NO332252B1 - Propionamide derivatives and pharmaceutical compositions useful in the treatment or prevention of androgen deficiency. - Google Patents

Propionamide derivatives and pharmaceutical compositions useful in the treatment or prevention of androgen deficiency. Download PDF

Info

Publication number
NO332252B1
NO332252B1 NO20060227A NO20060227A NO332252B1 NO 332252 B1 NO332252 B1 NO 332252B1 NO 20060227 A NO20060227 A NO 20060227A NO 20060227 A NO20060227 A NO 20060227A NO 332252 B1 NO332252 B1 NO 332252B1
Authority
NO
Norway
Prior art keywords
methyl
nitrophenyl
hydroxy
alkyl
propionamide
Prior art date
Application number
NO20060227A
Other languages
Norwegian (no)
Other versions
NO20060227L (en
Inventor
Olli Tormakangas
Paavo Huhtala
Arja Karjalainen
Jari Ratilainen
Anu Moilanen
Gerd Wohlfahrt
Pekka Kallio
Original Assignee
Orion Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FI20030958A external-priority patent/FI20030958A0/en
Application filed by Orion Corp filed Critical Orion Corp
Publication of NO20060227L publication Critical patent/NO20060227L/en
Publication of NO332252B1 publication Critical patent/NO332252B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Det er beskrevet forbindelser med formel (l) hvor R1 til R4, X og A er som definert i kravene, foruten farmasøytisk akseptable salter og estere av disse. Forbindelsene med formel (l) kan brukes som vevsselektive androgenreseptorinodulatorer (SARM) og kan brukes i hormonell terapi, for eksempel ved behandling eller forebygging av hannlig hypogonadisme og aldersrelaterte tilstander så som andropause.Compounds of formula (1) are described in which R1 to R4, X and A are as defined in the claims, in addition to pharmaceutically acceptable salts and esters thereof. The compounds of formula (I) may be used as tissue-selective androgen receptor inactivators (SARMs) and may be used in hormonal therapy, for example in the treatment or prevention of male hypogonadism and age-related conditions such as andropause.

Description

O ppfinnelsens område The field of the invention

Den foreliggende oppfinnelsen angår terapeutisk aktive forbindelser og farmasøytisk akseptable salter og estere av disse som kan brukes ved behandlingen av nukleær reseptor, da spesielt steroidreseptor og mer spesielt androgenreseptor (AR) -avhengige tilstander og farmasøytiske sammensetninger som inneholder slike forbindelser. Spesielt beskriver oppfinnelsen nye ikke-steroidale propionanilidstrukturerte forbindelser med anvendbarhet som vevsselektive androgenreseptormodulatorer (SARM). Forbindelsene ifølge den foreliggende oppfinnelsen som har AR-agonistaktivitet, kan brukes ved hormonell terapi, spesielt ved behandling og for å forebygge tilstander som hannlig hypogonadisme og aldersrelaterte tilstander så som andropause. The present invention relates to therapeutically active compounds and pharmaceutically acceptable salts and esters thereof which can be used in the treatment of nuclear receptor, especially steroid receptor and more particularly androgen receptor (AR)-dependent conditions and pharmaceutical compositions containing such compounds. In particular, the invention describes new non-steroidal propionanilide-structured compounds with applicability as tissue-selective androgen receptor modulators (SARMs). The compounds according to the present invention which have AR agonist activity can be used in hormonal therapy, especially in the treatment and prevention of conditions such as male hypogonadism and age-related conditions such as andropause.

Bakgrunn for oppfinnelsen Background for the invention

De nukleære hormonreseptorene er en gruppe eller familie av ligandinduserbare transkripsjonsfaktorer hvor de forskjellige proteinene inngår i flere forskjellige fysiologiske og utviklingsmessige funksjoner. I løpet av de siste 20 årene er det blitt identifisert mer enn seksti strukturelt og funksjonelt beslektede proteiner som hører til denne familien. Nukleærhormonreseptorfamilien inkluderer i tillegg til de klassiske steroidreseptorene (østrogenreseptor, progesteronreseptor, androgenreseptor, glukokortikoidreseptor og mineralokortikoidreseptor) også reseptorer for eksempel for tyroidhormon, vitamin D og retinoider. Videre er en underklasse av såkalt orfanreseptorer for hvilke man hittil ikke har maktet å identifisere noen ligander, hører til denne proteinfamilien. Se Mangelsdorf et al, Cell (1995) 83(6): 835-839 og referanser som der er angitt. Det foregår en intens forskning for å identifisere nye modulatorer av disse proteinene, hvor det endelige målet er å finne nye terapier og behandlingsmuligheter for tilstander og sykdommer som er modulert av nukleære/steroide reseptorer. The nuclear hormone receptors are a group or family of ligand-inducible transcription factors where the different proteins are involved in several different physiological and developmental functions. Over the past 20 years, more than sixty structurally and functionally related proteins belonging to this family have been identified. In addition to the classic steroid receptors (estrogen receptor, progesterone receptor, androgen receptor, glucocorticoid receptor and mineralocorticoid receptor), the nuclear hormone receptor family also includes receptors for thyroid hormone, vitamin D and retinoids, for example. Furthermore, a subclass of so-called orphan receptors for which no ligands have been identified so far belong to this protein family. See Mangelsdorf et al, Cell (1995) 83(6): 835-839 and references therein. Intense research is taking place to identify new modulators of these proteins, where the ultimate goal is to find new therapies and treatment options for conditions and diseases that are modulated by nuclear/steroid receptors.

Steroidale androgener er i flere tiår blitt brukt for behandling av sykdommer som skyldes sviktende androgenvirkning. De er også blitt brukt i forbindelse med hormonerstatningsterapi i forbindelse med aldring hos menn og ved regulering av hannlig fruktbarhet. De for tiden tilgjengelige steroidale androgenene så som syntetisert testosteron og dets derivater, har imidlertid alvorlige begrensninger. Testosteron brytes raskt ned av leveren og har således lav systemisk biotilgjengelighet etter oral administrering. Videre har oralt tilgjengelige testosteronpreparater, for eksempel metyltestosteron, blitt assosiert med endringer av leverens funksjon. Det er gjort flere forskjellige forsøk på å unngå disse ulempene ved steroidale androgener som terapeutiske midler, men uten særlig gode resultater. De for tiden brukte testosteronformuleringer eller preparater som brukes i klinisk praksis inkluderer for eksempel injeksjoner, plastre og geler. Steroidal androgens have been used for several decades for the treatment of diseases caused by insufficient androgen action. They have also been used in connection with hormone replacement therapy in connection with aging in men and in the regulation of male fertility. However, the currently available steroidal androgens such as synthesized testosterone and its derivatives have serious limitations. Testosterone is quickly broken down by the liver and thus has low systemic bioavailability after oral administration. Furthermore, orally available testosterone preparations, such as methyltestosterone, have been associated with changes in liver function. Several different attempts have been made to avoid these disadvantages of steroidal androgens as therapeutic agents, but without particularly good results. The currently used testosterone formulations or preparations used in clinical practice include, for example, injections, patches and gels.

I de senere år har det vært en voksende interesse for å utvikle ikke-steroidale modulatorer for steroidreseptorer for terapeutisk bruk. Det er blitt vist at ikke-steroidale ligander har eller kan ha bedre reseptorselektivitet og bedre fysiokjemiske, farmakokinetiske og farmakologiske egenskaper. For androgenreseptoren (AR), er nå ikke-steroidale antagonister (antiandrogener) blitt brukt klinisk for å motvirke uønskede virkninger av for høyt nivå av androgener. I motsetning til dette, er ikke-steroidale AR-agonister som vil kunne ha et potensial ved behandling av sykdommer som er et resultat av androgensvikt, bare nylig blitt rapportert. Ikke desto mindre så er de strukturelle elementene i ikke-steroidale ligander som ville kunne føre til optimal agonistaktivitet og vevsselektivitet, dårlig definert. In recent years there has been a growing interest in developing non-steroidal steroid receptor modulators for therapeutic use. It has been shown that non-steroidal ligands have or can have better receptor selectivity and better physiochemical, pharmacokinetic and pharmacological properties. For the androgen receptor (AR), non-steroidal antagonists (antiandrogens) have now been used clinically to counteract the adverse effects of excessive levels of androgens. In contrast, nonsteroidal AR agonists that may have potential in the treatment of diseases resulting from androgen deficiency have only recently been reported. Nevertheless, the structural elements of nonsteroidal ligands that would lead to optimal agonist activity and tissue selectivity are poorly defined.

Ikke-steroidale propionanilider med androgenreseptormodulerende aktivitet er blitt beskrevet for eksempel i patentpublikasjonene EP 100172, EP 253503, WO 98/53826 og WO 02/16310. Utformingen av propionanilidstrukturerte AR-modulatorer er blitt konsentrert omkring forbindelser hvor anilidringen er blitt substituert med to elektrontiltrekkende substituenter så som halogen, cyano, trifluormetyl eller nitro, ettersom det er blitt rapportert at en slik substitusjon bedrer den androgenreseptorbindende affiniteten til liganden. Se for eksempel Tucker, H. et al, J. Med. Chem., 1988, 31, 954-959. Non-steroidal propionanilides with androgen receptor modulating activity have been described for example in patent publications EP 100172, EP 253503, WO 98/53826 and WO 02/16310. The design of propionanilide-structured AR modulators has been concentrated around compounds where the anilide ring has been substituted with two electron-withdrawing substituents such as halogen, cyano, trifluoromethyl or nitro, as it has been reported that such a substitution improves the androgen receptor binding affinity of the ligand. See, for example, Tucker, H. et al, J. Med. Chem., 1988, 31, 954-959.

Sammendrag av oppfinnelsen Summary of the invention

Man har nå funnet at forbindelser med formel (I) er potente nukleærreseptor-modulatorer, da spesielt androgenreseptormodulatorer. Forbindelser med formel (I) har bemerkelsesverdig høy affinitet og aktivitet i androgenreseptorer og har anvendbarhet som vevsselektive androgenreseptormodulatorer (SARM). Forbindelsene med formel (I) som har AR-agonistaktivitet har vist seg å være spesielt godt egnet for bruk i hormonell terapi, spesielt ved behandling eller forebygging av tilstander så som hannlig hypogonadisme og aldersrelaterte tilstander så som andropause, for eksempel for å tilveiebringe vevsselektive androgene eller anabole effekter. Ifølge en foretrukket utførelse av oppfinnelsen, så vil de fordelaktige androgene effektene for eksempel oppnås uten en samtidig skadelig stimulering av prostata. Forbindelser ifølge oppfinnelsen har generelt også svake til moderate effekter i progesteronreseptoren, da spesielt antagonistisk effekt. Det kan antas at en samtidig progesteronantagonisme vil være fordelaktig, ettersom en progesteronantagonisme har vist seg å bedre glukosetoleransen i visse dyremodeller. Forbindelsene ifølge oppfinnelsen er også trygge og har lave risikofaktorer og har tilstrekkelig vannløselighet. It has now been found that compounds of formula (I) are potent nuclear receptor modulators, especially androgen receptor modulators. Compounds of formula (I) have remarkably high affinity and activity at androgen receptors and have utility as tissue-selective androgen receptor modulators (SARMs). The compounds of formula (I) having AR agonist activity have been found to be particularly well suited for use in hormonal therapy, particularly in the treatment or prevention of conditions such as male hypogonadism and age-related conditions such as andropause, for example to provide tissue-selective androgens or anabolic effects. According to a preferred embodiment of the invention, the beneficial androgenic effects will for example be achieved without a simultaneous harmful stimulation of the prostate. Compounds according to the invention generally also have weak to moderate effects in the progesterone receptor, particularly antagonistic effects. It can be assumed that a concomitant progesterone antagonism would be beneficial, as a progesterone antagonism has been shown to improve glucose tolerance in certain animal models. The compounds according to the invention are also safe and have low risk factors and have sufficient water solubility.

Forbindelsene ifølge den foreliggende oppfinnelsen har en struktur som angitt ved formel (I) The compounds according to the present invention have a structure as indicated by formula (I)

hvor where

Ri er metyl, etyl, hydroksymetyl eller -(CH2)n-CHO, hvor n er 0-6; R 1 is methyl, ethyl, hydroxymethyl or -(CH 2 ) n -CHO, where n is 0-6;

R2er nitro, cyano eller halogen; R 2 is nitro, cyano or halogen;

R3er hydrogen, (Ci-C7)alkyl eller halo(Ci-C7)alkyl; R 3 is hydrogen, (C 1 -C 7 )alkyl or halo(C 1 -C 7 )alkyl;

R4er hydrogen, (Ci-C7)alkyl, COR]0eller S02R]3; R 4 is hydrogen, (C 1 -C 7 )alkyl, COR 1 O or SO 2 R 3 ;

X er O eller NH; X is O or NH;

A er en gruppe valgt fra: A is a group selected from:

hvor R5, R6, R7, R« og R9uavhengig av hverandre er hydrogen, halogen, nitro, cyano, (Ci-C7)alkyl, halo(Ci-C7)alkyl, cyano(Ci-C7)alkyl, amino, mono- eller di(Ci-C7)alkylamino, amino(Ci-C7)alkyl, hydroksy(Ci-C7)alkyl, (Ci-C7)alkoksy(Ci-C7)alkyl, -NHCOR10, -N(CORi0)2, -CORn, -OR12, -OS02Ri3, -S02Ri4, -NHSO2R13eller -SR15; eller R5og R6, R6og R7, R7 og Rs eller Rg og R9kan sammen med ethvert av de ringatomene til hvilke de er knyttet, danne en kondensert 5- til 7-leddet alifatisk eller aromatisk karbosyklisk ring, eller en kondensert 5- til 7-leddet heterosyklisk ring som inneholder 1 til 3 heteroatomer valgt fra N, O og S; where R5, R6, R7, R« and R9 are independently hydrogen, halogen, nitro, cyano, (Ci-C7)alkyl, halo(Ci-C7)alkyl, cyano(Ci-C7)alkyl, amino, mono- or di(Ci-C7)alkylamino, amino(Ci-C7)alkyl, hydroxy(Ci-C7)alkyl, (Ci-C7)alkoxy(Ci-C7)alkyl, -NHCOR10, -N(CORi0)2, -CORn, -OR 12 , -OSO 2 Ri 3 , -SO 2 Ri 4 , -NHSO 2 R 13 or -SR 15 ; or R5 and R6, R6 and R7, R7 and Rs or Rg and R9 may, together with any of the ring atoms to which they are attached, form a fused 5- to 7-membered aliphatic or aromatic carbocyclic ring, or a fused 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

Rio og Rn er uavhengig av hverandre (Ci-C7)alkyl, (C2-C7)alkenyl, halo(Ci-C7)alkyl, amino(Ci-C7)alkyl, mono- eller di(Ci-C7)alkylamino(Ci-C7)alkyl, (C6-Cio)aryl, -N(Rj6)2eller -OR17; Rio and Rn are independently (Ci-C7)alkyl, (C2-C7)alkenyl, halo(Ci-C7)alkyl, amino(Ci-C7)alkyl, mono- or di(Ci-C7)alkylamino(Ci- C 7 -alkyl, (C 6 -C 10 )aryl, -N(R 6 ) 2 or -OR 17 ;

Ri2og Ri5er uavhengig av hverandre hydrogen, (Ci-C7)alkyl, (C2-C7)alkenyl, halo(Ci-C7)alkyl, amino(Ci-C7)alkyl, mono- eller di(Ci-C7)alkylamino(Ci-C7)alkyl, (C6-Cio)aryl, -COR]8; R 12 and R 15 are independently hydrogen, (C 1 -C 7 )alkyl, (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl, amino(C 1 -C 7 )alkyl, mono- or di(C 1 -C 7 )alkylamino(C 1 -C 7 C 7 -alkyl, (C 6 -C 10 )aryl, -COR] 8 ;

Ri3og Ru er uavhengig av hverandre (Ci-C7)alkyl eller (C2-C7)alkenyl, halo(Ci-C7)alkyl eller (C6-Ci0)aryl; R 13 and R 1 are independently (C 1 -C 7 )alkyl or (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl or (C 6 -C 10 )aryl;

Ri6og Rn er uavhengig av hverandre hydrogen, (Ci-C7)alkyl, (C2-C7)alkenyl, halo(Ci-C7)alkyl, amino(Ci-C7)alkyl eller (C6-Ci0)aryl; R 16 and R n are independently hydrogen, (C 1 -C 7 )alkyl, (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl, amino(C 1 -C 7 )alkyl or (C 6 -C 10 )aryl;

Ris er (Ci-C7)alkyl, (C2-C7)alkenyl, halo(Ci-C7)alkyl eller (C6-Ci0)aryl; Rice is (C 1 -C 7 )alkyl, (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl or (C 6 -C 10 )aryl;

R19og R20er uavhengig av hverandre hydrogen, halogen, (Ci-C7)alkyl eller (C2-C7)alkenyl; R 19 and R 20 are independently hydrogen, halogen, (C 1 -C 7 )alkyl or (C 2 -C 7 )alkenyl;

og farmasøytisk akseptable salter og estere av slike forbindelser. and pharmaceutically acceptable salts and esters of such compounds.

En klasse av foretrukne forbindelser er de med formel (Ib) hvor Ri, R2, R3, R4, R5, R6, R7, R8og R9er som definert ovenfor. A class of preferred compounds are those of formula (Ib) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined above.

En annen klasse av foretrukne forbindelser er de med formel (I) eller (Ib) hvor Ri er metyl eller hydroksymetyl og R2er nitro eller cyano. En annen klasse av foretrukne forbindelser er de med formel (I) eller (Ib) hvor R4er hydrogen og R3er metyl. En ytterligere klasse av foretrukne forbindelser er de med formel (I) eller (Ib) hvor R5, R6, R7, R8og R9uavhengig av hverandre er hydrogen, halogen, nitro, cyano, (Ci-C7)alkyl, (Ci-C7)alkoksy, halo(Ci-C7)alkyl, hydroksy(Ci-C7)alkyl eller -NHCOR10, hvor Rio er (Ci-C7)alkyl, halo(Ci-C7)alkyl, hydroksy eller (Ci-C7)alkoksy. Spesielt foretrukket er forbindelser med formel (I) eller (Ib) hvor minst en av R5, R6, R7, Rs og R9er et halogen, fortrinnsvis fluor. Mest foretrukket er det at minst to av R5, R6, R7, R8og R9er valgt fra gruppen bestående av halogen, fortrinnsvis fluor, cyano og acetamido. Det er spesielt foretrukket at R6er halogen, da spesielt fluor. Another class of preferred compounds are those of formula (I) or (Ib) where R 1 is methyl or hydroxymethyl and R 2 is nitro or cyano. Another class of preferred compounds are those of formula (I) or (Ib) where R 4 is hydrogen and R 3 is methyl. A further class of preferred compounds are those of formula (I) or (Ib) where R 5 , R 6 , R 7 , R 8 and R 9 independently of each other are hydrogen, halogen, nitro, cyano, (C 1 -C 7 )alkyl, (C 1 -C 7 )alkyl . Particularly preferred are compounds of formula (I) or (Ib) where at least one of R5, R6, R7, R5 and R9 is a halogen, preferably fluorine. It is most preferred that at least two of R5, R6, R7, R8 and R9 are selected from the group consisting of halogen, preferably fluorine, cyano and acetamido. It is particularly preferred that R6 is halogen, then especially fluorine.

Forbindelsene i følge den foreliggende oppfinnelsen er anvendelige i en fremgangsmåte for hormonell terapi som omfatter å administrere en pasient som har behov for dette en terapeutisk effektiv mengde av en forbindelse med formel (I). The compounds according to the present invention are useful in a method of hormonal therapy which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

Forbindelser i følge oppfinnelsen er anvendelige i behandling eller for å hindre en androgenreseptor (AR) -avhengig tilstand som omfatter at en pasient som har behov for dette administreres en terapeutisk effektiv mengde av en forbindelse med formel (I). Den foreliggende oppfinnelse tilveiebringer således forbindelser i følge oppfinnelsen for anvendelse eller forebygging av androgenmangel. Compounds according to the invention are useful in treating or preventing an androgen receptor (AR)-dependent condition which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I). The present invention thus provides compounds according to the invention for the use or prevention of androgen deficiency.

De foreliggende forbindelser er anvendelige i en fremgangsmåte for å behandle eller hindre androgensvikt som omfatter at en pasient som har behov for dette administreres en terapeutisk effektiv mengde av en forbindelse med formel (I). The present compounds are useful in a method for treating or preventing androgen deficiency which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

De foreliggende forbindelser er videre anvendelige i en fremgangsmåte for behandling eller for å hindre mannlig hypogonadisme og aldersrelaterte tilstander så som andropause, som omfatter at en pasient som har behov for dette administreres en terapeutisk effektiv mengde av en forbindelse med formel (I). The present compounds are further useful in a method for treating or preventing male hypogonadism and age-related conditions such as andropause, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

De foreliggende forbindelser er videre anvendelige i en fremgangsmåte for hormonell terapi, for eksempel for å behandle eller hindre androgensvikt, som omfatter en oral administrering av en forbindelse med formel (I). The present compounds are further useful in a method for hormonal therapy, for example to treat or prevent androgen deficiency, which comprises an oral administration of a compound of formula (I).

Den foreliggende oppfinnelsen tilveiebringer også en farmasøytisk sammensetning som omfatter en forbindelse med formel (I) sammen med en farmasøytisk akseptabel bærer. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier.

Kort beskrivelse av tegningene Brief description of the drawings

Figur 1 viser den androgene og anabole aktiviteten for en forbindelse ifølge oppfinnelsen i en levator a«/-muskelseminal vesikkel og i den ventrale prostata i en ikke kjønnsmoden Sprague Dawley hannrotte. Figure 1 shows the androgenic and anabolic activity of a compound according to the invention in a levator α/ muscle seminal vesicle and in the ventral prostate of an immature male Sprague Dawley rat.

Detaljert beskrivelse av oppfinnelsen Detailed description of the invention

Forbindelsene ifølge den foreliggende oppfinnelsen kan fremstilles ved en rekke forskjellige synteseveier som er analoge til de fremgangsmåter som er kjent i litteraturen ved å bruke egnede utgangsforbindelser. Spesielt kan forbindelsene ifølge den foreliggende oppfinnelsen fremstilles analogt til de generelle fremgangsmåtene som er beskrevet i WO 98/53826. For eksempel kan forbindelsene ifølge oppfinnelsen fremstilles analogt eller som vist i reaksjonsskjema 1 eller 2: Forbindelser med formel (I) hvor gruppe A er en pyridinring eller et derivat av dette, kan fremstilles på samme måte som vist i skjema 1 eller 2 ved å bruke et egnet hydroksylpyridinderivat i siste trinn. Forbindelser med formel (I) hvor X er -NH kan fremstilles på lignende måte som vist i skjema 1 eller 2 ved å bruke et egnet anilinderivat i det siste trinnet. The compounds according to the present invention can be prepared by a number of different synthesis routes which are analogous to the methods known in the literature by using suitable starting compounds. In particular, the compounds according to the present invention can be prepared analogously to the general methods described in WO 98/53826. For example, the compounds according to the invention can be prepared analogously or as shown in reaction scheme 1 or 2: Compounds of formula (I) where group A is a pyridine ring or a derivative thereof, can be prepared in the same way as shown in scheme 1 or 2 by using a suitable hydroxylpyridine derivative in the final step. Compounds of formula (I) where X is -NH can be prepared in a similar manner as shown in Schemes 1 or 2 by using a suitable aniline derivative in the last step.

Farmasøytisk akseptable salter, for eksempel syreaddisjonssalter med både organiske og uorganiske syrer, er velkjente innenfor den farmasøytiske industrien. Ikke-begrensende eksempler på slike salter inkluderer klorider, bromider, sulfater, nitrater, fosfater, sulfonater, formater, tartrater, maleater, citrater, benzoater, salisylater og askorbater. Farmasøytisk akseptable estere, når dette måtte være ønskelig, kan fremstilles ved hjelp av kjente fremgangsmåter ved å bruke farmasøytisk akseptable syrer som er velkjente innenfor den farmasøytiske industrien og som beholder de farmakologiske egenskapene til den frie formen. Ikke-begrensende eksempler på slike estere inkluderer estere av alifatiske eller aromatiske alkoholer, for eksempel metyl-, etyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl- og ter/-butylestere. Fosfatestere og karbonatestere ligger også innenfor oppfinnelsen. Pharmaceutically acceptable salts, for example acid addition salts with both organic and inorganic acids, are well known in the pharmaceutical industry. Non-limiting examples of such salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, and ascorbates. Pharmaceutically acceptable esters, when desired, can be prepared by known methods using pharmaceutically acceptable acids which are well known in the pharmaceutical industry and which retain the pharmacological properties of the free form. Non-limiting examples of such esters include esters of aliphatic or aromatic alcohols, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl esters. Phosphate esters and carbonate esters are also within the scope of the invention.

De begreper som brukes her har følgende betydninger: The terms used here have the following meanings:

Begrepet "halo" eller "halogen" slik det brukes her, enten som sådan eller som en del av en annen gruppe, refererer seg til klor, brom, fluor eller jod. The term "halo" or "halogen" as used herein, either as such or as part of another group, refers to chlorine, bromine, fluorine or iodine.

Begrepet "(Ci-C7)alkyl" slik det brukes her, som sådan eller som en del av en annen gruppe, refererer seg til rette, grenede eller sykliserte radikaler med fra 1 til 7 karbonatomer. Representative eksempler på (Ci-C7)alkyl inkluderer, men er ikke begrenset til, metyl, etyl, «-propyl, isopropyl, «-butyl, isobutyl, sec-butyl, tert-butyl, w-pentyl, isopentyl, neopentyl, w-heksyl, syklopentyl, sykloheksyl og lignende. The term "(C 1 -C 7 )alkyl" as used herein, as such or as part of another group, refers to straight, branched or cyclized radicals having from 1 to 7 carbon atoms. Representative examples of (C 1 -C 7 )alkyl include, but are not limited to, methyl, ethyl, "-propyl, isopropyl, "-butyl, isobutyl, sec-butyl, tert-butyl, w-pentyl, isopentyl, neopentyl, w -hexyl, cyclopentyl, cyclohexyl and the like.

Begrepet "(C2-C7)alkenyl" slik det brukes her, enten som sådan eller som en del av en annen gruppe, refererer seg til et rett, grenet eller syklisert radikal med fra 2 til 7 karbonatomer og som inneholder en eller flere dobbeltbindinger. The term "(C2-C7)alkenyl" as used herein, either as such or as part of another group, refers to a straight, branched or cyclized radical having from 2 to 7 carbon atoms and containing one or more double bonds.

Begrepet "hydroksy" slik det brukes her, enten som sådan eller som en del av en annen gruppe, refererer seg til en -OH-gruppe. The term "hydroxy" as used herein, either as such or as part of another group, refers to an -OH group.

Begrepet "hydroksy(Ci-C7)alkyl" slik det brukes her, refererer seg til minst én hydroksygruppe slik denne er definert her som er forbundet med en annen molekylær gruppe gjennom en (Ci-C7)alkylgruppe slik denne er definert her. Representative eksempler på hydroksy(Ci-C7)alkyl inkluderer, men er ikke begrenset til, hydroksymetyl, 2,2-dihydroksyetyl, 1-hydroksyetyl, 3-hydroksypropyl, 1-hydroksypropyl, 1-metyl-1-hydroksyetyl, 1-metyl-1-hydroksypropyl og lignende. The term "hydroxy(Ci-C7)alkyl" as used herein refers to at least one hydroxy group as defined herein which is linked to another molecular group through a (Ci-C7)alkyl group as defined herein. Representative examples of hydroxy(C 1 -C 7 )alkyl include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1-hydroxypropyl, 1-methyl-1-hydroxyethyl, 1-methyl- 1-hydroxypropyl and the like.

Begrepet "halo(Ci-C7)alkyl" slik det brukes her, refererer seg til minst ett halogen slik det er definert her som er forbundet med en molekylær gruppe gjennom en (Ci-C7)alkylgruppe slik denne er definert her. Representative eksempler på halo(Ci- C7)alkyl inkluderer, men er ikke begrenset til, fluormetyl, difluormetyl, trifluormetyl, 2-kloretyl, 3-brompropyl og lignende. The term "halo(C 1 -C 7 )alkyl" as used herein refers to at least one halogen as defined herein which is attached to a molecular group through a (C 1 -C 7 )alkyl group as defined herein. Representative examples of halo(C 1 -C 7 )alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 3-bromopropyl and the like.

Begrepet "cyano" slik det brukes her, enten som sådan eller som en del av en annen gruppe, refererer seg til en -CN-gruppe. The term "cyano" as used herein, either as such or as part of another group, refers to a -CN group.

Begrepet "cyano(Ci-C7)alkyl" slik det brukes her, refererer seg til en cyanogruppe slik denne er definert her som er forbundet med en molekylær gruppe gjennom en (Ci-C7)alkylgruppe slik denne er definert her. Representative eksempler på cyano(Ci-C7)alkyl inkluderer, men er ikke begrenset til, cyanometyl, 1-cyanoetyl, 1-cyanopropyl, 2-cyanopropyl og lignende. The term "cyano(Ci-C7)alkyl" as used herein refers to a cyano group as defined herein which is linked to a molecular group through a (Ci-C7)alkyl group as defined herein. Representative examples of cyano(C 1 -C 7 )alkyl include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 2-cyanopropyl and the like.

Begrepet "amino" slik det brukes her, som sådan eller som en del av en annen gruppe, refererer seg til en -NH2-gruppe. The term "amino" as used herein, as such or as part of another group, refers to an -NH 2 group.

Begrepet "amino(Ci-C7)alkyl" slik det brukes her, refererer seg til minst én aminogruppe slik denne er definert her, forbundet med en molekylær gruppe via en (Ci-C7)alkylgruppe slik denne er definert her. Representative eksempler på amino(Ci-C7)alkyl inkluderer, men er ikke begrenset til, aminometyl, 2-aminoetyl, 1-aminoetyl, 2,2-diaminoetyl, 3-aminopropyl, 2-aminopropyl, 4-aminobutyl, 1-metyl-1- amino etyl og lignende. The term "amino(Ci-C7)alkyl" as used herein refers to at least one amino group as defined herein, linked to a molecular group via a (Ci-C7)alkyl group as defined herein. Representative examples of amino(C 1 -C 7 )alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl, 2,2-diaminoethyl, 3-aminopropyl, 2-aminopropyl, 4-aminobutyl, 1-methyl- 1-amino ethyl and the like.

Begrepet "mono- eller di(Ci-C7)alkylamino" slik det brukes her, enten som sådan eller som en del av en annen gruppe, refererer seg til en eller to (Ci-C7)alkylgrupper slik disse er definert her som er forbundet med en molekylær gruppe gjennom eller via en aminogruppe som definert her. Representative eksempler på mono- eller di(Ci-C7)alkylamino inkluderer, men er ikke begrenset til, metylamino, etylamino, propylamino, butylamino, dimetylamino, dietylamino, Af-etyl-N-metylamino og lignende. The term "mono- or di(C 1 -C 7 )alkylamino" as used herein, either as such or as part of another group, refers to one or two (C 1 -C 7 )alkyl groups as defined herein which are joined with a molecular group through or via an amino group as defined herein. Representative examples of mono- or di(C 1 -C 7 )alkylamino include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino and the like.

Begrepet "mono- eller di(Ci-C7)alkylamino(Ci-C7)alkyl" slik det brukes her, refererer seg til en mono- eller di(Ci-C7)alkylaminogruppe slik denne er definert her som er forbundet med en molekylær gruppe som de er en del av gjennom en (Ci-C7)alkylgruppe slik denne er definert her. Representative eksempler på mono- eller di(Ci-C7)alkylamino(Ci-C7)alkyl inkluderer, men er ikke begrenset til, N, N-dimetylamino metyl, Ayy-dietylamino metyl, N-metylaminoetyl, N-metylaminopropyl, Af-etyl-N-metylaminometyl og lignende. The term "mono- or di(C 1 -C 7 )alkylamino(C 1 -C 7 )alkyl" as used herein refers to a mono- or di(C 1 -C 7 )alkylamino group as defined herein attached to a molecular group of which they are a part through a (Ci-C7)alkyl group as defined here. Representative examples of mono- or di(C1-C7)alkylamino(C1-C7)alkyl include, but are not limited to, N,N-dimethylamino methyl, Ayy-diethylamino methyl, N-methylaminoethyl, N-methylaminopropyl, Af-ethyl -N-methylaminomethyl and the like.

Begrepet "(Ci-C7)alkoksy" slik det brukes her, enten som sådan eller som en del av en annen gruppe, refererer seg til -0-(Ci-C7)alkyl hvor -(Ci-C7)alkyl er som definert her. Representative eksempler på (Ci-C7)alkoksy inkluderer, men er ikke begrenset til, metoksy, etoksy, propoksy, butoksy, isobutoksy, sec-butoksy, tert-butoksy og lignende. The term "(C 1 -C 7 )alkyl" as used herein, either as such or as part of another group, refers to -O-(C 1 -C 7 )alkyl wherein -(C 1 -C 7 )alkyl is as defined herein . Representative examples of (C 1 -C 7 ) alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

Begrepet "(Ci-C7)alkoksy(Ci-C7)alkyl" slik det brukes her, refererer seg til minst én (Ci-C7)alkoksygruppe slik denne er definert her som er forbundet med en molekylær struktur som den selv er en del av gjennom en (Ci-C7)alkylgruppe slik denne er definert her. Representative eksempler på (Ci-C7)alkoksy(Ci-C7)alkyl inkluderer, men er ikke begrenset til, metoksymetyl, etoksymetyl, 2-metoksyetyl, 2-etoksyetyl, 3,3-dimetoksypropyl, 2,4-dimetoksybutyl og lignende. The term "(C 1 -C 7 )alkoxy(C 1 -C 7 )alkyl" as used herein refers to at least one (C 1 -C 7 ) alkoxy group as defined herein which is associated with a molecular structure of which it is itself a part through a (Ci-C7)alkyl group as defined here. Representative examples of (C 1 -C 7 )alkoxy(C 1 -C 7 )alkyl include, but are not limited to, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3,3-dimethoxypropyl, 2,4-dimethoxybutyl and the like.

Begrepet "(C6-Cio)aryl" slik det brukes her, enten som sådan eller som en del av en annen gruppe, refererer seg til en monosyklisk eller bisyklisk gruppe med fra 6 til 10 karbonatomer i ringdelen. Representative eksempler på (C6-Cio)aryl inkluderer, men er ikke begrenset til, fenyl, naftyl og lignende. The term "(C 6 -C 10 )aryl" as used herein, either as such or as part of another group, refers to a monocyclic or bicyclic group having from 6 to 10 carbon atoms in the ring portion. Representative examples of (C 6 -C 10 )aryl include, but are not limited to, phenyl, naphthyl and the like.

Begrepet "(C2-C7)acyl" slik det brukes her, enten som sådan eller som en del av en annen gruppe, refererer seg til alkylkarbonyl eller alkenylkarbonyl med fra 2 til 7 karbonatomer og eksempler inkluderer acetyl, propanoyl, isopropanoyl, butanoyl, sec-butanoyl, ter/-butanoyl og pentanoyl. The term "(C2-C7)acyl" as used herein, either as such or as part of another group, refers to alkylcarbonyl or alkenylcarbonyl having from 2 to 7 carbon atoms and examples include acetyl, propanoyl, isopropanoyl, butanoyl, sec -butanoyl, tert-butanoyl and pentanoyl.

Begrepet "substituert" slik det brukes her i forbindelse med forskjellige grupper, refererer seg til halogensubstituenter så som fluor, klor, brom, jod eller (Ci-C7)alkyl, halo(Ci-C7)alkyl, hydroksy, amino, (Ci-C7)alkoksy, (C2-C7)acyl (Ci-C7)alkylamino, amino(Ci-C7)alkyl, nitro, cyano eller tiolsubstituenter. The term "substituted" as used herein in connection with various groups refers to halogen substituents such as fluorine, chlorine, bromine, iodine or (Ci-C7)alkyl, halo(Ci-C7)alkyl, hydroxy, amino, (Ci- C 7 ) alkoxy, (C 2 -C 7 )acyl (C 1 -C 7 )alkylamino, amino (C 1 -C 7 )alkyl, nitro, cyano or thiol substituents.

"Substituerte" grupper kan inneholde fra 1 til 3, fortrinnsvis 1 eller 2, mest foretrukket 1 av de ovennevnte substituentene. "Substituted" groups may contain from 1 to 3, preferably 1 or 2, most preferably 1 of the above-mentioned substituents.

Definisjonen på formel (I) som angitt ovenfor inkluderer alle mulige stereoisomerer av forbindelsene inklusive geometriske isomerer, for eksempel Z- og is-isomerer ( cis- og/ra/w-isomerer) og optiske isomerer, for eksempel diastereomerer og enantiomerer, alle forløpermedikamentestere, for eksempel fosfatestere og karbonatestere. Videre inkluderer oppfinnelsen både de individuelle isomerene og enhver blanding av disse, for eksempel rasemiske blandinger. De individuelle isomerene kan fremstilles ved å bruke de tilsvarende isomere formene av utgangsforbindelsene, eller kan skilles etter at syntesen er ferdig, ved hjelp av vanlig kjente separasjonsmetoder. For å skille ut optiske isomerer, for eksempel enantiomerer, fra blandinger av slike så kan man bruke vanlige oppløsningsmetoder, for eksempel fraksjonert utkrystallisering. The definition of formula (I) as set forth above includes all possible stereoisomers of the compounds including geometric isomers, for example Z and isomers ( cis and/ra/w isomers) and optical isomers, for example diastereomers and enantiomers, all prodrug esters , for example phosphate esters and carbonate esters. Furthermore, the invention includes both the individual isomers and any mixture thereof, for example racemic mixtures. The individual isomers can be prepared by using the corresponding isomeric forms of the starting compounds, or can be separated after the synthesis is completed, using commonly known separation methods. In order to separate optical isomers, for example enantiomers, from mixtures of such, you can use common resolution methods, for example fractional crystallization.

