Dette materiale tilsættes til 50 ml t-BuNH2 i 100 ml EtOH ved 5°C under N2~atmosfære. Efter 10 minutters omrøring får blandingen lov at varme op til 30°C hvilket giver en opløsning. Denne opløsning afkøles til 10°C, 5 og der tilsættes 4 g NaBH^ portionsvis. Efter 45 minutter får blandingen lov at varme op (42°C) og holdes ved 20°C, indtil varmen fra den eksoterme reaktion aftager. Derefter inddampes blandingen til tørhed, og remanensen vaskes med H20. Remanensen tørres og behandles med 200 ml kogende MeOH, og 10 den varme MeOH-opløsning filtreres. Filterkagen vaskes yderligere med varm MeOH, og de forenede filtrater inddampes, hvilket giver krystaller. Dette faste stof omkrystalliseres ud fra MeOH/2-PrOH, hvilket giver 2,08 mg af den i overskriften nævnte forbindelse, smeltepunkt 184-186°C.DK 171124 B1 28 8.08 g of phenacyl bromide. This material is added to 50 ml of t-BuNH 2 in 100 ml of EtOH at 5 ° C under N 2 atmosphere. After stirring for 10 minutes, the mixture is allowed to warm to 30 ° C to give a solution. This solution is cooled to 10 ° C, 5 g of NaBH 3 added portionwise. After 45 minutes, the mixture is allowed to warm (42 ° C) and kept at 20 ° C until the heat of the exothermic reaction decreases. The mixture is then evaporated to dryness and the residue is washed with H2 O. The residue is dried and treated with 200 ml of boiling MeOH and the hot MeOH solution filtered. The filter cake is further washed with hot MeOH and the combined filtrates are evaporated to give crystals. This solid is recrystallized from MeOH / 2-PrOH to give 2.08 mg of the title compound, mp 184-186 ° C.
15 På lignende måde fremstilles følgende beslægtede forbindelser, idet man går ud fra den rigtige acetophenon.Similarly, the following related compounds are prepared, starting from the correct acetophenone.
XX
20 RgRgU-/ y-CH-CH2-NHR3RgRgU- / γ-CH-CH2-NHR3
L 0HL 0H
25 Rg _Rg_R3_X SmP·_25 Rg _Rg_R3_X SmP · _
Η H 2~C3H7 H 155-159°CΗ H 2 ~ C3H7 H 155-159 ° C
H CH^ t-butyl H IR-spektrumH CH3 t-butyl H IR spectrum
CH3 CH3 t-butyl HCH3 CH3 t-butyl H
30 H t-butyl H30 H t-butyl H
H n-C^^ t-butyl HH n-C 18 t-butyl H
H 2-C3H7 t-butyl HH 2 -C 3 H 7 t-butyl H
H n-C^Hg t-butyl HH n -C 2 Hg t-butyl H
H CH3 2_C3H7 HH CH3 2_C3H7 H
35 ^2H5 ^2H5 t-butyl ClT-butyl Cl
n"C3H7 n_C3H7 t-butyl Cl 168-168,5°Cn "C3H7 n_C3H7 t-butyl Cl 168-168.5 ° C
t-butyl Cl IR-spektrum DK 171124 Bl 29t-butyl Cl IR spectrum DK 171124 B1 29
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Eksempel 12 3-Chlor-5-[2-(tert-butylamino)-1-hydroxyethyl]anthranlIon1tril I 100 ml toluen opvarmes 5 g 4-amino-3-cyanoacetophe-non ved tilbagesvalings temperatur i 20 minutter med 4,2 g N-5 -chlorsuccinimid. Blandingen afkøles og filtreres. Filtratet opvarmes yderligere ved tilbagesvalingstemperatur i 2 timer. Bundfaldet opsamles og vaskes med H^O. Det tilbageblevne faste stof behandles med 0,75 ml 6^/14 ml CHClj, der er sat til 75 ml CHCl^ og 4,9 ml EtOH. Blandingen inddampes til 10 tørhed, og remanensen opslaonmes med Cl^C^r opsamles og vaskes med CHjC^, hvilket giver 2,84 g phenacylbromid. Dette materiale får lov at reagere med t-BuNI^ og reduceres med NaBH^ ved hjælp af den i eksempel 18 beskrevne metode, hvilket giver den i overskriften nævnte forbindelse, smeltepunkt 128-138°C.Example 12 3-Chloro-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilonitrile In 100 ml of toluene, 5 g of 4-amino-3-cyanoacetopheone is heated at reflux for 20 minutes with 4.2 g of N -5-chlorosuccinimide. The mixture is cooled and filtered. The filtrate is further heated at reflux temperature for 2 hours. The precipitate is collected and washed with H 2 O. The residual solid is treated with 0.75 mL of 6 ^ / 14 mL of CHCl₂ added to 75 mL of CHCl ^ and 4.9 mL of EtOH. The mixture is evaporated to dryness and the residue is collected with Cl 2 Cl 2, collected and washed with CH 2 Cl 2 to give 2.84 g of phenacyl bromide. This material is allowed to react with t-BuNI 2 and reduced with NaBH 3 by the method described in Example 18 to give the title compound, mp 128-138 ° C.
