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NO324837B1 - Substituted Piperazine Compounds, Their Use and Pharmaceutical Compositions Including the Compounds - Google Patents

Substituted Piperazine Compounds, Their Use and Pharmaceutical Compositions Including the Compounds Download PDF

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Publication number
NO324837B1
NO324837B1 NO20023954A NO20023954A NO324837B1 NO 324837 B1 NO324837 B1 NO 324837B1 NO 20023954 A NO20023954 A NO 20023954A NO 20023954 A NO20023954 A NO 20023954A NO 324837 B1 NO324837 B1 NO 324837B1
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acetamide
dimethylphenyl
hydroxypropyl
group
fluorophenoxy
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NO20023954A
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Norwegian (no)
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NO20023954D0 (en
NO20023954L (en
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Prabha N Ibrahim
Jeff A Zablocki
Venkata P Palle
Vaibhav Varkhedkar
Brent K Blackburn
Elfatih O Elzein
Grigory Nudelman
Tim Marquart
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Cv Therapeutics Inc
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Publication of NO20023954D0 publication Critical patent/NO20023954D0/en
Publication of NO20023954L publication Critical patent/NO20023954L/en
Publication of NO324837B1 publication Critical patent/NO324837B1/en

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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Description

Foreliggende oppfinnelse vedrører substituerte piperazinforbindelser, anvendelse derav og farmasøytiske sammensetninger innbefattende forbindelsene. The present invention relates to substituted piperazine compounds, their use and pharmaceutical compositions including the compounds.

US patent nr. 4,567,264, hvor beskrivelsen av denne er innbefattet heri som referanse, beskriver en klasse substituerte piperazinforbindelser som inkluderer en forbindelse kjent som ranolasin, (±)-N-(2,6-dimetylfenyl)-4-[2-hydroksy-3-(2-metoksyfenoksy)-propyl]-l-piperazinacetamid og dens farmasøytisk akseptable salter, og dens anvendelse for behandling av kardiovaskulære sykdommer, som inkluderer arytmier, varierende og øvelsesindusert angina og myokardisk infarkt. US Patent No. 4,567,264, the disclosure of which is incorporated herein by reference, describes a class of substituted piperazine compounds which includes a compound known as ranolazine, (±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy- 3-(2-Methoxyphenoxy)-propyl]-1-piperazineacetamide and its pharmaceutically acceptable salts, and its use for the treatment of cardiovascular diseases, which include arrhythmias, variable and exercise-induced angina and myocardial infarction.

US patent nr. 5,506,229, som er innbefattet heri med referanse, beskriver anvendelsen av ranolasin og det farmasøytisk akseptable salter og estere for behandling av vev som opplever en fysisk eller kjemisk skade, som inkluderer kardoplegi, hypoksisk eller reperfusjonsskade på hjertet eller skjelettmuskel eller hjernevev, og for anvendelse i transplantater. Spesielt er ranolasin særlig anvendelig for behandling av arytmier, varierende og øvelsesindusert angina, og myokardisk infarkt ved delvis å inhibere hjertefettsyreoksidasjon. Vanlige orale og parenterale ranolasinformuleringer er beskrevet, hvilket inkluderer kontrollert frigivelsesformuleringer. Spesielt beskriver eksempel 7D i US patent nr. 5,506,229 en kontrollert fngivelsesformulering i kapselform som innbefatter mikrosfærer av ranolasin og mikrokrystallinsk cellulose belagt med frigivelseskontrollerende polymerer. US Patent No. 5,506,229, which is incorporated herein by reference, describes the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues experiencing physical or chemical injury, which includes cardioplegia, hypoxic or reperfusion injury to the heart or skeletal muscle or brain tissue, and for use in grafts. In particular, ranolazine is particularly useful for the treatment of arrhythmias, variable and exercise-induced angina, and myocardial infarction by partially inhibiting cardiac fatty acid oxidation. Common oral and parenteral ranolase formulations are described, including controlled release formulations. In particular, Example 7D of US Patent No. 5,506,229 describes a controlled release formulation in capsule form that includes microspheres of ranolazine and microcrystalline cellulose coated with release controlling polymers.