Eksempler på foretrukne forbindelser med formel (I) inkluderer 3-(4-acetylamino-3-fluorofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; Examples of preferred compounds of formula (I) include 3-(4-acetylamino-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

(2S)-3-(4-acetylamino-3-fluorofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; (2S)-3-(4-acetylamino-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-(4-acetylaminofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-(4-acetylaminophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

(2S)-3-(4-acetylaminofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; (2S)-3-(4-acetylaminophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-(3-klor-4-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-propionamid; 3-(3-chloro-4-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-propionamide;

3-(4-cyanofenoksy)-2-hydroksy-2-metyl-N-(3-ttietyl-4-nitrofenyl)propionamid; 3-(4-cyanophenoxy)-2-hydroxy-2-methyl-N-(3-triethyl-4-nitrophenyl)propionamide;

3-(2-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-(2-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-(3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-(3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-(3-klor-4-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-(3-chloro-4-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-(3,4-difluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-(3,4-difluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-(4-klorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-(4-chlorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

2- hydroksy-3-(4-metoksyfenoksy)-2-rnetyl-N-(3-metyl-4-nitrofenyl)propionamid; 2-hydroxy-3-(4-methoxyphenoxy)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3- (2,4-diklor-3,5-dimetylfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrophenyl)propionamid; 3-(2,4-dichloro-3,5-dimethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-(4-klor-3-nitrofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-(4-chloro-3-nitrophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-(4-cyano-3-fluor-fenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-(4-cyano-3-fluoro-phenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-(4-fluorfenylamino)-2-hydroksy-2-rnetyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-(4-fluorophenylamino)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-[4-(3-klorpropyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-[4-(3-chloropropyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

2-hydroksy-3-(4-metoksymetylfenoksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 2-hydroxy-3-(4-methoxymethylphenoxy)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

2- hydroxy-2-rnetyl-N-(3-metyl-4-nitrofenyl)-3-(pyridin-4-ylokso)propionarnid; 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(pyridin-4-yloxo)propionamide;

3- [4-(2-kloretoksy)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-[4-(2-chloroethoxy)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

{2-fluor-4-[2-hydroksy-2-(3-metyl-4-nitrofenylkarbamoyl)propoksy]-fenyl}karbaminsyreetylester; {2-fluoro-4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl)propoxy]-phenyl}carbamic acid ethyl ester;

3-(4-cyanofenylamino)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-(4-cyanophenylamino)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

(2S)-3-(4-cyano-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; (2S)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-(3-klor-4-cyanofenylamino)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-(3-chloro-4-cyanophenylamino)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-[4-(2-brometyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid; 3-[4-(2-bromomethyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide;

3-(4-cyano-3-fluorfenoksy)-N-(3-etyl-4-nitrofenyl)-2-hydroksy-2-metylpropionamid; og 3-(4-cyano-3-fluorophenoxy)-N-(3-ethyl-4-nitrophenyl)-2-hydroxy-2-methylpropionamide; and

3-(3-klor-4-cyanofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid. 3-(3-chloro-4-cyanophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide.

Forbindelser ifølge oppfinnelsen kan administreres til en pasient i en terapeutisk mengde som vanligvis varierer fra omtrent 0,1 til omtrent 1000 mg pr dag avhengig av pasientens alder, vekt, etnisk tilhørighet og tilstand, foruten den tilstanden som skal behandles, administreringsveien og den androgen (AR) -modulator som blir brukt. Forbindelsene ifølge den foreliggende oppfinnelsen kan opparbeides i doseringsformer som er velkjente innenfor den farmasøytiske industrien. Forbindelsene kan tilføres en pasient som sådan eller i kombinasjon med egnede farmasøytiske fortynningsmidler eller bærere i form av tabletter, granulater, kapsler, stikkpiller, emulsjoner, suspensjoner eller løsninger. Valg av egnede bestanddeler for sammensetningen vil rutinemessig kunne bestemmes av de som arbeider innenfor den farmasøytiske industrien. Det er således innlysende at egnede bærere og løsemidler, geldannende bestanddeler, dispersjonsdannende bestanddeler, antioksidanter, fargestoffer, søtningsmidler, fuktende forbindelser og andre bestanddeler som normalt brukes i den farmasøytiske industrien også kan brukes her. Sammensetningene som inneholder den aktive forbindelsen kan gis enteralt eller parenteralt, mest foretrukket oralt. Innholdet av den aktive forbindelsen i sammensetningen vil variere fra 0,5 til 100%, fortrinnsvis fra 0,5 til 20 %, regnet på vekt, i forhold til den totale sammensetningen. Compounds of the invention can be administered to a patient in a therapeutic amount usually ranging from about 0.1 to about 1000 mg per day depending on the age, weight, ethnicity and condition of the patient, in addition to the condition to be treated, the route of administration and the androgen ( AR) modulator being used. The compounds according to the present invention can be prepared in dosage forms which are well known within the pharmaceutical industry. The compounds can be administered to a patient as such or in combination with suitable pharmaceutical diluents or carriers in the form of tablets, granules, capsules, suppositories, emulsions, suspensions or solutions. Selection of suitable constituents for the composition will routinely be determined by those working within the pharmaceutical industry. It is thus obvious that suitable carriers and solvents, gel-forming ingredients, dispersion-forming ingredients, antioxidants, dyes, sweeteners, moisturizing compounds and other ingredients normally used in the pharmaceutical industry can also be used here. The compositions containing the active compound can be administered enterally or parenterally, most preferably orally. The content of the active compound in the composition will vary from 0.5 to 100%, preferably from 0.5 to 20%, calculated by weight, in relation to the total composition.

Oppfinnelsen vil i det etterfølgende bli mer detaljert beskrevet ved hjelp av eksempler. Eksemplene er utelukkende ment for illustrerende formål og vil som sådan ikke begrense oppfinnelsen slik denne er definert i de etterfølgende krav. The invention will subsequently be described in more detail by means of examples. The examples are intended solely for illustrative purposes and as such will not limit the invention as defined in the following claims.

EKSPERIMENTER EXPERIMENTS

Eksperiment 1. AR-bindingsprøve Experiment 1. AR binding assay

Ventrale prostatakjertler ble oppnådd fra rotter som var kastrert 24 timer før de ble avlivet. Friske prostatakjertler ble findelt og vasket med buffer A (Schilling og Liao, Prostate, 5: 581-588, 1984). De finopphakkede delene ble så homogenisert i 3 x volum av buffer A inneholdende proteasehemmere (Complete, Mini, EDTA-fritt Roche). Homogenatet ble så sentrifugert ved 30000 g i 30 minutter. De resulterende supernatantene ble behandlet med 1 x volum av dekstranbelagt trekulløsning (12,5 g aktivert trekull, 12,5 dekstran pr liter av buffer A) for å fjerne endogene steroider. Prøvene ble innkubert i 5 minutter og sentrifugert ved 16000 g i 10 minutter. Porsjoner av den trekullbehandlede cytosolen ble så brukt for androgenreseptorprøver. Alle eksperimentene ble utført ved temperaturer mellom 0 og 4°C. Ventral prostate glands were obtained from rats castrated 24 hours before they were sacrificed. Healthy prostate glands were minced and washed with buffer A (Schilling and Liao, Prostate, 5: 581-588, 1984). The finely chopped parts were then homogenized in 3 x volume of buffer A containing protease inhibitors (Complete, Mini, EDTA-free Roche). The homogenate was then centrifuged at 30,000 g for 30 minutes. The resulting supernatants were treated with 1 x volume of dextran-coated charcoal solution (12.5 g activated charcoal, 12.5 dextran per liter of buffer A) to remove endogenous steroids. The samples were incubated for 5 minutes and centrifuged at 16,000 g for 10 minutes. Aliquots of the charcoal-treated cytosol were then used for androgen receptor assays. All experiments were performed at temperatures between 0 and 4°C.

Cytosolandrogenreseptorkonsentrasjonen ble bestemt slik det tidligere er beskrevet (Isomaa et al, Endocrinology, 111: 833-843, 1982) med mindre modifikasjoner. Det ble fremstilt cytosolpreparater som beskrevet ovenfor, hvoretter bundne og frie steroider ble utskilt ved behandling med tilsvarende volum av dekstran-trekullsuspensjon i 5 minutter ved 4°C fulgt av en sentrifugering ved 16000 g i 10 minutter. Bundet radioaktivitet ble bestemt ved å telle supernatantfraksjoner i 1 ml av OptiPhase HiSafe3 eller OptiPhase Supermix (PerkinElmer). Cytosolic androgen receptor concentration was determined as previously described (Isomaa et al, Endocrinology, 111: 833-843, 1982) with minor modifications. Cytosol preparations were prepared as described above, after which bound and free steroids were secreted by treatment with an equivalent volume of dextran-charcoal suspension for 5 minutes at 4°C followed by centrifugation at 16,000 g for 10 minutes. Bound radioactivity was determined by counting supernatant fractions in 1 ml of OptiPhase HiSafe3 or OptiPhase Supermix (PerkinElmer).

Cytosolpreparatene ble merket med 1 nM [<3>H]-miboleron over natten ved 0°C (totalt). For å bestemme den AR-bindende aktiviteten for forbindelsene ifølge den foreliggende oppfinnelsen (testforbindelsene) og deres evne til å konkurrere med [3H]7a,17a-dimetyl-17P-hydroksy-4-estren-3-on, så ble ([<3>H]-miboleron)-bindingen undersøkt. 1 nM [<3>H]-miboleron og testforbindelsene i to konsentrasjoner (0,2 og 2 u.M) ble innkubert over natten ved 0°C. For å bestemme ikke-spesifikk binding, ble det utført parallelle innkuberinger ved å bruke 1 nM konsentrasjon av [<3>H]-miboleron med 500 molars overskudd av umerket testosteron. Det ble utført to til fire parallelle forsøk for hver prøve. Etter innkuberingen ble bundne og frie steroider utskilt som beskrevet ovenfor og bundet radioaktivitet ble bestemt. Testforbindelsenes evne til å binde AR er angitt som reduksjon av bundet radioaktivitet som ble oppnådd med 1 nM [<3>H]-miboleron. Resultatene er vist i tabell 1. Resultatene (% hemming) ble bestemt på følgende måte: % hemming = 100 The cytosolic preparations were labeled with 1 nM [<3>H]-mibolerone overnight at 0°C (total). To determine the AR-binding activity of the compounds of the present invention (the test compounds) and their ability to compete with [3H]7a,17a-dimethyl-17P-hydroxy-4-estren-3-one, ([< 3>H]-mibolerone) bond examd. 1 nM [<3>H]-mibolerone and the test compounds at two concentrations (0.2 and 2 µM) were incubated overnight at 0°C. To determine nonspecific binding, parallel incubations were performed using 1 nM concentration of [<3>H]-mibolerone with 500 molar excess of unlabeled testosterone. Two to four parallel experiments were performed for each sample. After the incubation, bound and free steroids were separated as described above and bound radioactivity was determined. The ability of the test compounds to bind AR is indicated as the reduction of bound radioactivity obtained with 1 nM [<3>H]-mibolerone. The results are shown in Table 1. The results (% inhibition) were determined as follows: % inhibition = 100

- (100 X (middeltestforbindelse/middeltotalt)). - (100 X (mean test compound/mean total)).

Eksperiment 2. AR-agonisme og antagonisme i ikke kjønnsmodne hannrotter Tittelforbindelsen fra eksempel 3, her forkortet som forbindelse A, ble ytterligere undersøkt i in vivo eksperimenter. Agonismen og antagonismen til forbindelsen med subkutan dosering ble testet i ikke kjønnsmodne Sprague Dawley hannrotter i en 3 dagers prøve ved å analysere de relative vektene av den ventrale prostatakjertelen, den seminale vesikkel og levator am-muskelen. Testosteronpropionat ble brukt som referanseforbindelse. Experiment 2. AR agonism and antagonism in immature male rats The title compound from Example 3, here abbreviated as compound A, was further investigated in in vivo experiments. The agonism and antagonism of the compound by subcutaneous dosing was tested in immature male Sprague Dawley rats in a 3 day trial by analyzing the relative weights of the ventral prostate gland, seminal vesicle and levator am muscle. Testosterone propionate was used as a reference compound.

Testosteronpropionat (her forkortet TP) og forbindelse A ble først løst i DMSO og i bærervæsken som var sesamolje. Sprague-Dawley ubehandlede hannrotter (18-19 dager gamle) som veide omtrent 50 g ble brukt i det første eksperimentet. Rottene ble veid og vilkårlig fordelt i fem grupper med 5 dyr pr gruppe (tabell 1). Forbindelse A (doser på 2 og 20 mg/kg) og testosteronpropionat (dose 5 mg/kg) ble gitt subkutant (s.c.) i nakken eller i ryggen på dyrene med et konstant volum på 100 mikromol doserende løsning/dyr/dag. Dyrene ble dosert en gang daglig i tre dager og kliniske tegn ble observert under doseringen. Ved slutten av undersøkelsen ble dyrene veid og bedøvet ved CC«2-kvelning. Den ventrale prostatakjertelen, seminale vesikler og levator am'-muskelen ble utdissekert, avkjølt og veid. For statistiske analyser ble vekten av alle organer normaliser i forhold til kroppsvekten og analysert for statistisk signifikant forskjell ved enkeltfaktor ANOVA. Testosterone propionate (here abbreviated as TP) and compound A were first dissolved in DMSO and in the carrier liquid which was sesame oil. Untreated male Sprague-Dawley rats (18-19 days old) weighing approximately 50 g were used in the first experiment. The rats were weighed and randomly divided into five groups with 5 animals per group (table 1). Compound A (doses of 2 and 20 mg/kg) and testosterone propionate (dose of 5 mg/kg) were administered subcutaneously (s.c.) in the neck or back of the animals at a constant volume of 100 micromol dosing solution/animal/day. The animals were dosed once daily for three days and clinical signs were observed during dosing. At the end of the study, the animals were weighed and anesthetized by CC2 asphyxiation. The ventral prostate gland, seminal vesicles and levator am' muscle were dissected, cooled and weighed. For statistical analyses, the weight of all organs was normalized in relation to body weight and analyzed for statistically significant difference by single factor ANOVA.

Resultatene er vist på figur 1. Forbindelse A viser androgen og anabolsk aktivitet. De relative vektene av den ventrale prostatakjertelen, de seminale vesikler og The results are shown in figure 1. Compound A shows androgenic and anabolic activity. The relative weights of the ventral prostate gland, the seminal vesicles and

levator an /'-muskelen økte signifikant med administrasjon av testosteronpropionat. Sammenlignet med testosteronpropionat, hadde forbindelse A vevsselektivitet. Ved en dose på 20 mg/kg ga den en relativ klar vektøkning av levator am'-muskelen og en signifikant relativ vektøkning av den seminale vesikkel, men bare minimal relativ vektøkning av prostatakjertelen. Videre viste forbindelse A signifikant antagonistisk aktivitet i den seminale vesikkel. Hverken testosteronpropionat eller of the levator an /' muscle increased significantly with testosterone propionate administration. Compared to testosterone propionate, compound A had tissue selectivity. At a dose of 20 mg/kg, it produced a relatively clear increase in the weight of the levator am' muscle and a significant relative increase in the weight of the seminal vesicle, but only a minimal relative increase in the weight of the prostate gland. Furthermore, compound A showed significant antagonistic activity in the seminal vesicle. Neither testosterone propionate nor

forbindelse A hadde noen effekt på kroppsvektene (data ikke vist). På figuren betyr "a" agonisme, p < 0,01 sammenlignet med bærervæskegruppen, "b" betyr antagonisme, p < 0,05 sammenlignet med testosterongruppen, og søylene betyr middel + standardavvik. compound A had some effect on body weights (data not shown). In the figure, "a" means agonism, p < 0.01 compared to the vehicle group, "b" means antagonism, p < 0.05 compared to the testosterone group, and the bars mean + standard deviation.

EKSEMPLER: EXAMPLES:

Eksempel 1. (Fremgangsmåte A) Example 1. (Procedure A)

3-(4-acetylaminofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-acetylaminophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) 2-metyl-N-(3-metyl-4-nitrofenyl)akrylamid a) 2-methyl-N-(3-methyl-4-nitrophenyl)acrylamide

3-metyl-4-nitroanilin (2,0 g, 13 mmol) i 6 ml N,N-dimetylacetamid (DMAC) ble 3-Methyl-4-nitroaniline (2.0 g, 13 mmol) in 6 mL of N,N-dimethylacetamide (DMAC) was

dråpevis tilsatt en avkjølt løsning av metakryloylklorid (2,0 ml, 20,7 mmol) i en nitrogenatmosfære mens temperaturen på reaksjonsblandingen ble holdt på mellom 0 og 5°C. Løsningen ble hensatt for oppvarming til romtemperatur og ble så rørt over natten. Den ble deretter helt over i 70 ml vann og ekstrahert med 4 x 40 ml etylacetat. Den organiske fasen ble vasket med 3 x 20 ml Na2CC«3 og med 50 ml vann, tørket over natriumsulfat og fordampet. Utbyttet av råproduktet var 4,17 g (inneholder DMA, teoretisk utbytte 2,9 g) og ble brukt uten ytterligere rensing.<]>H NMR (DMSO-d6): 1,97 (3H, s), 2,55 (3H, s), 5,62 (1H, m), 5,96 (1H, m), 7,80 (2H, m), 8,05 (1H, m), 10,22 (1H, s). a cooled solution of methacryloyl chloride (2.0 mL, 20.7 mmol) was added dropwise under a nitrogen atmosphere while the temperature of the reaction mixture was maintained between 0 and 5°C. The solution was allowed to warm to room temperature and was then stirred overnight. It was then poured into 70 ml of water and extracted with 4 x 40 ml of ethyl acetate. The organic phase was washed with 3 x 20 ml of Na 2 CC 3 and with 50 ml of water, dried over sodium sulfate and evaporated. The yield of the crude product was 4.17 g (contains DMA, theoretical yield 2.9 g) and was used without further purification. <]>H NMR (DMSO-d6): 1.97 (3H, s), 2.55 ( 3H, s), 5.62 (1H, m), 5.96 (1H, m), 7.80 (2H, m), 8.05 (1H, m), 10.22 (1H, s).

b) 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid m-klorperoksybenzosyre (6,7 g, 29,9 mmol) ble i porsjoner ved 60°C tilsatt en b) 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide m-chloroperoxybenzoic acid (6.7 g, 29.9 mmol) was added in portions at 60°C to a

løsning av 2-metyl-N-(3-metyl-4-nitrofenyl)akrylamid (2,9 g, 13,2 mmol) og 66 mg 2,6-di-tert-butyl-4-metylfenol i 80 ml 1,2-dikloretan. Røring ble fortsatt ved 60°C i 6 timer, hvoretter reaksjonsblandingen ble avkjølt til romtemperatur. Den utfelte m-klorbenzosyren ble frafiltrert og filtratet ble ekstrahert med 4 x 60 ml 1 M Na2CC*3. Den organiske fasen ble tørket over natriumsulfat og fordampet. Utbyttet ved 3,05 g.<]>H NMR (DMSO-d6): 1,54 (3H, s), 2,51 (3H, s), 2,99 (1H, d, J = 5,1 Hz), 3,05 (1H, d, J = 5,1 Hz), 7,79 (2H, m), 8,01 (1H, m), 9,98 (1H, s). solution of 2-methyl-N-(3-methyl-4-nitrophenyl)acrylamide (2.9 g, 13.2 mmol) and 66 mg of 2,6-di-tert-butyl-4-methylphenol in 80 ml of 1, 2-dichloroethane. Stirring was continued at 60°C for 6 hours, after which the reaction mixture was cooled to room temperature. The precipitated m-chlorobenzoic acid was filtered off and the filtrate was extracted with 4 x 60 ml of 1 M Na 2 CC* 3 . The organic phase was dried over sodium sulfate and evaporated. The yield at 3.05 g.<]>H NMR (DMSO-d6): 1.54 (3H, s), 2.51 (3H, s), 2.99 (1H, d, J = 5.1 Hz ), 3.05 (1H, d, J = 5.1 Hz), 7.79 (2H, m), 8.01 (1H, m), 9.98 (1H, s).

c) 3-(4-acetylaminofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid c) 3-(4-acetylaminophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

En løsning av 4-acetamidofenol (2,9 g, 19 mmol) i 60 ml THF ble dråpevis tilsatt en rørt suspensjon av natriumhydrid (0,46 g, 19 mmol, 60% dispersjon i mineralolje) i 60 ml THF og temperaturen ble holdt under 5°C under tilsetningen. Blandingen ble rørt i 10 minutter og så tilsatt en løsning av 2-methyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid (3,05 g, 13 mmol) i 120 ml THF. Blandingen ble oppvarmet til 60°C og rørt ved denne temperaturen i 7 timer og så hensatt for avkjøling til romtemperatur. Løsemiddelet ble fordampet og resten ble løst i en blanding av 150 ml vann og 150 ml etylacetat. pH ble justert til mellom 2 og 2 med 2 M HC1, hvoretter fasene ble skilt. Den vandige vasen ble ekstrahert med 4 x 150 ml etylacetat. De samlede organiske ekstraktene ble vasket med 5 x 100 ml 1 M Na2CC«3, tørket over natriumsulfat og fordampet. Den oljeaktige resten ble utkrystallisert fra en blanding av etylacetat og dietyleter (10:1). Råproduktet ble omkrystallisert fra etylacetat. Utbyttet var 2,5 g.<]>H NMR (DMSO-d6): 1,42 (3H, s), 1,99 (3H, s), 2,53 (3H, s), 3,93 (1H, d, J = 9,6 Hz), 4,16 (1H, d, J = 9,6 Hz), 6,20 (1H, bs), 6,84 (2H, d, J = 9,0 Hz), 7,44 (2H, d, J = 9,0 Hz), 7,88 (1H, dd, J = 9,0 Hz og 2,3 Hz), 7,93 (1H, d, J = 2,3 Hz), 8,04 (1H, d, J = 9,0 Hz), 9,76 (1H, s), 10,15 (1H, bs). A solution of 4-acetamidophenol (2.9 g, 19 mmol) in 60 mL THF was added dropwise to a stirred suspension of sodium hydride (0.46 g, 19 mmol, 60% dispersion in mineral oil) in 60 mL THF and the temperature was maintained below 5°C during the addition. The mixture was stirred for 10 minutes and then a solution of 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide (3.05 g, 13 mmol) in 120 mL of THF was added. The mixture was heated to 60°C and stirred at this temperature for 7 hours and then allowed to cool to room temperature. The solvent was evaporated and the residue was dissolved in a mixture of 150 ml of water and 150 ml of ethyl acetate. The pH was adjusted to between 2 and 2 with 2 M HCl, after which the phases were separated. The aqueous phase was extracted with 4 x 150 mL ethyl acetate. The combined organic extracts were washed with 5 x 100 mL of 1 M Na 2 CC 3 , dried over sodium sulfate and evaporated. The oily residue was crystallized from a mixture of ethyl acetate and diethyl ether (10:1). The crude product was recrystallized from ethyl acetate. The yield was 2.5 g. <]>H NMR (DMSO-d6): 1.42 (3H, s), 1.99 (3H, s), 2.53 (3H, s), 3.93 (1H , d, J = 9.6 Hz), 4.16 (1H, d, J = 9.6 Hz), 6.20 (1H, bs), 6.84 (2H, d, J = 9.0 Hz ), 7.44 (2H, d, J = 9.0 Hz), 7.88 (1H, dd, J = 9.0 Hz and 2.3 Hz), 7.93 (1H, d, J = 2 .3 Hz), 8.04 (1H, d, J = 9.0 Hz), 9.76 (1H, s), 10.15 (1H, bs).

Eksempel 2 Example 2

3-(4-acetylamino-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-acetylamino-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) N-(2- fluor-4-hydroksyfenyl)ac etamid a) N-(2-fluoro-4-hydroxyphenyl)acetamide

Eddiksyreanhydrid (1,3 ml, 13,8 mmol) ble dråpevis tilsatt en løsning av 4-amino-3-fluorfenol (1,0 g, 7,9 mmol) i 25 ml eddiksyre ved romtemperatur. Reaksjonsblandingen ble rørt ved romtemperatur i 2 timer og så tilsatt 2 ml vann, hvoretter røringen ble fortsatt i 30 minutter ved romtemperatur. Blandingen ble så fordampet til tørrhet i vakuum. Utbyttet av råproduktet var 1,3 g (100%), og dette ble brukt videre uten ytterligere rensing. Acetic anhydride (1.3 mL, 13.8 mmol) was added dropwise to a solution of 4-amino-3-fluorophenol (1.0 g, 7.9 mmol) in 25 mL of acetic acid at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then 2 ml of water was added, after which stirring was continued for 30 minutes at room temperature. The mixture was then evaporated to dryness in vacuo. The yield of the crude product was 1.3 g (100%) and this was used further without further purification.

<]>H NMR (DMSO-de): 2,00 (3H, s), 6,50-6,68 (2H, m), 7,39 (1H, m), 9,39 (1H, s), 9,72 (1H, s). <]>H NMR (DMSO-de): 2.00 (3H, s), 6.50-6.68 (2H, m), 7.39 (1H, m), 9.39 (1H, s) , 9.72 (1H, p).

b) 3-(4-acetylamino-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid b) 3-(4-acetylamino-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

Denne forbindelsen ble syntetisert ved den same fremgangsmåten som beskrevet i eksempel lc. N-(2-fluor-4-hydroksyfenyl)acetamid (0,5 g, 3,0 mmol) og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid (0,6 g, 2,5 mmol) ble brukt som utgangsforbindelser. Produktet ble utkrystallisert fra en blanding av etylacetat og dietyleter (1:1). Utbyttet var 0,39 g.<!>H NMR (DMSO-d6): 1,42 (3H, s), 2,02 (3H, s), 2,53 (3H, s), 3,97 (1H, d, J = 9,7 Hz), 4,21 (1H, d, J = 9,7 Hz), 6,23 (1H, bs), 6,72 (1H, m), 6,90 (1H, m), 7,56 (1H, m), 7,88 (1H, dd, J = 9,0 Hz og 2,2 Hz), 7,93 (1H, d, J = 2,2 Hz), 8,03 (1H, d, J = 9,0 Hz), 9,51 (1H, s), 10,15 (1H, bs). This compound was synthesized by the same method as described in example 1c. N-(2-fluoro-4-hydroxyphenyl)acetamide (0.5 g, 3.0 mmol) and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide (0.6 g, 2.5 mmol) were used as starting compounds. The product was crystallized from a mixture of ethyl acetate and diethyl ether (1:1). The yield was 0.39 g. <!>H NMR (DMSO-d6): 1.42 (3H, s), 2.02 (3H, s), 2.53 (3H, s), 3.97 (1H , d, J = 9.7 Hz), 4.21 (1H, d, J = 9.7 Hz), 6.23 (1H, bs), 6.72 (1H, m), 6.90 (1H , m), 7.56 (1H, m), 7.88 (1H, dd, J = 9.0 Hz and 2.2 Hz), 7.93 (1H, d, J = 2.2 Hz), 8.03 (1H, d, J = 9.0 Hz), 9.51 (1H, s), 10.15 (1H, bs).

Eksempel 3. (Fremgangsmåte B) Example 3. (Procedure B)

(2S)-3-(4-acetylaminofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid (2S)-3-(4-acetylaminophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) (2R)-1 -(2-metylakryloyl)pyrrolidin-2-karboksylsyre a) (2R)-1-(2-methylacryloyl)pyrrolidine-2-carboxylic acid

D-prolin (5 g, 43,4 mmol) ble lost i 26 ml 2 M NaOH og avkjølt på et isbad, hvoretter løsningen ble fortynnet med 26 ml aceton. En 26 ml acetonløsning av metakryloylklorid (6,3 ml, 65,1 mmol) og 34 ml av en 2 M NaOH-løsning ble samtidig tilsatt i løpet av 1 time til løsningen av D-prolin. Etter tilsetningen ble blandingen rørt i 3 timer ved romtemperatur. Den ble så fordampet ved 40°C, ekstrahert med 2 x 40 ml eter og surgjort til pH 2 med konsentrert HC1. Den resulterende blandingen ble ekstrahert med 3 x 50 ml etylacetat, tørket over natriumsulfat og fordampet. Utbyttet var 11,5 g (teoretisk 8,0 g), og det brukt uten ytterligere rensing. b) (3R,8aR)-3-brommetyl-3-metyltetrahydropyrrolo[2,1 -c][ 1,4]oksazine-1,4-dion NBS (16 g, 89,9 mmol) ble løst i 50 ml DMF og ved romtemperatur tilsatt en løsning av (2R)-l-(2-metylakryloyl)pyrrolidin-2-karboksylsyre (11,5 g, inneholder 8,0 g av det tilsvarende utgangsmaterialet, 43,4 mmol) i 50 ml DMF. Blandingen ble rørt i 20 timer og så fordampet ved 80-90°C. Resten ble blandet med 250 ml vann og ekstrahert med 4 x 80 ml etylacetat. De samlede etylacetatekstraktene ble vasket med 2 x 50 ml 1 M NaHCC>3-løsning og 50 ml vann. Den organiske fasen ble tørket over natriumsulfat og fordampet. Utbyttet av uren olje var 9,3 g. 10 ml etylacetat ble tilsatt og blandingen ble rørt på et isbad. Det utfelte produktet ble frafiltrert og vasket med avkjølt etylacetat. Utbyttet var 1,2 g.<]>H NMR (DMSO-d6): I, 58 (3H, s), 1,75-2,10 (3H, m), 2,25 (1H, m), 3,30-3,55 (2H, m), 3,87 (1H, d, J = II, 4 Hz), 4,03 (1H, d, J = 11,4 Hz), 4,70 (1H, m). c) (2R)-3-brom-2-hydroksy-2-metylpropionsyre (3R,8aR)-3-brommetyl-3-metyltetrahydropyrrolo[2,1 -c][ 1,4]oksazine-1,4-dion (1,1 g, 4,2 mmol) ble løst i 10 ml konsentrert HC1 og kokt under tilbake løp i 7 timer. Blandingen ble så avkjølt til romtemperatur, 20 ml vann ble tilsatt og blandingen ble ekstrahert med 3 x 20 ml etylacetat. De samlede organiske fasene ble fordampet og resten ble blandet med 5 ml toluen. Det utkrystalliserte produktet ble frafiltrert og vasket med toluen. Utbyttet var 0,74 g.<]>H NMR (DMSO-d*): 1,37 (3H, s), 3,54 (1H, d, J = 10,2 Hz), 3,64 (1H, d, J = 10,2 Hz), 5,35 (1H, bs), 12,80 (1H, bs). d) (2R)-3-brom-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid Tionylklorid (0,48 ml, 6,6 mmol) ble dråpevis tilsatt en løsning av (2R)-3-brom-2-hydroksy-2-metylpropionsyre (1,0 g, 5,5 mmol) i 10 ml DMA ved -5 til -10°C. D-proline (5 g, 43.4 mmol) was dissolved in 26 mL of 2 M NaOH and cooled in an ice bath, after which the solution was diluted with 26 mL of acetone. A 26 mL acetone solution of methacryloyl chloride (6.3 mL, 65.1 mmol) and 34 mL of a 2 M NaOH solution were simultaneously added over 1 hour to the solution of D-proline. After the addition, the mixture was stirred for 3 hours at room temperature. It was then evaporated at 40°C, extracted with 2 x 40 ml of ether and acidified to pH 2 with concentrated HCl. The resulting mixture was extracted with 3 x 50 mL ethyl acetate, dried over sodium sulfate and evaporated. The yield was 11.5 g (theoretical 8.0 g), and it was used without further purification. b) (3R,8aR)-3-bromomethyl-3-methyltetrahydropyrrolo[2,1-c][1,4]oxazine-1,4-dione NBS (16 g, 89.9 mmol) was dissolved in 50 mL DMF and at room temperature added a solution of (2R)-1-(2-methylacryloyl)pyrrolidine-2-carboxylic acid (11.5 g, containing 8.0 g of the corresponding starting material, 43.4 mmol) in 50 ml DMF. The mixture was stirred for 20 hours and then evaporated at 80-90°C. The residue was mixed with 250 ml of water and extracted with 4 x 80 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 2 x 50 ml of 1 M NaHCl>3 solution and 50 ml of water. The organic phase was dried over sodium sulfate and evaporated. The yield of crude oil was 9.3 g. 10 ml of ethyl acetate was added and the mixture was stirred in an ice bath. The precipitated product was filtered off and washed with cooled ethyl acetate. The yield was 1.2 g. <]>H NMR (DMSO-d6): I, 58 (3H, s), 1.75-2.10 (3H, m), 2.25 (1H, m), 3 .30-3.55 (2H, m), 3.87 (1H, d, J = II, 4 Hz), 4.03 (1H, d, J = 11.4 Hz), 4.70 (1H, m). c) (2R)-3-bromo-2-hydroxy-2-methylpropionic acid (3R,8aR)-3-bromomethyl-3-methyltetrahydropyrrolo[2,1-c][ 1,4]oxazine-1,4-dione ( 1.1 g, 4.2 mmol) was dissolved in 10 mL of concentrated HCl and refluxed for 7 h. The mixture was then cooled to room temperature, 20 ml of water was added and the mixture was extracted with 3 x 20 ml of ethyl acetate. The combined organic phases were evaporated and the residue was mixed with 5 ml of toluene. The crystallized product was filtered off and washed with toluene. The yield was 0.74 g. <]>H NMR (DMSO-d*): 1.37 (3H, s), 3.54 (1H, d, J = 10.2 Hz), 3.64 (1H, d, J = 10.2 Hz), 5.35 (1H, bs), 12.80 (1H, bs). d) (2R)-3-bromo-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide Thionyl chloride (0.48 mL, 6.6 mmol) was added dropwise to a solution of (2R )-3-bromo-2-hydroxy-2-methylpropionic acid (1.0 g, 5.5 mmol) in 10 mL DMA at -5 to -10 °C.

Blandingen ble rørt i 2 timer og så tilsatt en løsning av 3-metyl-4-nitroanilin (0,83 g, 5,5 mmol) i 7 ml DMA. Blandingen ble så rørt i 3 timer ved romtemperatur og helt over i 250 ml vann. Den vandige fasen ble ekstrahert med 4 x 50 ml etylacetat, tørket over natriumsulfat og fordampet. Utbyttet av den forønskede forbindelsen var 2,5 g (inneholder også DMA), og den ble brukt uten ytterligere rensing.<!>H NMR (DMSO-de): 1,48 (3H, s), 2,53 (3H, s), 3,58 (1H, d, J = 10,4 Hz), 3,82 (1H, d, J = 10,4 Hz), 6,34 (1H, bs), 7,86 (1H, dd, J = 9,0 Hz og 2,2 Hz), 7,91 (1H, d, J = 2,2 Hz), 8,04 (1H, d, J = 9,0 Hz), 10,09 (1H, bs). The mixture was stirred for 2 h and then a solution of 3-methyl-4-nitroaniline (0.83 g, 5.5 mmol) in 7 mL of DMA was added. The mixture was then stirred for 3 hours at room temperature and poured into 250 ml of water. The aqueous phase was extracted with 4 x 50 ml of ethyl acetate, dried over sodium sulfate and evaporated. The yield of the desired compound was 2.5 g (also containing DMA), and it was used without further purification. <!>H NMR (DMSO-de): 1.48 (3H, s), 2.53 (3H, s), 3.58 (1H, d, J = 10.4 Hz), 3.82 (1H, d, J = 10.4 Hz), 6.34 (1H, bs), 7.86 (1H, dd, J = 9.0 Hz and 2.2 Hz), 7.91 (1H, d, J = 2.2 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.09 (1H, bs).

e) (2S)-3-(4-acetylaminofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid e) (2S)-3-(4-acetylaminophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

En løsning av 4-acetamidofenol (0,62 g, 4,1 mmol) i 7 ml THF ble dråpevis tilsatt en rørt suspensjon av natriumhydrid (0,27 g, 6,8 mmol, 60% dispersjon i mineralolje) i 6 ml THF, og temperaturen ble holdt under 5°C under tilsetningen. Blandingen ble rørt i 10 minutter og så tilsatt en løsning av (2R)-3-brom-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid (0,86 g, 2,7 mmol) i 7 ml THF. Blandingen ble rørt ved romtemperatur i 30 minutter og så ved 60°C i 5, så hensatt for avkjøling til romtemperatur. Løsemiddelet ble fordampet og resten ble løst i en blanding av 80 ml vann og 80 ml etylacetat. pH ble justert til mellom 2 og 3 med 2 M HC1 og fasene ble skilt. Den organiske fasen ble vasket med 6 x 30 ml 1 M Na2CC>3, tørket over natriumsulfat og fordampet. Den oljeaktige resten ble utkrystallisert fra etylacetat. Utbyttet var 0,27 g.<!>H NMR (DMSO-d6): 1,42 (3H, s), 1,99 (3H, s), 2,53 (3H, s), 3,93 (1H, d, J = 9,6 Hz), 4,16 (1H, d, J = 9,6 Hz), 6,20 (1H, bs), 6,84 (2H, d, J = 9,0 Hz), 7,44 (2H, d, J = 9,0 Hz), 7,88 (1H, dd, J = 9,0 Hz og 2,3 Hz), 7,93 (1H, d, J = 2,3 Hz), 8,04 (1H, d, J = 9,0 Hz), 9,76 (1H, s), 10,15 (1H, bs). A solution of 4-acetamidophenol (0.62 g, 4.1 mmol) in 7 mL THF was added dropwise to a stirred suspension of sodium hydride (0.27 g, 6.8 mmol, 60% dispersion in mineral oil) in 6 mL THF , and the temperature was kept below 5°C during the addition. The mixture was stirred for 10 minutes and then a solution of (2R)-3-bromo-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide (0.86 g, 2.7 mmol ) in 7 mL of THF. The mixture was stirred at room temperature for 30 minutes and then at 60°C for 5, then allowed to cool to room temperature. The solvent was evaporated and the residue was dissolved in a mixture of 80 ml of water and 80 ml of ethyl acetate. The pH was adjusted to between 2 and 3 with 2 M HCl and the phases were separated. The organic phase was washed with 6 x 30 ml of 1 M Na 2 CC> 3 , dried over sodium sulfate and evaporated. The oily residue was crystallized from ethyl acetate. The yield was 0.27 g. <!>H NMR (DMSO-d6): 1.42 (3H, s), 1.99 (3H, s), 2.53 (3H, s), 3.93 (1H , d, J = 9.6 Hz), 4.16 (1H, d, J = 9.6 Hz), 6.20 (1H, bs), 6.84 (2H, d, J = 9.0 Hz ), 7.44 (2H, d, J = 9.0 Hz), 7.88 (1H, dd, J = 9.0 Hz and 2.3 Hz), 7.93 (1H, d, J = 2 .3 Hz), 8.04 (1H, d, J = 9.0 Hz), 9.76 (1H, s), 10.15 (1H, bs).