15 På lignende måde fremstilles følgende forbindelser:Similarly, the following compounds are prepared:
ClCl
LL
R.R.N—V —CH-CH,-NH-R, 20 8 9 \-/ | 2 3R.R.N-V -CH-CH, -NH-R, 20 8 9 \ - / | 2 3
dT bHdT bH
26 J4_^9_^3_ Η H 2-propyl H CH^ t-butyl CH^ CH^ t-butyl H t-butyl 30 ^ ^ H 2-propyl t-butyl H n-butyl t-butyl 35 0 DK 171124 B1 30H 2 -propyl H CH 2 t-butyl CH 2 CH 2 t-butyl H t-butyl 30 H 2 H -propyl t-butyl H n-butyl t-butyl 35 0 DK 171124 B1 30
Eksempel 13 5-[2-(tert-butylamino)-l-hydroxyethyl]-3-chloranthranilinsyre-methylester-hydrochloridExample 13 5- [2- (tert-Butylamino) -1-hydroxyethyl] -3-chloranthranilic acid methyl ester hydrochloride
En blanding indeholdende 1,36 g 5-[2-(tert-butylami-5 no)-1-hydroxyethyl]-3-chloranthranilonitril i 21 ml 50%'s van dig NaOH og 21 ml EtOH omrøres under N2 i 0,5 time. Blandingen inddampes for at fjerne EtOH og syrnes til pH 3 og inddampes yderligere til tørhed. Remanensen behandles flere gange med MeOH og inddampes til tørhed. Det faste stof behandles 10 derefter med en opløsning fremstillet af 40 ml MeOH og 2 ml acetylchlorid. Efter henstand natten over filtreres blandingen, og filtratet inddampes til tørhed. Filterkagen vaskes også med MeOH og tilsættes til det forudgående filtrat. Remanensen opløses i acetone, filtreres og inddampes til tørhed. 15 Det faste stof tritureres med Et20 og filtreres, hvilket giver 1,49 g af den i overskriften nævnte forbindelse, smeltepunkt 95-115°C.A mixture containing 1.36 g of 5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthranilonitrile in 21 ml of 50% aqueous NaOH and 21 ml of EtOH is stirred under N hour. The mixture is evaporated to remove EtOH and acidified to pH 3 and further evaporated to dryness. The residue is treated several times with MeOH and evaporated to dryness. The solid is then treated with a solution made of 40 ml of MeOH and 2 ml of acetyl chloride. After standing overnight, the mixture is filtered and the filtrate is evaporated to dryness. The filter cake is also washed with MeOH and added to the preceding filtrate. The residue is dissolved in acetone, filtered and evaporated to dryness. The solid is triturated with Et 2 O and filtered to give 1.49 g of the title compound, mp 95-115 ° C.