Til tross for den viktige oppdagelsen at ranolasin er et svært anvendelig hjerte-terapeutisk middel er det behov for forbindelser som er spesielle fettsyreoksidasjons-inhibitorer som har en halveringstid større enn ranolasin og som har aktiviteter minst tilsvarende ranolasin. Despite the important discovery that ranolazine is a very useful cardiac therapeutic agent, there is a need for compounds which are special fatty acid oxidation inhibitors which have a half-life greater than ranolazine and which have activities at least equivalent to ranolazine.

Foreliggende oppfinnelse inkluderer nye substituerte piperazinforbindelser som er delvise fettsyre oksidasjonsinhibitorer med gode terapeutiske halveringstider. The present invention includes new substituted piperazine compounds which are partial fatty acid oxidation inhibitors with good therapeutic half-lives.

Foreliggende oppfinnelse angir nye substituerte piperazinforbindelser som kan administreres til et pattedyr for å beskytte skjelettmuskler overfor skade som resultat av traumer, og beskytte skjelettmuskler etterfølgende muskel- eller systemiske sykdommer slik som periodisk klaudikasjon, for å behandle sjokktilstander, for å ivareta donorvev og organer anvendt i transplantater, og å behandle kardiovaskulære sykdommer som inkluderer atrial og ventrikulære arytmier, Prinzmetars (variant) angina, stabil angina, og treningsindusert angina, kongestiv hjertesykdom, og myokardisk infarkt. Foreliggende oppfinnelse tilveiebringer en klasse av substituerte piperazinforbindelse kjennetegnet ved følgende formel: hvori X er utvalgt fra gruppen som består av: The present invention provides novel substituted piperazine compounds which can be administered to a mammal to protect skeletal muscle from injury as a result of trauma, and to protect skeletal muscle following muscular or systemic diseases such as periodic claudication, to treat shock states, to preserve donor tissues and organs used in grafts, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetar's (variant) angina, stable angina, and exercise-induced angina, congestive heart disease, and myocardial infarction. The present invention provides a class of substituted piperazine compounds characterized by the following formula: wherein X is selected from the group consisting of:

hvori m = 1 eller 2 eller 3; wherein m = 1 or 2 or 3;

Ri, R.2, R3, R4 og R5 er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, SR23, N(R23)2, COR23, NR23SO2R22, Ci-5alkyl, morfolinyl og pyrrolyl, hvori alkylsubstituenten eventuelt er substituert med 1 substituent utvalgt fra OR23, hvori R2 og R3 kan bindes sammen og danne et sammensmeltet ringsystem som har fra tre til fire karbonatomer, hvori R4 og R5 kan bindes sammen og danne -CH=CH-CH=CH-; R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 , SR 23 , N(R 23 ) 2 , COR 23 , NR 23 SO 2 R 22 , C 1-5 alkyl, morpholinyl and pyrrolyl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from OR 23 , wherein R 2 and R 3 may be linked together to form a fused ring system having from three to four carbon atoms, wherein R 4 and R 5 may be linked together to form -CH=CH-CH=CH-;

R6, R7 og Rg er hver uavhengig utvalgt fra gruppen som består av hydrogen og C1-6 alkyl; R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;