Eksempel 4. Example 4.

(2S)-3-(4-acetylamino-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid (2S)-3-(4-acetylamino-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

(2S)-3-(4-acetylamino-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt ifølge fremgangsmåte B slik det er beskrevet i eksempel 3e, ved å starte fra 4-acetylamino-3-fluorfenol og N-[3-metyl-4-(nitro)fenyl]-(2R)-3-brom-2-hydroksy-2-metylpropanamid.<]>H NMR (DMSO-d6): 1,42 (3H, s), 2,02 (3H, s), 2,53 (3H, s), 3,97 (1H, d, J = 9,7 Hz), 4,21 (1H, d, J = 9,7 Hz), 6,23 (1H, bs), 6,72 (1H, m), 6,90 (1H, m), 7,56 (1H, m), 7,88 (1H, dd, J = 9,0 Hz og 2,2 Hz), 7,93 (1H, d, J = 2,2 Hz), 8,03 (1H, d, J = 9,0 Hz), 9,51 (1H, s), 10,15 (1H, bs). (2S)-3-(4-acetylamino-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared according to method B as described in example 3e, by starting from 4-acetylamino-3-fluorophenol and N-[3-methyl-4-(nitro)phenyl]-(2R)-3-bromo-2-hydroxy-2-methylpropanamide.<]>H NMR (DMSO- d6): 1.42 (3H, s), 2.02 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J = 9.7 Hz), 4.21 ( 1H, d, J = 9.7 Hz), 6.23 (1H, bs), 6.72 (1H, m), 6.90 (1H, m), 7.56 (1H, m), 7, 88 (1H, dd, J = 9.0 Hz and 2.2 Hz), 7.93 (1H, d, J = 2.2 Hz), 8.03 (1H, d, J = 9.0 Hz) , 9.51 (1H, s), 10.15 (1H, bs).

Eksempel 5. Example 5.

4-[2-hydroksy-2-(3-metyl-4-nitrofenylkarbamoyl)propoksy]benzarnid 4-[2-hydroksy-2-(3-metyl-4-nitrofenylkarbamoyl)propoksy]benzamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-hydroksybenzamid og l,2-epoksy-2-metyl-N-(3-metyl-4-nitrofenyl)-2-propanamid.<!>H NMR (400 MHz, DMSO-d6): 1,45 (3H, s), 2,53 (3H, s), 4,04 (1H, d, J = 9,7 Hz), 4,28 (1H, d, J = 9,7 Hz), 6,26 (1H, s), 6,94-6,98 (2H, m), 7,19 (1 H, br s), 7,80-7,83 (3H, m), 7,89 (1H, dd, J = 9,0 Hz, J = 2,2 Hz), 7,95 (1H, d, J = 2,0 Hz), 8,05 (1H, d, J = 9,0 Hz), 10,19 (1H, s). 4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl)propoxy]benzanide 4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl)propoxy]benzamide was prepared as described in Example 1 by starting from 4-hydroxybenzamide and 1,2-epoxy-2-methyl-N-(3-methyl-4-nitrophenyl)-2-propanamide. <!>H NMR (400 MHz, DMSO-d6): 1.45 (3H, s), 2.53 (3H, s), 4.04 (1H, d, J = 9.7 Hz), 4.28 (1H, d, J = 9.7 Hz), 6.26 (1H, s), 6.94-6.98 (2H, m), 7.19 (1H, br s), 7.80-7.83 (3H, m), 7.89 (1H, dd , J = 9.0 Hz, J = 2.2 Hz), 7.95 (1H, d, J = 2.0 Hz), 8.05 (1H, d, J = 9.0 Hz), 10, 19 (1H, p).

Eksempel 6. Example 6.

3-(3,4-diklorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3- (3,4-diklorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel ved å starte fra 3,4-diklorfenol og l,2-epoksy-2-metyl-N-(3-metyl-4-nitrofenyl)-2-propanamid. 3-(3,4-dichlorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(3,4-dichlorophenoxy)-2-hydroxy-2-methyl-N- (3-methyl-4-nitrophenyl)propionamide was prepared as described in Example by starting from 3,4-dichlorophenol and 1,2-epoxy-2-methyl-N-(3-methyl-4-nitrophenyl)-2- propanamide.

<]>H NMR (400 MHz, DMSO-d6): 1,43 (3H, s), 2,53 (3H, s), 4,02 (1H, d, J = 9,9 Hz), 4,28 (1H, d, J = 9,9 Hz), 6,27 (1H, s), 6,95 (1H, dd, J = 8,9 Hz, J = 2,8 Hz), 7,25 (1 H, d, J = 2,8 Hz), 7,49 (1 H, d, J = 8,9 Hz), 7,88 (1H, dd, J = 9,0 Hz, J = 2,3 Hz), 7,93 (1H, d, J = 2,0 Hz), 8,04 (1H, d, J = 9,0 Hz), 10,17 (1H, s). <]>H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 4.02 (1H, d, J = 9.9 Hz), 4, 28 (1H, d, J = 9.9 Hz), 6.27 (1H, s), 6.95 (1H, dd, J = 8.9 Hz, J = 2.8 Hz), 7.25 ( 1 H, d, J = 2.8 Hz), 7.49 (1 H, d, J = 8.9 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 2.0 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.17 (1H, s).

Eksempel 7. Example 7.

4- [2-hydroksy-2-(3-metyl-4-nitrofenylkarbamoyl)propoksy]benzosyreetylester 4-[2-hydroksy-2-(3-metyl-4-nitrofenylkarbamoyl)propoksy]benzosyreetylester ble fremstilt som beskrevet i eksempel 1 ved å starte fra etyl 4-hydroksybenzoat og 1,2-epoksy-2-metyl-N-(3-metyl-4-nitrofenyl)-2-propanamid. 4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl)propoxy]benzoic acid ethyl ester 4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl)propoxy]benzoic acid ethyl ester was prepared as described in example 1 by starting from ethyl 4-hydroxybenzoate and 1,2-epoxy-2-methyl-N-(3-methyl-4-nitrophenyl)-2-propanamide.

<]>H NMR (400 MHz, DMSO-d6): 1,30 (3H, t, J = 7,1 Hz), 1,45 (3H, s), 2,53 (3H, s), 4,07 (1H, d, J = 9,7 Hz), 4,26 (2H, q, J = 7,1 Hz), 4,30 (1H, d, J = 9,7 Hz), 6,29 (1H, s), 7,01-7,05 (2H, m), 7,86-7,91 (3H, m), 7,94 (1H, d, J = 1,9 Hz), 8,04 (1H, d, J = 9,0 Hz), 10,20 (1H, s). <]>H NMR (400 MHz, DMSO-d6): 1.30 (3H, t, J = 7.1 Hz), 1.45 (3H, s), 2.53 (3H, s), 4, 07 (1H, d, J = 9.7 Hz), 4.26 (2H, q, J = 7.1 Hz), 4.30 (1H, d, J = 9.7 Hz), 6.29 ( 1H, s), 7.01-7.05 (2H, m), 7.86-7.91 (3H, m), 7.94 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.20 (1H, s).

Eksempel 8. Example 8.

3 -(3 -kloro-4-fluorfenoksy)-2 -hydroksy-2-mety l-N-(3 -metyl-4-nitrofenyl)propionamid 3-(3-chloro-4-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(3-kloro-4-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 3-klor-4-fluorofenol og 1,2-epoksy-2-metyl-N-(3-metyl-4-nitrofenyl)-2-propanamid. 3-(3-Chloro-4-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 3-chloro-4-fluorophenol and 1,2-epoxy-2-methyl-N-(3-methyl-4-nitrophenyl)-2-propanamide.

<]>H NMR (400 MHz, DMSO-d6): 1,42 (3H, s), 2,53 (3H, s), 4,00 (1H, d, J = 9,8 Hz), 4,25 (1H, d, J = 9,8 Hz), 6,21 (1H, s), 6,89-6,95 (1H, m), 7,15-7,19 (1H, m), 7,26-7,32 (1H, m), 7,87 (1H, dd, J = 8,9 Hz, J = 2,3 Hz), 7,91 (1H, d, J = 1,9 Hz), 8,03 (1H, d, J = 8,9 Hz), 10,12 (1H, s). <]>H NMR (400 MHz, DMSO-d6): 1.42 (3H, s), 2.53 (3H, s), 4.00 (1H, d, J = 9.8 Hz), 4, 25 (1H, d, J = 9.8 Hz), 6.21 (1H, s), 6.89-6.95 (1H, m), 7.15-7.19 (1H, m), 7 .26-7.32 (1H, m), 7.87 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.91 (1H, d, J = 1.9 Hz) , 8.03 (1H, d, J = 8.9 Hz), 10.12 (1H, s).

Eksempel 9. Example 9.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(4-trifluormetoksyfenoksy)-propionamid 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(4-trifluoromethoxyphenoxy)-propionamide

2- hydroksy-2-rnetyl-N-(3-metyl-4-nitrofenyl)-3-(4-trifluormetoksyfenoksy)-propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-(trifluormetoksy)fenol og 1,2-epoksy-2-metyl-N-(3-metyl-4-nitrofenyl)-2-propanamid.<]>H NMR (400 MHz, DMSO-d*;): 1,44 (3H, s), 2,53 (3H, s), 4,01 (1H, d, J = 9,7 Hz), 4,24 (1H, d, J = 9,7 Hz), 6,24 (1H, s), 6,99-7,05(2H, m), 7,22-7,30 (2H, m), 7,88 (1H, dd, J = 8,9 Hz, J = 2,3 Hz), 7,93 (1H, d, J = 1,9 Hz), 8,03 (1H, d, J = 8,9 Hz), 10,14 (1H, s). 2-Hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(4-trifluoromethoxyphenoxy)-propionamide was prepared as described in Example 1 by starting from 4-(trifluoromethoxy)phenol and 1,2 -epoxy-2-methyl-N-(3-methyl-4-nitrophenyl)-2-propanamide.<]>H NMR (400 MHz, DMSO-d*;): 1.44 (3H, s), 2, 53 (3H, s), 4.01 (1H, d, J = 9.7 Hz), 4.24 (1H, d, J = 9.7 Hz), 6.24 (1H, s), 6, 99-7.05(2H, m), 7.22-7.30 (2H, m), 7.88 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.03 (1H, d, J = 8.9 Hz), 10.14 (1H, s).

Eksempel 10. Example 10.

3- (2,3-diklorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(2,3-diklorfenoksy)-2-hydroksy-2-metyl-N-(3-mety 1-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 2,3-diklorfenol og 1,2-epoksy-2- metyl-N-(3-metyl-4-nitrofenyl)-2-propanamid. 3-(2,3-dichlorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(2,3-dichlorophenoxy)-2-hydroxy-2-methyl-N- (3-methyl 1-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 2,3-dichlorophenol and 1,2-epoxy-2-methyl-N-(3-methyl-4-nitrophenyl)- 2-propanamide.

<]>H NMR (400 MHz, DMSO-d6): 1,46 (3H, s), 2,53 (3H, s), 4,16 (1H, d, J = 9,8 Hz), 4,27 (1H, d, J = 9,8 Hz), 6,27 (1H, s), 7,16-7,21 (2H, m), 7,27-7,33 (1H, m), 7,87 (1H, dd, J = 8,9 Hz, J = 2,3 Hz), 7,91 (1H, d, J = 1,9 Hz), 8,03 (1H, d, J = 8,9 Hz), 10,14 (1H, s). <]>H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4.16 (1H, d, J = 9.8 Hz), 4, 27 (1H, d, J = 9.8 Hz), 6.27 (1H, s), 7.16-7.21 (2H, m), 7.27-7.33 (1H, m), 7 .87 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.91 (1H, d, J = 1.9 Hz), 8.03 (1H, d, J = 8, 9 Hz), 10.14 (1H, s).

Eksempel 11. Example 11.

3- (4-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte frap-fluorfenol og l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<!>H NMR (400 MHz, DMSO-d6): 1,43 (3H, s), 2,53 (3H, s), 3,96 (1H, d, J = 9,6 Hz), 4,20 (1H, d, J= 9,6 Hz), 6,21 (1H, s), 6,90-6,96 (2H, m), 7,06-7,12 (2H, m), 7,89 (1H, åå, J= 9,0 Hz,J= 2,2 Hz), 7,90 (1H, d, J= 1,9 Hz), 8,04 (1H, d, J= 9,0 Hz), 10,15 (1H, s). 3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl -4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from p-fluorophenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.<!>H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.96 (1H, d, J = 9.6 Hz), 4.20 (1H, d, J= 9.6 Hz), 6.21 (1H, s), 6.90-6.96 (2H, m), 7.06-7.12 (2H, m), 7.89 (1H , yy, J= 9.0 Hz,J= 2.2 Hz), 7.90 (1H, d, J= 1.9 Hz), 8.04 (1H, d, J= 9.0 Hz), 10.15 (1H, p).

Eksempel 12. Example 12.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-/»-tolyloksypropionamid 2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-/»-tolyloksypropionamid ble fremstilt som beskrevet i eksempel 1 ved å starte frap-metylfenol og l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<!>H NMR (400 MHz, DMSO-d6): 1,43 (3H, s), 2,21 (3H, s), 2,53 (3H, s), 3,93 (1H, d, .7=9,6 Hz), 4,17 (1H, d,7 = 9,5 Hz), 6,18 (1H, s), 8,53 (2H, d, 7 = 8,5 Hz), 7,06 (2H, d, 7 = 8,4 Hz), 7,89 (1H, dd, 7 = 2,2 Hz, 7 = 9,0 Hz), 7,94 (1H, d, 7 = 1,8 Hz), 8,04 (1H, d, 7 = 9,0 Hz), 10,14 (1H, s). 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-/»-tolyloxypropionamide 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-/» -tolyloxypropionamide was prepared as described in Example 1 starting from p-methylphenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide. <!>H NMR (400 MHz , DMSO-d6): 1.43 (3H, s), 2.21 (3H, s), 2.53 (3H, s), 3.93 (1H, d, .7=9.6 Hz), 4.17 (1H, d,7 = 9.5 Hz), 6.18 (1H, s), 8.53 (2H, d, 7 = 8.5 Hz), 7.06 (2H, d, 7 = 8.4 Hz), 7.89 (1H, dd, 7 = 2.2 Hz, 7 = 9.0 Hz), 7.94 (1H, d, 7 = 1.8 Hz), 8.04 ( 1H, d, 7 = 9.0 Hz), 10.14 (1H, s).

Eksempel 13. Example 13.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-[4-(2,2,2-trifluoracetylamino)fenoksy]propionamid 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-[4-(2,2,2-trifluoroacetylamino)phenoxy]propionamide

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-[4-(2,2,2-trifluoracetylamino)fenoksy]propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte frap-N-trifluoracetamidofenol og l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d6): 1,43 (3H, s), 2,53 (3H, s), 3,98 (1H, d, 7 = 9,6 Hz), 4,22 (1H, d, 7 = 9,6 Hz), 6,22 (1H, s), 6,93-6,98 (2H, m), 7,52-7,56 (2H, m), 7,88 (1H, dd, J = 9,0 Hz, J = 2,2 Hz), 7,93 (1H, d, J= 1,9 Hz), 8,04 (1H, d, 7=9,0 Hz). 2-Hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-[4-(2,2,2-trifluoroacetylamino)phenoxy]propionamide was prepared as described in Example 1 starting from p-N -trifluoroacetamidophenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide. <]>H NMR (400 MHz, DMSO-d6): 1.43 (3H, s ), 2.53 (3H, s), 3.98 (1H, d, 7 = 9.6 Hz), 4.22 (1H, d, 7 = 9.6 Hz), 6.22 (1H, s ), 6.93-6.98 (2H, m), 7.52-7.56 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz) , 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, 7 = 9.0 Hz).

Eksempel 14. Example 14.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-fenoksypropionamid 2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-fenoksypropionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra fenol og l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d6): 1,44 (3H, s), 2,53 (3H, s), 3,97 (1H, d, J= 9,6 Hz), 4,21 (1H, d, J= 9,6 Hz), 6,21 (1H, s), 6,90-6,95 (3H, m), 7,24-7,29 (2H, m), 7,89 (1H, dd, J= 2,3 Hz, 7= 9,0 Hz), 7,94 (1H, d, 7= 2,0 Hz), 8,04 (1H, d,<3>J= 9,0 Hz), 10,16 (1H, s). 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-phenoxypropionamide 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-phenoxypropionamide was prepared as described in Example 1 by starting from phenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide. <]>H NMR (400 MHz, DMSO-d6): 1 .44 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J= 9.6 Hz), 4.21 (1H, d, J= 9.6 Hz), 6 .21 (1H, s), 6.90-6.95 (3H, m), 7.24-7.29 (2H, m), 7.89 (1H, dd, J= 2.3 Hz, 7 = 9.0 Hz), 7.94 (1H, d, 7= 2.0 Hz), 8.04 (1H, d,<3>J= 9.0 Hz), 10.16 (1H, s) .

Eksempel 15. Example 15.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(4-trifluormetylfenoksy)propionamid 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(4-trifluoromethylphenoxy)propionamide

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(4-trifluormetylfenoksy)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra /»-hydroksybenzotrifluorid og 2-metyloksiran-2-karbosyklisk syre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat (95:5) som elueringsmiddel. Utkrystallisering fra toluen.<]>H NMR 2-Hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(4-trifluoromethylphenoxy)propionamide was prepared as described in Example 1 starting from /»-hydroxybenzotrifluoride and 2-methyloxirane-2- carbocyclic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate (95:5) as eluent. Crystallization from toluene.<]>H NMR

(400 MHz, CDCI3): 1,62 (3H, s), 2,65 (3H,s), 3,25 (1H, s, -OH), 4,05 (1H, d,<2>Jgem=9,1 Hz), 4,51 (1H, d,<2>Jgem=9,0 Hz), 7,00 (2H, d, 3J = 8,8 Hz), 7,57 (2H, d, 3J = 8,8 Hz), 7,58 (1H, dd,<3>J= 8,9 Hz,<4>J= 2,7 Hz), 7,66 (1H, d,<4>J= 2, 2 Hz), 8,08 (1H, d,<3>J= 8,9 Hz), 8,9 (1H, bred s, -NHCO-). (400 MHz, CDCl3): 1.62 (3H, s), 2.65 (3H, s), 3.25 (1H, s, -OH), 4.05 (1H, d,<2>Jgem= 9.1 Hz), 4.51 (1H, d,<2>Jgem=9.0 Hz), 7.00 (2H, d, 3J = 8.8 Hz), 7.57 (2H, d, 3J = 8.8 Hz), 7.58 (1H, dd,<3>J= 8.9 Hz,<4>J= 2.7 Hz), 7.66 (1H, d,<4>J= 2 , 2 Hz), 8.08 (1H, d,<3>J= 8.9 Hz), 8.9 (1H, broad s, -NHCO-).

Eksempel 16. Example 16.

3-(4-acetylfenoksy)-2-hydroksy-2-metyl-N-(3-rnetyl-4-nitrofenyl)propionarnid 3-(4-acetylfenoksy)-2-hydroksy-2-metyl-N-(3-ttietyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4'-hydroksyacetofenon og 2-metyloksiran-2-karbosyklisk syre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat (95:5) som elueringsmiddel. Utkrystallisering fra toluen, smeltepunkt 153-155°C.<]>H NMR (400 MHz, CDCI3): 1,62 (3H, s), 2,57 (3H, s), 2,65 (3H, s), 3,26 (1H, s, -OH), 4,07 (1H, d,<2>Jgem=9,1 Hz), 4,53 (1H, d,<2>Jgem=9,1 Hz), 6,96 (2H, d, 3J = 8,9 Hz), 7,58 (1H, dd,<3>J= 8,9 Hz, 4J = 2,4 Hz), 7,66 (1H, d,<4>J= 2,3 Hz), 7,94 (2H, d,<3>J= 8,9 Hz), 8,09 (1H, d,<3>J= 9,0 Hz), 8,95 (1H, bred s, -NHCO-). 3-(4-Acetylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(4-Acetylphenoxy)-2-hydroxy-2-methyl-N-(3-thiethyl) -4-nitrophenyl)propionamide was prepared as described in example 1 by starting from 4'-hydroxyacetophenone and 2-methyloxirane-2-carbocyclic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate (95:5) as eluent. Crystallization from toluene, melting point 153-155°C. <]>H NMR (400 MHz, CDCl3): 1.62 (3H, s), 2.57 (3H, s), 2.65 (3H, s), 3.26 (1H, s, -OH), 4.07 (1H, d,<2>Jgem=9.1 Hz), 4.53 (1H, d,<2>Jgem=9.1 Hz), 6.96 (2H, d, 3J = 8.9 Hz), 7.58 (1H, dd,<3>J= 8.9 Hz, 4J = 2.4 Hz), 7.66 (1H, d, <4>J= 2.3 Hz), 7.94 (2H, d,<3>J= 8.9 Hz), 8.09 (1H, d,<3>J= 9.0 Hz), 8 .95 (1H, broad s, -NHCO-).

Eksempel 17. Example 17.

3-(4-cyanofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-cyanofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-cyanofenol og 2-metyloksiran-2-karbosyklisk syre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som gradientelueringsmiddel. Utkrystallisering fra toluen.<]>H NMR (400 MHz, DMSO-d6) : 1,44 (3H, s), 2,53 (3H, s), 4,08 (1H, d,<2>Jgem=9,8 Hz), 4,33 (1H, d,<2>Jgem=9, 9 Hz), omtrent 6,3 (1H, bred s, -OH), 7,10 (2H, d,<3>J= 8,8 Hz), 7,75 (2H, d, 3J = 8,8 Hz), 7,88 (1H, dd,<3>J= 9,0 Hz,<4>J= 2,3 Hz), 7,93 (1H, d,<4>J= 2,0 Hz), 8,04 (1H, d,<3>J= 9,0 Hz), omtrent 10,2 (1H, bred s, -NHCO-). 3-(4-cyanophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(4-cyanophenoxy)-2-hydroxy-2-methyl-N-(3-methyl -4-nitrophenyl)propionamide was prepared as described in example 1 by starting from 4-cyanophenol and 2-methyloxirane-2-carbocyclic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as gradient eluent. Crystallization from toluene.<]>H NMR (400 MHz, DMSO-d6) : 1.44 (3H, s), 2.53 (3H, s), 4.08 (1H, d,<2>Jgem=9 ,8 Hz), 4.33 (1H, d,<2>Jgem=9, 9 Hz), about 6.3 (1H, broad s, -OH), 7.10 (2H, d,<3>J = 8.8 Hz), 7.75 (2H, d, 3J = 8.8 Hz), 7.88 (1H, dd,<3>J= 9.0 Hz,<4>J= 2.3 Hz ), 7.93 (1H, d,<4>J= 2.0 Hz), 8.04 (1H, d,<3>J= 9.0 Hz), about 10.2 (1H, wide s, -NHCO-).

Eksempel 18. Example 18.

3-(3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 3-fluorfenol og 2-metyloksiran-2-karbosyklisk syre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som gradientelueringsmiddel. Utkrystallisering fra toluen/heptan, smeltepunkt 83-86°C.<]>H NMR (400 MHz, DMSO-tftf):1,43 (3H,s), 2,53 (3H,s), 3,99 (1H, d,<2>Jgem= 9,7 Hz), 4,24 (1H, d,<2>Jgem= 9,7 Hz), 6,26 (1H, bred s, -OH), 6,73-7,78 (2H, m), 6,81 3-(3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl -4-nitrophenyl)propionamide was prepared as described in example 1 by starting from 3-fluorophenol and 2-methyloxirane-2-carbocyclic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as gradient eluent. Crystallization from toluene/heptane, melting point 83-86°C. <]>H NMR (400 MHz, DMSO-tftf): 1.43 (3H,s), 2.53 (3H,s), 3.99 (1H , d,<2>Jgem= 9.7 Hz), 4.24 (1H, d,<2>Jgem= 9.7 Hz), 6.26 (1H, broad s, -OH), 6.73- 7.78 (2H, m), 6.81

(1H, m), 7,28 (1H, m), 7,89 (1H, dd,<3>J= 9,0 Hz,<4>J=2,3 Hz), 7,94 (1H, d,<4>J=2,0Hz), 8,04 (1H, d,<3>J= 8,9 Hz), 10,17 (1H, bred s, -NHCO-). (1H, m), 7.28 (1H, m), 7.89 (1H, dd,<3>J= 9.0 Hz,<4>J=2.3 Hz), 7.94 (1H, d,<4>J=2.0Hz), 8.04 (1H, d,<3>J= 8.9 Hz), 10.17 (1H, broad s, -NHCO-).

Eksempel 19. Example 19.

3-(2-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(2-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 2-fluorfenol og 2-metyloksiran-2-karbosyklisk syre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat (90:10) som elueringsmiddel. Utkrystallisering fra etylacetat/heptan, smeltepunkt 94-96°C.<!>H NMR (400 MHz, DMSO-tftf): 1,44 (3H,s), 2,53 (3H,s), 4,07 (1H, d,<2>Jgem= 9,8 Hz), 4,27 (1H, d,<2>Jgem= 9,8 Hz), 6,27 (1H, bred s, -OH), 6,93 (1H, m), 7,10 (1H, m), 7,14-7,21 (2H, m), 7,88 (1H, dd,<3>J= 9,0 Hz,<4>J= 2,2 Hz), 7,93 (1H, d,<4>J= 2,0 Hz), 8,04 (1H, d,<3>J= 9,0 Hz), 10,17 (1H, bred s, -NHCO-). 3-(2-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(2-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl -4-nitrophenyl)propionamide was prepared as described in example 1 by starting from 2-fluorophenol and 2-methyloxirane-2-carbocyclic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate (90:10) as eluent. Crystallization from ethyl acetate/heptane, melting point 94-96°C.<!>H NMR (400 MHz, DMSO-tftf): 1.44 (3H,s), 2.53 (3H,s), 4.07 (1H , d,<2>Jgem= 9.8 Hz), 4.27 (1H, d,<2>Jgem= 9.8 Hz), 6.27 (1H, broad s, -OH), 6.93 ( 1H, m), 7.10 (1H, m), 7.14-7.21 (2H, m), 7.88 (1H, dd,<3>J= 9.0 Hz,<4>J= 2.2 Hz), 7.93 (1H, d,<4>J= 2.0 Hz), 8.04 (1H, d,<3>J= 9.0 Hz), 10.17 (1H, broad s, -NHCO-).

Eksempel 20. Example 20.

2-hydroksy-3-[4-(2-hydroksyetyl)fenoksy]-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 2-hydroxy-3-[4-(2-hydroxyethyl)phenoxy]-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

2- hydroksy-3-[4-(2-hydroksyetyl)fenoksy]-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-hydroksyfenylalkohol (1,45 ekvivalenter), natriumhydrid (2,9 ekvivalenter) og 2-metyloksiran-2-karbosyklisk syre (3-metyl-4-nitrofenyl)amid (1 ekvivalent). Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel (9:1-4:6).<]>H NMR (400 MHz, DMSO-c/tf): 1,43 (3H, s), 2,53 (3H,s), 2,63 (2H, t,<3>J= 7,1 Hz), 3,53 (2H, m), 3,94 (1H, d,<2>Jgem= 9,6 Hz), 4,17 (1H, d,<2>Jgem= 9,6 Hz), 4,56 (1H, t,<3>J= 5,2 Hz, CH2OH), 6,17 (1H, bred s, -OH), 6,81 (2H, d,<3>J= 8,7 Hz), 7,09 (2H, d), 7,88 (1H, dd,<3>J=9,0 Hz,<4>J= 2,3 Hz), 7,93 (1H, d,<4>J= 1,9 Hz), 8,04 (1H, d, 3J = 9,0 Hz), 10,13 (1H, bred s, 2-hydroxy-3-[4-(2-hydroxyethyl)phenoxy]-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 4-hydroxyphenyl alcohol (1, 45 equivalents), sodium hydride (2.9 equivalents) and 2-methyloxirane-2-carbocyclic acid (3-methyl-4-nitrophenyl)amide (1 equivalent). The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (9:1-4:6). <]>H NMR (400 MHz, DMSO-c/tf): 1.43 (3H, s), 2 .53 (3H,s), 2.63 (2H, t,<3>J= 7.1 Hz), 3.53 (2H, m), 3.94 (1H, d,<2>Jgem= 9 .6 Hz), 4.17 (1H, d,<2>Jgem= 9.6 Hz), 4.56 (1H, t,<3>J= 5.2 Hz, CH2OH), 6.17 (1H , broad s, -OH), 6.81 (2H, d,<3>J= 8.7 Hz), 7.09 (2H, d), 7.88 (1H, dd,<3>J=9 ,0 Hz,<4>J= 2.3 Hz), 7.93 (1H, d,<4>J= 1.9 Hz), 8.04 (1H, d, 3J = 9.0 Hz), 10.13 (1H, wide s,

-NHCO-). -NHCO-).

Eksempel 21. Example 21.

3- (2,6-diklorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(2,6-diklorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 2,6-diklorfenol og 1,2-epoksy-2-metyl-N-(3-metyl-4-nitrofenyl)-2-propanamid.<]>H NMR (400 MHz, DMSO-d6): 1,47 (3H, s), 2,53 (3H, s), 4,12 (1H, d, J = 9,0 Hz), 4,18 (1H, d, J = 9,0 Hz), 6,14 (1H, s), 7,12-7,18 (1H, m), 7,43-7,46 (2 H, m), 7,86-7,90 (2H, m), 8,02-8,05 (1H, m), 10,11 (1H, s). 3-(2,6-dichlorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(2,6-dichlorophenoxy)-2-hydroxy-2-methyl-N- (3-Methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 2,6-dichlorophenol and 1,2-epoxy-2-methyl-N-(3-methyl-4-nitrophenyl)-2 -propanamide.<]>H NMR (400 MHz, DMSO-d6): 1.47 (3H, s), 2.53 (3H, s), 4.12 (1H, d, J = 9.0 Hz) , 4.18 (1H, d, J = 9.0 Hz), 6.14 (1H, s), 7.12-7.18 (1H, m), 7.43-7.46 (2H, m), 7.86-7.90 (2H, m), 8.02-8.05 (1H, m), 10.11 (1H, s).

Eksempel 22. Example 22.

3-(4-brorn-2-fluorfenoksy)-2-hydroksy-2-rnetyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-brom-2-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(4-brom-2-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-brom-2-fluorfenol og 1,2-epoksy-2-metyl-N-(3-metyl-4-nitrofenyl)-2-propanamid.<]>H NMR (400 MHz, DMSO-d6): 1,43 (3H, s), 2,53 (3H, s), 4,08 (1H, d, J = 9,9 Hz), 4,28 (1H, d, J = 9,9 Hz), 6,26 (1H, s), 7,15-7,22 (1H, m), 7,29-7,33 (1H, m), 7,46-7,50 (1H, m), 7,86 (1H, dd, J = 8,9 Hz, J = 2,3 Hz), 7,88 (1H, d, J = 1,9 Hz), 8,03 (1H, J = 8,9 Hz), 10,13 (1H, s). 3-(4-bromo-2-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 4-bromo-2-fluorophenol and 1,2-epoxy-2-methyl-N-(3-methyl-4-nitrophenyl)-2-propanamide. <]>H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 4.08 (1H, d, J = 9.9 Hz), 4.28 (1H, d, J = 9.9 Hz), 6.26 (1H, s), 7.15-7.22 (1H, m), 7.29-7.33 (1H, m), 7.46-7.50 (1H, m), 7.86 (1H, dd, J = 8 .9 Hz, J = 2.3 Hz), 7.88 (1H, d, J = 1.9 Hz), 8.03 (1H, J = 8.9 Hz), 10.13 (1H, s) .

Eksempel 23. Example 23.

3-(4-klorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-klorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte frap-klorfenol og l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<!>H NMR (400 MHz, DMSO-d6): 1,43 (3H, s), 2,53 (3H, s), 3,98 (1H, d, J= 9,7 Hz), 4,22 (1H, å, J= 9,7 Hz), 6,23 (1H, s), 6,93-7,00 (2H, m), 7,28-7,32 (2H, m), 7,88 (1H, åå, J= 9,0 Hz, .7 = 2,2 Hz), 7,93 (1H, d, J= 1,9 Hz), 8,04 (1H, d, .7=9,0 Hz), 10,51 (1H, s). 3-(4-Chlorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(4-Chlorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl -4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from p-chlorophenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.<!>H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.98 (1H, d, J= 9.7 Hz), 4.22 (1H, å, J= 9.7 Hz), 6.23 (1H, s), 6.93-7.00 (2H, m), 7.28-7.32 (2H, m), 7.88 (1H , yy, J= 9.0 Hz, .7 = 2.2 Hz), 7.93 (1H, d, J= 1.9 Hz), 8.04 (1H, d, .7=9.0 Hz ), 10.51 (1H, p).

Eksempel 24. Example 24.

3-(4-bromfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-bromfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte frap-bromfenol og l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d6): 1,43 (3H, s), 2,53 (3H, s), 3,97 (1H, d, J = 9,7 Hz), 4,21 (1H, d, J= 9,7 Hz), 6,23 (1H, s), 6,88-6,93 (2H, m), 7,39-7,44 (2H, m), 7,88 (1H, dd, .7= 9,0 Hz, .7= 2,2 Hz), 7,93 (1H, å, J= 1,8 Hz), 8,04 (1H, d, J= 9,0 Hz), 10,15 (1H, s). 3-(4-Bromophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(4-Bromophenoxy)-2-hydroxy-2-methyl-N-(3-methyl -4-nitrophenyl)propionamide was prepared as described in Example 1 starting from p-bromophenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.<]>H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J = 9.7 Hz), 4.21 (1H, d, J= 9.7 Hz), 6.23 (1H, s), 6.88-6.93 (2H, m), 7.39-7.44 (2H, m), 7.88 (1H , dd, .7= 9.0 Hz, .7= 2.2 Hz), 7.93 (1H, å, J= 1.8 Hz), 8.04 (1H, d, J= 9.0 Hz ), 10.15 (1H, p).

Eksempel 25. Example 25.

2-hydroksy-3-(4-metoksyfenoksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 2-hydroksy-3-(4-metoksyfenoksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra />-metoksyfenol og 1,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d6): 1,42 (3H, s), 2,53 (3H, s), 3,68 (3H, s), 3,91 (1H, d, J = 9,5 Hz), 4,15 (1H, d, J = 9,5 Hz), 6,17 (1H, s), 6,80-6,87 (4H, m), 7,88 (1H, dd, 7= 9,0 Hz, 7 = 2,2 Hz), 7,93 (1H, d, J= 2,0 Hz), 8,04 (1H, d, J= 9,0 Hz), 10,13 (1H, s). 2-hydroxy-3-(4-methoxyphenoxy)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 2-hydroxy-3-(4-methoxyphenoxy)-2-methyl-N-(3-methyl -4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from />-methoxyphenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.<] >H NMR (400 MHz, DMSO-d6): 1.42 (3H, s), 2.53 (3H, s), 3.68 (3H, s), 3.91 (1H, d, J = 9 .5 Hz), 4.15 (1H, d, J = 9.5 Hz), 6.17 (1H, s), 6.80-6.87 (4H, m), 7.88 (1H, dd , 7= 9.0 Hz, 7 = 2.2 Hz), 7.93 (1H, d, J= 2.0 Hz), 8.04 (1H, d, J= 9.0 Hz), 10, 13 (1H, p).

Eksempel 26. Example 26.

3-(benzo[l,3]dioksol-5-yloksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(Benzo[1,3]dioxol-5-yloxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(benzo[l,3]dioksol-5-yloksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 3,4-metylendioksylfenol og l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d*;): 1,41 (3H, s), 2,53 (3H, s), 3,90 (1H, d, 7 = 9,6 Hz), 4,15 (1H, d, 7 = 9,6 Hz), 5,94 (2H, s), 6,18 (1H, s), 6,35 (1H, dd, 7 = 8,5 Hz, 7 = 2,5 Hz), 6,59 (1H, d, 7 = 2,5 Hz), 6,78 (1H, d, 7 = 8,5 Hz), 7,88 (1H, dd, 7=9,0 Hz, 7= 2,2 Hz), 7,93 (1H, d,7= 1,6 Hz), 8,04 (1H, d,7=9,0 Hz), 10,13 (1H, s). 3-(Benzo[1,3]dioxol-5-yloxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 3,4 -methylenedioxyphenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.<]>H NMR (400 MHz, DMSO-d*;): 1.41 (3H , s), 2.53 (3H, s), 3.90 (1H, d, 7 = 9.6 Hz), 4.15 (1H, d, 7 = 9.6 Hz), 5.94 (2H , s), 6.18 (1H, s), 6.35 (1H, dd, 7 = 8.5 Hz, 7 = 2.5 Hz), 6.59 (1H, d, 7 = 2.5 Hz ), 6.78 (1H, d, 7 = 8.5 Hz), 7.88 (1H, dd, 7=9.0 Hz, 7= 2.2 Hz), 7.93 (1H, d,7 = 1.6 Hz), 8.04 (1H, d,7=9.0 Hz), 10.13 (1H, s).

Eksempel 27. Example 27.