På lignende måde fremstilles følgende beslægtede estere: 20 Cl R8R9N-(/y—eH-CH2-NH-R3 COOCH3 25 R8_^9_^3_ Η H 2-propyl H CH3 t-butyl 30 CH3 CH3 t-butyl H C2H5 t-butyl H n-propyl t-butyl H n-butyl t-butyl H allyl t-butyl 35 C2H5 C2H5 t-butyl n-C4H9 n-C4H9 t-butyl n-C3H7 n_C3H7 t-butyl DK 171124 B1 31Similarly, the following related esters are prepared: 20 C1 R8R9N - ([γ-eH-CH2-NH-R3 COOCH3 25 R8_9 9_3 3 Η H 2-propyl H CH3 t-butyl 30 CH3 CH3 t-butyl H C butyl H n-propyl t-butyl H n-butyl t-butyl H allyl t-butyl C2H5 C2H5 t-butyl n-C4H9 n-C4H9 t-butyl n-C3H7 n_C3H7 t-butyl DK 171124 B1 31
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Eksempel 14 2-Åmino-3-brom-5- [2- (tert-butylamlno) -1-hydroxyethyl] -benzamid En blanding indeholdende 1,02 g 3-brom-5-[2-(tert--butylamino)-1-hydroxyethyl] anthranilonitril i 25 ml H20, 5 5 ml 50%'s NaOH og 30 ml EtOH omrøres og opvarmes ved 55-65°C under N2~atmosfære i 1,25 time. Blandingen inddampes for at fjerne EtOH og ekstraheres med CHC1.J. CHCl^-ekstrakten vaskes med 25 ml 2%'s NaOH, tørres (MgSO^) og inddampes til tørhed, hvilket giver 0,74 g. Dette faste stof omrøres med pen- 10 tan og filtreres, hvilket giver 0,6 g af den i overskriften nævnte forbindelse, smeltepunkt 135-145°C.Example 14 2-Amino-3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] benzamide A mixture containing 1.02 g of 3-bromo-5- [2- (tert -butylamino) - 1-hydroxyethyl] anthranilonitrile in 25 ml of H2 O, 5 ml of 50% NaOH and 30 ml of EtOH is stirred and heated at 55-65 ° C under N 2 atmosphere for 1.25 hours. The mixture is evaporated to remove EtOH and extracted with CHCl 3. The CHCl4 extract is washed with 25 ml of 2% NaOH, dried (MgSO4) and evaporated to dryness to give 0.74 g. This solid is stirred with pentane and filtered to give 0.6 g of the title compound, mp 135-145 ° C.
På lignende måde fremstilles følgende forbindelser conh2 ----- ί CH-CH2-NH-C (ch3) 3Similarly, the following compounds are prepared conh2 ----- ί CH-CH2-NH-C (ch3) 3
I r OH XI r OH X
20 *8_^9_ H CH3 Cl H C2H5 Cl CH, CH-, Cl 25 3 3 H 2-C3H7 Cl H n-C4Hg Cl H CH3 Br c2h5 c2h5 Cl 30 n-C3H? n-C3H7 C1 n-C4H9 n-C4H9 Cl 3520 * 8_ ^ 9_ H CH3 Cl H C2H5 Cl CH, CH-, Cl 25 3 3 H 2-C3H7 Cl H n-C4Hg Cl H CH3 Br c2h5 c2h5 Cl 30 n-C3H? n-C3H7 C1 n-C4H9 n-C4H9 Cl 35
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Eksempel 15 4-Amino-N-tert-butyl-3,5-dichlor~3-(methylthio)phenethyl amin- -hydrochlorid På den i eksempel 3 beskrevne måde fremstilles N-5 -tert-butyl-3,5-dichlor-3-chlor-4-aminophenethylamin-hydro-chlorid. 11 g af dette produkt tilsættes portionsvis til 5 ml methylmercaptan i 100 ml tør ethylendichlorid ved -10 til 0°C. Blandingen omrøres og får lov gradvis at stige til stuetemperatur i løbet af et tidsrum på 4 dage. Blandingen 10 filtreres, filterkagen vaskes med 2 x 500 ml ethylendichlorid. Det faste stof dispergeres i 200 ml H20, afkøles til 5°C og gøres basisk med 6N NaOH-opløsning, hvilket giver en hvid olie, der ekstraheres med 3 x 100 ml CH2C12· CH2C12~ -ekstrakten tørres (MgS04) og inddampes til tørhed, hvilket 15 giver 6,41 g mørkegrøn olie. Denne olie omrøres i HCl/iso- propanol, og blandingen inddampes til tørhed. Remanensen omrøres i 35 ml