R9, Rio, Rn, Ri2, Rn, Rn, R15 og Ri6 er hver uavhengig utvalgt fra gruppen som består av hydrogen, Cm alkyl, hvori R9 og Rio sammen kan danne et karbonyl, eller Rn og R12 kan sammen danne et karbonyl, eller Rn og Ri 4 kan sammen danne et karbonyl, eller R15 og Ri6 kan sammen danne et karbonyl hvori Ri 1 og R13 eller Rg og R15 og Ri 1 eller Rn og Ri 5 eller R9 og Ri 3 kan binde sammen og danne et brodannet ringsystem som har fra 1 til 4 karbonatomer hvori R9 og Rio eller Ri 1 eller R12 eller R13 og R14 eller R15 og Ri6 kan binde sammen og danne et brodannende ringsystem som har fra 1 til 5 karbonatomer med den betingelsen at R9, Rio, Rn, R12, R13, Rh, Ris og Ri6 ikke alle er hydrogen når R24 er fenyl og når X er R9, Rio, Rn, Ri2, Rn, Rn, R15 and Ri6 are each independently selected from the group consisting of hydrogen, C1 alkyl, wherein R9 and Rio together form a carbonyl, or Rn and R12 together form a carbonyl, or Rn and Ri 4 can together form a carbonyl, or R15 and Ri6 can together form a carbonyl in which Ri 1 and R13 or Rg and R15 and Ri 1 or Rn and Ri 5 or R9 and Ri 3 can bond together and form a bridged ring system which has from 1 to 4 carbon atoms in which R9 and Rio or Ri 1 or R12 or R13 and R14 or R15 and Ri6 can bond together to form a bridging ring system having from 1 to 5 carbon atoms with the proviso that R9, Rio, Rn, R12, R13, Rh, Ris and Ri6 are not all hydrogen when R24 is phenyl and when X is

R22 er C1-6 alkyl; R 22 is C 1-6 alkyl;

R23 er utvalgt fra gruppen som består av H og Ci.6; og R23 is selected from the group consisting of H and C1.6; and

R24 er utvalgt fra gruppen som består av Ci.6 alkyl, C3.8 sykloalkyl, naftyl og R 24 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, naphthyl and

hvori R17, Ri<g>, R19, R23 og R21 hver er uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, OR23, Ci-salkyl eller to av Ri7-R2i danner en C1.2 alkylendioksyfenyl. wherein R 17 , R 10 , R 19 , R 23 and R 21 are each independently selected from the group consisting of hydrogen, halo, CF 3 , OR 23 , C 1-6 alkyl or two of R 17 -R 21 form a C 1-2 alkylenedioxyphenyl.

En fordelaktig utførelsesform av oppfinnelsen omfatter substituerte piperazinforbindelser som har følgende formel (I): An advantageous embodiment of the invention comprises substituted piperazine compounds having the following formula (I):

hvori m = 1 eller 2 eller 3; wherein m = 1 or 2 or 3;

Ri, R2, R3, R4 og R5 er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, SR23, N(R23)2, NR23SO2R22, Ci.5alkyl, morfolinyl, pyrrolyl, hvori alkylsubstituenten eventuelt er substituert med 1 substituent, hvori R2 og R3 kan bindes sammen og danne et sammensmeltet ringsystem som har fra tre til fire karbonatomer, hvori R4 og R5 kan bindes sammen og danne -CH=CH-CH=CH-; R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 , SR 23 , N(R 23 ) 2 , NR 23 SO 2 R 22 , C 1-5 alkyl, morpholinyl, pyrrolyl, wherein the alkyl substituent is optionally substituted with 1 substituent , wherein R 2 and R 3 may be bonded together to form a fused ring system having from three to four carbon atoms, wherein R 4 and R 5 may be bonded to form -CH=CH-CH=CH-;

R6, R7 og Rg er hver uavhengig utvalgt fra gruppen som består av hydrogen og C1-6 alkyl; R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;