3-(3,4-dimetoksyfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(3,4-dimethoxyphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(3,4-dimetoksyfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 3,4-dimetoksyfenol og l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<!>H NMR (400 MHz, DMSO-d6): 1,43 (3H, s), 2,53 (3H, s), 3,67 (3H, s), 3,70 (3H, s), 3,91 (1H, d, 7= 9,6 Hz), 4,17 (1H, d, 7= 9,6 Hz), 6,17 (1H, s), 6,42 (1H, dd, 7 = 8,8 Hz, 7 = 2,8 Hz), 6,52 (1H, d, 7= 2,8 Hz), 6,82 (1H, d, 7= 8,8 Hz), 7,89 (1H, dd, 7= 9,0 Hz, 7= 2,2 Hz), 7,94 (1H, d, 7= 1,9 Hz), 8,04 (1H, d, 7= 9,0 Hz), 10,13 (1H, s). 3-(3,4-dimethoxyphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 3,4-dimethoxyphenol and 1,2 -epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.<!>H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 ( 3H, s), 3.67 (3H, s), 3.70 (3H, s), 3.91 (1H, d, 7= 9.6 Hz), 4.17 (1H, d, 7= 9 .6 Hz), 6.17 (1H, s), 6.42 (1H, dd, 7 = 8.8 Hz, 7 = 2.8 Hz), 6.52 (1H, d, 7= 2.8 Hz), 6.82 (1H, d, 7= 8.8 Hz), 7.89 (1H, dd, 7= 9.0 Hz, 7= 2.2 Hz), 7.94 (1H, d, 7= 1.9 Hz), 8.04 (1H, d, 7= 9.0 Hz), 10.13 (1H, s).

Eksempel 28. Example 28.

3-(3,4-difluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(3,4-difluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 3,4-difluorfenol og 1,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d6): 1,43 (3H, s), 2,53 (3H, s), 3,97 (1H, d, 7= 9,8 Hz), 4,23 (1H, d, 7= 9,8 Hz), 6,24 (1H, s), 6,72-6,79 (1H, m), 7,02-7,10 (1H, m), 7,20-7,33 (1H, m), 7,88 (1H, dd, 7= 9,0 Hz, 7= 2,2 Hz), 7,93 (1H, d, 7= 1,9 Hz), 8,04 (1H, d, 7 = 9,9 Hz), 10,15 (1H, s). 3-(3,4-difluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(3,4-difluorophenoxy)-2-hydroxy-2-methyl-N- (3-Methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 3,4-difluorophenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2 -propanamide.<]>H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.97 (1H, d, 7= 9.8 Hz) , 4.23 (1H, d, 7= 9.8 Hz), 6.24 (1H, s), 6.72-6.79 (1H, m), 7.02-7.10 (1H, m ), 7.20-7.33 (1H, m), 7.88 (1H, dd, 7= 9.0 Hz, 7= 2.2 Hz), 7.93 (1H, d, 7= 1, 9 Hz), 8.04 (1H, d, 7 = 9.9 Hz), 10.15 (1H, s).

Eksempel 29. Example 29.

3-(2,4-diklor-3,5-dimetylfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(2,4-dichloro-3,5-dimethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(2,4-diklor-3,5-dimetylfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 2,4-diklor-3,5-dimetylfenol og 1,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d*;): 1,46 (3H, s), 2,31 (3H, s), 2,36 (3H, s), 2,53 (3H, s), 4,41 (1H, d, 7 = 9,7 Hz), 4,21 (1H, d, 7 = 9,7 Hz), 6,25 (1H, s), 7,87 (1H, dd, 7 = 9,0 Hz, 7 = 2,3 Hz), 7,91 (1H, d, 7 = 1,9 Hz), 8,04 (1H, d, 7 = 9,0 Hz), 10,12 (1H, s). 3-(2,4-dichloro-3,5-dimethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 2,4 -dichloro-3,5-dimethylphenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.<]>H NMR (400 MHz, DMSO-d*;) : 1.46 (3H, s), 2.31 (3H, s), 2.36 (3H, s), 2.53 (3H, s), 4.41 (1H, d, 7 = 9.7 Hz), 4.21 (1H, d, 7 = 9.7 Hz), 6.25 (1H, s), 7.87 (1H, dd, 7 = 9.0 Hz, 7 = 2.3 Hz) , 7.91 (1H, d, 7 = 1.9 Hz), 8.04 (1H, d, 7 = 9.0 Hz), 10.12 (1H, s).

Eksempel 30. Example 30.

3-(6-bromnaftalen-2-yloksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(6-bromonaphthalen-2-yloxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(6-bromnaftalen-2-yloksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 6-brom-2-naftol og l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d6): 1,49 (3H, s), 2,53 (3H, s), 4,11 (1H, d, 7 = 9,7 Hz), 4,35 (1H, d, 7=9,7 Hz), 6,29 (1H, s), 7,18 (1H, dd, 7 =9,0 Hz, 7 = 2,5 Hz), 7,41 (1H, d, 7 = 2,4 Hz), 7,57 (1H, dd, 7 = 8,7 Hz, 7 = 2,0 Hz), 7,77 (1H, d, 7 = 9,1 Hz), 7,80 (1H, d, J= 9,3 Hz), 7,90 (1H, dd, 7= 9,0 Hz, 7= 2,2 Hz), 7,95 (1H, d, 1,9 Hz), 8,05 (1H, d,7=9,0 Hz), 8,10 (1H, d,7= 1,9 Hz), 10,21 (1H, s). 3-(6-Bromonaphthalen-2-yloxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 6-bromo-2-naphthol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide. <]>H NMR (400 MHz, DMSO-d6): 1.49 (3H, s), 2.53 (3H, s), 4.11 (1H, d, 7 = 9.7 Hz), 4.35 (1H, d, 7=9.7 Hz), 6.29 (1H, s), 7.18 (1H, dd, 7 =9.0 Hz, 7 = 2.5 Hz), 7.41 (1H, d, 7 = 2.4 Hz), 7.57 (1H, dd, 7 = 8 .7 Hz, 7 = 2.0 Hz), 7.77 (1H, d, 7 = 9.1 Hz), 7.80 (1H, d, J= 9.3 Hz), 7.90 (1H, dd, 7= 9.0 Hz, 7= 2.2 Hz), 7.95 (1H, d, 1.9 Hz), 8.05 (1H, d,7=9.0 Hz), 8.10 (1H, d,7 = 1.9 Hz), 10.21 (1H, s).

Eksempel 31. Example 31.

3- (4-acetylamino-3-trifluormetylfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-acetylamino-3-trifluoromethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) 4-amino-3-trifluormetylfenol a) 4-amino-3-trifluoromethylphenol

4- nitro-3-trifluormetylfenol (0,414 g, 2,0 mmol) ble løst i 25 ml iseddik og tilsatt 4-nitro-3-trifluoromethylphenol (0.414 g, 2.0 mmol) was dissolved in 25 mL of glacial acetic acid and added

sinkstøv (2,62 g, 40 mmol) i små porsjoner i løpet av 10 minutter mens temperaturen steg til +40°C. Blandingen ble rørt i ti minutter og så filtrert. Sinkstøvet ble vasket med 3 x 10 ml iseddik og filtratet ble fordampet til tørrhet, noe som ga 0,212 g av 4-amino-3-trifluormetylfenol.<!>H NMR (400 MHz, DMSO-d6): 4,86 (2H, s), 6,72 (1H, d, 7 = 8,7 Hz), 6,74 (1H, d, 7 = 2,6 Hz), 6,78 (1H, dd, 7 = 8,7 Hz, 7= 2,7 Hz), 8,91 (1H, s). zinc dust (2.62 g, 40 mmol) in small portions over 10 minutes while the temperature rose to +40°C. The mixture was stirred for ten minutes and then filtered. The zinc dust was washed with 3 x 10 mL of glacial acetic acid and the filtrate was evaporated to dryness, yielding 0.212 g of 4-amino-3-trifluoromethylphenol. <!>H NMR (400 MHz, DMSO-d6): 4.86 (2H, s), 6.72 (1H, d, 7 = 8.7 Hz), 6.74 (1H, d, 7 = 2.6 Hz), 6.78 (1H, dd, 7 = 8.7 Hz, 7= 2.7 Hz), 8.91 (1H, s).

b) N-(4-hydroksy-2-trifluormetylfenyl)acetamid b) N-(4-hydroxy-2-trifluoromethylphenyl)acetamide

4-amino-3-trifluormetylfenol (0,212 g, 1,2 mmol) ble løst i 10 ml iseddik under en 4-Amino-3-trifluoromethylphenol (0.212 g, 1.2 mmol) was dissolved in 10 mL of glacial acetic acid under a

nitrogenatmosfære og så tilsatt eddiksyreanhydrid (0,3 ml, 3,0 mmol) fulgt av nitrogen atmosphere and then added acetic anhydride (0.3 mL, 3.0 mmol) followed by

røring i en time ved romtemperatur. 0,5 ml vann ble tilsatt reaksjonsblandingen som så ble fordampet til tørrhet. 50 ml toluen ble tilsatt og fordampningen ble gjentatt, noe som ga et kvantitativt utbytte av rent N-(4-hydroksy-2-trifluormetylfenyl)acetamid.<]>H NMR (400 MHz, DMSO-d6): 1,99 (3H, s), 7,01 (1H, dd, J = 8,6 Hz, J = 2,6 Hz), 7,02 (1H, d, J = 2,5 Hz), 7,19 (1H, d, J = 8,4 Hz), 9,33 (1H, s), 10,08 (1H, br s). stirring for one hour at room temperature. 0.5 ml of water was added to the reaction mixture which was then evaporated to dryness. 50 mL of toluene was added and the evaporation was repeated, giving a quantitative yield of pure N-(4-hydroxy-2-trifluoromethylphenyl)acetamide. <]>H NMR (400 MHz, DMSO-d6): 1.99 (3H , s), 7.01 (1H, dd, J = 8.6 Hz, J = 2.6 Hz), 7.02 (1H, d, J = 2.5 Hz), 7.19 (1H, d , J = 8.4 Hz), 9.33 (1H, s), 10.08 (1H, br s).

c) 3-(4-acetylamino-3-trifluormetylfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid c) 3-(4-acetylamino-3-trifluoromethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(4-acetylamino-3-trifluormetylfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra N-(4-hydroksy-2-trifluormetylfenyl)acetamid og 1,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d6): 1,46 (3H, s), 2,00 (3H, s), 2,53 (3H, s), 4,07 (1H, d, J = 9,8 Hz), 4,32 (1H, d, J = 9,8 Hz), 6,27 (1H, s), 7,19 (1H, d, J = 2,7 Hz), 7,22 (1H, dd, J = 9,0 Hz, J = 2,5 Hz), 7,31 (1H, d, J = 8,7 Hz), 7,88 (1H, dd, J = 9,0 Hz, J = 2,3 Hz), 7,93 (1H, d, J = 2,0 Hz), 8,04 (1H, d, J = 9,0 Hz), 9,43 (1H, s), 10,17 (1H, s). 3-(4-acetylamino-3-trifluoromethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from N-(4-hydroxy- 2-trifluoromethylphenyl)acetamide and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.<]>H NMR (400 MHz, DMSO-d6): 1.46 ( 3H, s), 2.00 (3H, s), 2.53 (3H, s), 4.07 (1H, d, J = 9.8 Hz), 4.32 (1H, d, J = 9 .8 Hz), 6.27 (1H, s), 7.19 (1H, d, J = 2.7 Hz), 7.22 (1H, dd, J = 9.0 Hz, J = 2.5 Hz), 7.31 (1H, d, J = 8.7 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.93 (1H, d, J = 2.0 Hz), 8.04 (1H, d, J = 9.0 Hz), 9.43 (1H, s), 10.17 (1H, s).

Eksempel 32. Example 32.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(3,4,5-trifluorfenoksy)propionamid 2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(3,4,5-trifluorfenoksy)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 3,4,5-trifluorfenol og 1,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<!>H NMR (400 MHz, DMSO-d6): 1,42 (3H, s), 2,53 (3H, s), 3,98 (1H, d, J = 9,9 Hz), 4,26 (1H, d, J = 9,0 Hz), 6,27 (1H, s), 6,92-7,02 (2H, m), 7,88 (1H, dd, J= 9,0 Hz,J= 2,2 Hz), 7,92 (1H, d, J = 1,9 Hz), 8,04 (1H, d, J = 9,0 Hz), 10,14 (1H, s). 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(3,4,5-trifluorophenoxy)propionamide 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl) )-3-(3,4,5-trifluorophenoxy)propionamide was prepared as described in Example 1 by starting from 3,4,5-trifluorophenol and 1,2-epoxy-2-methyl-N-[3-methyl- 4-nitrophenyl]-2-propanamide.<!>H NMR (400 MHz, DMSO-d6): 1.42 (3H, s), 2.53 (3H, s), 3.98 (1H, d, J = 9.9 Hz), 4.26 (1H, d, J = 9.0 Hz), 6.27 (1H, s), 6.92-7.02 (2H, m), 7.88 (1H , dd, J= 9.0 Hz,J= 2.2 Hz), 7.92 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.14 (1H, p).

Eksempel 33. Example 33.

2-hydroksy-3-(lH-indol-5-yloksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 2-hydroksy-3-(lH-indol-5-yloksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-hydroksyindol og 1,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d6): 1,49 (3H, s), 2,53 (3H, s), 4,10 (1H, d, J = 9,4 Hz), 4,23 (1H, d, J = 9,4 Hz), 6,22 (1H, s), 6,31 (1H, d, J = 2,2 Hz), 6,47 (1H, dd, J = 6,8 Hz, J= 1,5 Hz), 6,93-7,00 (2H, m), 7,12-7,17 (1H, m), 7,92 (1H, dd, 7= 9,0 Hz, 7= 2,1 Hz), 7,98 (1H, å, J= 1,6 Hz), 8,05 (1H, d, .7=9,0 Hz), 10,24 (1H, s), 11,02 (1H, s). 2-hydroxy-3-(1H-indol-5-yloxy)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 2-hydroxy-3-(1H-indol-5-yloxy)-2- methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 4-hydroxyindole and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl] -2-propanamide.<]>H NMR (400 MHz, DMSO-d6): 1.49 (3H, s), 2.53 (3H, s), 4.10 (1H, d, J = 9.4 Hz), 4.23 (1H, d, J = 9.4 Hz), 6.22 (1H, s), 6.31 (1H, d, J = 2.2 Hz), 6.47 (1H, dd, J = 6.8 Hz, J= 1.5 Hz), 6.93-7.00 (2H, m), 7.12-7.17 (1H, m), 7.92 (1H, dd , 7= 9.0 Hz, 7= 2.1 Hz), 7.98 (1H, å, J= 1.6 Hz), 8.05 (1H, d, .7=9.0 Hz), 10 .24 (1H, s), 11.02 (1H, s).

Eksempel 34. Example 34.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(4-metylsulfanylfenoksy)propionamid 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(4-methylsulfanylphenoxy)propionamide

2- hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(4-metylsulfanylfenoksy)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-(metyltio)fenol og l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d*;): 1,43 (3H, s), 2,41 (3H, s), 2,53 (3H, s), 3,96 (1H, d, J = 9,6 Hz), 4,20 (1H, d, J = 9,6 Hz), 6,21 (1H, s), 6,87-6,93 (2H, m), 7,17-7,25 (2H, m), 7,88 (1H, dd, J = 9,0 Hz, J= 2,3 Hz), 7,93 (1H, d, J = 2,0 Hz), 8,04 (1H, d, 7=9,0 Hz), 10,15 (1H, s). 2-Hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(4-methylsulfanylphenoxy)propionamide was prepared as described in Example 1 by starting from 4-(methylthio)phenol and 1,2- epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.<]>H NMR (400 MHz, DMSO-d*;): 1.43 (3H, s), 2.41 (3H, s), 2.53 (3H, s), 3.96 (1H, d, J = 9.6 Hz), 4.20 (1H, d, J = 9.6 Hz), 6.21 (1H, s), 6.87-6.93 (2H, m), 7.17-7.25 (2H, m), 7.88 (1H, dd, J = 9.0 Hz, J= 2 .3 Hz), 7.93 (1H, d, J = 2.0 Hz), 8.04 (1H, d, 7=9.0 Hz), 10.15 (1H, s).

Eksempel 35. Example 35.

3- (3-fluor-4-nitrofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(3-fluoro-4-nitrophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(3-fluor-4-nitrofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 3-fluor-4-nitrofenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid.<]>H NMR (DMSO-d6): 1,46 (3H, s), 2,53 (3H, s), 4,16 (1H, d, J = 10,1 Hz), 4,41 (1H, d, J = 10,1 Hz), 6,36 (1H, bs), 6,96 (1H, m), 7,22 (1H, m), 7,88 (1H, dd, J = 9,0 Hz og 2,1 Hz), 7,90 (1H, d, J = 2,1 Hz), 8,04 (1H, d, J = 9,0 Hz), 8,24 (1H, m), 10,19 (1H, s). 3-(3-Fluoro-4-nitrophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 3-fluoro-4-nitrophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. <]>H NMR (DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4, 16 (1H, d, J = 10.1 Hz), 4.41 (1H, d, J = 10.1 Hz), 6.36 (1H, bs), 6.96 (1H, m), 7, 22 (1H, m), 7.88 (1H, dd, J = 9.0 Hz and 2.1 Hz), 7.90 (1H, d, J = 2.1 Hz), 8.04 (1H, d, J = 9.0 Hz), 8.24 (1H, m), 10.19 (1H, s).

Eksempel 36. Example 36.

3-[4-(4-klorbenzoyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-[4-(4-chlorobenzoyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-[4-(4-klorbenzoyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-klor-4'-hydroksybenzofenon og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel. Utkrystallisering fra isopropanol.<]>H NMR (400 MHz, DMSO-tftf): 1,46 (3H,s), 2,53 (3H,s), 4,11 (1H, d,<2>Jgem= 9,7 Hz), 4,33 (1H, d,<2>Jgem= 9,7 Hz), omtrent 6,3 (1H, bred s, -OH), 7,09 (2H, d, 3J = 8,8 Hz), 7,62 (2H, d,<3>J= 8,5 Hz), 7,70 (2H, d,<3>J= 8,6 Hz), 7,72 (2H, d,<3>J= 9,0 Hz), 7,89 (1H, dd,<3>J= 9,0 Hz,<4>J= 2,3 Hz), 7,94 (1H, d,<4>J= 2, 2 Hz), 8,05 (1H, d,<3>J= 9,0 Hz), omtrent 10,2 (1H, bred s, -NHCO-). 3-[4-(4-Chlorobenzoyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 4-chloro-4' -hydroxybenzophenone and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent. Crystallization from isopropanol.<]>H NMR (400 MHz, DMSO-tftf): 1.46 (3H,s), 2.53 (3H,s), 4.11 (1H, d,<2>Jgem= 9 ,7 Hz), 4.33 (1H, d,<2>Jgem= 9.7 Hz), about 6.3 (1H, broad s, -OH), 7.09 (2H, d, 3J = 8, 8 Hz), 7.62 (2H, d,<3>J= 8.5 Hz), 7.70 (2H, d,<3>J= 8.6 Hz), 7.72 (2H, d, <3>J= 9.0 Hz), 7.89 (1H, dd,<3>J= 9.0 Hz,<4>J= 2.3 Hz), 7.94 (1H, d,<4 >J= 2.2 Hz), 8.05 (1H, d,<3>J= 9.0 Hz), about 10.2 (1H, broad s, -NHCO-).

Eksempel 37. Example 37.

3-(3-klorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(3-klorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 3-klorfenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel (10:90-40:90). Utkrystallisering fra toluen, smeltepunkt 104-107°C.<]>H NMR (400 MHz, DMSO-tftf): 1,43 (3H, s), 2,53 (3H, s), 4,00 (1H, d,<2>Jgem= 9,8 Hz), 4,26 (1H, d,<2>Jgem=9,8 Hz), 6,25 (1H, bred s, -OH), 6,88-6,91 (1H, m), 6,97-7,00 (1H, m), 7.02 (1H, t,<4>J= 2,1 Hz), 7,28 (1H, t, 3J = 8,2 Hz), 7,89 (1H, dd, 3J = 9,0 Hz, 4J = 2.3 Hz), 7,94 (1H, d,<4>J= 2,2 Hz), 8,04 (1H, d,<3>J= 9,0 Hz), 10,17 (1H, bred s, 3-(3-chlorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(3-chlorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl -4-nitrophenyl)propionamide was prepared as described in example 1 by starting from 3-chlorophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (10:90-40:90). Crystallization from toluene, mp 104-107°C. <]>H NMR (400 MHz, DMSO-tftf): 1.43 (3H, s), 2.53 (3H, s), 4.00 (1H, d ,<2>Jgem= 9.8 Hz), 4.26 (1H, d,<2>Jgem=9.8 Hz), 6.25 (1H, broad s, -OH), 6.88-6, 91 (1H, m), 6.97-7.00 (1H, m), 7.02 (1H, t,<4>J= 2.1 Hz), 7.28 (1H, t, 3J = 8.2 Hz), 7.89 (1H, dd, 3J = 9.0 Hz, 4J = 2.3 Hz), 7.94 (1H, d,<4>J= 2.2 Hz), 8.04 (1H, d ,<3>J= 9.0 Hz), 10.17 (1H, wide s,

-NHCO-). -NHCO-).

Eksempel 38. Example 38.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-pentafluorfenyloksypropionamid 2- hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-pentafluorfenyloksypropionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra pentafluorfenol og 1,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-d6): 1,40 (3H, s), 2,53 (3H, s), 4,24 (1H, d, J = 10,2 Hz), 4,44 (1H, d, J = 10,2 Hz), 6,28 (1H, s), 7,87 (1H, dd, 7= 9,0 Hz, J= 2,1 Hz), 7,89 (1H, d, J= 2,1 Hz), 8,05 (1H, d, J= 8,9 Hz), 10,13 (1H, s). 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-pentafluorophenyloxypropionamide 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-pentafluorophenyloxypropionamide was prepared as described in Example 1 by starting from pentafluorophenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.<]>H NMR (400 MHz, DMSO-d6): 1 .40 (3H, s), 2.53 (3H, s), 4.24 (1H, d, J = 10.2 Hz), 4.44 (1H, d, J = 10.2 Hz), 6 .28 (1H, s), 7.87 (1H, dd, 7= 9.0 Hz, J= 2.1 Hz), 7.89 (1H, d, J= 2.1 Hz), 8.05 (1H, d, J= 8.9 Hz), 10.13 (1H, s).

Eksempel 39. Example 39.

(25')-3-(4-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid (25<r>)-3-(4-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 3 ved å starte fra p-fluorfenol og (2R)-3-brom-2-hydroksy-2-metylpropansyre.<!>H NMR (400 MHz, DMSO-d6): 1,43 (3H, s), 2,53 (3H, s), 3,95 (1H, å, J= 9,6 Hz), 4,20 (1H, d, J= 9,6 Hz), 6,21 (1H, s), 6,90-6,97 (2H, m), 7,06-7,12 (2H, m), 7,88 (1H, dd, J= 9,0 Hz, J= 2,3 Hz), 7,93 (1H, d, J= 1,9 Hz), 8,04 (1H, d, J= 9,0 Hz), 10,15 (1H, s). (25')-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide (25<r>)-3-(4-fluorophenoxy)-2- Hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 3 by starting from p-fluorophenol and (2R)-3-bromo-2-hydroxy-2-methylpropanoic acid.< !>H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.95 (1H, å, J= 9.6 Hz), 4.20 (1H, d, J= 9.6 Hz), 6.21 (1H, s), 6.90-6.97 (2H, m), 7.06-7.12 (2H, m), 7, 88 (1H, dd, J= 9.0 Hz, J= 2.3 Hz), 7.93 (1H, d, J= 1.9 Hz), 8.04 (1H, d, J= 9.0 Hz), 10.15 (1H, s).

Eksempel 40. Example 40.

N-(4-cyano-3-metylfenyl)-3-(4-fluorfenoksy)-2-hydroksy-2-metyl-propionamid N-(4-cyano-3-methylphenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-propionamide

a) 4-amino-2-metylbenzonitril a) 4-amino-2-methylbenzonitrile

3- metyl-4-nitrobenzonitril (1,0 g, 6 mmol) ble løst i 15 ml eddiksyre. 3,75 ml vann 3-Methyl-4-nitrobenzonitrile (1.0 g, 6 mmol) was dissolved in 15 mL of acetic acid. 3.75 ml of water

ble tilsatt og blandingen ble oppvarmet til mellom 90 og 95°C. 2,5 g jernpulver ble tilsatt i løpet av 1,5 timer og den resulterende blandingen ble oppvarmet i 1 time. was added and the mixture was heated to between 90 and 95°C. 2.5 g of iron powder was added over 1.5 hours and the resulting mixture was heated for 1 hour.

Ytterligere 3,75 ml vann ble tilsatt og oppvarming ble fortsatt i ytterligere 2 timer. Løsningen ble hensatt for avkjøling til romtemperatur, hvoretter den ble fortynnet med 100 ml vann og ekstrahert med 4 x 40 ml etylacetat. Den organiske fasen ble vasket med 50 ml 5% NaHCC>3 og 50 ml vann, tørket over natriumsulfat og fordampet. Råproduktet ble brukt uten ytterligere rensing.<!>H NMR (DMSO-de): 2,28 (3H, s), 6,04 (2H, bs), 6,44 (1H, m), 6,48 (1H, m), 7,31 (1H, m). An additional 3.75 mL of water was added and heating was continued for an additional 2 hours. The solution was allowed to cool to room temperature, after which it was diluted with 100 ml of water and extracted with 4 x 40 ml of ethyl acetate. The organic phase was washed with 50 ml of 5% NaHCO3 and 50 ml of water, dried over sodium sulfate and evaporated. The crude product was used without further purification. <!>H NMR (DMSO-de): 2.28 (3H, s), 6.04 (2H, bs), 6.44 (1H, m), 6.48 (1H , m), 7.31 (1H, m).

b) N-(4-cyano-3-metylfenyl)-2-metylakrylamid b) N-(4-cyano-3-methylphenyl)-2-methylacrylamide

N-(4-cyano-3-metylfenyl)-2-metylakrylamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-amino-2-metylbenzonitril og metakryloylklorid.<]>H NMR (DMSO-de): 1,96 (3H, s), 2,45 (3H, s), 5,60 (1H, m), 5,85 (1H, m), 7,70 (2H, m), 7,81 (1H, m), 10,12 (1H, s). N-(4-cyano-3-methylphenyl)-2-methylacrylamide was prepared as described in Example 1 starting from 4-amino-2-methylbenzonitrile and methacryloyl chloride. <]>H NMR (DMSO-de): 1.96 (3H, s), 2.45 (3H, s), 5.60 (1H, m), 5.85 (1H, m), 7.70 (2H, m), 7.81 (1H, m) , 10.12 (1H, p).

c) 2-metyloksiran-2-karboksylsyre (4-cyano-3-metylfenyl)amid 2- metyloksiran-2-karboksylsyre (4-cyano-3-metylfenyl)amid ble fremstilt som c) 2-methyloxirane-2-carboxylic acid (4-cyano-3-methylphenyl)amide 2-methyloxirane-2-carboxylic acid (4-cyano-3-methylphenyl)amide was prepared as

beskrevet i eksempel 1 ved å starte fra N-(4-cyano-3-metylfenyl)-2-metylacrylamid.<]>H NMR (DMSO-de): 1,54 (3H, s), 2,43 (3H, s), 2,99 (1H, d, J = 5,1 Hz), 3,04 (1H, d, J = 5,1 Hz), 7,70 (2H, m), 7,89 (1H, m), 9,77 (1H, s). described in Example 1 starting from N-(4-cyano-3-methylphenyl)-2-methylacrylamide. <]>H NMR (DMSO-de): 1.54 (3H, s), 2.43 (3H, s), 2.99 (1H, d, J = 5.1 Hz), 3.04 (1H, d, J = 5.1 Hz), 7.70 (2H, m), 7.89 (1H, m), 9.77 (1H, p).

d) N-(4-cyano-3-metylfenyl)-3-(4-fluorfenoksy)-2-hydroksy-2-metylpropionamid N-(4-cyano-3-metylfenyl)-3-(4-fluorfenoksy)-2-hydroksy-2-metylpropionamid ble d) N-(4-cyano-3-methylphenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropionamide N-(4-cyano-3-methylphenyl)-3-(4-fluorophenoxy)-2 -hydroxy-2-methylpropionamide was

fremstilt som beskrevet i eksempel 1 ved å starte fra 4-fluorfenol og 2-metyloksiran-2-karboksylsyre (4-cyano-3-metylfenyl)amid.<]>H NMR (DMSO-de): 1,42 (3H, s), 2,44 (3H, s), 3,94 (1H, d, J = 9,6 Hz), 4,18 (1H, d, J = 9,6 Hz), 6,18 (1H, bs), 6,93 (2H, m), 7,08 (2H, m), 7,69 (1H, d, J = 9,0 Hz), 7,78 (1H, dd, J = 9,0 Hz og 2,1 Hz), 7,93 (1H, d, J = 2,1 Hz), 10,02 (1H, s). prepared as described in Example 1 starting from 4-fluorophenol and 2-methyloxirane-2-carboxylic acid (4-cyano-3-methylphenyl)amide. <]>H NMR (DMSO-de): 1.42 (3H, s ), 2.44 (3H, s), 3.94 (1H, d, J = 9.6 Hz), 4.18 (1H, d, J = 9.6 Hz), 6.18 (1H, bs ), 6.93 (2H, m), 7.08 (2H, m), 7.69 (1H, d, J = 9.0 Hz), 7.78 (1H, dd, J = 9.0 Hz and 2.1 Hz), 7.93 (1H, d, J = 2.1 Hz), 10.02 (1H, s).

Eksempel 41. Example 41.

3- (4-acetylamino-3-fluorfenoksy)-N-(4-cyano-3-metylfenyl)-2-hydroksy-2-metylpropionamid 3-(4-acetylamino-3-fluorophenoxy)-N-(4-cyano-3-methylphenyl)-2-hydroxy-2-methylpropionamide

3-(4-acetylamino-3-fluorfenoksy)-N-(4-cyano-3-metylfenyl)-2-hydroksy-2-metylpropionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra N-(2-fluor-4-hydroksyfenyl)acetamid og 2-metyloksiran-2-karboksylsyre (4-cyano-3-metylfenyl)amid.<!>H NMR (DMSO-de): 1,41 (3H, s), 2,02 (3H, s), 2,44 (3H, s), 3,95 (1H, d, J = 9,8 Hz), 4,26 (1H, d, J = 9,8 Hz), 6,21 (1H, bs), 6,72 (1H, m), 6,86 (1H, m), 7,56 (1H, m), 7,69 (1H, d, J = 9,0 Hz), 7,78 (1H, dd, J = 9,0 Hz og 2,2 Hz), 7,93 (1H, d, J = 2,2 Hz), 9,51 (1H, s), 9,99 (1H, bs). 3-(4-acetylamino-3-fluorophenoxy)-N-(4-cyano-3-methylphenyl)-2-hydroxy-2-methylpropionamide was prepared as described in Example 1 by starting from N-(2-fluoro-4 -hydroxyphenyl)acetamide and 2-methyloxirane-2-carboxylic acid (4-cyano-3-methylphenyl)amide.<!>H NMR (DMSO-de): 1.41 (3H, s), 2.02 (3H, s ), 2.44 (3H, s), 3.95 (1H, d, J = 9.8 Hz), 4.26 (1H, d, J = 9.8 Hz), 6.21 (1H, bs ), 6.72 (1H, m), 6.86 (1H, m), 7.56 (1H, m), 7.69 (1H, d, J = 9.0 Hz), 7.78 (1H , dd, J = 9.0 Hz and 2.2 Hz), 7.93 (1H, d, J = 2.2 Hz), 9.51 (1H, s), 9.99 (1H, bs).

Eksempel 42. Example 42.

3-(4-cyano-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(4-cyano-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 2-fluor-4-hydroksybenzonitril og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid.<]>H NMR (DMSO-d6): 1,46 (3H, s), 2,53 (3H, s), 4,11 (1H, d, J = 10,1 Hz), 4,371 (1H, d, J = 10,1 Hz), 6,33 (1H, bs), 6,96 (1H, m), 7,18 (1H, m), 7,80 (1H, m), 7,88 (1H, dd, J = 9,0 Hz og 2,1 Hz), 7,91 (1H, d, J = 2,1 Hz), 8,03 (1H, d, J = 9,0 Hz), 10,21 (1H, s). 3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 2-fluoro-4-hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. <]>H NMR (DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4, 11 (1H, d, J = 10.1 Hz), 4.371 (1H, d, J = 10.1 Hz), 6.33 (1H, bs), 6.96 (1H, m), 7.18 ( 1H, m), 7.80 (1H, m), 7.88 (1H, dd, J = 9.0 Hz and 2.1 Hz), 7.91 (1H, d, J = 2.1 Hz) , 8.03 (1H, d, J = 9.0 Hz), 10.21 (1H, s).

Eksempel 43. Example 43.

(2S)-3-(4-cyano-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid (2S)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

(2S)-3-(4-cyano-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 3 ved å starte fra 2-fluor-4-hydroksybenzonitril og (2R)-3-brom-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ved å anvende den følgende fremgangsmåten. En løsning av 2- fluor-4-hydroksybenzonitril (0,2 g, 1,4 mmol), (2R)-3-brom-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid (0,37 g, 1,2 mmol), K2CO3(0,34 g, 2,5 mmol) og benzyltrietylammoniumklorid (0,028 g, 0,1 mmol) i 40 ml metyletylketon ble kokt under tilbake løp i 5 timer. Blandingen ble avkjølt til romtemperatur og fordampet. Resten ble så delt mellom 50 ml etylacetat og 50 ml vann, hvoretter fasene ble skilt. Den organiske fasen ble vasket med 4 x 20 ml 1 M Na2CC«3 og 20 ml vann, tørket over natriumsulfat og fordampet. Råproduktet ble renset ved (2S)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 3 by starting from 2-fluoro -4-hydroxybenzonitrile and (2R)-3-bromo-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide using the following procedure. A solution of 2-fluoro-4-hydroxybenzonitrile (0.2 g, 1.4 mmol), (2R)-3-bromo-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide (0.37 g, 1.2 mmol), K 2 CO 3 (0.34 g, 2.5 mmol) and benzyltriethylammonium chloride (0.028 g, 0.1 mmol) in 40 mL of methyl ethyl ketone was refluxed for 5 h. The mixture was cooled to room temperature and evaporated. The residue was then divided between 50 ml of ethyl acetate and 50 ml of water, after which the phases were separated. The organic phase was washed with 4 x 20 ml of 1 M Na 2 CC 3 and 20 ml of water, dried over sodium sulfate and evaporated. The crude product was purified by wood

flashkromatografi (elueringsmiddel metylenklorid).<]>H NMR (DMSO-d*): 1,46 (3H, s), 2,53 (3H, s), 4,11 (1H, d, J = 10,1 Hz), 4,371 (1H, d, J = 10,1 Hz), 6,33 (1H, bs), 6,96 (1H, m), 7,18 (1H, m), 7,80 (1H, m), 7,88 (1H, dd, J = 9,0 Hz og 2,1 Hz), 7,91 (1H, d, J = 2,1 Hz), 8,03 (1H, d, J = 9,0 Hz), 10,21 (1H, s). flash chromatography (eluent methylene chloride).<]>H NMR (DMSO-d*): 1.46 (3H, s), 2.53 (3H, s), 4.11 (1H, d, J = 10.1 Hz ), 4.371 (1H, d, J = 10.1 Hz), 6.33 (1H, bs), 6.96 (1H, m), 7.18 (1H, m), 7.80 (1H, m ), 7.88 (1H, dd, J = 9.0 Hz and 2.1 Hz), 7.91 (1H, d, J = 2.1 Hz), 8.03 (1H, d, J = 9 .0 Hz), 10.21 (1H, s).

Eksempel 44. Example 44.

3- (4-klor-3-nitrofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-klor-3-nitrofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-klor-3-nitrokenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 0,2% metanol).<]>H NMR (400 MHz, DMSO-de): 1,45 (3H, s), 2,53 (3H, s), 4,10 (1H, d, J = 9,9 Hz), 4,36 (1H, d, J = 9,9 Hz), 6,28 (1H, s), 7,28 (1H, dd, J = 9,0 Hz, J = 3,0 Hz), 7,62 (1H, d, J = 9,0 Hz), 7,68 3-(4-chloro-3-nitrophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(4-chloro-3-nitrophenoxy)-2-hydroxy-2- methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in example 1 by starting from 4-chloro-3-nitrokenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide . The crude product was purified by flash chromatography (dichloromethane - 0.2% methanol). <]>H NMR (400 MHz, DMSO-de): 1.45 (3H, s), 2.53 (3H, s), 4.10 (1H, d, J = 9.9 Hz), 4.36 (1H, d, J = 9.9 Hz), 6.28 (1H, s), 7.28 (1H, dd, J = 9, 0 Hz, J = 3.0 Hz), 7.62 (1H, d, J = 9.0 Hz), 7.68

(1H, d, J = 3,0 Hz), 7,88 (1H, dd, J = 9,0 Hz, J = 2,3 Hz), 7,92 (1H, d, J = 2,0 Hz), 8,03 (1H, d, J = 9,0 Hz), 10,15 (1H, s). (1H, d, J = 3.0 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.92 (1H, d, J = 2.0 Hz ), 8.03 (1H, d, J = 9.0 Hz), 10.15 (1H, s).

Eksempel 45. Example 45.