ethylether i 16 timer og filtreres, hvilket giver 3,63 g, smeltepunkt 178-181°C, sønderdeling. Dette faste stof opvarmes i ethylacetat under tilbagesvaling og filtreres, 20 hvilket giver 2,07 g, smeltepunkt 188-193°C. Omkrystallisation ud fra 75 ml ethylendichlorid giver 1,45 g af den i overskriften nævnte forbindelse, smeltepunkt 191-196°C.Example 15 4-Amino-N-tert-butyl-3,5-dichloro-3- (methylthio) phenethyl amine hydrochloride In the manner described in Example 3, N-5-tert-butyl-3,5-dichloro is prepared. 3-chloro-4-aminophenethylamine-hydro-chloride. 11 g of this product are added portionwise to 5 ml of methyl mercaptan in 100 ml of dry ethylene dichloride at -10 to 0 ° C. The mixture is stirred and allowed to gradually rise to room temperature over a period of 4 days. The mixture is filtered, the filter cake washed with 2 x 500 ml of ethylene dichloride. The solid is dispersed in 200 mL of H 2 O, cooled to 5 ° C and basified with 6N NaOH solution to give a white oil extracted with 3 x 100 mL CH 2 Cl 2 · CH 2 Cl 2 extract (MgSO 4) and evaporated to dryness. , which gives 6.41 g of dark green oil. This oil is stirred in HCl / isopropanol and the mixture is evaporated to dryness. The residue is stirred in 35 ml of ethyl ether for 16 hours and filtered to give 3.63 g, mp 178-181 ° C, dec. This solid is heated under reflux in ethyl acetate and filtered to give 2.07 g, mp 188-193 ° C. Recrystallization from 75 ml of ethylene dichloride gives 1.45 g of the title compound, mp 191-196 ° C.
Den i overskriften nævnte forbindelse kan også fås ved at tilsætte et 5-10 foldigt overskud af natriummercaptid i te-25 trahydrofuran ved 0-10°C og følge ovenstående oparbejdning.The title compound may also be obtained by adding a 5-10 fold excess sodium captide in tetrahydrofuran at 0-10 ° C and following the above work-up.
Eksempel 16 På samme måde som beskrevet i eksempel 15 fremstilles de følgende thioestere ved i stedet for methylmercaptan 30 at anvende de tilsvarende mercaptaner:Example 16 In the same way as described in Example 15, the following thioesters are prepared by using the corresponding mercaptans instead of methyl mercaptan 30:
ClCl
LL
H2N ft 'y*CH-CH2-NH-R3 I SR *HC1H2N ft 'y * CH-CH2-NH-R3 I SR * HC1
Cl DK 171124 Bl 33Cl DK 171124 Bl 33
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R_R3 methyl 2-propyl ethyl t-butyl 2-propyl t-butyl 5 n-butyl t-butyl t-butyl t-butyl n-hexyl t-butyl phenyl t-butyl 10 Eksempel 17 På den i eksempel 15 beskrevne måde fås ved i stedet for N-tert-butyl-3,5-dichlor-3~chlor-4-aminophenethylamin--hydrochlorid at anvende den tilsvarende chlorforbindelse og tilsætte de passende mercaptaner de følgende thioethere:R_R3 methyl 2-propyl ethyl t-butyl 2-propyl t-butyl 5 n-butyl t-butyl t-butyl t-butyl n-hexyl t-butyl phenyl t-butyl Example 17 In the manner described in Example 15, instead of N-tert-butyl-3,5-dichloro-3-chloro-4-aminophenethylamine hydrochloride to use the corresponding chlorine compound and add the appropriate mercaptans to the following thioethers:
Cl SRCl SR