R9, Rio, Rn, Ri2, R13, R14, R15 og Ri6 er hver uavhengig utvalgt fra gruppen som består av hydrogen og Cm alkyl, hvori R9 og Rio sammen kan danne et karbonyl, eller Rn og Ri 2 kan sammen danne et karbonyl, eller Ri3 og Rh kan sammen danne et karbonyl, eller Ri 5 og Ri 6 kan sammen danne et karbonyl hvori Ri 1 og Ri 3 eller R9 og Ri 5 og R9 eller Ri 1 og Ri 5 eller R9 og Ri 3 kan binde sammen og danne et brodannende ringsystem som har fra 1 til 4 karbonatomer hvori R9 og Rio eller Rn eller Ri2 eller Rn og Ri4 eller Ri 5 og Ri 6 sammen kan danne et brodannende ringsystem som har fra 1 til 5 karbonatomer med den betingelsen at R9, Rio, Rn, R12, R13, R14, R15 og Ri6ikke alle er hydrogen når Rn, Rig, R19, R20 og R21 alle er hydrogen; R 9 , R 10 , R n , R 12 , R 13 , R 14 , R 15 , and R 6 are each independently selected from the group consisting of hydrogen and C 1 -C 1 alkyl, wherein R 9 and R 10 can together form a carbonyl, or R 1 and R 1 2 can together form a carbonyl, or Ri3 and Rh can together form a carbonyl, or Ri5 and Ri6 can together form a carbonyl in which Ri1 and Ri3 or R9 and Ri5 and R9 or Ri1 and Ri5 or R9 and Ri3 can bond together and form a bridging ring system having from 1 to 4 carbon atoms in which R9 and Rio or Rn or Ri2 or Rn and Ri4 or Ri 5 and Ri 6 together can form a bridging ring system having from 1 to 5 carbon atoms with the condition that R9, Rio, Rn , R 12 , R 13 , R 14 , R 15 and R 16 are not all hydrogen when R 11 , R 19 , R 20 and R 21 are all hydrogen;

R22 er C1-6 alkyl; R 22 is C 1-6 alkyl;

Rn, Ri<g>, R19, R2o og R21 hver er uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, OR23, Ci-salkyl, to av R17-R20 danner Ci.2alkendioksyfenyl; Rn, R1<g>, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23, C1-6alkyl, two of R17-R20 form C1-2alkenedioxyphenyl;

R23 er utvalgt fra gruppen som består av H og C1-6 alkyl. R 23 is selected from the group consisting of H and C 1-6 alkyl.

Mest foretrukket er substituerte piperazinforbindelser med formel I utvalgt fra: N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)propyl]-3-oksopiperazinyl} acetamid, N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)propyl]-3,5-dimetylpiperazinyl} acetamid, Most preferred are substituted piperazine compounds of formula I selected from: N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-oxopiperazinyl} acetamide, N-( 2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3,5-dimethylpiperazinyl} acetamide,

2-{(5S,2R)-4-[-hydroksy-3-(2-metoksyfenoksy)propyl]-2,5-dimetylpiperazinyl}-N-(2,6-dimetylfenyl)acetamid, 2-{(5S,2R)-4-[-hydroxy-3-(2-methoxyphenoxy)propyl]-2,5-dimethylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide,

2-{2,5-diasa-5-[2-hydroksy-3-(2-metoksyfenoksy)propyl]bisyklo[4.4.0]des-2-yl}-N-(2,6-dimetylfenyl)acetamid, 2-{2,5-diaza-5-[2-hydroxy-3-(2-methoxyphenoxy)propyl]bicyclo[4.4.0]des-2-yl}-N-(2,6-dimethylphenyl)acetamide,

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)propyl]-3-oksopiperazinyl} acetamid, N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)propyl]-3,3-dimetylpiperazinyl} acetamid, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-oxopiperazinyl} acetamide, N-(2,6-dimethylphenyl)-2-{4 -[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3,3-dimethylpiperazinyl} acetamide,

2- {5-[(2S)-2-hydroksy-3-(2-metoksyfenoksy)propyl](l S,4S)-2,5- 2- {5-[(2S)-2-hydroxy-3-(2-methoxyphenoxy)propyl](1S,4S)-2,5-

diazabisyklo[2.2.1 ]hept-2-yl} -N-(2,6-dimetylfenyl)acetamid, diazabicyclo[2.2.1]hept-2-yl}-N-(2,6-dimethylphenyl)acetamide,