3-(4-fluor-3-trifluormetylfenoksy)-2-hydroksy-2-metyl-N-(3-rnetyl-4-nitrofenyl)propionamid 3-(4-fluoro-3-trifluoromethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(4-fluor-3-trifluormetylfenoksy)-2-hydroksy-2-metyl-N-(3-rnetyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-fluor-3-(trifluormetyl)fenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 1% metanol).<]>H NMR (400 MHz, DMSO-d6): 1,44 (3H, s), 2,53 (3H, s), 4,06 (1H, d, J = 9,9 Hz), 4,32 (1H, d, J = 9,9 Hz), 6,23 (1H, s), 7,24-7,31 (2H, m), 7,38-7,43 (1H, m), 7,87 (1H, dd, J = 9,0 Hz, J = 2,1 Hz), 7,91 (1H, d, J = 2,0 Hz), 8,03 (1H, d, J = 9,0 Hz), 10,14 (1H, s). 3-(4-Fluoro-3-trifluoromethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 4-fluoro-3-( trifluoromethyl)phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 1% methanol). <]>H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.53 (3H, s), 4.06 (1H , d, J = 9.9 Hz), 4.32 (1H, d, J = 9.9 Hz), 6.23 (1H, s), 7.24-7.31 (2H, m), 7 .38-7.43 (1H, m), 7.87 (1H, dd, J = 9.0 Hz, J = 2.1 Hz), 7.91 (1H, d, J = 2.0 Hz) , 8.03 (1H, d, J = 9.0 Hz), 10.14 (1H, s).

Eksempel 46. Example 46.

2- hydroksy-3-[4-(2-metoksyetyl)fenoksy]-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 2 -hydroksy-3 -[4-(2 -metoksy ety l)fenoksy ]-2 -me ty l-N-(3 -mety 1-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-metoksyetylfenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofhenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 1% metanol).<]>H NMR (400 MHz, DMSO-de): 1,43 (3H, s), 2,53 (3H, s), 2,71 (2H, t, J = 6,8 Hz), 3,21 (3H, s), 3,45 (2H, t, J = 6,8 Hz), 3,94 (1H, d, J = 9,5 Hz), 4,17 (1H, d, J = 9,5 Hz), 6,20 (1H, s), 6,82 (2H, d, J = 7,8 Hz), 7,10 (2H, d, J = 8,0 Hz), 7,89 (1H, d, J = 9,0 Hz), 7,94 (1H, s), 8,03 (1H, d, J = 8,8 Hz), 10,16 (1H, s). 2- hydroxy-3-[4-(2-methoxyethyl)phenoxy]-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 2-hydroxy-3-[4-(2-methoxyethyl)phenoxy ]-2-methyl-N-(3-methyl-1-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 4-methoxyethylphenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product was purified by flash chromatography (dichloromethane - 1% methanol). <]>H NMR (400 MHz, DMSO-de): 1.43 (3H, s), 2.53 (3H, s), 2.71 (2H , t, J = 6.8 Hz), 3.21 (3H, s), 3.45 (2H, t, J = 6.8 Hz), 3.94 (1H, d, J = 9.5 Hz ), 4.17 (1H, d, J = 9.5 Hz), 6.20 (1H, s), 6.82 (2H, d, J = 7.8 Hz), 7.10 (2H, d , J = 8.0 Hz), 7.89 (1H, d, J = 9.0 Hz), 7.94 (1H, s), 8.03 (1H, d, J = 8.8 Hz), 10.16 (1H, p).

Eksempel 47. Example 47.

3- (4-fluorfenoksy)-2-hydroksy-2-metyl-N-(2-metyl-3-nitrofenyl)propionamid 3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide

a) 2-metyl-N-(2-metyl-3-nitrofenyl)akrylamid a) 2-methyl-N-(2-methyl-3-nitrophenyl)acrylamide

2-metyl-N-(2-metyl-3-nitrofenyl)akrylamid ble fremstilt beskrevet i eksempel la 2-Methyl-N-(2-methyl-3-nitrophenyl)acrylamide was prepared as described in Example 1a

ved å starte fra 2-metyl-3-nitroanilin og metakryloylklorid.<]>H NMR (400 MHz, DMSO-de): 1,97 (3H, s), 2,23 (3H, s), 5,56 (1H, s), 5,90 (1H, s), 7,40-7,46 (1H, m), 7,57-7,60 (1H, m), 7,74-7,77 (1H, m), 9,71 (1H, s). starting from 2-methyl-3-nitroaniline and methacryloyl chloride.<]>H NMR (400 MHz, DMSO-de): 1.97 (3H, s), 2.23 (3H, s), 5.56 ( 1H, s), 5.90 (1H, s), 7.40-7.46 (1H, m), 7.57-7.60 (1H, m), 7.74-7.77 (1H, m), 9.71 (1H, p).

b) 2-metyloksirane-2-karboksylsyre (2-metyl-3-nitrofenyl)amid 2-metyloksirane-2-karboksylsyre (2-metyl-3-nitrofenyl)amid ble fremstilt som b) 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide was prepared as

beskrevet i eksempel lb ved å starte fra 2-metyl-N-(2-metyl-3-nitrofenyl)akrylamid. described in example 1b by starting from 2-methyl-N-(2-methyl-3-nitrophenyl)acrylamide.

<]>H NMR (400 MHz, DMSO-d6): 1,54 (3H, s), 2,19 (3H, s), 2,99 (1H, d, J = 5,1 Hz), 3,09 (1H, d, J = 5,1 Hz), 7,40-7,45 (1H, m), 7,57-7,60 (1H, m), 7,74-7,77 (1H, m), 9,47 (1H, s). <]>H NMR (400 MHz, DMSO-d6): 1.54 (3H, s), 2.19 (3H, s), 2.99 (1H, d, J = 5.1 Hz), 3, 09 (1H, d, J = 5.1 Hz), 7.40-7.45 (1H, m), 7.57-7.60 (1H, m), 7.74-7.77 (1H, m), 9.47 (1H, p).

c) 3-(4-fluorfenoksy)-2-hydroksy-2-metyl-N-(2-metyl-3-nitrofenyl)propionamid 3-(4-fluorfenoksy)-2-hydroksy-2-metyl-N-(2-metyl-3-nitrofenyl)propionamid ble c) 3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide 3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(2 -methyl-3-nitrophenyl)propionamide was

fremstilt som beskrevet i eksempel lc ved å starte fra 4-fluorfenol og 2-metyloksiran-2-karboksylsyre (2-metyl-3-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 1% metanol).<!>H NMR (400 MHz, DMSO-d6): 1,44 (3H, s), 2,28 (3H, s), 3,96 (1H, d, J = 9,5 Hz), 4,17 (1H, d, J = 9,5 Hz), 6,14 (1H, s), 6,93-6,97 (2H, m), 7,08-7,13 (2H, m), 7,41-7,45 (1H, m), 7,66-7,68 (1H, m), 7,72-7,75 (1H, m), 9,72 (1H, s). prepared as described in example 1c by starting from 4-fluorophenol and 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 1% methanol). <!>H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.28 (3H, s), 3.96 (1H , d, J = 9.5 Hz), 4.17 (1H, d, J = 9.5 Hz), 6.14 (1H, s), 6.93-6.97 (2H, m), 7 .08-7.13 (2H, m), 7.41-7.45 (1H, m), 7.66-7.68 (1H, m), 7.72-7.75 (1H, m) , 9.72 (1H, p).

Eksempel 48. Example 48.

3-(3-klor-4-fluorfenoksy)-2-hydroksy-2-metyl-N-(2-metyl-3-nitrofenyl)propionamid 3-(3-chloro-4-fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide

3-(3-klor-4-fluorfenoksy)-2-hydroksy-2-metyl-N-(2-metyl-3-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 3-klor-4-fluorfenol og 2-metyloksiran-2-karboksylsyre (2-metyl-3-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 1% metanol).<!>H NMR (400 MHz, DMSO-de): 1,44 (3H, s), 2,27 (3H, s), 3,99 (1H, d, J = 9,8 Hz), 4,23 (1H, d, J = 9,8 Hz), 6,15 (1H, s), 6,92-6,97 (1H, m), 7,17-7,20 (1H, m), 7,29-7,35 (1H, m), 7,41-7,46 (1H, m), 7,66-7,69 (1H, m), 7,72-7,75 (1H, m), 9,72 (1H, s). 3-(3-Chloro-4-fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 3-chloro-4-fluorophenol and 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 1% methanol). <!>H NMR (400 MHz, DMSO-de): 1.44 (3H, s), 2.27 (3H, s), 3.99 (1H , d, J = 9.8 Hz), 4.23 (1H, d, J = 9.8 Hz), 6.15 (1H, s), 6.92-6.97 (1H, m), 7 .17-7.20 (1H, m), 7.29-7.35 (1H, m), 7.41-7.46 (1H, m), 7.66-7.69 (1H, m) , 7.72-7.75 (1H, m), 9.72 (1H, s).

Eksempel 49. Example 49.

2-hydroksy-3-[4-(2-metoksyetyl)fenoksy]-2-metyl-N-(2-metyl-3-nitrofenyl)propionamid 2-hydroxy-3-[4-(2-methoxyethyl)phenoxy]-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide

2-hydroksy-3-[4-(2-metoksyetyl)fenoksy]-2-metyl-N-(2-metyl-3-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-metoksyetylfenol og 2-metyloksiran-2-karboksylsyre (2-metyl-3-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 2% metanol).<]>H NMR (400 MHz, DMSO-de): 1,44 (3H, s), 2,28 (3H, s), 2,72 (2H, t, J = 6,8 Hz), 3,22 (3H, s), 3,47 (2H, t, J = 6,8 Hz), 3,94 (1H, d, J = 9,4 Hz), 4,15 (1H, d, J = 9,4 Hz), 6,11 (1H, s), 6,84 (2H, d, J = 7,9 Hz), 7,12 (2H, d, J = 7,9 Hz), 7,41-7,45 (1H, m), 7,65-7,68 (1H, m), 7,72-7,75 (1H, m), 9,71 (1H, s). 2-Hydroxy-3-[4-(2-methoxyethyl)phenoxy]-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 4-methoxyethylphenol and 2- methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 2% methanol). <]>H NMR (400 MHz, DMSO-de): 1.44 (3H, s), 2.28 (3H, s), 2.72 (2H , t, J = 6.8 Hz), 3.22 (3H, s), 3.47 (2H, t, J = 6.8 Hz), 3.94 (1H, d, J = 9.4 Hz ), 4.15 (1H, d, J = 9.4 Hz), 6.11 (1H, s), 6.84 (2H, d, J = 7.9 Hz), 7.12 (2H, d , J = 7.9 Hz), 7.41-7.45 (1H, m), 7.65-7.68 (1H, m), 7.72-7.75 (1H, m), 9, 71 (1H, p).

Eksempel 50. Example 50.

{2-fluor-4-[2-hydroksy-2-(3-metyl-4-nitrofenylkarbamoyl)propoksy]fenyl}-karbaminsyreetylester {2-fluoro-4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl)propoxy]phenyl}carbamic acid ethyl ester

a) (2-fluor-4-hydroksyfenyl)karbaminsyreetylester a) (2-fluoro-4-hydroxyphenyl)carbamic acid ethyl ester

Etylklorformat (0,37 ml, 3,9 mmol) ble tilsatt under røring en løsning av 4-amino-3-fluorfenol (0,5 g, 3,9 mmol) i 2 ml 10% NaOH. Reaksjonsblandingen ble holdt på 80°C i 30 minutter. Etter avkjøling ble løsningen surgjort med saltsyre, noe som ga produktet.<]>H NMR (400 MHz, DMSO-d6): 1,20 (3H, t, J = 7,0 Hz), 4,06 (2H, q, J = 7,0 Hz), 6,53-6,59 (2H, m), 7,16-7,21 (1H, m), 8,79 (1H, s), 9,72 (1H, s). Ethyl chloroformate (0.37 mL, 3.9 mmol) was added with stirring to a solution of 4-amino-3-fluorophenol (0.5 g, 3.9 mmol) in 2 mL of 10% NaOH. The reaction mixture was held at 80°C for 30 minutes. After cooling, the solution was acidified with hydrochloric acid to give the product.<]>H NMR (400 MHz, DMSO-d6): 1.20 (3H, t, J = 7.0 Hz), 4.06 (2H, q , J = 7.0 Hz), 6.53-6.59 (2H, m), 7.16-7.21 (1H, m), 8.79 (1H, s), 9.72 (1H, s).

b) {2-fluor-4-[2-hydroksy-2-(3-metyl-4-nitrofenylkarbamoyl)propoksy]fenyl}-karbaminsyreetylester b) {2-fluoro-4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl)propoxy]phenyl}carbamic acid ethyl ester

{2-fluor-4-[2-hydroksy-2-(3-metyl-4-nitrofenylkarbamoyl)propoksy]fenyl}-karbaminsyreetylester ble fremstilt som beskrevet i eksempel 1 ved å starte fra (2-fluor-4-hydroksyfenyl)karbaminsyreetylester og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 1,8% metanol).<]>H NMR (400 MHz, DMSO-d6): 1,20 (3H, t, J = 7,0 Hz), 1,43 (3H, s), 2,53 (3H, s), 3,97 (1H, d, J = 9,7 Hz), 4,07 (2H, q, J = 7,0 Hz), 4,22 (1H, d, J = 9,7 Hz), 6,21 (1H, s), 6,71-6,73 (1H, m), 6,83-6,87 (1H, m), 7,31-7,35 (1H, m), 7,86-8,05 (3H, m), 8,95 (1H, s), 10,12 (1H, s). {2-Fluoro-4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl)propoxy]phenyl}carbamic acid ethyl ester was prepared as described in Example 1 by starting from (2-fluoro-4-hydroxyphenyl)carbamic acid ethyl ester and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 1.8% methanol). <]>H NMR (400 MHz, DMSO-d6): 1.20 (3H, t, J = 7.0 Hz), 1.43 (3H , s), 2.53 (3H, s), 3.97 (1H, d, J = 9.7 Hz), 4.07 (2H, q, J = 7.0 Hz), 4.22 (1H , d, J = 9.7 Hz), 6.21 (1H, s), 6.71-6.73 (1H, m), 6.83-6.87 (1H, m), 7.31- 7.35 (1H, m), 7.86-8.05 (3H, m), 8.95 (1H, s), 10.12 (1H, s).

Eksempel 51. Example 51.

3-(4-cyano-3-fluorfenoksy)-2-hydroksy-N-(3-hydroksymetyl-4-nitrofenyl)-2-metylpropionamid 3-(4-cyano-3-fluorophenoxy)-2-hydroxy-N-(3-hydroxymethyl-4-nitrophenyl)-2-methylpropionamide

a) (5-amino-2-nitrofenyl)metanol a) (5-amino-2-nitrophenyl)methanol

En løsning av 5-amino-2-nitrobenzosyre (3,0 g, 16,4 mmol) i 40 ml tetrahydrofuran A solution of 5-amino-2-nitrobenzoic acid (3.0 g, 16.4 mmol) in 40 mL of tetrahydrofuran

ble tilsatt 50 ml av et boran-tetrahydrofurankompleks (1,0 M løsning i THF). Blandingen ble kokt under tilbakeløp i en time. Vanlig opparbeiding ga produktet.<!>H NMR (400 MHz, DMSO-d6): 4,79 (2H, d, J = 5,4 Hz), 5,37 (1H, t, J = 5,4 Hz), 6,48 (1H, dd, J = 9,0 Hz, J = 2,5 Hz), 6,68 (2H, s), 6,99 (1H, d, J = 2,5 Hz), 7,94 (1H, d, J = 9,0 Hz). was added 50 ml of a borane-tetrahydrofuran complex (1.0 M solution in THF). The mixture was refluxed for one hour. Usual workup gave the product.<!>H NMR (400 MHz, DMSO-d6): 4.79 (2H, d, J = 5.4 Hz), 5.37 (1H, t, J = 5.4 Hz) , 6.48 (1H, dd, J = 9.0 Hz, J = 2.5 Hz), 6.68 (2H, s), 6.99 (1H, d, J = 2.5 Hz), 7 .94 (1H, d, J = 9.0 Hz).

b) N-(3-hydroksymetyl-4-nitrofenyl)-2-metylakrylamid b) N-(3-hydroxymethyl-4-nitrophenyl)-2-methylacrylamide

N-(3-hydroksymetyl-4-nitrofenyl)-2-metylakrylamid ble fremstilt som beskrevet i N-(3-Hydroxymethyl-4-nitrophenyl)-2-methylacrylamide was prepared as described in

eksempel la ved å starte fra (5-amino-2-nitrofenyl)metanol og metakryloylklorid.<]>H NMR (400 MHz, DMSO-d6): 1,97 (3H, s), 4,85 (2H, d, J = 5,2 Hz), 5,56 (1H, t, J = 5,2 Hz), 5,61 (1H, s), 5,90 (1H, s), 7,93 (1H, dd, J = 9,0 Hz, J = 2,1 Hz), 8,11 (1H, d, J = 9,0 Hz), 8,20 (1H, d, J = 2,1 Hz), 10,32 (1H, s). example la by starting from (5-amino-2-nitrophenyl)methanol and methacryloyl chloride. <]>H NMR (400 MHz, DMSO-d6): 1.97 (3H, s), 4.85 (2H, d, J = 5.2 Hz), 5.56 (1H, t, J = 5.2 Hz), 5.61 (1H, s), 5.90 (1H, s), 7.93 (1H, dd, J = 9.0 Hz, J = 2.1 Hz), 8.11 (1H, d, J = 9.0 Hz), 8.20 (1H, d, J = 2.1 Hz), 10.32 (1H, p).

c) 2-metyloksiran-2-karboksylsyre (3-hydroksymetyl-4-nitrofenyl)amid 2- metyloksiran-2-karboksylsyre (3-hydroksymetyl-4-nitrofenyl)amid ble fremstilt c) 2-methyloxirane-2-carboxylic acid (3-hydroxymethyl-4-nitrophenyl)amide 2-methyloxirane-2-carboxylic acid (3-hydroxymethyl-4-nitrophenyl)amide was prepared

som beskrevet i eksempel lb ved å starte fra N-(3-hydroksymetyl-4-nitrofenyl)-2-metylakrylamid.<]>H NMR (400 MHz, DMSO-d6): 1,55 (3H, s), 2,98 (1H, d, J = 5,1 Hz), 3,07 (1H, d, J = 5,1 Hz), 4,82 (2H, d, J = 5,3 Hz), 5,53 (1H, t, J = 5,3 Hz), 7,84 (1H, dd, J = 8,9 Hz, J = 2,4 Hz), 8,08 (1H, d, J = 8,9 Hz), 8,24 (1H, d, J = 2,4 Hz), 9,99 (1H, s). as described in Example 1b starting from N-(3-hydroxymethyl-4-nitrophenyl)-2-methylacrylamide. <]>H NMR (400 MHz, DMSO-d6): 1.55 (3H, s), 2, 98 (1H, d, J = 5.1 Hz), 3.07 (1H, d, J = 5.1 Hz), 4.82 (2H, d, J = 5.3 Hz), 5.53 ( 1H, t, J = 5.3 Hz), 7.84 (1H, dd, J = 8.9 Hz, J = 2.4 Hz), 8.08 (1H, d, J = 8.9 Hz) , 8.24 (1H, d, J = 2.4 Hz), 9.99 (1H, s).

d) 3-(4-cyano-3-fluorfenoksy)-2-hydroksy-N-(3-hydroksymetyl-4-nitrofenyl)-2-metylpropionamid d) 3-(4-cyano-3-fluorophenoxy)-2-hydroxy-N-(3-hydroxymethyl-4-nitrophenyl)-2-methylpropionamide

3- (4-cyano-3-fluorfenoksy)-2-hydroksy-N-(3-hydroksymetyl-4-nitrofenyl)-2-metylpropionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 2-fluor-4- hydroksybenzonitril og 2-metyloksiran-2-karboksylsyre (3-hydroksymetyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 6,6% metanol).<]>H NMR (400 MHz, DMSO-d6): 1,45 (3H, s), 4,13 (1H, d, J = 10,0 Hz), 4,38 (1H, d, J = 10,0 Hz), 4,83 (2H, d, J = 5,4 Hz), 5,51 (1H, t, J = 5,4 Hz), 6,25 (1H, s), 6,94-6,98 (1H, m), 7,16-7,20 (1H, m), 7,77-7,82 (1H, m), 7,88 (1H, dd, J = 9,0 Hz, J =2,4 Hz), 8,09 (1H, d, J = 9,0 Hz), 8,34 (1H, d, J = 2,4 Hz), 10,24 (1H, s). 3-(4-cyano-3-fluorophenoxy)-2-hydroxy-N-(3-hydroxymethyl-4-nitrophenyl)-2-methylpropionamide was prepared as described in Example 1c by starting from 2-fluoro-4-hydroxybenzonitrile and 2-Methyloxirane-2-carboxylic acid (3-hydroxymethyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 6.6% methanol). <]>H NMR (400 MHz, DMSO-d6): 1.45 (3H, s), 4.13 (1H, d, J = 10, 0 Hz), 4.38 (1H, d, J = 10.0 Hz), 4.83 (2H, d, J = 5.4 Hz), 5.51 (1H, t, J = 5.4 Hz ), 6.25 (1H, s), 6.94-6.98 (1H, m), 7.16-7.20 (1H, m), 7.77-7.82 (1H, m), 7.88 (1H, dd, J = 9.0 Hz, J =2.4 Hz), 8.09 (1H, d, J = 9.0 Hz), 8.34 (1H, d, J = 2 .4 Hz), 10.24 (1H, s).

Eksempel 52. Example 52.

3-(4-fluorfenylamino)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid En blanding av 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid (0,2 g, 0,85 mmol), 4-fluoranilin (0,18 g, 1,7 mmol) og natriumperklorat (0,21 g, 1,7 mmol) i 2 ml acetonitril ble kokt under tilbake løp i 6 timer. Etter opparbeiding av reaksjonsblandingen ble råproduktet renset ved flashkromatografi (diklormetan - 1% metanol).<]>H NMR (400 MHz, DMSO-d6): 1,41 (3H, s), 2,51 (3H, s), 3,10 (1H, dd, J = 12,7 Hz, J = 4,6 Hz), 3,41 (1H, dd, J = 12,7 Hz, J = 7,7 Hz), 5,26 (1H, m), 6,02 (1H, s), 6,62-6,66 (2H, m), 6,84-6,89 (2H, m), 7,79-7,83 (2H, m), 8,02 (1H, d, J = 8,9 Hz), 9,99 (1H, s). 3-(4-fluorophenylamino)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide A mixture of 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide (0 .2 g, 0.85 mmol), 4-fluoroaniline (0.18 g, 1.7 mmol) and sodium perchlorate (0.21 g, 1.7 mmol) in 2 mL of acetonitrile were refluxed for 6 h. After working up the reaction mixture, the crude product was purified by flash chromatography (dichloromethane - 1% methanol). <]>H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.51 (3H, s), 3 .10 (1H, dd, J = 12.7 Hz, J = 4.6 Hz), 3.41 (1H, dd, J = 12.7 Hz, J = 7.7 Hz), 5.26 (1H , m), 6.02 (1H, s), 6.62-6.66 (2H, m), 6.84-6.89 (2H, m), 7.79-7.83 (2H, m ), 8.02 (1H, d, J = 8.9 Hz), 9.99 (1H, s).

Eksempel 53. Example 53.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(4-trifluormetylfenyl-amino)propionamid 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(4-trifluoromethylphenyl-amino)propionamide

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(4-trifluormetylfenyl-amino)propionamid ble fremstilt som beskrevet i eksempel 52 ved å starte fra 4-(trifluormetyl)anilin og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 1,5% metanol).<]>H NMR (400 MHz, DMSO-d6): 1,42 (3H, s), 2,51 (3H, s), 3,23 (1H, dd, J = 13,3 Hz, J = 5,0 Hz), 3,51 (1H, dd, J = 13,3 Hz, J = 7,0 Hz), 6,06 (1H, s), 6,18 (1H, m), 6,77 2-Hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(4-trifluoromethylphenyl-amino)propionamide was prepared as described in Example 52 by starting from 4-(trifluoromethyl)aniline and 2- methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 1.5% methanol). <]>H NMR (400 MHz, DMSO-d6): 1.42 (3H, s), 2.51 (3H, s), 3.23 (1H, dd, J = 13.3 Hz, J = 5.0 Hz), 3.51 (1H, dd, J = 13.3 Hz, J = 7.0 Hz), 6.06 (1H, s ), 6.18 (1H, m), 6.77

(2H, d, J = 8,4 Hz), 7,31 (2H, d, J = 8,4 Hz), 7,79-7,83 (2H, m), 8,01 (1H, d, J = 8,9 Hz), 10,02 (1H, s). (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.79-7.83 (2H, m), 8.01 (1H, d, J = 8.9 Hz), 10.02 (1H, s).

Eksempel 54. Example 54.

2-hydroksy-3-(4-metoksy-3-trifluormetylfenylamino)-2-rnetyl-N-(3-metyl-4-nitrofenyl)propionamid 2-hydroxy-3-(4-methoxy-3-trifluoromethylphenylamino)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

2- hydroksy-3-(4-metoksy-3-trifluormetylfenylarnino)-2-rnetyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 52 ved å starte fra 3-amino-6-metoksybenzotrifluorid og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 1,5% metanol).<]>H NMR (400 MHz, DMSO-d6): 1,41 (3H, s), 2,51 (3H, s), 3,12 (1H, dd, J = 13,0 Hz, J = 4,8 Hz), 3,45 (1H, dd, J = 13,0 Hz, J = 7,7 Hz), 3,71 (3H, s), 5,42 (1H, m), 6,00 (1H, s), 6,88 (1H, dd, J = 8,9 Hz, J = 2,7 Hz), 6,92 (1H, d, J = 2,7 Hz), 6,97 (1H, d, J = 8,9 Hz), 7,78 (1H, dd, J = 8,9 Hz, J = 2,3 Hz), 7,81 (1H, d, J = 1,9 Hz), 8,00 (1H, d, J = 8,9 Hz), 9,98 (1H, s). 2-Hydroxy-3-(4-methoxy-3-trifluoromethylphenylarnino)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 52 starting from 3-amino-6-methoxybenzotrifluoride and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 1.5% methanol). <]>H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.51 (3H, s), 3.12 (1H, dd, J = 13.0 Hz, J = 4.8 Hz), 3.45 (1H, dd, J = 13.0 Hz, J = 7.7 Hz), 3.71 (3H, s ), 5.42 (1H, m), 6.00 (1H, s), 6.88 (1H, dd, J = 8.9 Hz, J = 2.7 Hz), 6.92 (1H, d , J = 2.7 Hz), 6.97 (1H, d, J = 8.9 Hz), 7.78 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7, 81 (1H, d, J = 1.9 Hz), 8.00 (1H, d, J = 8.9 Hz), 9.98 (1H, s).

Eksempel 55. Example 55.

3- (4-cyanofenylamino)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-cyanofenylamino)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 52 ved å starte fra 4-aminobenzonitril og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 5% metanol).<]>H NMR (400 MHz, DMSO-d6): 1,41 (3H, s), 2,52 (3H, s), 3,25 (1H, dd, J = 13,5 Hz, J = 5,3 Hz), 3,52 (1H, dd, J,= 13,5 Hz, J = 7,0 Hz), 6,08 (1H, s), 6,53 (1H, m), 6,75 (2H, d, J = 8,8 Hz), 7,39 (2H, d, J = 8,8 Hz), 7,79-7,83 (2H, m), 8,01 (1H, d, J = 8,9 Hz), 10,02 (1H, s). 3-(4-cyanophenylamino)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(4-cyanophenylamino)-2-hydroxy-2-methyl-N-(3-methyl -4-nitrophenyl)propionamide was prepared as described in Example 52 by starting from 4-aminobenzonitrile and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 5% methanol). <]>H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.52 (3H, s), 3.25 (1H , dd, J = 13.5 Hz, J = 5.3 Hz), 3.52 (1H, dd, J,= 13.5 Hz, J = 7.0 Hz), 6.08 (1H, s) , 6.53 (1H, m), 6.75 (2H, d, J = 8.8 Hz), 7.39 (2H, d, J = 8.8 Hz), 7.79-7.83 ( 2H, m), 8.01 (1H, d, J = 8.9 Hz), 10.02 (1H, s).

Eksempel 56. Example 56.

3-(3-klor-4-cyanofenylamino)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(3-chloro-4-cyanophenylamino)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(3-klor-4-cyanofenylamino)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 52 ved å starte fra 4-amino-2-klorbenzonitril og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 3% metanol).<]>H NMR (400 MHz, DMSO-d6): 1,40 (3H, s), 2,52 (3H, s), 3,27 (1H, dd, J = 13,8 Hz, J = 5,5 Hz), 3,55 (1H, dd, J = 13,8 Hz, J = 6,9 Hz), 6,12 (1H, s), 6,72 (1H, dd, J =8,8 Hz, J = 2,2 Hz), 6,90 (1H, d, J = 2,2 Hz), 6,95-6,98 (1H, m), 7,46 (1H, d, J = 8,7 Hz), 7,80 (1H, dd, J = 8,9 Hz, J = 2,3 Hz), 7,83 (1H, d, J = 2,0 Hz), 8,02 (1H, d, J = 8,9 Hz), 10,05 (1H, s). 3-(3-Chloro-4-cyanophenylamino)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 52 starting from 4-amino-2-chlorobenzonitrile and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 3% methanol). <]>H NMR (400 MHz, DMSO-d6): 1.40 (3H, s), 2.52 (3H, s), 3.27 (1H , dd, J = 13.8 Hz, J = 5.5 Hz), 3.55 (1H, dd, J = 13.8 Hz, J = 6.9 Hz), 6.12 (1H, s), 6.72 (1H, dd, J =8.8 Hz, J = 2.2 Hz), 6.90 (1H, d, J = 2.2 Hz), 6.95-6.98 (1H, m ), 7.46 (1H, d, J = 8.7 Hz), 7.80 (1H, dd, J = 8.9 Hz, J = 2.3 Hz), 7.83 (1H, d, J = 2.0 Hz), 8.02 (1H, d, J = 8.9 Hz), 10.05 (1H, s).

Eksempel 57. Example 57.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(pyridin-3-ylokso)propionamid 2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(pyridin-3-ylokso)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 3-hydroksypyridin og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 9% metanol).<]>H NMR (400 MHz, DMSO-d6): 1,45 (3H, s), 2,53 (3H, s), 4,06 (1H, d, J = 9,8 Hz), 4,31 (1H, d, J = 9,8 Hz), 6,26 (1H, s), 7,28-7,32 (1H, m), 7,38-7,41 (1H, m), 7,87-7,93 (2H, m), 8,03 (1H, d, J = 8,9 Hz), 8,15-8,17 (1H, m), 8,26 (1H, d, J = 2,4 Hz), 10,15 (1H, s). 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(pyridin-3-yloxo)propionamide 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)- 3-(Pyridin-3-yloxo)propionamide was prepared as described in Example 1 by starting from 3-hydroxypyridine and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 9% methanol).<]>H NMR (400 MHz, DMSO-d6): 1.45 (3H, s), 2.53 (3H, s), 4.06 (1H , d, J = 9.8 Hz), 4.31 (1H, d, J = 9.8 Hz), 6.26 (1H, s), 7.28-7.32 (1H, m), 7 .38-7.41 (1H, m), 7.87-7.93 (2H, m), 8.03 (1H, d, J = 8.9 Hz), 8.15-8.17 (1H , m), 8.26 (1H, d, J = 2.4 Hz), 10.15 (1H, s).

Eksempel 58. Example 58.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(pyridin-4-ylokso)propionamid 2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(pyridin-4-ylokso)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-hydroksypyridin og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 7% metanol).<!>H NMR (400 MHz, CDC13): 1,62 (3H, s), 2,63 (3H, s), 4,08 (1H, d, J = 9,2 Hz), 4,46 (1H, d, J = 9,2 Hz), 6,79 (2H, d, J = 5,1 Hz), 7,57 (1H, d, J = 9,0 Hz), 7,66 (1H, s), 8,05 (1H, d, J = 8,8 Hz), 8,35 (2H, d, J = 5,1 Hz), 9,14 (1H, s). 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(pyridin-4-yloxo)propionamide 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)- 3-(Pyridin-4-yloxo)propionamide was prepared as described in Example 1 by starting from 4-hydroxypyridine and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 7% methanol). , J = 9.2 Hz), 4.46 (1H, d, J = 9.2 Hz), 6.79 (2H, d, J = 5.1 Hz), 7.57 (1H, d, J = 9.0 Hz), 7.66 (1H, s), 8.05 (1H, d, J = 8.8 Hz), 8.35 (2H, d, J = 5.1 Hz), 9, 14 (1H, p).

Eksempel 59. Example 59.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(pyridin-2-ylokso)propionamid 2- hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(pyridin-2-ylokso)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 2-hydroksypyridin og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 2% metanol).<]>H NMR (400 MHz, CDC13): 1,53 (3H, s), 2,61 (3H, s), 4,58 (1H, d, J = 12,3 Hz), 4,72 (1H, d, J = 12,3 Hz), 6,87 (1H, d, J = 8,3 Hz), 7,00 (1H, t, J = 6,1 Hz), 7,56 (1H, d, J = 8,9 Hz), 7,64-7,69 (2H, m), 7,81 (1H, s), 8,03 (1H, d, J = 8,9 Hz), 8,11 (1H, d, J = 5,0 Hz), 9,33 (1H, s). 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(pyridin-2-yloxo)propionamide 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)- 3-(pyridin-2-yloxo)propionamide was prepared as described in example 1 by starting from 2-hydroxypyridine and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 2% methanol). , J = 12.3 Hz), 4.72 (1H, d, J = 12.3 Hz), 6.87 (1H, d, J = 8.3 Hz), 7.00 (1H, t, J = 6.1 Hz), 7.56 (1H, d, J = 8.9 Hz), 7.64-7.69 (2H, m), 7.81 (1H, s), 8.03 (1H , d, J = 8.9 Hz), 8.11 (1H, d, J = 5.0 Hz), 9.33 (1H, s).

Eksempel 60. Example 60.

3- (2-klorpyridin-3-ylokso)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(2-chloropyridin-3-yloxo)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(2-klorpyridin-3-ylokso)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 2-klor-3-hydroksypyridin og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 2% metanol).<]>H NMR (400 MHz, DMSO-d6): 1,47 (3H, s), 2,53 (3H, s), 4,18 (1H, d, J 3-(2-chloropyridin-3-yloxo)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 2-chloro-3-hydroxypyridine and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 2% methanol). <]>H NMR (400 MHz, DMSO-d6): 1.47 (3H, s), 2.53 (3H, s), 4.18 (1H , d, J

= 9,9 Hz), 4,31 (1H, d, J = 9,9 Hz), 6,28 (1H, s), 7,35-7,39 (1H, m), 7,63 (1H, d, J = 8.2 Hz), 7,77-7,97 (3H, m), 8,04 (1H, d, J = 8,9 Hz), 10,13 (1H, s). = 9.9 Hz), 4.31 (1H, d, J = 9.9 Hz), 6.28 (1H, s), 7.35-7.39 (1H, m), 7.63 (1H , d, J = 8.2 Hz), 7.77-7.97 (3H, m), 8.04 (1H, d, J = 8.9 Hz), 10.13 (1H, s).

Eksempel 61. Example 61.

N-(4-fluor-3-metylfenyl)-3-(4-fluorfenoksy)-2-hydroksy-2-metylpropionamid N-(4-fluoro-3-methylphenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropionamide

a) N-(4- fluor-3-metylfeny 1)-2 -metylakrylamid a) N-(4-fluoro-3-methylphenyl)-2-methylacrylamide

N-(4-fluor-3-metylfenyl)-2-metylakrylamid ble fremstilt som beskrevet i eksempel N-(4-fluoro-3-methylphenyl)-2-methylacrylamide was prepared as described in Example

la ved å starte fra 4-fluor-3-metylanilin og metakryloylklorid.<]>H NMR (400 MHz, DMSO-d6): 1,94 (3H, s), 2,21 (3H, s), 5,50 (1H, s), 5,78 (1H, s), 7,05-7,10 (1H, m), 7,48-7,51 (1H, m), 7,57-7,59 (1H, m), 9,75 (1H, s). la by starting from 4-fluoro-3-methylaniline and methacryloyl chloride.<]>H NMR (400 MHz, DMSO-d6): 1.94 (3H, s), 2.21 (3H, s), 5.50 (1H, s), 5.78 (1H, s), 7.05-7.10 (1H, m), 7.48-7.51 (1H, m), 7.57-7.59 (1H , m), 9.75 (1H, s).

b) 2-metyloksiran-2-karboksylsyre (4-fluor-3-metylfenyl)amid 2- metyloksiran-2-karboksylsyre (4-fluor-3-metylfenyl)amid ble fremstilt som b) 2-methyloxirane-2-carboxylic acid (4-fluoro-3-methylphenyl)amide 2-methyloxirane-2-carboxylic acid (4-fluoro-3-methylphenyl)amide was prepared as

beskrevet i eksempel lb ved å starte fra N-(4-fluor-3-metylfenyl)-2-metylakrylamid.<!>H NMR (400 MHz, DMSO-d6): 1,52 (3H, s), 2,19 (3H, s), 2,94 (1H, d, J =,5,3 Hz), 2,99 (1H, d, J = 5,3 Hz), 7,02-7,07 (1H, m), 7,44-7,48 (1H, m), 7,56-7,59 (1H, m), 9,40 (1H, s). described in Example 1b starting from N-(4-fluoro-3-methylphenyl)-2-methylacrylamide. <!>H NMR (400 MHz, DMSO-d6): 1.52 (3H, s), 2.19 (3H, s), 2.94 (1H, d, J =.5.3 Hz), 2.99 (1H, d, J = 5.3 Hz), 7.02-7.07 (1H, m ), 7.44-7.48 (1H, m), 7.56-7.59 (1H, m), 9.40 (1H, s).

c) N-(4-fluor-3-metylfenyl)-3-(4-fluorfenoksy)-2-hydroksy-2-metylpropionamid N-(4-fluor-3-metylfenyl)-3-(4-fluorfenoksy)-2-hydroksy-2-metylpropionamid ble c) N-(4-fluoro-3-methylphenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropionamide N-(4-fluoro-3-methylphenyl)-3-(4-fluorophenoxy)-2 -hydroxy-2-methylpropionamide was

fremstilt som beskrevet i eksempel lc ved å starte fra 4-fluorfenol og 2-metyloksiran-2-karboksylsyre (4-fluor-3-metylfenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 1,4% metanol).<]>H NMR (400 MHz, DMSO-de): 1,40 (3H, s), 2,20 (3H, s), 3,92 (1H, d, J = 9,5 Hz), 4,17 (1H, d, J = 9,5 Hz), 6.03 (1H, s), 6,91-6,95 (2H, m), 7,03-7,10 (3H, m), 7,53-7,57 (1H, m), 7,66-7,68 (1H, m), 9,62 (1H, s). prepared as described in example 1c by starting from 4-fluorophenol and 2-methyloxirane-2-carboxylic acid (4-fluoro-3-methylphenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 1.4% methanol). <]>H NMR (400 MHz, DMSO-de): 1.40 (3H, s), 2.20 (3H, s), 3.92 (1H, d, J = 9.5 Hz), 4.17 (1H, d, J = 9.5 Hz), 6.03 (1H, s), 6.91-6.95 (2H, m), 7 .03-7.10 (3H, m), 7.53-7.57 (1H, m), 7.66-7.68 (1H, m), 9.62 (1H, s).