20 Ar R R3 4-Amino-3-cyanophenyl methyl 2-propyl 4-Methylamino-3,5-dichlorphenyl methyl t-butyl 4-Amino-3-chlor-5-trifluormethyl methyl t-butyl 25 4-Amino-3-chlor-5-cyanophenyl methyl t-butyl 4-Amino-3-chlor-5-cyanophenyl ethyl t-butyl 4-Acetamido-3,5-dichlorphenyl methyl t-butyl 4-Amino-3-chlor-5-H2NCO-phenyl methyl t-butyl 4-Amino-3-chlor-5-HOCO-phenyl methyl t-butyl 30 4-Amino-3-chlor-5-methylphenyl ethyl t-butyl 4-Amino-3-chlor-5-methoxyphenyl n-butyl t-butyl 4-Amino-3-chlor-5-nitrophenyl methyl t-butyl 4-Amino-3-chlor-5-CH30-C0-phenyl methyl t-butyl 35Ar R R 3 4-Amino-3-cyanophenyl methyl 2-propyl 4-Methylamino-3,5-dichlorophenyl methyl t-butyl 4-Amino-3-chloro-5-trifluoromethyl methyl t-butyl 4-Amino-3- chloro-5-cyanophenyl methyl t-butyl 4-Amino-3-chloro-5-cyanophenyl ethyl t-butyl 4-Acetamido-3,5-dichlorophenyl methyl t-butyl 4-Amino-3-chloro-5-H2NCO-phenyl methyl t-butyl 4-Amino-3-chloro-5-HOCO-phenyl methyl t-butyl 4-Amino-3-chloro-5-methylphenyl ethyl t-butyl 4-Amino-3-chloro-5-methoxyphenyl n - butyl t-butyl 4-Amino-3-chloro-5-nitrophenyl methyl t-butyl 4-Amino-3-chloro-5-CH30-CO-phenyl methyl t-butyl
OISLAND
DK 171124 B1 34DK 171124 B1 34
Eksempel 18 g- [ (Tert-butylamino)methyl]-3,5-dichlor-4-diethylaminobenzy1- -alkohol På den i eksempel 9 beskrevne måde oxideres 3,5-di-5 chlor-4-diethylaminoacetophenon med Se02 og alkyleres reduktivt med t-BuNI^/NaBH^, hvilket giver den i overskriften nævnte forbindelse, smeltepunkt 93-96°C.Example 18 g- [(Tert-Butylamino) methyl] -3,5-dichloro-4-diethylaminobenzyl-alcohol In the manner described in Example 9, 3,5-dichloro-4-diethylaminoacetophenone is oxidized with SeO2 and reductively alkylated with t-BuNI 2 / NaBH 4 to give the title compound, mp 93-96 ° C.
På lignende måde fremstilles g-[(tert-butylamino)-methyl]-3,5-dichlor-4-(n-dipropyl)aminobenzylalkohol og o-10 -t(tert-butylamino)methyl]-3,5-dichlor-4-(n-dibutyl)aminoben zylalkohol.Similarly, g - [(tert-butylamino) methyl] -3,5-dichloro-4- (n-dipropyl) aminobenzyl alcohol and o-10-t (tert-butylamino) methyl] -3,5-dichloro 4- (n-dibutyl) aminobenzyl alcohol.
Eksempel 19 15 4- (Allylamino) -a- [ (tert-butylamino) methyl]-3,5-dichlorbenzy 1- -alkohol 20 CHo*CHCH,NH-CHCH-NHC (CH,) 3 r*« (a) 17,0 g (0,168 mol) triethylamin tilsættes på én 25 gang til 105,9 g (0,875 mol) allylbromid under nitrogenatmosfære. Den fremkomne hvide emulsion giver en varmeudvikling til 70°C og bliver en tyk hvid fast masse inden for 5 minutter. Den opløsning, der dannes ved tilsætning af r^lOO ml DMF, omrøres i 1 time ved 70-95°C. En opløsning 30 af 25,0 g (0,088 mol) 4'-amino-2-brom-3',5'-dichloracetophe-non i 50 ml DMF tilsættes på én gang, og den fremkomne brune reaktionsblanding holdes på 80-90°C i 2 timer. Reaktionsforløbet kontrolleres hyppigt ved tyndtlagschromatografi (Si02/CH2Cl2/hexaner (1/1)), eftersom for langvarig opvarm-35 ning resulterer i sønderdeling af såvel udgangsmaterialer som produkter. Reaktionsblandingen hældes i 1,5 liter H20Example 19 4- (Allylamino) -a- [(tert-butylamino) methyl] -3,5-dichlorobenzy-1-alcohol 20 CH0 * CHCH, NH-CHCH-NHC (CH2) 3 r * '(a) 17.0 g (0.168 mole) of triethylamine are added at once to 105.9 g (0.875 mole) of allyl bromide under a nitrogen atmosphere. The resulting white emulsion gives a heat generation to 70 ° C and becomes a thick white solid mass within 5 minutes. The