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)butyl]- N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)butyl]-

piperazinyl} acetamid, piperazinyl} acetamide,

N-(2,6-dimetylfenyl)-2- {4- [4-(4-fluorfenoksy)-2-hydroksybutyl] -piperazinyl} acetamid, 2-(4-{4-[4-(tert-butyl)fenoksy]-2-hydroksybutyl}piperazinyl)-N-(2,6-dimetylfenyl)acetamid, N-(2,6-dimethylphenyl)-2- {4- [4-(4-fluorophenoxy)-2-hydroxybutyl] -piperazinyl} acetamide, 2-(4-{4-[4-(tert-butyl)phenoxy ]-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide,

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)butyl]- N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)butyl]-

piperazinyl} acetamid, piperazinyl} acetamide,

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)butyl]-piperazinyl} acetamid, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)butyl]-piperazinyl} acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2,6-dimetylfenyl)-acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2,6-dimethylphenyl)-acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2,6-diklorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2,6-dichlorophenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-sulfamoyl-fenyl)acetamid, • 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-sulfamoyl-phenyl)acetamide, •

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(5-metoksy-3 -(trifluormetyl)fenyl] acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(5-methoxy-3-(trifluoromethyl)phenyl] acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinylj-N-indan-5 ylacetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl-N-indan-5 ylacetamide,

2- {(3S)-4-[(2S)-3-(2-fiuorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl} -N-naftylacetamid, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-naphthylacetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-klomaftyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-chloronaphthyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2-pyrrolylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-pyrrolylphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazin}-N-fenylacetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine}-N-phenylacetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-N-(2-klorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2-klor-4-metylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-N-(2-chlorophenyl)acetamide, 2-{(3S)-4-[(2S)- 3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-chloro-4-methylphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-[2-(l-metylvinyl)fenyl] acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[2-(1-methylvinyl)phenyl] acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)^ metylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-Fluorophenoxy)^methylphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-[6 metyl-2-(metyletyl)fenyl]acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[6 methyl-2-(methylethyl)phenyl]acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(3-metyltiofenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-methylthiophenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-kl^ 2-metoksy-5 -metylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-cl^ 2-methoxy-5-methylphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-[4-(dimetylamino)fenyl]acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4-(dimethylamino)phenyl]acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2,4-dimetoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2,4-dimethoxyphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(3,4-diklorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,4-dichlorophenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-klorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-chlorophenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(3-klorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-chlorophenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hyckoksypropyl]-3-metylpiperazinyl}-N-(3,^ diklorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,^ dichlorophenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-metoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methoxyphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-metylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methylphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(3-metylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-methylphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-fiuorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-fluorophenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-rnetylpiperazinyl}-N-(4-syanofenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-cyanophenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-84-asetylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-84-acetylphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]0-metylpiperazinyl}-N-(2-metoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]0-methylpiperazinyl}-N-(2-methoxyphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-[4-(trifluormetyl)fenyl] acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4-(trifluoromethyl)phenyl] acetamide,

2- {(3S)-4-[(2S)-3-(2-fluorfenoksy)-2^ 3- (trifluormetyl)fenyl]acetarnid, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2^ 3-(trifluoromethyl)phenyl]acetarnide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hyd^oksypropyl]-3-metylpiperazinyl}-N-(3,5^ dimetoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-Fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,5^dimethoxyphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-morfolin-4-ylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-morpholin-4-ylphenyl)acetamide,

2- {(3 S)-4-[(2S)-3-(2-lfuorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl} -N-(3-fluor-4- metoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-fluoro-4-methoxyphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(3,4,5-trimetoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,4,5-trimethoxyphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hy(koksypropyl]0-metylpiperazinyl}-N-(3,4 dimetoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hy(oxypropyl]0-methylpiperazinyl}-N-(3,4 dimethoxyphenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-^ 2-fluorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-^2-fluorophenyl)acetamide,

2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-[2-(hydroksy-metyl-6-metylfenyl]acetamid. 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[2-(hydroxy-methyl-6-methylphenyl]acetamide.