Eksempel 62. Example 62.

3- (4-acetylaminofenoksy)-N-(4-fluor-3-metylfenyl)-2-hydroksy-2-metylpropionamid 3-(4-acetylaminophenoxy)-N-(4-fluoro-3-methylphenyl)-2-hydroxy-2-methylpropionamide

3-(4-acetylaminofenoksy)-N-(4-fluor-3-metylfenyl)-2-hydroksy-2-metylpropionamid ble fremstilt som beskrevet i eksempel 61c ved å starte fra 4-acetamidofenol og 2-metyloksiran-2-karboksylsyre (4-fluor-3-metylfeny 1)amid.<!>H NMR (400 MHz, DMSO-d6): 1,40 (3H, s), 2,00 (3H, s), 2,20 (3H, s), 3,90 (1H, d, J = 9,5 Hz), 4,15 (1H, d, J = 9,5 Hz), 6,03 (1H, s), 6,84 (2H, d, J = 8,7 Hz), 7,03-7,08 (1H, m), 7,44 (2H, d, J = 8,7 Hz), 7,54-7,57 (1H, m), 7,67-7,69 (1H, m), 9,62 (1H, s), 9,75 (lH,s). 3-(4-Acetylaminophenoxy)-N-(4-fluoro-3-methylphenyl)-2-hydroxy-2-methylpropionamide was prepared as described in Example 61c starting from 4-acetamidophenol and 2-methyloxirane-2-carboxylic acid ( 4-fluoro-3-methylphenyl 1)amide.<!>H NMR (400 MHz, DMSO-d6): 1.40 (3H, s), 2.00 (3H, s), 2.20 (3H, s ), 3.90 (1H, d, J = 9.5 Hz), 4.15 (1H, d, J = 9.5 Hz), 6.03 (1H, s), 6.84 (2H, d , J = 8.7 Hz), 7.03-7.08 (1H, m), 7.44 (2H, d, J = 8.7 Hz), 7.54-7.57 (1H, m) , 7.67-7.69 (1H, m), 9.62 (1H, s), 9.75 (1H, s).

Eksempel 63. Example 63.

3-(3-klor-4-cyanofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(3-chloro-4-cyanophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(3-klor-4-cyanofenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 2-klor-4-hydroksybenzonitril og 2-metyloksiran-2-karboksylsyre (2-metyl-3-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 1,2% metanol).<!>H NMR (400 MHz, DMSO-d6): 1,44 (3H, s), 2,53 (3H, s), 4,13 (1H, d, J = 10,1 Hz), 4,39 (1H, d, J = 10,1 Hz), 6,29 (1H, s), 7,09 (1H, dd, J = 8,8 Hz, J = 2,4 Hz), 7,36 (1H, d, J = 2,4 Hz), 7,84-7,91 (3H, m), 8,03 (1H, d, J = 8,9 Hz), 10,15 (1H, s). 3-(3-Chloro-4-cyanophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 2-chloro-4-hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 1.2% methanol). <!>H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.53 (3H, s), 4.13 (1H, d, J = 10.1 Hz), 4.39 (1H, d, J = 10.1 Hz), 6.29 (1H, s), 7.09 (1H, dd, J = 8, 8 Hz, J = 2.4 Hz), 7.36 (1H, d, J = 2.4 Hz), 7.84-7.91 (3H, m), 8.03 (1H, d, J = 8.9 Hz), 10.15 (1H, s).

Eksempel 64. Example 64.

3-(4-cyano-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(2-metyl-4-nitro-fenyl)propionamid 3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-4-nitro-phenyl)propionamide

a) 2-metyl-N-(2-metyl-4-nitrofenyl)akrylamid a) 2-methyl-N-(2-methyl-4-nitrophenyl)acrylamide

2-metyl-N-(2-metyl-4-nitrofenyl)akrylamid ble fremstilt som beskrevet i eksempel 2-Methyl-N-(2-methyl-4-nitrophenyl)acrylamide was prepared as described in Example

la ved å starte fra 2-metyl-4-nitroanilin og metakryloylklorid.<]>H NMR (400 MHz, DMSO-d6): 1,98 (3H, s), 2,34 (3H, s), 5,59 (1H, s), 5,91 (1H, s), 7,74 (1H, d, J = 8,8 Hz), 8,07 (1H, dd, J = 8,8 Hz, J = 2,7 Hz), 8,15 (1H, d, J = 2,6 Hz), 9,53 (1H, s). la by starting from 2-methyl-4-nitroaniline and methacryloyl chloride. <]>H NMR (400 MHz, DMSO-d6): 1.98 (3H, s), 2.34 (3H, s), 5.59 (1H, s), 5.91 (1H, s), 7.74 (1H, d, J = 8.8 Hz), 8.07 (1H, dd, J = 8.8 Hz, J = 2, 7 Hz), 8.15 (1H, d, J = 2.6 Hz), 9.53 (1H, s).

b) 2-metyloksiran-2-karboksylsyre (2-metyl-4-nitrofenyl)amid 2- metyloksiran-2-karboksylsyre (2-metyl-4-nitrofenyl)amid ble fremstilt som b) 2-methyloxirane-2-carboxylic acid (2-methyl-4-nitrophenyl)amide 2-methyloxirane-2-carboxylic acid (2-methyl-4-nitrophenyl)amide was prepared as

beskrevet i eksempel lb ved å starte fra 2-metyl-N-(2-metyl-4-nitrofenyl)akrylamid.<]>H NMR (400 MHz, DMSO-d6): 1,55 (3H, s), 2,30 (3H, s), 3,03 (1H, d, J = 5,1 Hz), 3,15 (1H, d, J = 5,1 Hz), 7,86 (1H, d, J = 8,9 Hz), 8,08 (1H, dd, J = 8,9 Hz, J = 2,6 Hz), 8,15 (1H, d, J = 2,5 Hz), 9,13 (1H, s). described in Example 1b starting from 2-methyl-N-(2-methyl-4-nitrophenyl)acrylamide. <]>H NMR (400 MHz, DMSO-d6): 1.55 (3H, s), 2, 30 (3H, s), 3.03 (1H, d, J = 5.1 Hz), 3.15 (1H, d, J = 5.1 Hz), 7.86 (1H, d, J = 8 .9 Hz), 8.08 (1H, dd, J = 8.9 Hz, J = 2.6 Hz), 8.15 (1H, d, J = 2.5 Hz), 9.13 (1H, s).

c) 3-(4-cyano-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(2-metyl-4-nitro-fenyl)propionamid c) 3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-4-nitro-phenyl)propionamide

3- (4-cyano-3-fluorfenoksy)-2-hydroksy-2-metyl-N-(2-metyl-4-nitro-fenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 2-fluor-4-hydroksybenzonitril og 2-metyloksiran-2-karboksylsyre (2-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 1,3% metanol).<]>H NMR (400 MHz, DMSO-d6): 1,46 (3H, s), 2,37 (3H, s), 4,13 (1H, d, J = 10,1 Hz), 4,37 (1H, d, J = 10,1 Hz), 6,51 (1H, s), 6,95-6,98 (1H, m), 7,17-7,21 (1H, m), 7,78-7,83 (1H, m), 8,05-8,12 (2H, m), 8,18 (1H, d, J = 2,3 Hz), 9,57 (1H, s). 3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-4-nitro-phenyl)propionamide was prepared as described in Example 1c starting from 2-fluoro-4 -hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (2-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 1.3% methanol). <]>H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.37 (3H, s), 4.13 (1H, d, J = 10.1 Hz), 4.37 (1H, d, J = 10.1 Hz), 6.51 (1H, s), 6.95-6.98 (1H, m) , 7.17-7.21 (1H, m), 7.78-7.83 (1H, m), 8.05-8.12 (2H, m), 8.18 (1H, d, J = 2.3 Hz), 9.57 (1H, s).

Eksempel 65. Example 65.

3-(3-klor-4-cyanofenoksy)-2-hydroksy-2-metyl-N-(2-metyl-4-nitrofenyl)propionamid 3-(3-chloro-4-cyanophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-4-nitrophenyl)propionamide

3-(3-klor-4-cyanofenoksy)-2-hydroksy-2-metyl-N-(2-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 64c ved å starte fra 2- klor-4-hydroksybenzonitril og 2-metyloksiran-2-karboksylsyre (2-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi (diklormetan - 1,3% metanol).<!>H NMR (400 MHz, DMSO-d6): 1,46 (3H, s), 2,37 (3H, s), 4,15 (1H, d, J = 10,1 Hz), 4,39 (1H, d, J = 10,1 Hz), 6,51 (1H, s), 7,10 (1H, dd, J = 8,8 Hz, J = 2,4 Hz), 7,37 (1H, d, J = 2,4 Hz), 7,86 (1H, d, J = 8,8 Hz), 8,05-8,12 (2H, m), 8,18 (1H, d, J = 2,3 Hz), 9,56 (1H, s). 3-(3-Chloro-4-cyanophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-4-nitrophenyl)propionamide was prepared as described in Example 64c starting from 2-chloro-4-hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (2-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane - 1.3% methanol). <!>H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.37 (3H, s), 4.15 (1H, d, J = 10.1 Hz), 4.39 (1H, d, J = 10.1 Hz), 6.51 (1H, s), 7.10 (1H, dd, J = 8, 8 Hz, J = 2.4 Hz), 7.37 (1H, d, J = 2.4 Hz), 7.86 (1H, d, J = 8.8 Hz), 8.05-8.12 (2H, m), 8.18 (1H, d, J = 2.3 Hz), 9.56 (1H, s).

Eksempel 66. Example 66.

3- (4-cyano-3-fluorfenoksy)-N-(3-formyl-4-nitrofenyl)-2-hydroksy-2-metylpropionamid 3-(4-cyano-3-fluorophenoxy)-N-(3-formyl-4-nitrophenyl)-2-hydroxy-2-methylpropionamide

3-(4-cyano-3-fluorfenoksy)-2-hydroksy-N-(3-hydroksymetyl-4-nitrofenyl)-2-metylpropionamid (0,2 g, 0,51 mmol) ble løst i 10 ml diklormetan og tilsatt mangan(IV)oksid (0,4 g, 4,6 mmol). Blandingen ble rørt ved romtemperatur i 48 timer. Det faste oksidasjonsmiddelet ble frafiltrert og løsemiddelet fordampet. Råproduktet ble renset ved flashkromatografi (diklormetan - 3% metanol).<]>H NMR (400 MHz, DMSO-de): 1,45 (3H, s), 4,13 (1H, d, J = 10,0 Hz), 4,38 (1H, d, J = 10,0 Hz), 6,32 (1H, s), 6,94-6,97 (1H, m), 7,16-7,20 (1H, m), 7,77-7,82 (1H, m), 8,18-8,24 (2H, m), 8,36 (1H, d, J = 2,1 Hz), 10,28 (1H, s), 10,55 (1H, s). 3-(4-cyano-3-fluorophenoxy)-2-hydroxy-N-(3-hydroxymethyl-4-nitrophenyl)-2-methylpropionamide (0.2 g, 0.51 mmol) was dissolved in 10 mL of dichloromethane and added manganese(IV) oxide (0.4 g, 4.6 mmol). The mixture was stirred at room temperature for 48 hours. The solid oxidizing agent was filtered off and the solvent evaporated. The crude product was purified by flash chromatography (dichloromethane - 3% methanol). <]>H NMR (400 MHz, DMSO-de): 1.45 (3H, s), 4.13 (1H, d, J = 10.0 Hz ), 4.38 (1H, d, J = 10.0 Hz), 6.32 (1H, s), 6.94-6.97 (1H, m), 7.16-7.20 (1H, m), 7.77-7.82 (1H, m), 8.18-8.24 (2H, m), 8.36 (1H, d, J = 2.1 Hz), 10.28 (1H , p), 10.55 (1H, p).

Eksempel 67. Example 67.

3- [4-(2-dimetylaminoetoksy)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3- [4-(2-dimethylaminoethoxy)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) [2-(4-benzyloksyfenoksy)etyl]dimetylamin a) [2-(4-benzyloxyphenoxy)ethyl]dimethylamine

4- (benzyloksy)fenol (2,89 g, 0,01443 mol) i 15 ml dimetylformamid og 2-(dimetylamino)etylkloridhydroklorid (2,32 g, 0,01611 mol) ble samtidig i små porsjoner tilsatt en 55-65% natriumhydriddispersjon i mineralolje (0,033 mol) i 5 ml dimetylformamid ved 0°C. Blandingen ble så oppvarmet til 90°C og røring fortsatt i 1,5 timer. Den avkjølte blandingen ble helt over i vann og så ekstrahert med toluen. De samlede ekstraktene ble vasket med 2,5 M NaOH og vann og så tørket over natriumsulfat. Toluen ble fordampet og det gjenværende produktet ble brukt som sådan i det neste trinnet.<]>H NMR (300 MHz, DMSO-rf<$): 2,20 (6H, s), 2,58 (2H, t,<3>J= 5,9 Hz), 3,96 (2H, t,<3>J= 5,9 Hz), 5,03 (2H, s), 6,85 (2H, d, 3J = 9,3 Hz), 6,92 (2H, d,<3>J= 9,3 Hz), 7,30-7,44 (5H, m). 4-(Benzyloxy)phenol (2.89 g, 0.01443 mol) in 15 ml of dimethylformamide and 2-(dimethylamino)ethyl chloride hydrochloride (2.32 g, 0.01611 mol) were simultaneously added in small portions at a 55-65% sodium hydride dispersion in mineral oil (0.033 mol) in 5 ml of dimethylformamide at 0°C. The mixture was then heated to 90°C and stirring continued for 1.5 hours. The cooled mixture was poured into water and then extracted with toluene. The combined extracts were washed with 2.5 M NaOH and water and then dried over sodium sulfate. The toluene was evaporated and the remaining product was used as such in the next step.<]>H NMR (300 MHz, DMSO-rf<$): 2.20 (6H, s), 2.58 (2H, t,< 3>J= 5.9 Hz), 3.96 (2H, t,<3>J= 5.9 Hz), 5.03 (2H, s), 6.85 (2H, d, 3J = 9, 3 Hz), 6.92 (2H, d,<3>J = 9.3 Hz), 7.30-7.44 (5H, m).

b) 4-(2-dimetylaminoetoksy)fenol b) 4-(2-dimethylaminoethoxy)phenol

En rørt løsning av [2-(4-benzyloksyfenoksy)etyl]dimetylamin (3,36 g, 0,01238 mol) A stirred solution of [2-(4-benzyloxyphenoxy)ethyl]dimethylamine (3.36 g, 0.01238 mol)

i blandingen av 67 ml 6 M HC1 og 33,5 ml etanol ble kokt under tilbakeløp i 6,5 timer. Etanolen ble fordampet og pH ble justert til 8 med 2,5 M NaOH. Produktet ble så ekstrahert over i etylacetat. Ekstraktene ble vasket med vann og tørket over natriumsulfat. Fjerning av løsemiddelet under redusert trykk ga et råprodukt som in the mixture of 67 ml of 6 M HCl and 33.5 ml of ethanol was refluxed for 6.5 h. The ethanol was evaporated and the pH was adjusted to 8 with 2.5 M NaOH. The product was then extracted into ethyl acetate. The extracts were washed with water and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a crude product which

ble renset ved flashkromatografi på silikagel ved å bruke heptan/etylacetat (9:1-6:4) som et gradientelueringsmiddel.<]>H NMR (300 MHz, DMSO- d6) : 2,20 (6H, s), 2,57 (2H, t, 3J = 5,9 Hz), 3,92 (2H, t,<3>J= 5,9 Hz), 6,65 (2H, d,<3>J= 9,1 Hz), 6,74 (2H, d,<3>J= 9,0 Hz), 8,85 (1H, s, -OH). was purified by flash chromatography on silica gel using heptane/ethyl acetate (9:1-6:4) as a gradient eluent. <]>H NMR (300 MHz, DMSO-d6) : 2.20 (6H, s), 2, 57 (2H, t, 3J = 5.9 Hz), 3.92 (2H, t,<3>J= 5.9 Hz), 6.65 (2H, d,<3>J= 9.1 Hz ), 6.74 (2H, d,<3>J = 9.0 Hz), 8.85 (1H, s, -OH).

c) 3-[4-(2-dimetylaminoetoksy)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid c) 3-[4-(2-dimethylaminoethoxy)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-[4-(2-dimetylaminoetoksy)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 4-(2-dimetylaminoetoksy)fenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Produktet ble ekstrahert ved pH 8. Råproduktet ble renset ved 3-[4-(2-Dimethylaminoethoxy)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 4-(2-dimethylaminoethoxy )phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The product was extracted at pH 8. The crude product was purified by

flashkromatografi ved å bruke diklormetan/metanol som et gradientelueringsmiddel (metanol 0-20%). Utkrystallisering fra toluen.<]>H NMR (400 MHz, DMSO- d6) : 1,42 (3H, s), 2,19 (6H, s), 2,53 (3H, s), 2,57 (2H, t,<3>J= 5,8 Hz), 3,90 (1H, d,<2>Jgem= 9,6 Hz), 3,95 (2H, t, 3J = 5,9 Hz), 4,14 (1H, d,<2>Jgem= 9,5 Hz), 6,18 (1H, s, -OH), 6,83 (4H, s), 7,88 (1H, dd,<3>J= 9,0 Hz, V =2,3 Hz), 7,93 (1H, d,<4>J= 1,8 Hz), 8,04 (1H, d, 3J = 9,0 Hz), 10,14 (1H, s, -NHCO-). flash chromatography using dichloromethane/methanol as a gradient eluent (methanol 0-20%). Crystallization from toluene.<]>H NMR (400 MHz, DMSO- d6 ) : 1.42 (3H, s), 2.19 (6H, s), 2.53 (3H, s), 2.57 (2H , t,<3>J= 5.8 Hz), 3.90 (1H, d,<2>Jgem= 9.6 Hz), 3.95 (2H, t, 3J = 5.9 Hz), 4 .14 (1H, d,<2>Jgem= 9.5 Hz), 6.18 (1H, s, -OH), 6.83 (4H, s), 7.88 (1H, dd,<3> J= 9.0 Hz, V =2.3 Hz), 7.93 (1H, d,<4>J= 1.8 Hz), 8.04 (1H, d, 3J = 9.0 Hz), 10.14 (1H, s, -NHCO-).

Eksempel 68. Example 68.

3-(4-cyanometylfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(4-cyanometylfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 4-hydroksybenzylcyanid og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel (9:1-7:3). Utkrystallisering fra toluen, smeltepunkt 143-145°C.<]>H NMR (300 MHz, DMSO-tf*): 1,43 (3H, s), 2,53 (3H, s), 3,92 (2H, s), 3,98 (1H, d,<2>Jgem= 9,7 Hz), 4,21 (1H, d,<2>Jgem= 9,7 Hz), 6.17 (1H, bred s, -OH), 6,94 (2H, d,<3>J= 8,7 Hz), 7,23 (2H, d,<3>J= 8,7 Hz), 7,87 (1H, dd,<3>J= 9,0 Hz, 4J = 2, 2 Hz), 7,92 (1H, s), 8,03 (1H, d,<3>J= 8,9 Hz), 10,09 (1H, bred s, -NHCO-). 3-(4-cyanomethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(4-cyanomethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl -4-nitrophenyl)propionamide was prepared as described in example 1c by starting from 4-hydroxybenzylcyanide and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (9:1-7:3). Crystallization from toluene, mp 143-145°C. <]>H NMR (300 MHz, DMSO-tf*): 1.43 (3H, s), 2.53 (3H, s), 3.92 (2H, s), 3.98 (1H, d,<2>Jgem= 9.7 Hz), 4.21 (1H, d,<2>Jgem= 9.7 Hz), 6.17 (1H, broad s, -OH ), 6.94 (2H, d,<3>J= 8.7 Hz), 7.23 (2H, d,<3>J= 8.7 Hz), 7.87 (1H, dd,<3 >J= 9.0 Hz, 4J = 2, 2 Hz), 7.92 (1H, s), 8.03 (1H, d,<3>J= 8.9 Hz), 10.09 (1H, broad s, -NHCO-).

Eksempel 69. Example 69.

3-[4-(2-kloretyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-[4-(2-kloretyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionarnid ble fremstilt som beskrevet i eksempel lc ved å starte fra 4-(2-kloretyl)fenol (A.C. Spivey et al. J. Org. Chem. 65 (2000) 5253; P.G. Baraldi et al. J. Med. Chem. 45 3-[4-(2-chloroethyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-[4-(2-chloroethyl)phenoxy]-2-hydroxy- 2-Methyl-N-(3-methyl-4-nitrophenyl)propionarnide was prepared as described in Example 1c starting from 4-(2-chloroethyl)phenol (A.C. Spivey et al. J. Org. Chem. 65 (2000 ) 5253; P. G. Baraldi et al. J. Med. Chem. 45

(2002) 115) og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset to ganger ved flashkromatografi ved først å bruke heptan/etylacetat som et gradientelueringsmiddel (9:1-8:2) og så bare diklormetan.<]>H NMR (400 MHz, DMSO-tftf): 1,43 (3H, s), 2,53 (3H, s), 2,93 (2H, t, 3J = 7,1 Hz), 3,77 (2H, t, 3J = 7,1 Hz), 3.95 (1H, d,<2>Jgem=9,6 Hz), 4,19 (1H, d,<2>Jgem=9,6 Hz), omtrent 6,2 (1H, bred s, -OH), 6,85 (2H, d,<3>J= 8,6 Hz), 7,16 (2H, d,<3>J= 8,7 Hz), 7,89 (1H, dd,<3>J= 9,0 Hz,<4>J= 2,3 Hz), 7,94 (1H, d,<4>J= 2, 2 Hz), 8,04 (1H, d, 3J = 9,0 Hz), omtrent 10,2 (1H, bred s, -NHCO-). (2002) 115) and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified twice by flash chromatography using first heptane/ethyl acetate as a gradient eluent (9:1-8:2) and then only dichloromethane. <]>H NMR (400 MHz, DMSO-tftf): 1.43 (3H , s), 2.53 (3H, s), 2.93 (2H, t, 3J = 7.1 Hz), 3.77 (2H, t, 3J = 7.1 Hz), 3.95 (1H, d ,<2>Jgem=9.6 Hz), 4.19 (1H, d,<2>Jgem=9.6 Hz), about 6.2 (1H, broad s, -OH), 6.85 (2H , d,<3>J= 8.6 Hz), 7.16 (2H, d,<3>J= 8.7 Hz), 7.89 (1H, dd,<3>J= 9.0 Hz ,<4>J= 2.3 Hz), 7.94 (1H, d,<4>J= 2, 2 Hz), 8.04 (1H, d, 3J = 9.0 Hz), about 10, 2 (1H, broad s, -NHCO-).

Eksempel 70. Example 70.

2-hydroksy-3-(4-hydroksymetylfenoksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 2-hydroxy-3-(4-hydroxymethylphenoxy)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

2-hydroksy-3-(4-hydroksymetylfenoksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 4-hydroksybenzylalkohol og 2-metyloksiran-2-karboksylsyre (3-mety 1-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel (95:5-25:75).<!>H NMR (400 MHz, DMSO-^):1,43 (3H,s), 2,53 (3H,s), 3,95 (1H, d,<2>Jgem= 9,6 Hz), 4,18 (1H, d,<2>Jgem=9,6 Hz), 4,39 (2H, d,<3>J= 5,3 Hz), 5,05 (1H, t,<3>J= 5,7 Hz), 6,22 (1H, s, -OH), 6,86 (2H, d, 3J = 8,6 Hz), 7,19 (2H, d, 3J = 8,8 Hz), 7,89 (1H, dd,<3>J= 9,0 Hz, 4J = 2,3 Hz), 7,94 (1H, d, 4J = 2, 2 Hz), 8,04 (1H, d,<3>J= 9,0 Hz), 10,16 (1H, s, 2-Hydroxy-3-(4-hydroxymethylphenoxy)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c starting from 4-hydroxybenzyl alcohol and 2-methyloxirane-2-carboxylic acid (3-methyl 1-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (95:5-25:75). <!>H NMR (400 MHz, DMSO-^): 1.43 (3H,s), 2.53 (3H,s), 3.95 (1H, d,<2>Jgem= 9.6 Hz), 4.18 (1H, d,<2>Jgem=9.6 Hz), 4.39 (2H, d,<3>J= 5.3 Hz), 5.05 (1H, t,<3>J= 5.7 Hz), 6.22 (1H, s, -OH), 6.86 (2H, d, 3J = 8.6 Hz), 7.19 (2H, d, 3J = 8.8 Hz), 7.89 (1H, dd,<3>J= 9.0 Hz, 4J = 2.3 Hz ), 7.94 (1H, d, 4J = 2.2 Hz), 8.04 (1H, d,<3>J= 9.0 Hz), 10.16 (1H, s,

-NHCO-). -NHCO-).

Eksempel 71. Example 71.

2-hydroksy-3-(4-hydroksyfenoksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 2-hydroksy-3-(4-hydroksyfenoksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra hydrokinon og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel (9:1-6:4).<]>H NMR (400 MHz, DMSO-c/tf): 1,40 (3H, s), 2,53 (3H, s), 3,86 (1H, d,<2>Jgem=9,4 Hz), 4,10 (1H, d,<2>Jgem=9,4 Hz), 5,76 (1H, bred s, -OH), 6,63 (2H, d,<3>J = 9,0 Hz), 6,73 (2H, d,<3>J= 9,0 Hz), 7,88 (1H, dd,<3>J= 9,0 Hz,<4>J= 2,4 Hz), 7,93 (1H, d,<4>J= 2,1 Hz), 8,04 (1H, d,<3>J= 9,0 Hz), 8,92 (1H, bred s, ArOH), 10,13 (1H, bred s, -NHCO-). 2-hydroxy-3-(4-hydroxyphenoxy)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 2-hydroxy-3-(4-hydroxyphenoxy)-2-methyl-N-(3-methyl -4-nitrophenyl)propionamide was prepared as described in example 1c by starting from hydroquinone and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (9:1-6:4). <]>H NMR (400 MHz, DMSO-c/tf): 1.40 (3H, s), 2 .53 (3H, s), 3.86 (1H, d,<2>Jgem=9.4 Hz), 4.10 (1H, d,<2>Jgem=9.4 Hz), 5.76 ( 1H, broad s, -OH), 6.63 (2H, d,<3>J = 9.0 Hz), 6.73 (2H, d,<3>J= 9.0 Hz), 7.88 (1H, dd,<3>J= 9.0 Hz,<4>J= 2.4 Hz), 7.93 (1H, d,<4>J= 2.1 Hz), 8.04 (1H , d,<3>J= 9.0 Hz), 8.92 (1H, broad s, ArOH), 10.13 (1H, broad s, -NHCO-).

Eksempel 72. Example 72.

3-(3-cyanofenoksy)-2-hydroksy-2-metyl-N-(3-rnetyl-4-nitrofenyl)propionamid 3-(3-cyanofenoksy)-2-hydroksy-2-metyl-N-(3-rnetyl-4-nitrofenyl)propionarnid ble fremstilt som beskrevet i eksempel lc ved å starte fra 3-cyanofenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et 3-(3-cyanophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(3-cyanophenoxy)-2-hydroxy-2-methyl-N-(3-methyl) -4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 3-cyanophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as e.t

gradientelueringsmiddel. Utkrystallisering fra toluen, smeltepunkt 107-110°C.<]>H NMR (300 MHz, DMSO-^): 1,44 (3H,s), 2,53 (3H,s), 4,06 (1H, d,<2>Jgem= 10,0 Hz), 4,31 (1H, d,<2>Jgem= 9,9 Hz), omtrent 6,3 (1H, bred s, -OH), 7,27 (1H, m), 7,38 (1H, dt, 3J = 7,5 Hz,<4>J=1,3 Hz), 7,43 (1H, m), 7,46 (1H, t, 3J = 7,8 Hz), 7,87 (1H, dd, 3J =9,0 Hz, V =2,3 Hz), 7,91 (1H, d, V =9,0 Hz,V=1,9 Hz), 8,03 (1H, d,<3>J = 9,0 Hz), omtrent 10,1 (1H, bred s, -NHCO-). gradient eluent. Crystallization from toluene, melting point 107-110°C. <]>H NMR (300 MHz, DMSO-^): 1.44 (3H,s), 2.53 (3H,s), 4.06 (1H, d ,<2>Jgem= 10.0 Hz), 4.31 (1H, d,<2>Jgem= 9.9 Hz), about 6.3 (1H, broad s, -OH), 7.27 (1H , m), 7.38 (1H, dt, 3J = 7.5 Hz,<4>J=1.3 Hz), 7.43 (1H, m), 7.46 (1H, t, 3J = 7 ,8 Hz), 7.87 (1H, dd, 3J =9.0 Hz, V =2.3 Hz), 7.91 (1H, d, V =9.0 Hz,V=1.9 Hz) , 8.03 (1H, d,<3>J = 9.0 Hz), about 10.1 (1H, broad s, -NHCO-).

Eksempel 73. Example 73.

3-(3-fluor-5-trifluormetylfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(3-fluoro-5-trifluoromethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(3-fluor-5-trifluormetylfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 3-fluor-5-(trifluormetyl)fenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel. Utkrystallisering fra toluen/heptan.<!>H NMR (400 MHz, DMSO-c/tf): 1,44 (3H, s), 2,53 (3H, s), 4,15 (1H, d,<2>Jgem=10,0 Hz), 4,37 (1H, d,<2>Jgem=10,0 Hz), 6,26 (1H, bred s, -OH), 7,12 (1H, s), 7,19-7,22 (2H, m), 7,87 (1H, dd,<3>J= 8,9 Hz,<4>J= 2,3 Hz), 7,92 (1H, d,<4>J= 1,9 Hz), 8,03 (1H, d,<3>J= 9,0 Hz), 10,15 (1H, bred s, -NHCO-). 3-(3-Fluoro-5-trifluoromethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 3-fluoro-5-( trifluoromethyl)phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent. Crystallization from toluene/heptane.<!>H NMR (400 MHz, DMSO-c/tf): 1.44 (3H, s), 2.53 (3H, s), 4.15 (1H, d,<2 >Jgem=10.0 Hz), 4.37 (1H, d,<2>Jgem=10.0 Hz), 6.26 (1H, broad s, -OH), 7.12 (1H, s), 7.19-7.22 (2H, m), 7.87 (1H, dd,<3>J= 8.9 Hz,<4>J= 2.3 Hz), 7.92 (1H, d, <4>J= 1.9 Hz), 8.03 (1H, d,<3>J= 9.0 Hz), 10.15 (1H, broad s, -NHCO-).

Eksempel 74. Example 74.

3-(3,5-difluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(3,5-difluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 3,5-difluorfenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel (95:5-70:30). Utkrystallisering fra toluen, smeltepunkt 104-106°C.<]>H NMR (400 MHz, DMSO-tftf):1,43 (3H,s), 2,53 (3H,s), 4,01 (1H, d,<2>Jgem= 9,9 Hz), 4,27 (1H, d,<2>Jgem= 9,8 Hz), omtrent 6,3 (1H, bred s, -OH), 6,71 (2H, dd, 3JHF=9, 5 Hz,<4>JHH= 2,1 Hz), 6,76 (1H, tt, 3Jhf=9A Hz,<4>Jhh=2,3 Hz), 7,87 (1H, dd,<3>J=9,0 Hz, 4J = 2,4 Hz), 7,92 (1H, d, 4J=2, 2 Hz), 8,04 (1H, d,<3>J= 9,0 Hz), omtrent 10,1 (1H, bred s, -NHCO-). 3-(3,5-difluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(3,5-difluorophenoxy)-2-hydroxy-2-methyl-N- (3-Methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 3,5-difluorophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (95:5-70:30). Crystallization from toluene, melting point 104-106°C. <]>H NMR (400 MHz, DMSO-tftf): 1.43 (3H,s), 2.53 (3H,s), 4.01 (1H, d ,<2>Jgem= 9.9 Hz), 4.27 (1H, d,<2>Jgem= 9.8 Hz), about 6.3 (1H, broad s, -OH), 6.71 (2H , dd, 3JHF=9.5 Hz,<4>JHH= 2.1 Hz), 6.76 (1H, tt, 3Jhf=9A Hz,<4>Jhh=2.3 Hz), 7.87 (1H , dd,<3>J=9.0 Hz, 4J = 2.4 Hz), 7.92 (1H, d, 4J=2, 2 Hz), 8.04 (1H, d,<3>J= 9.0 Hz), about 10.1 (1H, broad s, -NHCO-).

Eksempel 75. Example 75.

3-(2,3-difluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(2,3-difluorfenoksy)-2-hydroksy-2-rnetyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 2,3-difluorofenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset to ganger ved flashkromatografi ved først å bruke heptan/etylacetat (8:2) og så ren diklormetan som elueringsmiddel. Gniing i heptan, smeltepunkt 68-73°C.<]>H NMR (300 MHz, DMSO-tftf): 1,44 (3H, s), 2,53 (3H, s), 4,11 (1H, d,<2>Jgem= 9, 9 Hz), 4,31 (1H, d,<2>Jgem= 9,8 Hz), 6,28 (1H, s, -OH), 6,93-7,14 (3H,m), 7,86 (1H, dd, 3J = 8,9 Hz,<4>J= 2,3 Hz), 7,91 (1H, d,<4>J= 2,1 Hz), 8,03 (1H, d, 3J = 8,9 Hz), 10,15 (1H, s, 3-(2,3-difluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(2,3-difluorophenoxy)-2-hydroxy-2-rnethyl-N- (3-Methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 2,3-difluorophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified twice by flash chromatography using first heptane/ethyl acetate (8:2) and then pure dichloromethane as eluent. Trituration in heptane, mp 68-73°C. <]>H NMR (300 MHz, DMSO-tftf): 1.44 (3H, s), 2.53 (3H, s), 4.11 (1H, d ,<2>Jgem= 9.9 Hz), 4.31 (1H, d,<2>Jgem= 9.8 Hz), 6.28 (1H, s, -OH), 6.93-7.14 (3H,m), 7.86 (1H, dd, 3J = 8.9 Hz,<4>J= 2.3 Hz), 7.91 (1H, d,<4>J= 2.1 Hz) , 8.03 (1H, d, 3J = 8.9 Hz), 10.15 (1H, s,

-NHCO-). -NHCO-).

Eksempel 76. Example 76.

3-(2,6-difluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(2,6-difluorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 2,6-difluorofenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel (9:1-7:3).<!>H NMR (400 MHz, DMSO-tftf): 1,40 (3H, s), 2,53 (3H, s), 4,16 (1H, d,<2>Jgem=10,0 Hz), 4,31 (1H, d,<2>Jgem=10,0 Hz), 6,18 (1H, bred s, -OH), 7,06-7,12 (3H, m), 7,86 (1H, dd,<3>J= 8,9 Hz,<4>J= 2,3 Hz), 7,88 (1H, d,<4>J= 2,3 Hz), 8,04 (1H, d,<3>J= 8,8 Hz), 10,08 (1H, bred s, -NHCO-). 3-(2,6-difluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(2,6-difluorophenoxy)-2-hydroxy-2-methyl-N- (3-Methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 2,6-difluorophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (9:1-7:3). <!>H NMR (400 MHz, DMSO-tftf): 1.40 (3H, s), 2.53 (3H, s), 4.16 (1H, d,<2>Jgem=10.0 Hz), 4.31 (1H, d,<2>Jgem=10.0 Hz), 6.18 (1H, broad s, -OH), 7.06-7.12 (3H, m), 7.86 (1H, dd,<3>J= 8.9 Hz,<4>J= 2.3 Hz), 7 .88 (1H, d,<4>J= 2.3 Hz), 8.04 (1H, d,<3>J= 8.8 Hz), 10.08 (1H, broad s, -NHCO-) .

Eksempel 77. Example 77.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(3-trifluormetylfenoksy)propionamid 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(3-trifluoromethylphenoxy)propionamide

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(3-trifluormetylfenoksy)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 3-hydroksybenzotrifluorid og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel (9:1-5:5). Utkrystallisering fra 2-Hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(3-trifluoromethylphenoxy)propionamide was prepared as described in Example 1c starting from 3-hydroxybenzotrifluoride and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (9:1-5:5). Crystallization from

metylenklorid/etanol/heptan, smeltepunkt 84-87°C.<]>H NMR (400 MHz, DMSO- d6) : 1,45 (3H,s), 2,53 (3H,s), 4,07 (1H, d,<2>Jgem=9,8 Hz), 4,33 (1H, d,<2>Jgem=9,8 Hz), 6,25 (1H, bred s, -OH), 7,23 (1H, s), 7,24 (1H, d,<3>J= 6,7 Hz,), 7,28 (1H, d,<3>J= 1, 1 Hz), 7,50 (1H, t,<3>J= 8,3 Hz,), 7,88 (1H, dd,<3>J= 8,9 Hz,<4>J= 2,3 Hz), 7,92 (1H, d,<4>J= 2,0 Hz), 8,03 (1H, d,<3>J= 9,0 Hz), 10,15 (1H, bred s, -NHCO-). methylene chloride/ethanol/heptane, melting point 84-87°C. <]>H NMR (400 MHz, DMSO- d6 ) : 1.45 (3H,s), 2.53 (3H,s), 4.07 (1H , d,<2>Jgem=9.8 Hz), 4.33 (1H, d,<2>Jgem=9.8 Hz), 6.25 (1H, broad s, -OH), 7.23 ( 1H, s), 7.24 (1H, d,<3>J= 6.7 Hz,), 7.28 (1H, d,<3>J= 1, 1 Hz), 7.50 (1H, t,<3>J= 8.3 Hz,), 7.88 (1H, dd,<3>J= 8.9 Hz,<4>J= 2.3 Hz), 7.92 (1H, d ,<4>J= 2.0 Hz), 8.03 (1H, d,<3>J= 9.0 Hz), 10.15 (1H, broad s, -NHCO-).