solution formed by the addition of r 1 100 ml of DMF is stirred for 1 hour at 70-95 ° C. A solution of 25.0 g (0.088 mol) of 4'-amino-2-bromo-3 ', 5'-dichloroacetopheone in 50 ml of DMF is added at one time and the resulting brown reaction mixture is maintained at 80-90 ° C for 2 hours. The course of the reaction is frequently controlled by thin layer chromatography (SiO 2 / CH 2 Cl 2 / hexanes (1/1)), since prolonged heating results in decomposition of both starting materials and products. The reaction mixture is poured into 1.5 liters of H 2 O
OISLAND
DK 171124 B1 35 og omrøres i 0,5 time. Efter en yderligere vandig triture-ring omrøres de tiloversblevne brune halvfaste stoffer med rvl50 ml CC14 i 0,5 time, hvorved der fås en suspension. De gulbrune faste stoffer opsamles ved filtrering og lufttørres, 5 hvilket giver 14,9 g (59,6%) udvundet phenacylbromidudgangs-materiale. CCl^-filtratet omrøres med MgSO^, filtreres og inddampes, hvilket som udbytte giver 9,42 g af en brun sirup. Lynchromatografi på en 23 x 5 cm kolonne af "Silica Gel 60" med gradient eluering (hexaner/C^C^ (10/0 —> 8/2) giver 10 to store fraktioner: (A) : 1,82 g (5,7%) af en ravfarvet sirup, der bevæger sig hurtigst, identificeret som 2-brom-3',5'-dichlor--4'-diallylaminoacetophenon ved hjælp af IR (rent) 1680 cm NMR (CDC13) S 7,93 (s, 2, AR-H), 6,25-5,55 (kompleks m, 2, 15 CH=) , 5,40-4,95 (kompleks ,.m, 4, CI^*) , 4,40 (s, 2, Cl^Br) og 3,87 (m, der ligner d, 4, J = 6 Hz, CH9N); kemisk ioni-seringsmassespektrum (M + H) = 3,62, og (B) : 3,49 g (12,2%) af en brun sirup, der bevæger sig langsomst, identificeret som 4'-(allylamino)-2-brom-3',5'- 20 -dichloracetophenon ved hjælp af IR (rent) 3330, 1670 cm NMR (CDC13) 6 7,83 (s, 2, AR-H), 6,35-5,65 (kompleks m, 1, CH=) , 5,50-5,00 (kompleks m, 2, (2^=) , 4,84 (br t, 1, NH) , 4,37 (s, 2, CH9Br) og 4,20 (br m, 2, CH9N); kemisk ioniserings-1 Δ massespektruk (M + H) = 322.DK 171124 B1 35 and stirred for 0.5 hour. After a further aqueous trituration, the remaining brown semi-solids are stirred with rvl50 ml CC14 for 0.5 hour to give a suspension. The tan solids are collected by filtration and air dried to give 14.9 g (59.6%) of recovered phenacyl bromide starting material. The CCl ^ filtrate is stirred with MgSO ^, filtered and evaporated to yield 9.42 g of a brown syrup. Flash chromatography on a 23 x 5 cm column of "Silica Gel 60" with gradient elution (hexanes / C CC ^ (10/0 -> 8/2) gives 10 two large fractions: (A): 1.82 g (5) , 7%) of a fast-moving amber syrup identified as 2-bromo-3 ', 5'-dichloro-4'-diallylaminoacetophenone by IR (pure) 1680 cm NMR (CDCl3) δ 7.93 (s, 2, AR-H), 6.25-5.55 (complex m, 2, CH =), 5.40-4.95 (complex, m, 4, Cl 2), 4, 40 (s, 2, Cl 2 Br) and 3.87 (m, similar to d, 4, J = 6 Hz, CH 9 N); chemical ionization mass spectrum (M + H) = 3.62 and (B): 3.49 g (12.2%) of a slow-moving brown syrup identified as 4 '- (allylamino) -2-bromo-3', 5'-20-dichloroacetophenone by IR (pure) 3330 , 1670 cm NMR (CDCl 3) δ 7.83 (s, 2, AR-H), 6.35-5.65 (complex m, 1, CH =), 5.50-5.00 (complex m, 2 , (2 + =), 4.84 (br t, 1, NH), 4.37 (s, 2, CH 9 Br) and 4.20 (br m, 2, CH 9 N); chemical ionization 1 Δ mass spectral pressure (M + H) = 322.
25 (b) En opløsning af 2,88 g (8,92 mmol) 4'-(allylamino)- -2-brom-31,51-dichloracetophenon i 10 ml tilsættes dråbevis i løbet af en time til en omrørt opløasning af 1,34 g (18,3 mmol) t-butylamin i 20 ml THF. Reaktionstemperaturen holdes på -24 til 13°C ved afkøling i et bad af tøris og CCl^. Den 30 fremkomne ravfarvede suspension opvarmes til stuetemperatur i løbet af 30 minutter og omrøres ved 21-22°C i 1,5 time.(B) A solution of 2.88 g (8.92 mmol) of 4 '- (allylamino) -2-bromo-31,51-dichloroacetophenone in 10 ml is added dropwise over an hour to a stirred solution of 1 34 g (18.3 mmol) of t-butylamine in 20 ml of THF. The reaction temperature is maintained at -24 to 13 ° C by cooling in a bath of dry ice and CCl The resulting amber suspension was warmed to room temperature over 30 minutes and stirred at 21-22 ° C for 1.5 hours.
2,80 g (44,6 mmol) natriumcyanoborhydrid tilsættes i to portioner i løbet af 5 minutter, hvilket giver en tyk gyldenbrun suspension med varmeudvikling fra 22 til 25°C. Der til-35 sættes dråbevis /vlO ml iseddike, så at der gradvis dannes en gul opløsning, der omrøres ved stuetemperatur i 3 dage.2.80 g (44.6 mmol) of sodium cyanoborohydride are added in two portions over 5 minutes to give a thick golden brown suspension with heat generation from 22 to 25 ° C. 35 drops / 100 ml of glacial acetic acid are added to gradually form a yellow solution, which is stirred at room temperature for 3 days.
36 DK 171124 B136 DK 171124 B1
Reaktionsblandingen hældes i en opløsning af 100 ml H^O og 100 ml mættet vandig NaCl, som derefter indstilles til pH 7 med 10%'s Na^O^ og ekstraheres tre gange med Et20. De forenede ekstrakter rystes med to portioner fortyndet vandig 5 HC1, som forenes, neutraliseres med 10%'s Na2C03 til pH 8 og ekstraheres tre gange med Et20. Efter omrøring af de kombinerede ekstrakter med vandfrit K2C03 filtreres den bleggulgrønne opløsning og inddampes, hvilket som udbytte giver 2,04 g (72,1%) af en bleggul sirup, der identificeres som 10 4-(allylamino)-a-[(tert-butylamino)methyl]-3,5-dichlorbenzyl-alkohol ved hjælp af IR (rent) 3400 cm NMR (CDCl^) S 7,32 (s, 2, Ar-H), 6,35-5,60 (kompleks m, 1, CH=), 5,45-4,95 (kompleks m, 2, CH2=), 4,52 (d af d, 1, Ar-CH), 3,97 (overlappende m, 3, Ar-NHCH2), 3,03 (br s, 2, NH og OH), 2,68 (m, 2, 15 CH2N) og 1,13 (s, 9, C(CH3)3); kemisk ioniseringsmassespektrum (M + M)+ = 317. CH2Cl2/CH3OH/konc. NH4OH (80/19/1) viser en større plet (Rf = 0,6) med spor af 9 urenheder. Siruppen krystalliserer gradvis til et gyldenbrunt fast stof ved henstand.The reaction mixture is poured into a solution of 100 ml of H 2 O and 100 ml of saturated aqueous NaCl, which is then adjusted to pH 7 with 10% Na 2 O 3 and extracted three times with Et 2 O. The combined extracts are shaken with two portions of dilute aqueous 5 HCl, which are combined, neutralized with 10% Na 2 CO 3 to pH 8 and extracted three times with Et 2 O. After stirring the combined extracts with anhydrous K 2 CO 3, the pale yellow-green solution is filtered and evaporated to yield 2.04 g (72.1%) of a pale yellow syrup identified as 4- (allylamino) -α - [(tert) -butylamino) methyl] -3,5-dichlorobenzyl alcohol by IR (neat) 3400 cm NMR NMR (CDCl ^) δ 7.32 (s, 2, Ar-H), 6.35-5.60 (complex m, 1, CH =), 5.45-4.95 (complex m, 2, CH 2 =), 4.52 (d of d, 1, Ar-CH), 3.97 (overlapping m, 3, Ar -NHCH 2), 3.03 (br s, 2, NH and OH), 2.68 (m, 2, CH 2 N) and 1.13 (s, 9, C (CH 3) 3); chemical ionization mass spectrum (M + M) + = 317. CH 2 Cl 2 / CH 3 OH / conc. NH 4 OH (80/19/1) shows a larger stain (Rf = 0.6) with traces of 9 impurities. The syrup gradually crystallizes to a golden brown solid upon standing.