Eksempel 78. Example 78.

3-(3,5-diklorfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(3,5-diklorfenoksy)-2-hydroksy-2-rnetyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 3,5-diklorofenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som elueringsmiddel (9:1). Utkrystallisering fra toluen, smeltepunkt 141-143°C.<]>H NMR (400 MHz, DMSO-d6) : 1,42 (3H,s), 2,53 (3H,s), 4,05 (1H, d,<2>Jgem=10,1 Hz), 4,31 (1H, d,<2>Jgem=10,1 Hz), omtrent 6,2 (1H, bred s, -OH), 7,04 (2H, forvrengt d,<4>J= 1,9 Hz), 7,13 (1H, forvrengt t,<4>J= 1,7 Hz), 7,87 (1H, d, 3J = 8,9 Hz), 7,92 (1H, s), 8,04 (1H, d,<3>J = 8,90 Hz), omtrent 10,1 (1H, bred s, -NHCO-). 3-(3,5-dichlorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide 3-(3,5-dichlorophenoxy)-2-hydroxy-2-rnethyl-N- (3-Methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 3,5-dichlorophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as eluent (9:1). Crystallization from toluene, melting point 141-143°C. <]>H NMR (400 MHz, DMSO-d6) : 1.42 (3H,s), 2.53 (3H,s), 4.05 (1H,d ,<2>Jgem=10.1 Hz), 4.31 (1H, d,<2>Jgem=10.1 Hz), about 6.2 (1H, broad s, -OH), 7.04 (2H , distorted d,<4>J= 1.9 Hz), 7.13 (1H, distorted t,<4>J= 1.7 Hz), 7.87 (1H, d, 3J = 8.9 Hz) , 7.92 (1H, s), 8.04 (1H, d,<3>J = 8.90 Hz), about 10.1 (1H, broad s, -NHCO-).

Eksempel 79. Example 79.

3-[4-(3-klorpropyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-[4-(3-chloropropyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) 4-(3-klorpropyl)fenol a) 4-(3-chloropropyl)phenol

3-(4-hydroksyfenyl)-l-propanol (0,97 g, 0,006374 mol) og 20 ml konsentrert HC1 3-(4-Hydroxyphenyl)-1-propanol (0.97 g, 0.006374 mol) and 20 mL of concentrated HCl

ble holdt på 100°C i 14 timer. Etter avkjøling ble reaksjonsblandingen helt over i vann og ekstrahert med etylacetat. Ekstraktene ble vasket med vann, tørket og konsentrert i vakuum til et råprodukt. Rensing ved flashkromatografi (heptan/etylacetat 9:1) ga et rent produkt (0,98 g, 90%).<]>H NMR (400 MHz, DMSO-tftf): 1,95 (2H, kvintett,<3>J=7,0 Hz), 2,59 (2H, t, 3J = 7,5 Hz), 3,58 (2H, t,<3>J = 6,5 Hz), 6,67 (2H, d,<3>J= 8,2 Hz), 6,99 (2H, d,<3>J= 8,2 Hz), 9,15 (1H, s, -OH). was kept at 100°C for 14 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated in vacuo to a crude product. Purification by flash chromatography (heptane/ethyl acetate 9:1) gave a pure product (0.98 g, 90%).<]>H NMR (400 MHz, DMSO-tftf): 1.95 (2H, quintet,<3> J=7.0 Hz), 2.59 (2H, t, 3J = 7.5 Hz), 3.58 (2H, t,<3>J = 6.5 Hz), 6.67 (2H, d ,<3>J= 8.2 Hz), 6.99 (2H, d,<3>J= 8.2 Hz), 9.15 (1H, s, -OH).

b) 3-[4-(3-klorpropyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid b) 3-[4-(3-chloropropyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-[4-(3-klorpropyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 4-(3-klorpropyl)fenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Rensing ble utført to ganger med flashkromatografi (først bare diklormetan og så heptan/etylacetat 9:1 som et elueringsmiddel), og dette ga et rent produkt, smeltepunkt 110-112°C.<]>H NMR (400 MHz, DMSO-</tf): 1,43 (3H, s), 1,95 (2H, kvintett,<3>J= 7,0 Hz), 2,53 (3H, s), 2,62 (2H, t,<3>J= 7,4 Hz), 3,58 (2H, t,<3>J=6,5 Hz), 3,95 (1H, d,<2>Jgem= 9,6 Hz), 4,18 (1H, d,<2>Jgem= 9,5 Hz), 6,15 (1H, bred s, -OH), 6,84 (2H, d,<3>J= 8,5 Hz), 7,10 (2H, d,<3>J= 8,4 Hz), 7,88 (1H, d,<3>J= 9,1 Hz), 7,93 (1H, s), 8,03 (1H, d,<3>J= 9,0 Hz), 10,14 (1H, bred s, -NHCO-). 3-[4-(3-chloropropyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 4-(3-chloropropyl )phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. Purification was carried out twice by flash chromatography (first only dichloromethane and then heptane/ethyl acetate 9:1 as an eluent) and this gave a pure product, mp 110-112°C.<]>H NMR (400 MHz, DMSO-< /tf): 1.43 (3H, s), 1.95 (2H, quintet,<3>J= 7.0 Hz), 2.53 (3H, s), 2.62 (2H, t,< 3>J= 7.4 Hz), 3.58 (2H, t,<3>J=6.5 Hz), 3.95 (1H, d,<2>Jgem= 9.6 Hz), 4, 18 (1H, d,<2>Jgem= 9.5 Hz), 6.15 (1H, broad s, -OH), 6.84 (2H, d,<3>J= 8.5 Hz), 7 .10 (2H, d,<3>J= 8.4 Hz), 7.88 (1H, d,<3>J= 9.1 Hz), 7.93 (1H, s), 8.03 ( 1H, d,<3>J= 9.0 Hz), 10.14 (1H, broad s, -NHCO-).

Eksempel 80. Example 80.

3-[4-(2-kloretoksy)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-[4-(2-chloroethoxy)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-[4-(2-kloretoksy)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 4-(2-kloretoksy)fenol (H.K.A.C. Coolen et al., Recueil des Travaux Chimiques des Pays-Bas 114(2) (1995) 65) og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat (75:25) som elueringsmiddel, smeltepunkt 131-133°C.<]>H NMR (400 MHz, DMSO-tftf): 1,42 (3H, s), 2,53 (3H, s), 3,88-3,93 (3H, m), 4,14-4,18 (3H, m), omtrent 6,2 (1H, bred s, -OH), 6,86 (4H, s), 7,88 (1H, d, 3J = 9,0 Hz), 7,92 (1H, s), 8,04 (1H, d,<3>J= 9,0 Hz), omtrent 10,1 (1H, bred s, -NHCO-). 3-[4-(2-chloroethoxy)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 4-(2-chloroethoxy )phenol (H.K.A.C. Coolen et al., Recueil des Travaux Chimiques des Pays-Bas 114(2) (1995) 65) and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate (75:25) as eluent, mp 131-133°C. <]>H NMR (400 MHz, DMSO-tftf): 1.42 (3H, s), 2 .53 (3H, s), 3.88-3.93 (3H, m), 4.14-4.18 (3H, m), about 6.2 (1H, broad s, -OH), 6, 86 (4H, s), 7.88 (1H, d, 3J = 9.0 Hz), 7.92 (1H, s), 8.04 (1H, d,<3>J= 9.0 Hz) , about 10.1 (1H, broad s, -NHCO-).

Eksempel 81. Example 81.

2-hydroxy-3-(4-metoksymetylfenoksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 2-hydroxy-3-(4-methoxymethylphenoxy)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

2- hydroxy-3-(4-metoksymetylfenoksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 4-(metoksymetyl)fenol (J.M. Saå et al., J. Org. Chem. 53 (1988) 4263; D.R. Dimmel og D. Shepard, J. Org. Chem. 47 (1982) 22) og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved å bruke flashkromatografi flere ganger (diklormetan/metanol 99:1, heptan/etylacetat som et gradientelueringsmiddel (9:1-7:3) og diklormetan/metanol 99,5:0,5).<]>H NMR (400 MHz, DMSO-tftf): 1,43 (3H,s), 2,53 (3H, s), 3,22 (3H, s), 3,97 (1H, d,<2>Jgem=9,6 Hz), 4,20 (1H, d,<2>Jgem=9,5 Hz), 4,30 (2H, s), 6,19 (1H, bred s, -OH), 6,89 (2H, d, 3J = 7,9 Hz), 7,20 (2H, d,<3>J= 8,2 Hz), 7,88 (1H, d, 3J = 9,0 Hz), 7,93 (1H, s), 8,04 (1H, d, 3J = 9,0 Hz), 10,13 (1H, bred s, -NHCO-). 2-hydroxy-3-(4-methoxymethylphenoxy)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 4-(methoxymethyl)phenol (J.M. Saå et al ., J. Org. Chem. 53 (1988) 4263; D. R. Dimmel and D. Shepard, J. Org. Chem. 47 (1982) 22) and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl) amide. The crude product was purified using flash chromatography several times (dichloromethane/methanol 99:1, heptane/ethyl acetate as a gradient eluent (9:1-7:3) and dichloromethane/methanol 99.5:0.5).<]>H NMR (400 MHz, DMSO-tftf): 1.43 (3H,s), 2.53 (3H, s), 3.22 (3H, s), 3.97 (1H, d,<2>Jgem=9 .6 Hz), 4.20 (1H, d,<2>Jgem=9.5 Hz), 4.30 (2H, s), 6.19 (1H, broad s, -OH), 6.89 ( 2H, d, 3J = 7.9 Hz), 7.20 (2H, d,<3>J= 8.2 Hz), 7.88 (1H, d, 3J = 9.0 Hz), 7.93 (1H, s), 8.04 (1H, d, 3J = 9.0 Hz), 10.13 (1H, broad s, -NHCO-).

Eksempel 82. Example 82.

3- [4-(2-fluoretyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3- [4-(2-fluoroethyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

En løsning av 2-hydroksy-3-[4-(2-hydroksyetylfenoksy]-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid (fremstilt som beskrevet i eksempel 20, 300 mg, 0,0008012 mol) i 3 ml tørr metylenklorid ble behandlet med Deoxo-Fluor® (195 mg, 0,0008813 mol) i 1 ml tørr metylenklorid ved -15 til -10°C. Løsningen ble rørt i 2 timer ved 0°C og så i 3 dager ved romtemperatur. En mettet NaHC03-løsning ble tilsatt, og blandingen ble ekstrahert med diklormetan. De samlede ekstraktene ble vasket med vann, tørket over natriumsulfat, filtrert og fordampet i vakuum. Råproduktet ble renset ved flashkromatografi ved å bruke diklormetan som et elueringsmiddel. Utkrystallisering fra toluen ga den forønskede forbindelsen som rene krystaller: Smeltepunkt 102-105°C.<!>H NMR (400 MHz, DMSO-^): 1,43 (3H,s), 2,53 (3H,s), 2,88 (2H, dt,<3>JHF= 24,4 Hz,<3>J = 6,4 Hz), 3,95 (1H, d,<2>Jgem=9,8 Hz), 4,18 (1H, d,<2>Jgem= 9,5 Hz), 4,56 (2H, dt,<2>JHF= 47,4 Hz,<3>J= 6,4 Hz), 6,18 (1H, bred s, -OH), 6,85 (2H, d,<3>J= 8,5 Hz), 7,15 (2H, d,<3>J= 8,4 Hz), 7,88 (1H, d,<3>J= 9,0 Hz), 7,93 (1H, s), 8,03 (1H, d,<3>J= 9,0 Hz), 10,13 (1H, bred s, -NHCO-). A solution of 2-hydroxy-3-[4-(2-hydroxyethylphenoxy]-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide (prepared as described in Example 20, 300 mg, 0.0008012 mol) in 3 mL of dry methylene chloride was treated with Deoxo-Fluor® (195 mg, 0.0008813 mol) in 1 mL of dry methylene chloride at -15 to -10° C. The solution was stirred for 2 hours at 0° C. and then for 3 days at room temperature. A saturated NaHCO 3 solution was added, and the mixture was extracted with dichloromethane. The combined extracts were washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography using dichloromethane as an eluent. Crystallization from toluene gave the desired compound as pure crystals: mp 102-105°C. <!>H NMR (400 MHz, DMSO-^): 1.43 (3H,s), 2.53 (3H,s), 2 .88 (2H, dt,<3>JHF= 24.4 Hz,<3>J = 6.4 Hz), 3.95 (1H, d,<2>Jgem=9.8 Hz), 4.18 (1H, d,<2>Jgem= 9.5 Hz), 4.56 (2H, dt,<2>JHF= 47.4 Hz,<3>J= 6.4 Hz), 6.18 (1H , broad s, -OH), 6.85 (2H, d,<3>J= 8.5 Hz), 7.15 (2H, d,<3>J= 8.4 Hz), 7.88 (1H, d,<3>J= 9.0 Hz), 7.93 (1H, s), 8.03 (1H, d,<3>J= 9.0 Hz), 10.13 (1H, broad s, -NHCO-).

Eksempel 83. Example 83.

3-(4-fluormetylfenoksy)-2-hydroksy-2-metyl-N-(3-metyl-4-nitroenyl)propionamid En løsning av 2-hydroksy-3-(4-hydroksymetylfenoksy)-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid (fremstilt som beskrevet i eksempel 70, 950 mg, 0,002636 mol) i 6,5 ml tørr metylenklorid ble behandlet med Deoxo-Fluor® (875 mg, 0,003954 mol) i 3 ml metylenklorid ved -76°C. Løsningen ble rørt ved -10°C i 3 timer. En mettet NaHC03-løsning ble tilsatt, og blandingen ble ekstrahert med diklormetan. De samlede ekstraktene ble vasket med vann, tørket over natriumsulfat, filtrert og fordampet i vakuum. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel (9:1-5:5). Utkrystallisering fra diklormetan/heptan ga den forønskede forbindelsen.<]>H NMR (400 MHz, DMSO-c/tf): 1,44 (3H,s), 2,53 (3H,s), 4,00 (1H, d,<2>Jgem= 9,7 Hz), 4,24 (1H, d,<2>Jgem= 9,6 Hz), 5,30 (2H, d,<2>JHF= 48,6 Hz), 6,21 (1H, s, -OH), 6,95 (2H, d,<3>J= 8,4 Hz), 7,34 (2H, d,<3>J= 8,6 Hz), 7,84 (1H, dd,<3>J= 9,0 Hz, 4J = 2,0 Hz), 7,93 (1H, bred s), 8,03 (1H, d,<3>J= 9,0 Hz), 10,14 (1H, s, -NHCO-). 3-(4-fluoromethylphenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitroenyl)propionamide A solution of 2-hydroxy-3-(4-hydroxymethylphenoxy)-2-methyl-N-( 3-Methyl-4-nitrophenyl)propionamide (prepared as described in Example 70, 950 mg, 0.002636 mol) in 6.5 mL of dry methylene chloride was treated with Deoxo-Fluor® (875 mg, 0.003954 mol) in 3 ml of methylene chloride at -76°C. The solution was stirred at -10°C for 3 hours. A saturated NaHCO 3 solution was added and the mixture was extracted with dichloromethane. The combined extracts were washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (9:1-5:5). Crystallization from dichloromethane/heptane gave the desired compound. <]>H NMR (400 MHz, DMSO-c/tf): 1.44 (3H,s), 2.53 (3H,s), 4.00 (1H, d,<2>Jgem= 9.7 Hz), 4.24 (1H, d,<2>Jgem= 9.6 Hz), 5.30 (2H, d,<2>JHF= 48.6 Hz) , 6.21 (1H, s, -OH), 6.95 (2H, d,<3>J= 8.4 Hz), 7.34 (2H, d,<3>J= 8.6 Hz) , 7.84 (1H, dd,<3>J= 9.0 Hz, 4J = 2.0 Hz), 7.93 (1H, wide s), 8.03 (1H, d,<3>J= 9.0 Hz), 10.14 (1H, s, -NHCO-).

Eksempel 84. Example 84.

3-[4-(2-brometyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-[4-(2-bromomethyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) 4-(2-brometyl)fenol a) 4-(2-bromomethyl)phenol

(4-hydroksyfenetyl)alkohol (1,50 g, 0,01086 mol) og 10 ml 48 vekt& (4-Hydroxyphenethyl)alcohol (1.50 g, 0.01086 mol) and 10 ml of 48 wt.

hydrobromsyre ble holdt på 100°C i 1,5 timer. Etter avkjøling ble reaksjonsblandingen helt over i vann og ekstrahert med etylacetat. Ekstraktene ble vasket med vann, tørket og konsentrert i vakuum til et råprodukt. Rensing ved flashkromatografi (heptan/etylacetat 9:1) ga et rent produkt (2,01 g, 92%).<]>H NMR (400 MHz, DMSO-tftf): 2,99 (2H, t,<3>J= 7,4 Hz), 3,63 (2H, t,<3>J= 7,4 Hz), 6,68 (2H, d,<3>J=8,5 Hz), 7,05 (2H, d,<3>J= 8,3 Hz), 9,24 (1H, s, -OH). hydrobromic acid was held at 100°C for 1.5 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated in vacuo to a crude product. Purification by flash chromatography (heptane/ethyl acetate 9:1) gave a pure product (2.01 g, 92%).<]>H NMR (400 MHz, DMSO-tftf): 2.99 (2H, t,<3> J= 7.4 Hz), 3.63 (2H, t,<3>J= 7.4 Hz), 6.68 (2H, d,<3>J=8.5 Hz), 7.05 ( 2H, d,<3>J = 8.3 Hz), 9.24 (1H, s, -OH).

b) 3-[4-(2-brometyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid b) 3-[4-(2-bromomethyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-[4-(2-brometyl)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 4- 3-[4-(2-bromomethyl)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 4-

(2-brometyl)fenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Rensing ved flashkromatografi på silikagel (diklormetan/metanol 99:1 eller toluen/metanol 99,5:0,5) ga et urent produkt. Den endelige rensingen ble utført ved hjelp av preparativ HPLC.<]>H NMR (400 MHz, CDC13): 1,59 (3H, s), 2,63 (3H, s), 3,10 (2H, t, 3J = 7,5 Hz), omtrent 3,5 (-OH), 3,52 (2H, t,<3>J= 7,4 Hz), 3,98 (1H, d,<2>Jgem=9,0 Hz), 4,44 (1H, d,<2>Jgem=9,0 Hz), 6,87 (2H, d,<3>J=8,6 Hz), 7,13 (2H, d,<3>J= 8,6 Hz), 7,57 (1H, dd,<3>J= 8,9 Hz,<4>J= 2,3 Hz), 7,65 (1H, d,<4>J= 2,2 Hz), 8,06 (1H, d,<3>J= 8,9 Hz), 9,00 (1H, s, -NHCO-). (2-bromomethyl)phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. Purification by flash chromatography on silica gel (dichloromethane/methanol 99:1 or toluene/methanol 99.5:0.5) gave an impure product. Final purification was performed by preparative HPLC. <]>H NMR (400 MHz, CDCl 3 ): 1.59 (3H, s), 2.63 (3H, s), 3.10 (2H, t, 3J = 7.5 Hz), about 3.5 (-OH), 3.52 (2H, t,<3>J= 7.4 Hz), 3.98 (1H, d,<2>Jgem=9, 0 Hz), 4.44 (1H, d,<2>Jgem=9.0 Hz), 6.87 (2H, d,<3>J=8.6 Hz), 7.13 (2H, d, <3>J= 8.6 Hz), 7.57 (1H, dd,<3>J= 8.9 Hz,<4>J= 2.3 Hz), 7.65 (1H, d,<4 >J= 2.2 Hz), 8.06 (1H, d,<3>J= 8.9 Hz), 9.00 (1H, s, -NHCO-).

Eksempel 85. Example 85.

2-hydroksy-3-[4-(2-jodetyl)fenoksy]-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 2-hydroxy-3-[4-(2-iodoethyl)phenoxy]-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) 4-(2-jodetyl)fenol a) 4-(2-iodoethyl)phenol

Trifenylfosfin (1,57 g, 0,006 mol) og imidazol (0,41 g, 0,006 mol) ble tilsatt 20 ml Triphenylphosphine (1.57 g, 0.006 mol) and imidazole (0.41 g, 0.006 mol) were added to 20 mL

tørr diklormetan. Da imidazolen var løst, ble det tilsatt jod (1,52 g, 0,006 mol). Etter utfelling av imidazolen ble det tilsatt hydrojodid (4-hydroksyfenetyl)alkohol (0,69 g, 0,005 mol). Blandingen ble så rørt ved romtemperatur i 4 timer. Vann ble tilsatt, og blandingen ble ekstrahert med diklormetan. Ekstraktene ble vasket med vann, tørket og konsentrert i vakuum, noe som ga et råprodukt. Rensing ble utført ved flashkromatografi (heptan/etylacetat som et gradientelueringsmiddel 9:1-6:4), noe som ga et rent produkt.<]>H NMR (400 MHz, DMSO- d6) : 2,99 (2H, t,<3>J= 7,6 Hz), 3,38 (2H, t,<3>J= 7,6 Hz), 6,68 (2H, d,<3>J= 8,5 Hz), 7,03 (2H, d,<3>J= 8,5 Hz), 9,24 (1H, s, -OH). dry dichloromethane. When the imidazole was dissolved, iodine (1.52 g, 0.006 mol) was added. After precipitation of the imidazole, hydroiodide (4-hydroxyphenethyl)alcohol (0.69 g, 0.005 mol) was added. The mixture was then stirred at room temperature for 4 hours. Water was added and the mixture was extracted with dichloromethane. The extracts were washed with water, dried and concentrated in vacuo to give a crude product. Purification was carried out by flash chromatography (heptane/ethyl acetate as a gradient eluent 9:1-6:4), which gave a pure product. <]>H NMR (400 MHz, DMSO- d6 ) : 2.99 (2H, t, <3>J= 7.6 Hz), 3.38 (2H, t,<3>J= 7.6 Hz), 6.68 (2H, d,<3>J= 8.5 Hz), 7 .03 (2H, d,<3>J = 8.5 Hz), 9.24 (1H, s, -OH).

b) 2-hydroksy-3-[4-(2-jodetyl)fenoksy]-2-metyl-N-(3-metyl-4-nitrofenyl)-propionamid b) 2-hydroxy-3-[4-(2-iodoethyl)phenoxy]-2-methyl-N-(3-methyl-4-nitrophenyl)-propionamide

2-hydroksy-3-[4-(2-jodetyl)fenoksy]-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 4-(2-jodetyl)fenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Rensing ved flashkromatografi på silikagel (heptan/etylacetat som et gradientelueringsmiddel 9:1-6:4) ga et urent produkt. Den avsluttende rensingen ble utført ved preparativ HPLC.<!>H NMR (400 MHz, DMSO- d6) : 1,43 (3H, s), 2,53 (3H, s), 3,03 (2H, t,<3>J = 7,4 Hz), 3,40 (2H, t, 3J = 7,4 Hz), 3,96 (1H, d,<2>Jgem=9,6 Hz), 4,19 (1H, d, 2Jgem=9,6 Hz), 6,17 (1H, s, -OH), 6,85 (2H, d,<3>J= 8,6 Hz), 7,14 (2H, d,<3>J= 8,6 Hz), 7,88 (1H, dd,<3>J= 9,0 Hz,<4>J= 2,2 Hz), 7,93 (1H, d,<4>J= 2,0 Hz), 8,03 (1H, d,<3>J= 9,0 Hz), 10,13 (1H, s, -NHCO-). 2-Hydroxy-3-[4-(2-iodoethyl)phenoxy]-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 4-(2-iodoethyl )phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. Purification by flash chromatography on silica gel (heptane/ethyl acetate as a gradient eluent 9:1-6:4) gave an impure product. The final purification was performed by preparative HPLC. <!>H NMR (400 MHz, DMSO- d6 ) : 1.43 (3H, s), 2.53 (3H, s), 3.03 (2H, t,< 3>J = 7.4 Hz), 3.40 (2H, t, 3J = 7.4 Hz), 3.96 (1H, d,<2>Jgem=9.6 Hz), 4.19 (1H , d, 2Jgem=9.6 Hz), 6.17 (1H, s, -OH), 6.85 (2H, d,<3>J= 8.6 Hz), 7.14 (2H, d, <3>J= 8.6 Hz), 7.88 (1H, dd,<3>J= 9.0 Hz,<4>J= 2.2 Hz), 7.93 (1H, d,<4 >J= 2.0 Hz), 8.03 (1H, d,<3>J= 9.0 Hz), 10.13 (1H, s, -NHCO-).

Eksempel 86. Example 86.

3-[4-(2-brometoksy)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-[4-(2-bromomethoxy)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) 4-(2-brometoksy)fenol a) 4-(2-bromoethoxy)phenol

Kaliumkarbonat (7,53 g, 0,05488 mol) ble tilsatt 50 ml av en acetonløsning av Potassium carbonate (7.53 g, 0.05488 mol) was added to 50 mL of an acetone solution of

hydrokinon (2,00 g, 0,01816 mol) og 1,2-dibrometan (3,39 g, 0,01805 mol). Blandingen ble kokt under tilbakeløp i 6 timer under nitrogen. Den resulterende blandingen ble filtrert, vann ble tilsatt og pH ble justert til 2-3. Blandingen ble så ekstrahert med etylacetat, hvoretter ekstraktene ble vasket med vann, tørket over vannfritt natriumsulfat, filtrert og fordampet. Råproduktet ble renset ved flashkromatografi på silikagel ved å bruke heptan/etylacetat som et hydroquinone (2.00 g, 0.01816 mol) and 1,2-dibromoethane (3.39 g, 0.01805 mol). The mixture was refluxed for 6 hours under nitrogen. The resulting mixture was filtered, water was added and the pH was adjusted to 2-3. The mixture was then extracted with ethyl acetate, after which the extracts were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using heptane/ethyl acetate as e.t

gradientelueringsmiddel (95:5-70:30), noe som ga den rene forønskede forbindelsen som hvite krystaller.<]>H NMR (400 MHz, DMSO-^): 3,74 (2H, t,<3>J= 5,5 Hz), 4,19 (2H, t, 3J = 5,5 Hz), 6,67 (2H, d,<3>J= 8,9 Hz), 6,78 (2H, d,<3>J= 8,9 Hz), 8,95 (1H, s, gradient eluent (95:5-70:30), which gave the pure desired compound as white crystals.<]>H NMR (400 MHz, DMSO-^): 3.74 (2H, t,<3>J= 5 .5 Hz), 4.19 (2H, t, 3J = 5.5 Hz), 6.67 (2H, d,<3>J= 8.9 Hz), 6.78 (2H, d,<3 >J= 8.9 Hz), 8.95 (1H, s,

-OH). -OH).

b) 3-[4-(2-brometoksy)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid b) 3-[4-(2-bromomethoxy)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-[4-(2-brometoksy)fenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 4-(2-brometoksy)fenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi på silikagel ved å bruke heptan/etylacetat som et gradientelueringsmiddel (9:1-6:4). Den forønskede forbindelsen ble utkrystallisert fra diklormetan, smeltepunkt 135-138°C.<]>H NMR (400 MHz, DMSO-tftf): 1,42 (3H, s), 2,53 (3H, s), 3,75 (2H, t,<3>J= 5,5 Hz), 3,92 (1H, d,<2>Jgem=9,6 Hz), 4,15 (1H, d,<2>Jgem=9,5 Hz), 4,23 (2H, t,<3>J=5,4 Hz), 6,16 (1H, bred s, -OH), 6,86 (4H, s), 7,88 (1H, dd, 3J = 9,0 Hz,<4>J= 2,2 Hz), 7,92 (1H, d,<4>J= 1,7 Hz), 8,04 (1H, d,<3>J= 8,9 Hz), 10,12 (1H, bred s, -NHCO-). 3-[4-(2-bromomethoxy)phenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 4-(2-bromomethoxy )phenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography on silica gel using heptane/ethyl acetate as a gradient eluent (9:1-6:4). The desired compound was crystallized from dichloromethane, mp 135-138°C. <]>H NMR (400 MHz, DMSO-tftf): 1.42 (3H, s), 2.53 (3H, s), 3.75 (2H, t,<3>J= 5.5 Hz), 3.92 (1H, d,<2>Jgem=9.6 Hz), 4.15 (1H, d,<2>Jgem=9, 5 Hz), 4.23 (2H, t,<3>J=5.4 Hz), 6.16 (1H, broad s, -OH), 6.86 (4H, s), 7.88 (1H , dd, 3J = 9.0 Hz,<4>J= 2.2 Hz), 7.92 (1H, d,<4>J= 1.7 Hz), 8.04 (1H, d,<3 >J= 8.9 Hz), 10.12 (1H, broad s, -NHCO-).

Eksempel 87. Example 87.

3-[4-(2-kloretyl)-3-fluorfenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-[4-(2-chloroethyl)-3-fluorophenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) 3-fluor-4-(2-hydroksyetyl)fenol a) 3-fluoro-4-(2-hydroxyethyl)phenol

Boran-tetrahydrofurankompleks (1,0 M løsning i THF, 22 ml, 0,02200 mol) ble Borane-tetrahydrofuran complex (1.0 M solution in THF, 22 mL, 0.02200 mol) was

dråpevis tilsatt en løsning av (2-fluor-4-hydroksyfenyl)eddiksyre (P.C. Belanger et al. EP 106565 Bl, 2,27 g, 0,01145 mol) i 40 ml tørr THF i en nitrogenatmosfære ved -10°C, og den resulterende løsingen ble rørt i 2 timer ved -10°C. Vann ble tilsatt og produktet ble ekstrahert over i etylacetat. De samlede ekstraktene ble added dropwise a solution of (2-fluoro-4-hydroxyphenyl)acetic acid (P.C. Belanger et al. EP 106565 Bl, 2.27 g, 0.01145 mol) in 40 ml of dry THF in a nitrogen atmosphere at -10°C, and the resulting solution was stirred for 2 hours at -10°C. Water was added and the product was extracted into ethyl acetate. The combined extracts were

vasket med vann, tørket og fordampet i vakuum, noe som ga produktet.<]>H NMR (400 MHz, DMSO-tftf): 2,62 (2H, t, 3J = 7,2 Hz), 3,50 (2H, m), 4,63 (1H, t,<3>J= 5,4 Hz, -CH2OH), 6,47-6,53 (2H, m), 7,06 (1H, t,<3>JHh=<4>Jhf=8, 5 Hz), 9,60 (1H, s, ArOH). washed with water, dried and evaporated in vacuo to give the product. <]>H NMR (400 MHz, DMSO-tftf): 2.62 (2H, t, 3J = 7.2 Hz), 3.50 (2H , m), 4.63 (1H, t,<3>J= 5.4 Hz, -CH2OH), 6.47-6.53 (2H, m), 7.06 (1H, t,<3> JHh=<4>Jhf=8.5Hz), 9.60 (1H, s, ArOH).

b) 4-(2-kloretyl)-3-fluorfenol b) 4-(2-chloroethyl)-3-fluorophenol

4-(2-kloretyl)-3-fluorfenol ble fremstilt som beskrevet i eksempel 74a ved å starte 4-(2-Chloroethyl)-3-fluorophenol was prepared as described in Example 74a by starting

fra 3-fluor-4-(2-hydroksyetyl)fenol. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som elueringsmiddel (85:15).<!>H NMR (400 MHz, DMSO-^): 2,93 (2H, t,<3>J= 7,1 Hz), 3,74 (2H, t,<3>J= 7,1 Hz), 6,51-6,57 (2H, m), 7,13 (1H, t, 3Jhh=4Jhf=S, 1 Hz), 9,75 (1H, s, ArOH). from 3-fluoro-4-(2-hydroxyethyl)phenol. The crude product was purified by flash chromatography using heptane/ethyl acetate as eluent (85:15).<!>H NMR (400 MHz, DMSO-^): 2.93 (2H, t,<3>J= 7.1 Hz ), 3.74 (2H, t,<3>J= 7.1 Hz), 6.51-6.57 (2H, m), 7.13 (1H, t, 3Jhh=4Jhf=S, 1 Hz ), 9.75 (1H, s, ArOH).

c) 3-[4-(2-kloretyl)-3-fluorfenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid c) 3-[4-(2-chloroethyl)-3-fluorophenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-[4-(2-kloretyl)-3-fluorfenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 4-(2-kloretyl)-3-fluorfenol og 2-metyloksiran-2-karboksylsyre (3-metyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke diklormetan som elueringsmiddel. Produktet ble utkrystallisert fra diklormetan/heptan: Smeltepunkt 77-79°C.<]>H NMR (400 MHz, DMSO-</«$): 1,43 (3H, s), 2,53 (3H, s), 2,97 (2H, t,<3>J= 6,9 Hz), 3,76 (2H, t,<3>J= 7,0 Hz), 3,98 (1H, d,<2>Jgem= 9,8 Hz), 4,23 (1H, d,<2>Jgem= 9,7 Hz), omtrent 6,2 (1H, bred s, -OH), 6,73 (1H, dd,<3>J= 8,5 Hz,<4>J= 2,4 Hz), 6,80 (1H, dd, 3JHF = 12,1 Hz, 4JHh = 2,5 Hz), 7,24 (1H, t,<3>Jhh=<4>Jhf<=>8,& Hz), 7,87 (1H, dd,<3>J= 9,0 Hz,<4>J=2,3 Hz), 7,92 (1H, d,<4>J = 2,0 Hz), 8,03 (1H, d,<3>J= 9,0 Hz), omtrent 10,1 (1H, bred s, -NHCO-). 3-[4-(2-chloroethyl)-3-fluorophenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c by starting from 4-( 2-chloroethyl)-3-fluorophenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using dichloromethane as eluent. The product was crystallized from dichloromethane/heptane: Melting point 77-79°C. <]>H NMR (400 MHz, DMSO-</«$): 1.43 (3H, s), 2.53 (3H, s), 2.97 (2H, t,<3>J= 6.9 Hz), 3.76 (2H, t,<3>J= 7.0 Hz), 3.98 (1H, d,<2>Jgem = 9.8 Hz), 4.23 (1H, d,<2>Jgem= 9.7 Hz), about 6.2 (1H, broad s, -OH), 6.73 (1H, dd,<3 >J= 8.5 Hz,<4>J= 2.4 Hz), 6.80 (1H, dd, 3JHF = 12.1 Hz, 4JHh = 2.5 Hz), 7.24 (1H, t, <3>Jhh=<4>Jhf<=>8,& Hz), 7.87 (1H, dd,<3>J= 9.0 Hz,<4>J=2.3 Hz), 7.92 (1H, d,<4>J = 2.0 Hz), 8.03 (1H, d,<3>J= 9.0 Hz), about 10.1 (1H, broad s, -NHCO-).

Eksempel 88. Example 88.