2020
Eksempel 20 g-[(Tert-butylamino)methyl]-3,5-dichlor-4-diallylaminobenzyl- -alkohol 25 -Example 20 g - [(Tert-butylamino) methyl] -3,5-dichloro-4-diallylaminobenzyl-alcohol
Cl <CH2=CHCH2) 2-N—^^-CHCH2-NH-C (CH3) 3Cl <CH2 = CHCH2) 2-N - ^^ - CHCH2-NH-C (CH3) 3
Cl OHCl OH
3030
Den i overskriften nævnte forbindelse fremstilles under anvendelse af en udgangsmaterialefraktion (A) fra eksempel 19(a) og ved den i eksempel 19(b) beskrevne fremgangsmåde. Den bleggule sirup, der gradvis krystalliserer 35 ved henstand, identificeres ved hjælp af IR (rent) 3300 og 1630 cm-1; NMR (CDC13) δ 7,26 (s, 2, Ar-H), 6,23-5,54 (kom- DK 171124 B1 37 pleks m, 2, CH=), 5,32-4,87 (kompleks m, 4, CH2=), 4,48 (m, 1, Ar-CH), 3,78 (m, der ligner d, 4, J = 6 Hz, Ar-NCH2), 3,4-2,0 (br S, 2, NH og OH), 2,62 (m, 2, CH2N) og 1,13 (3, 9, C(CH3)3); kemisk ioniseringsmassespektrum (M + H)+ = 357 5 svarende til det, der forventes for den i overskriften nævnte forbindelse.The title compound is prepared using a starting material fraction (A) of Example 19 (a) and by the method described in Example 19 (b). The pale yellow syrup that gradually crystallizes on standing is identified by IR (pure) 3300 and 1630 cm -1; NMR (CDCl3) δ 7.26 (s, 2, Ar-H), 6.23-5.54 (com 171124 B1 37 instead of m, 2, CH =), 5.32-4.87 (complex m, 4, CH 2 =), 4.48 (m, 1, Ar-CH), 3.78 (m, similar to d, 4, J = 6 Hz, Ar-NCH 2), 3.4-2.0 (br S, 2, NH and OH), 2.62 (m, 2, CH 2 N) and 1.13 (3, 9, C (CH 3) 3); chemical ionization mass spectrum (M + H) + = 357 5 similar to that expected for the title compound.
10 15 20 25 30 3510 15 20 25 30 35
Claims (4)
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US18125580A | 1980-08-25 | 1980-08-25 | |
US18125480A | 1980-08-25 | 1980-08-25 | |
US18125580 | 1980-08-25 | ||
US18125480 | 1980-08-25 | ||
US06/219,054 US4404222A (en) | 1980-08-25 | 1980-12-22 | Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and improving the efficiency of feed utilization thereby |
US21905580 | 1980-12-22 | ||
US21905480 | 1980-12-22 | ||
US06/219,055 US4407819A (en) | 1980-08-25 | 1980-12-22 | Phenylethanolamine derivatives and acid addition salts thereof for the depression of fat deposition in warm blooded animals |
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DD (1) | DD208758A5 (en) |
DK (1) | DK171124B1 (en) |
GR (1) | GR75746B (en) |
HU (1) | HU188686B (en) |
LU (1) | LU83580A1 (en) |
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RO (1) | RO85450B (en) |
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- 1981-08-24 HU HU812451A patent/HU188686B/en not_active IP Right Cessation
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- 1981-08-24 PT PT73560A patent/PT73560B/en not_active IP Right Cessation
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NZ196249A (en) | 1984-09-28 |
GR75746B (en) | 1984-08-02 |
DD208758A5 (en) | 1984-04-11 |
PT73560B (en) | 1982-11-09 |
ATA368581A (en) | 1985-04-15 |
RO85450B (en) | 1984-11-30 |
AT379055B (en) | 1985-11-11 |
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RO85450A (en) | 1984-11-25 |
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