3-(4-cyanofenoksy)-N-(3-etyl-4-nitrofenyl)-2-hydroksy-2-metylpropionamid 3-(4-cyanophenoxy)-N-(3-ethyl-4-nitrophenyl)-2-hydroxy-2-methylpropionamide

a) N-(3-etyl-4-nitrofenyl)-2-metylakrylamid a) N-(3-ethyl-4-nitrophenyl)-2-methylacrylamide

N-(3-etyl-4-nitrofenyl)-2-metylakrylamid ble fremstilt som beskrevet i eksempel la N-(3-ethyl-4-nitrophenyl)-2-methylacrylamide was prepared as described in Example 1a

ved å starte fra 3-etyl-4-nitrofenylamin (W. Pfleiderer et al. US 2002/0146737 Al) og metakryloylklorid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat (9:1) som elueringsmiddel.<]>H NMR (400 MHz, DMSO-c/tf): 1,22 (3H, t, 3J = 7,4 Hz), 1,97 (3H, s), 2,87 (2H, q,<3>J= 7,4 Hz), 5,62 (1H, s), 5,88 (1H, s), 7,81 (1H, dd,<3>J= 8,9 Hz, 4J = 2,3 Hz), 7,83 (1H, d,<4>J= 2,2 Hz), 8,00 (1H, d,<3>J = 8,8 Hz), 10,21 (1H, s, -NHCO-). by starting from 3-ethyl-4-nitrophenylamine (W. Pfleiderer et al. US 2002/0146737 A1) and methacryloyl chloride. The crude product was purified by flash chromatography using heptane/ethyl acetate (9:1) as eluent. <]>H NMR (400 MHz, DMSO-c/tf): 1.22 (3H, t, 3J = 7.4 Hz) , 1.97 (3H, s), 2.87 (2H, q,<3>J= 7.4 Hz), 5.62 (1H, s), 5.88 (1H, s), 7.81 (1H, dd,<3>J= 8.9 Hz, 4J = 2.3 Hz), 7.83 (1H, d,<4>J= 2.2 Hz), 8.00 (1H, d, <3>J = 8.8 Hz), 10.21 (1H, s, -NHCO-).

b) 2-metyloksiran-2-karboksylsyre (3-etyl-4-nitrofenyl)amid 3-klorperoksybenzosyre (14,71 g, 0,08524 mol) ble i porsjoner tilsatt en kokende b) 2-methyloxirane-2-carboxylic acid (3-ethyl-4-nitrophenyl)amide 3-chloroperoxybenzoic acid (14.71 g, 0.08524 mol) was added in portions to a boiling

løsning av N-(3-etyl-4-nitrofenyl)-2-metylakrylamid (6,68 g, 0,02852 mol) og 149 solution of N-(3-ethyl-4-nitrophenyl)-2-methylacrylamide (6.68 g, 0.02852 mol) and 149

mg 2,6-di-ter/-butyl-4-metylfenol i 180 ml diklormetan. Etter koking med tilbakeløp i 5 timer ble reaksjonsblandingen hensatt for avkjøling til romtemperatur. Den utfelte 3-klorbenzosyren ble frafiltrert og filtratet ble ekstrahert tre ganger med 1 M Na2CC«3 og vann. Den organiske fasen ble tørket over natriumsulfat, filtrert og fordampet. Råproduktet ble renset ved flashkromatografi ved å bruke diklormetan som elueringsmiddel.<]>H NMR (400 MHz, DMSO-^): 1,20 (3H, t,<3>J= 7,4 Hz), 1,55 (3H, s), 2,84 (2H, q, 3J = 7,4 Hz), 2,99 (1H, d,<2>Jgem= 5,1 Hz), 3,06 (1H, d,<2>Jgem=5,1 Hz), 7,81 (1H, dd, 3J = 9,0 Hz, 4J = 2,3 Hz), 7,85 (1H, d,<4>J= 2,2 Hz), 7,97 (1H, d,<3>J= 9,0 Hz), 9,88 (1H, s, -NHCO-). mg of 2,6-di-tert/-butyl-4-methylphenol in 180 ml of dichloromethane. After refluxing for 5 hours, the reaction mixture was allowed to cool to room temperature. The precipitated 3-chlorobenzoic acid was filtered off and the filtrate was extracted three times with 1 M Na 2 CC 3 and water. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography using dichloromethane as eluent.<]>H NMR (400 MHz, DMSO-^): 1.20 (3H, t,<3>J= 7.4 Hz), 1.55 (3H , s), 2.84 (2H, q, 3J = 7.4 Hz), 2.99 (1H, d,<2>Jgem= 5.1 Hz), 3.06 (1H, d,<2> Jgem=5.1 Hz), 7.81 (1H, dd, 3J = 9.0 Hz, 4J = 2.3 Hz), 7.85 (1H, d,<4>J= 2.2 Hz), 7.97 (1H, d,<3>J = 9.0 Hz), 9.88 (1H, s, -NHCO-).

c) 3-(4-cyanofenoksy)-N-(3-etyl-4-nitrofenyl)-2-hydroksy-2-metylpropionamid 3-(4-cyanofenoksy)-N-(3-etyl-4-nitrofenyl)-2-hydroksy-2-metylpropionamid ble c) 3-(4-cyanophenoxy)-N-(3-ethyl-4-nitrophenyl)-2-hydroxy-2-methylpropionamide 3-(4-cyanophenoxy)-N-(3-ethyl-4-nitrophenyl)-2 -hydroxy-2-methylpropionamide was

fremstilt som beskrevet i eksempel lc ved å starte fra 4-cyanofenol og 2-metyloksiran-2-karboksylsyre (3-etyl-4-nitrofenyl)amid. Råproduktet ble renset ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel (9:1-6:4).<]>H NMR (400 MHz, DMSO-^): 1,21 (3H, t,<3>J= 7,4 Hz), 1,45 (3H, s), 2,86 (2H, q, 3J = 7,5 Hz), 4,09 (1H, d,<2>Jgem=9,9 Hz), 4,33 (1H, d,<2>Jgem=9,8 Hz), 6,26 (1H, bred s, -OH), 7,11 (2H, d,<3>J= 8,8 Hz), 7,74 (2H, d,<3>J= 8,7 Hz), 7,89 (1H, d,<3>J= 9,1 Hz), 7,94 (1H, s), 7,98 (1H, d,<3>J= 8,9 Hz), 10,17 (1H, bred s, prepared as described in example 1c by starting from 4-cyanophenol and 2-methyloxirane-2-carboxylic acid (3-ethyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (9:1-6:4).<]>H NMR (400 MHz, DMSO-^): 1.21 (3H, t,<3>J = 7.4 Hz), 1.45 (3H, s), 2.86 (2H, q, 3J = 7.5 Hz), 4.09 (1H, d,<2>Jgem=9.9 Hz) , 4.33 (1H, d,<2>Jgem=9.8 Hz), 6.26 (1H, broad s, -OH), 7.11 (2H, d,<3>J= 8.8 Hz ), 7.74 (2H, d,<3>J= 8.7 Hz), 7.89 (1H, d,<3>J= 9.1 Hz), 7.94 (1H, s), 7 .98 (1H, d,<3>J= 8.9 Hz), 10.17 (1H, wide s,

-NHCO-). -NHCO-).

Eksempel 89. Example 89.

3-(4-cyano-3-fluorfenoksy)-N-(3-etyl-4-nitrofenyl)-2-hydroksy-2-metylpropionamid 3-(4-cyano-3-fluorophenoxy)-N-(3-ethyl-4-nitrophenyl)-2-hydroxy-2-methylpropionamide

3- (4-cyano-3-fluorfenoksy)-N-(3-etyl-4-nitrofenyl)-2-hydroksy-2-metylpropionamid ble fremstilt som beskrevet i eksempel lc ved å starte fra 2-fluor-4- hydroksybenzonitril og 2-metyloksiran-2-karboksylsyre (3-etyl-4-nitrofenyl)amid. Råproduktet ble renset to ganger ved flashkromatografi ved å bruke heptan/etylacetat som et gradientelueringsmiddel, mens den avsluttende rensingen ble utført ved preparativ HPLC.<]>H NMR (400 MHz, DMSO-^): 1,21 (3H, t, 3J = 7,4 Hz), 1,44 (3H, s), 2,86 (2H, q,<3>J= 7,5 Hz), 4,12 (1H, d,<2>Jgem= 10,0 Hz), 4,38 (1H, d,<2>Jgem= 10,0 Hz), 6,30 (1H, bred s, -OH), 6,96 (1H, dd,<3>J= 8,7 Hz,<4>J= 2,2 Hz), 7,18 (1H, dd, 3JHF = 11,8 Hz,<4>JHH= 2,3 Hz), 7,80 (1H, t,<3>JHH= 4JHF = 8,3 Hz), 7,89 (1H, dd,<3>J= 8,9 Hz,<4>J= 2,2 Hz), 7,95 (1H, d,<4>J= 2,3 Hz), 7,98 (1H, d,<3>J= 9,0 Hz), 10,18 (1H, s, -NHCO-). 3-(4-cyano-3-fluorophenoxy)-N-(3-ethyl-4-nitrophenyl)-2-hydroxy-2-methylpropionamide was prepared as described in Example 1c by starting from 2-fluoro-4-hydroxybenzonitrile and 2-Methyloxirane-2-carboxylic acid (3-ethyl-4-nitrophenyl)amide. The crude product was purified twice by flash chromatography using heptane/ethyl acetate as a gradient eluent, while the final purification was performed by preparative HPLC. <]>H NMR (400 MHz, DMSO-^): 1.21 (3H, t, 3J = 7.4 Hz), 1.44 (3H, s), 2.86 (2H, q,<3>J= 7.5 Hz), 4.12 (1H, d,<2>Jgem= 10, 0 Hz), 4.38 (1H, d,<2>Jgem= 10.0 Hz), 6.30 (1H, broad s, -OH), 6.96 (1H, dd,<3>J= 8 ,7 Hz,<4>J= 2.2 Hz), 7.18 (1H, dd, 3JHF = 11.8 Hz,<4>JHH= 2.3 Hz), 7.80 (1H, t,< 3>JHH= 4JHF = 8.3 Hz), 7.89 (1H, dd,<3>J= 8.9 Hz,<4>J= 2.2 Hz), 7.95 (1H, d,< 4>J= 2.3 Hz), 7.98 (1H, d,<3>J= 9.0 Hz), 10.18 (1H, s, -NHCO-).

Eksempel 90. Example 90.

2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(3-metyl-4-nitrofenylamino)propionamid 2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(3-methyl-4-nitrophenylamino)propionamide

2- hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)-3-(3-metyl-4-nitrofenylamino)propionamid ble fremstilt som beskrevet i eksempel 52 ved å starte fra l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid. 'H-NMR (400 MHz, DMSO-de): 1,62 (3H, s), 2,54 (3H, s), 2,60 (3H, s), 3,41 (1H, dd, J = 13,6 Hz, J = 6,0 Hz), 3,83 (1H, dd, J = 13,6 Hz, J = 6,9 Hz), 4,81 (1H, t, J = 6,3 Hz), 6,46 (1H, d, 2,1 Hz), 6,51 (1H, dd, J = 9,1 Hz, J = 2,5 Hz), 7,54 (1H, dd, J = 8,9 Hz, J = 2,2 Hz), 7,59 (1H, d, J = 1,8 Hz), 7,97 (1H, d, J = 9,0 Hz), 8,02 (1H, d, J = 8,9 Hz), 8,96 (1H, s). 2-Hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(3-methyl-4-nitrophenylamino)propionamide was prepared as described in Example 52 starting from 1,2-epoxy-2 -methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide. 1H-NMR (400 MHz, DMSO-de): 1.62 (3H, s), 2.54 (3H, s), 2.60 (3H, s), 3.41 (1H, dd, J = 13.6 Hz, J = 6.0 Hz), 3.83 (1H, dd, J = 13.6 Hz, J = 6.9 Hz), 4.81 (1H, t, J = 6.3 Hz ), 6.46 (1H, d, 2.1 Hz), 6.51 (1H, dd, J = 9.1 Hz, J = 2.5 Hz), 7.54 (1H, dd, J = 8 .9 Hz, J = 2.2 Hz), 7.59 (1H, d, J = 1.8 Hz), 7.97 (1H, d, J = 9.0 Hz), 8.02 (1H, d, J = 8.9 Hz), 8.96 (1H, s).

Eksempel 91. Example 91.

3- [4-(3,3-dimetylureido)-3-fluorfenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-[4-(3,3-dimethylureido)-3-fluorophenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) 3-(2-fluor-4-hydroksyfenyl)-1,1 -dimetylurea a) 3-(2-fluoro-4-hydroxyphenyl)-1,1-dimethylurea

4- amino-3-fluorfenol (0,47 g, 3,0 mmol) ble løst i 15 ml tørr THF under nitrogen, 4-amino-3-fluorophenol (0.47 g, 3.0 mmol) was dissolved in 15 mL of dry THF under nitrogen,

hvoretter løsningen ble avkjølt til 0°C og dråpevis tilsatt N,N'-dimetylkarbamylklorid (0,28 ml, 3,0 mmol). Reaksjonsblandingen ble hensatt for oppvarming til romtemperatur og så kokt under tilbakeløp i 4 timer. Blandingen ble igjen avkjølt til 0°C og så tilsatt 0,2 ml vann og deretter filtrert. Moderluten ble fordampet, løst i 25 ml etylacetat, vasket med 10 ml IM Na2C03, 10 ml vann og så tørket over natriumsulfat. Produktet ble renset ved kromatografi (EtOAc:toluen 1:1).<!>H NMR (400 MHz, DMSO-de): 2,88 (6H, s), 6,48-6,58 (2H, m), 7,02-7,10 (1H, m), 9,65 (1H, s). after which the solution was cooled to 0°C and N,N'-dimethylcarbamyl chloride (0.28 ml, 3.0 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and then refluxed for 4 hours. The mixture was again cooled to 0°C and then 0.2 ml of water was added and then filtered. The mother liquor was evaporated, dissolved in 25 ml ethyl acetate, washed with 10 ml 1M Na 2 CO 3 , 10 ml water and then dried over sodium sulfate. The product was purified by chromatography (EtOAc:toluene 1:1).<!>H NMR (400 MHz, DMSO-de): 2.88 (6H, s), 6.48-6.58 (2H, m), 7.02-7.10 (1H, m), 9.65 (1H, s).

b) 3-[4-(3,3-dimetylureido)-3-fluorfenoksy]-2-hydroksy-2-metyl-N-(3-mety 1-4-nitrofenyl)propionamid 3 - [4-(3,3 -dimety lureido)-3 - fluorfenoksy] -2 -hydroksy-2- metyl-N-(3 -mety 1-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 3-(2-fluor-4-hydroksyfenyl)-l,l-dimetylurea og l,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-de): 1,42 (3H, s), 2,53 (3H, s), 2,88 (6H, s), 3,96 (1H, d, J = 9,7 Hz), 4,21 (1H, d, J = 9,7 Hz), 6,25 (1H, s), 6,68 (1H, dd, J = 8,8 Hz, J = 2,4 Hz), 6,81 (1H, dd, J = 12,3 Hz, J = 2,7 Hz), 7,10-7,30 (1H, m), 7,86 (1H, s), 7,88 (1H, dd, J = 9,1 Hz, J = 2,2 Hz), 7,93 (1H, d, J = 1,9 Hz), 8,04 (1H, d, J = 9,0 Hz), 10,15 (1H, s). b) 3-[4-(3,3-dimethylureido)-3-fluorophenoxy]-2-hydroxy-2-methyl-N-(3-methyl 1-4-nitrophenyl)propionamide 3 - [4-(3,3 -dimethyl lureido)-3-fluorophenoxy]-2-hydroxy-2-methyl-N-(3-methyl 1-4-nitrophenyl)propionamide was prepared as described in Example 1 by starting from 3-(2-fluoro-4 -hydroxyphenyl)-1,1-dimethylurea and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.<]>H NMR (400 MHz, DMSO-de): 1.42 (3H, s), 2.53 (3H, s), 2.88 (6H, s), 3.96 (1H, d, J = 9.7 Hz), 4.21 (1H, d , J = 9.7 Hz), 6.25 (1H, s), 6.68 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.81 (1H, dd, J = 12.3 Hz, J = 2.7 Hz), 7.10-7.30 (1H, m), 7.86 (1H, s), 7.88 (1H, dd, J = 9.1 Hz , J = 2.2 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 10.15 (1H, s).

Eksempel 92. Example 92.

3- (3-fluor-4-metansulfonylaminofenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-(3-Fluoro-4-methanesulfonylaminophenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) N-(2-fluoro-4-hydroksyfenyl)metansulfonamid a) N-(2-fluoro-4-hydroxyphenyl)methanesulfonamide

4- amino-3-fluorfenol (0,254 g, 2,0 mmol) ble løst i 10 ml tørr pyridin under 4-amino-3-fluorophenol (0.254 g, 2.0 mmol) was dissolved in 10 mL of dry pyridine under

nitrogen og avkjølt til 0°C. Metansulfonylklorid (0,17 ml, 2,1 mmol) ble dråpevis tilsatt, hvoretter reaksjonsblandingen ble rørt i tre døgn ved romtemperatur. De flyktige forbindelsene ble fjernet ved fordampning, 25 ml toluen ble tilsatt og blandingen ble så igjen fordampet. Toluenfordampningen ble så gjentatt. Resten ble løst i 25 ml etylacetat, vasket med 20 ml vann og fordampet til tørrhet, noe som ga et rødbrunt fast N-(2-fluoro-4-hydroksyfenyl)metansulfonamid.<]>H NMR (400 MHz, DMSO-de): 2,93 (3H, s), 6,6-6,66 (2H, m), 7,14 (1H, t, J = 9,0 Hz), 9,17 (1H, s), 9,98 (1H, s). nitrogen and cooled to 0°C. Methanesulfonyl chloride (0.17 ml, 2.1 mmol) was added dropwise, after which the reaction mixture was stirred for three days at room temperature. The volatile compounds were removed by evaporation, 25 ml of toluene was added and the mixture was then evaporated again. The toluene evaporation was then repeated. The residue was dissolved in 25 mL of ethyl acetate, washed with 20 mL of water, and evaporated to dryness, yielding a reddish-brown solid N-(2-fluoro-4-hydroxyphenyl)methanesulfonamide.<]>H NMR (400 MHz, DMSO-de) : 2.93 (3H, s), 6.6-6.66 (2H, m), 7.14 (1H, t, J = 9.0 Hz), 9.17 (1H, s), 9, 98 (1H, p).

b) 3-(3-fluor-4-metansulfonylaminofenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid b) 3-(3-fluoro-4-methanesulfonylaminophenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

3-(3-fluor-4-metansulfonylaminofenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid ble fremstilt som beskrevet i eksempel 1 ved å starte fra 4-amino-2-fluorfenol og 1,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid.<]>H NMR (400 MHz, DMSO-de): 1,43 (3H, s), 2,53 (3H, s), 2,92 (3H, s), 3,99 (1H, d, J = 9,8 Hz), 4,24 (1H, d, J = 9,8 Hz), 6,25 (1H, s), 6,76 (1H, dd, J = 8,9 Hz, J = 2,0 Hz), 6,93 (1H, dd, J = 12,1 Hz, J = 2,7 Hz), 7,23 (1H, t, J = 9,1 Hz), 7,88 (1H, dd, J = 9,0 Hz, J = 2,2 Hz), 7,93 (1H, d, J = 1,9 Hz), 8,04 (1H, d, J = 9,0 Hz), 9,29 (1H, s), 10,16 (1H, s). 3-(3-Fluoro-4-methanesulfonylaminophenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 4-amino-2-fluorophenol and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide. <]>H NMR (400 MHz, DMSO-de): 1.43 (3H, s), 2.53 (3H, s), 2.92 (3H, s), 3.99 (1H, d, J = 9.8 Hz), 4.24 (1H, d, J = 9.8 Hz), 6.25 (1H, s), 6.76 (1H, dd, J = 8.9 Hz, J = 2.0 Hz), 6.93 (1H, dd, J = 12.1 Hz, J = 2 .7 Hz), 7.23 (1H, t, J = 9.1 Hz), 7.88 (1H, dd, J = 9.0 Hz, J = 2.2 Hz), 7.93 (1H, d, J = 1.9 Hz), 8.04 (1H, d, J = 9.0 Hz), 9.29 (1H, s), 10.16 (1H, s).

Eksempel 93. Example 93.

3-[4-(2-aminoacetylamino)-3-fluorfenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid 3-[4-(2-aminoacetylamino)-3-fluorophenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

a) [(2-fluor-4-hydroksyfenylkarbamoyl)karbaminsyre-/er/-butylester Tert-butoksykarbonylaminoeddiksyre (= Boc-glysin) (0,256 g, 2,0 mmol) ble løst i 10 ml metylenklorid under nitrogen og avkjølt til 0°C. DCC (0,412 g, 2,0 mmol) ble tilsatt, hvoretter reaksjonsblandingen ble oppvarmet til romtemperatur. 4-amino-3-fluorfenol (0,350 g, 2,0 mmol) ble tilsatt i 10 ml metylenklorid fulgt av 5 ml THF. Reaksjonsblandingen ble rørt i 2 timer ved romtemperatur, kokt under tilbakeløp i 2 timer og så rørt over natten ved romtemperatur. Blandingen ble så fordampet, resten ble løst i 30 ml etylacetat og noe heptan ble så tilsatt for å få utfelt de restene (DHU) som var dannet fra DCC. Bunnfallet ble frafiltrert og vasket med heptan. Moderluten ble fordampet, løst i 10 ml etylacetat og dråpevis tilsatt 2 ml toluen for å frembringe en utfelling. Etter filtrering ble filtratet fordampet, noe som ga [(2-fluor-4-hydroksyfenylkarbamoyl)karbaminsyre-etr/-butylester.<!>H-NMR (400 MHz, DMSO-d6): 1,39 (9H, s), 3,71 (2H, d, J = 6,0 Hz), 6,52-6,65 (2H, m), 7,00-7,07 (1H, m), 7,41-7,49 (1H, m), 9,34 (1H, s), 9,74 (1H, s). a) [(2-fluoro-4-hydroxyphenylcarbamoyl)carbamic acid-/er/-butyl ester Tert-butoxycarbonylaminoacetic acid (= Boc-glycine) (0.256 g, 2.0 mmol) was dissolved in 10 ml of methylene chloride under nitrogen and cooled to 0° C. DCC (0.412 g, 2.0 mmol) was added, after which the reaction mixture was warmed to room temperature. 4-Amino-3-fluorophenol (0.350 g, 2.0 mmol) was added in 10 mL of methylene chloride followed by 5 mL of THF. The reaction mixture was stirred for 2 hours at room temperature, refluxed for 2 hours and then stirred overnight at room temperature. The mixture was then evaporated, the residue was dissolved in 30 ml of ethyl acetate and some heptane was then added to precipitate the residues (DHU) formed from DCC. The precipitate was filtered off and washed with heptane. The mother liquor was evaporated, dissolved in 10 ml of ethyl acetate and 2 ml of toluene added dropwise to produce a precipitate. After filtration, the filtrate was evaporated to give [(2-fluoro-4-hydroxyphenylcarbamoyl)carbamic acid-etr/-butyl ester.<!>H-NMR (400 MHz, DMSO-d6): 1.39 (9H, s), 3.71 (2H, d, J = 6.0 Hz), 6.52-6.65 (2H, m), 7.00-7.07 (1H, m), 7.41-7.49 ( 1H, m), 9.34 (1H, s), 9.74 (1H, s).

b) ({2-fluor-4-[2-hydroksy-2-(3-metyl-4-nitrofenylkarbamoyl}metyl)karbaminsyre-ter/-butylester b) ({2-Fluoro-4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl}methyl)carbamic acid tert-butyl ester

({2-fluor-4-[2-hydroksy-2-(3-metyl-4-nitrofenylkarbamoyl}metyl)karbaminsyre-ter/-butylester ble fremstilt som beskrevet i eksempel 1 ved å starte fra [(2-fluor-4-hydroksyfenylkarbamoyl)karbaminsyre-terf-butylester og 1,2-epoksy-2-metyl-N-[3-metyl-4-nitrofenyl]-2-propanamid. 'H-NMR (400 MHz, DMSO-d6): 1,39 (9H, s), 1,43 (3H, s), 2,53 (3H, s), 3,73 (2H, d, J = 5,4 Hz), 3,97 (1H, d, J = 9,8 Hz), 4,22 (1H, d, J = 9,8 Hz), 6,24 (1H, s), 6,74 (1H, d, J = 9,3 Hz), 6,89 (1H, d, J = 12,0 Hz), 7,00-7,10 (1H, m), 7,60 (1H, t, J = 8,9 Hz), 7,88 (1H, d, J = 9,0 Hz), 7,93 (1H, s), 8,04 (1H, d, J = 9,0 Hz), 9,46 (1H, s), 10,15 (1H, s). ({2-Fluoro-4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl}methyl)carbamic acid tert butyl ester was prepared as described in Example 1 by starting from [(2-fluoro-4 -hydroxyphenylcarbamoyl)carbamic acid tert-butyl ester and 1,2-epoxy-2-methyl-N-[3-methyl-4-nitrophenyl]-2-propanamide.'H-NMR (400 MHz, DMSO-d6): 1, 39 (9H, s), 1.43 (3H, s), 2.53 (3H, s), 3.73 (2H, d, J = 5.4 Hz), 3.97 (1H, d, J = 9.8 Hz), 4.22 (1H, d, J = 9.8 Hz), 6.24 (1H, s), 6.74 (1H, d, J = 9.3 Hz), 6, 89 (1H, d, J = 12.0 Hz), 7.00-7.10 (1H, m), 7.60 (1H, t, J = 8.9 Hz), 7.88 (1H, d , J = 9.0 Hz), 7.93 (1H, s), 8.04 (1H, d, J = 9.0 Hz), 9.46 (1H, s), 10.15 (1H, s ).

c) 3-[4-(2-aminoacetylamino)-3-fluorfenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid c) 3-[4-(2-aminoacetylamino)-3-fluorophenoxy]-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide

({2-fluor-4-[2-hydroksy-2-(3-metyl-4-nitrofenylkarbamoyl}metyl)karbaminsyre-ter/-butylester (0,160 g, 0,3 mmol) ble løst i 5 ml metylenklorid under nitrogen og så avkjølt til 0°C. 0,5 ml trifluoreddiksyre ble dråpevis tilsatt, og reaksjonsblandingen ble hensatt for oppvarming til romtemperatur og deretter rørt i 2 timer ved denne temperaturen. Blandingen ble så fordampet til tørrhet, hvoretter resten ble løst i 25 ml etylacetat og vasket med 10 ml vann. 25 ml toluen ble tilsatt, hvoretter blandingen ble forsiktig fordampet til tørrhet, noe som ga 3-[4-(2-aminoacetylamino)-3-fluorfenoksy]-2-hydroksy-2-metyl-N-(3-metyl-4-nitrofenyl)propionamid.<]>H-NMR (400 MHz, DMSO-d6): 1,43 (3H, s), 2,53 (3H, s), 3,75-3,85 (2H, m), 3,98 (1H, d, J = 9,1 Hz), 4,24 (1H, d, J = 9,3 Hz), 6,25 (1H, s), 6,78 (1H, d, J = 9,0 Hz), 6,95 (1H, d, J = 13,0 Hz), 7,60-7,72 (1H, m), 7,88 (1H, d, J = 8,8 Hz), 7,93 (1H, s), 8,00-8,15 (4H, m), 10,05 (1H, s), 10,12 (1H, s). ({2-Fluoro-4-[2-hydroxy-2-(3-methyl-4-nitrophenylcarbamoyl}methyl)carbamic acid tert-butyl ester (0.160 g, 0.3 mmol) was dissolved in 5 mL of methylene chloride under nitrogen and then cooled to 0° C. 0.5 ml of trifluoroacetic acid was added dropwise, and the reaction mixture was allowed to warm to room temperature and then stirred for 2 hours at this temperature. The mixture was then evaporated to dryness, after which the residue was dissolved in 25 ml of ethyl acetate and washed with 10 mL of water. 25 mL of toluene was added, after which the mixture was carefully evaporated to dryness, yielding 3-[4-(2-aminoacetylamino)-3-fluorophenoxy]-2-hydroxy-2-methyl-N-( 3-methyl-4-nitrophenyl)propionamide.<]>H-NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 3.75-3.85 (2H, m), 3.98 (1H, d, J = 9.1 Hz), 4.24 (1H, d, J = 9.3 Hz), 6.25 (1H, s), 6.78 (1H, d, J = 9.0 Hz), 6.95 (1H, d, J = 13.0 Hz), 7.60-7.72 (1H, m), 7.88 (1H, d, J = 8.8 Hz), 7.93 (1H, s), 8.00-8.15 (4H, m), 10.05 (1H, s), 10.12 (1H, s).

Claims (12)

1. Forbindelse,karakterisert vedformel (I) 1. Compound characterized by formula (I) Ri er metyl, etyl, hydroksymetyl eller -(CH^VCHO, hvor n er 0-6; R2er nitro, cyano eller halogen; R3er hydrogen, (Ci-C7)alkyl eller halo(Ci-C7)alkyl; R4er hydrogen, (Ci-C7)alkyl, COR10eller SO2R13; X er O eller NH; A er en gruppe valgt fra: R 1 is methyl, ethyl, hydroxymethyl or -(CH^VCHO, where n is 0-6; R 2 is nitro, cyano or halogen; R 3 is hydrogen, (C 1 -C 7 )alkyl or halo(C 1 -C 7 )alkyl; R 4 is hydrogen, (C 1 -C 7 )alkyl, COR 10 or SO 2 R 13 ; X is O or NH; A is a group selected from: hvor R5, R6, R7, Rg og R9uavhengig av hverandre er hydrogen, halogen, nitro, cyano, (Ci-C7)alkyl, halo(Ci-C7)alkyl, cyano(Ci-C7)alkyl, amino, mono- eller di(Ci-C7)alkylamino, amino(Ci-C7)alkyl, hydroksy(Ci-C7)alkyl, (Ci-C7)alkoksy(Ci-C7)alkyl, -NHCOR10, -N(CORi0)2, -CORn, -OR12, -OSO2R13, -S02Ri4, -NHSO2R13eller -SR15; eller R5og Rt, R6og R7>R7og Rg eller Rg og R9kan sammen med ethvert av de ringatomene til hvilke de er knyttet, danne en kondensert 5- til 7-leddet alifatisk eller aromatisk karbosyklisk ring, eller en kondensert 5- til 7-leddet heterosyklisk ring som inneholder 1 til 3 heteroatomer valgt fra N, O og S; Rio og Rn er uavhengig av hverandre (Ci-C7)alkyl, (C2-C7)alkenyl, halo(Ci-C7)alkyl, amino(Ci-C7)alkyl, mono- eller di(Ci-C7)alkylamino(Ci-C7)alkyl, (C6-Cio)aryl, -N(Ri6)2eller -OR]7; Ri2og Ri5er uavhengig av hverandre hydrogen, (Ci-C7)alkyl, (C2-C7)alkenyl, halo(Ci-C7)alkyl, amino(Ci-C7)alkyl, mono- eller di(Ci-C7)alkylamino(Ci-C7)alkyl, (C6-Cio)aryl, -CORi8; Ri3og Ru er uavhengig av hverandre (Ci-C7)alkyl eller (C2-C7)alkenyl, halo(Ci-C7)alkyl eller (C6-Ci0)aryl; Ri6og Rn er uavhengig av hverandre hydrogen, (Ci-C7)alkyl, (C2-C7)alkenyl, halo(Ci-C7)alkyl, amino(Ci-C7)alkyl eller (C6-Ci0)aryl; Ris er (Ci-C7)alkyl, (C2-C7)alkenyl, halo(Ci-C7)alkyl eller (C6-Ci0)aryl; R19og R20er uavhengig av hverandre hydrogen, halogen, (Ci-C7)alkyl eller (C2-C7)alkenyl; og farmasøytisk akseptable salter og estere av slike forbindelser.where R5, R6, R7, Rg and R9 are independently hydrogen, halogen, nitro, cyano, (Ci-C7)alkyl, halo(Ci-C7)alkyl, cyano(Ci-C7)alkyl, amino, mono- or di (Ci-C7)alkylamino, amino(Ci-C7)alkyl, hydroxy(Ci-C7)alkyl, (Ci-C7)alkoxy(Ci-C7)alkyl, -NHCOR10, -N(CORi0)2, -CORn, - OR 12 , -OSO 2 R 13 , -SO 2 Ri 4 , -NHSO 2 R 13 or -SR 15 ; or R5 and Rt, R6 and R7>R7 and Rg or Rg and R9 can, together with any of the ring atoms to which they are attached, form a fused 5- to 7-membered aliphatic or aromatic carbocyclic ring, or a fused 5- to 7-membered heterocyclic ring ring containing 1 to 3 heteroatoms selected from N, O and S; Rio and Rn are independently (Ci-C7)alkyl, (C2-C7)alkenyl, halo(Ci-C7)alkyl, amino(Ci-C7)alkyl, mono- or di(Ci-C7)alkylamino(Ci- C 7 -alkyl, (C 6 -C 10 )aryl, -N(R 16 ) 2 or -OR] 7 ; R 12 and R 15 are independently hydrogen, (C 1 -C 7 )alkyl, (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl, amino(C 1 -C 7 )alkyl, mono- or di(C 1 -C 7 )alkylamino(C 1 -C 7 C 7 -alkyl, (C 6 -C 10 )aryl, -CO R 18 ; R 13 and R 1 are independently (C 1 -C 7 )alkyl or (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl or (C 6 -C 10 )aryl; R 16 and R n are independently hydrogen, (C 1 -C 7 )alkyl, (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl, amino(C 1 -C 7 )alkyl or (C 6 -C 10 )aryl; Rice is (C 1 -C 7 )alkyl, (C 2 -C 7 )alkenyl, halo(C 1 -C 7 )alkyl or (C 6 -C 10 )aryl; R 19 and R 20 are independently hydrogen, halogen, (C 1 -C 7 )alkyl or (C 2 -C 7 )alkenyl; and pharmaceutically acceptable salts and esters of such compounds. 2. Forbindelse ifølge krav 1, karakterisert vedatR4er hydrogen og R3 er metyl.2. Connection according to claim 1, characterized in that R4 is hydrogen and R3 is methyl. 3. Forbindelse ifølge krav 1 eller 2, karakterisert vedat X er O.3. Connection according to claim 1 or 2, characterized in that X is O. 4. Forbindelse ifølge ethvert av kravene 1 til 3, karakterisert vedat Ri er metyl eller hydroksymetyl og R2er nitro eller cyano.4. Compound according to any one of claims 1 to 3, characterized in that R 1 is methyl or hydroxymethyl and R 2 is nitro or cyano. 5. Forbindelse ifølge ethvert av kravene 1 til 4, karakterisert vedat R5, R6, R7, Rs og R9uavhengig av hverandre er hydrogen, halogen, nitro, cyano, (Ci-C7)alkyl, (Ci-C7)alkoksy, halo(Ci-C7)alkyl, hydroksy(Ci-C7)alkyl eller -NHCOR10, hvor Rio er (Ci-C7)alkyl, halo(Ci-C7)alkyl, hydroksy eller (Ci-C7)alkoksy.5. Compound according to any one of claims 1 to 4, characterized in that R5, R6, R7, R5 and R9 are independently hydrogen, halogen, nitro, cyano, (Ci-C7)alkyl, (Ci-C7)alkyl, halo(Ci-C7)alkyl, hydroxy(Ci-C7) alkyl or -NHCOR 10 , wherein R 10 is (C 1 -C 7 )alkyl, halo(C 1 -C 7 )alkyl, hydroxy, or (C 1 -C 7 )alkoxy. 6. Forbindelse ifølge krav 5, karakterisert vedat minst en av R5, R6, R7, Rs og R9 er et halogen.6. Connection according to claim 5, characterized in that at least one of R5, R6, R7, Rs and R9 is a halogen. 7. Forbindelse ifølge krav 6, karakterisert vedat minst to av R5, R6, R7, Rs og R9er valgt fra gruppen bestående av halogen, cyano og acetamido.7. Connection according to claim 6, characterized in that at least two of R5, R6, R7, Rs and R9 are selected from the group consisting of halogen, cyano and acetamido. 8. Farmasøytisk sammensetning, karakterisert vedå omfatte en forbindelse med formel (I) sammen med en farmasøytisk akseptabel bærer.8. Pharmaceutical composition, characterized by comprising a compound of formula (I) together with a pharmaceutically acceptable carrier. 9. Forbindelse i følge hvilket som helst av kravene 1-7 for anvendelse ved behandling eller forebygging av androgenmangel.9. A compound according to any one of claims 1-7 for use in the treatment or prevention of androgen deficiency. 10. Forbindelse i følge krav 9 for oral administrering.10. Compound according to claim 9 for oral administration. 11. Anvendelse av en forbindelse i følge hvilket som helst av kravene 1-7 for fremstilling av et medikament, for å behandle eller å forebygge androgenmangel.11. Use of a compound according to any one of claims 1-7 for the preparation of a medicament, to treat or prevent androgen deficiency. 12 . Anvendelse ifølge krav 9 eller 10, der medikamentet administreres oralt.12 . Use according to claim 9 or 10, where the drug is administered orally.
NO20060227A 2003-06-27 2006-01-16 Propionamide derivatives and pharmaceutical compositions useful in the treatment or prevention of androgen deficiency. NO332252B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US48271303P 2003-06-27 2003-06-27
FI20030958A FI20030958A0 (en) 2003-06-27 2003-06-27 New compounds
PCT/FI2004/000387 WO2005000794A1 (en) 2003-06-27 2004-06-24 Propionamide derivatives useful as androgen receptor modulators

Publications (2)

Publication Number Publication Date
NO20060227L NO20060227L (en) 2006-01-16
NO332252B1 true NO332252B1 (en) 2012-08-06

Family

ID=33553916

Family Applications (1)

Application Number Title Priority Date Filing Date
NO20060227A NO332252B1 (en) 2003-06-27 2006-01-16 Propionamide derivatives and pharmaceutical compositions useful in the treatment or prevention of androgen deficiency.

Country Status (9)

Country Link
KR (1) KR20060035629A (en)
AR (1) AR044934A1 (en)
DE (1) DE602004026583D1 (en)
HK (1) HK1093964A1 (en)
HR (1) HRP20060036B1 (en)
IL (1) IL172279A0 (en)
IS (1) IS2752B (en)
MX (1) MXPA05013619A (en)
NO (1) NO332252B1 (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0100172B1 (en) * 1982-07-23 1987-08-12 Imperial Chemical Industries Plc Amide derivatives
GEP20053586B (en) * 2000-08-24 2005-07-25 Univ Tennessee Res Corp Selective Androgen Receptor Modulators and Pharmaceutical Compositions Containing the Same
US7547728B2 (en) * 2001-12-06 2009-06-16 University Of Tennessee Research Foundation Treating muscle wasting with selective androgen receptor modulators
AU2003216174C1 (en) * 2002-02-07 2010-01-28 University Of Tennessee Research Foundation Treating benign prostate hyperplasia with SARMs

Also Published As

Publication number Publication date
IS2752B (en) 2011-09-15
AR044934A1 (en) 2005-10-12
IS8256A (en) 2006-01-23
HRP20060036A2 (en) 2006-03-31
HK1093964A1 (en) 2007-03-16
HRP20060036B1 (en) 2014-04-25
NO20060227L (en) 2006-01-16
KR20060035629A (en) 2006-04-26
IL172279A0 (en) 2006-04-10
MXPA05013619A (en) 2006-03-10
DE602004026583D1 (en) 2010-05-27

Similar Documents

Publication Publication Date Title
US7390923B2 (en) Propionamide derivatives useful as androgen receptor modulators
US11655226B2 (en) KDM1A inhibitors for the treatment of disease
JP6063455B2 (en) Deuterated derivatives of Ibakaftor
JP6146990B2 (en) Deuterated CFTR enhancer
US7709516B2 (en) Helix 12 directed non-steroidal antiandrogens
IL264310A (en) Histone acetyltransferase activators and compositions and uses thereof
US20100286204A1 (en) Compound capable of inhibiting 17-beta hydroxysteriod dehydrogenase
NO332252B1 (en) Propionamide derivatives and pharmaceutical compositions useful in the treatment or prevention of androgen deficiency.
CN100462353C (en) Propionamide derivatives useful as androgen receptor modulators
JP6654223B2 (en) Deuterated CFTR enhancer
WO1997030019A1 (en) Aniline derivatives having antihyperglycemic activity
JP2017105824A (en) Deuterated cftr enhancement material

Legal Events

Date Code Title Description
MM1K Lapsed by not paying the annual fees