Foreliggende oppfinnelse tilveiebringer videre en substituert piperazinforbindelse, kjennetegnet ved at den har følgende formel: The present invention further provides a substituted piperazine compound, characterized in that it has the following formula:

hvori m = 0,1 eller 2 eller 3; where m = 0.1 or 2 or 3;

R<1>, R<2>, R<3>, R<4> og R<5> er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, SR23, N(R23)2, COR23, NR23S02R22, Ci-5 alkyl, morfolinyl, pyrrolyl, hvori alkylsubstituenten eventuelt er substituert med 1 substituent OR23; R<1>, R<2>, R<3>, R<4> and R<5> are each independently selected from the group consisting of hydrogen, halo, CF3, SR23, N(R23)2, COR23, NR23S02R22 , C1-5 alkyl, morpholinyl, pyrrolyl, in which the alkyl substituent is optionally substituted with 1 substituent OR23;

R<6>, R<7> og R<8> er uavhengig utvalgt fra gruppen som består av hydrogen og Ci-6 alkyl; R<9>, R<10>, R1<1>, R1<2>, R13, R1<4>, R<15> og R<16> er hver uavhengig utvalgt fra gruppen som består av hydrogen og Cm alkyl, hvori R9 og R<10> sammen kan danne en karbonyl, eller R<11> og R<12> kan sammen danne en karbonyl, eller R13 og R<14> kan sammen danne en karbonyl, eller R<1>5 og R1<6> kan sammen danne en karbonyl, hvori R11 og R<13> eller R<9> og R13 eller R<9> og R<11> eller R<11> og R<15> eller R<9> og R<13> sammen kan danne et brodannet ringsystem hvori de to R gruppene sammen omfatter fra 1 til 4 karbonatomer og hvori R<9> og R<10 >eller R<11> og R<12> eller R<13> og R<14> eller R15 og R<16> sammen kan danne et spiro ringsystem hvori de to R gruppene sammen omfatter fra 1 til 5 karbonatomer; R<6>, R<7> and R<8> are independently selected from the group consisting of hydrogen and C1-6 alkyl; R<9>, R<10>, R1<1>, R1<2>, R13, R1<4>, R<15> and R<16> are each independently selected from the group consisting of hydrogen and C 1 -C alkyl, wherein R9 and R<10> can together form a carbonyl, or R<11> and R<12> can together form a carbonyl, or R13 and R<14> can together form a carbonyl, or R<1>5 and R1 <6> can together form a carbonyl, in which R11 and R<13> or R<9> and R13 or R<9> and R<11> or R<11> and R<15> or R<9> and R <13> together can form a bridged ring system in which the two R groups together comprise from 1 to 4 carbon atoms and in which R<9> and R<10 >or R<11> and R<12> or R<13> and R< 14> or R15 and R<16> together can form a spiro ring system in which the two R groups together comprise from 1 to 5 carbon atoms;

R<17>, R<18>, R1<9>, R20 og R<21> har betydningen angitt i krav 1; R<17>, R<18>, R1<9>, R20 and R<21> have the meaning stated in claim 1;

R22 er C1-5 alkyl; og R 22 is C 1-5 alkyl; and

R23 er utvalgt fra gruppen som består av H og C1-6 alkyl. R 23 is selected from the group consisting of H and C 1-6 alkyl.

I en foretrukket sammensetning er m = 1 eller 2; In a preferred composition, m = 1 or 2;

R<1>, R<2>, R<3>, R<4> og R<5> hver er uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, OR<23> og C1-2 alkyl, hvori R23 er Ci-2 alkyl; R<1>, R<2>, R<3>, R<4> and R<5> are each independently selected from the group consisting of hydrogen, halo, CF3, OR<23> and C1-2 alkyl, wherein R 23 is C 1-2 alkyl;

R<6>, R<7> og R<8> er hver uavhengig utvalgt fra gruppen som består av hydrogen og metyl; R<9>, R1<0>, R<11>, R<12>, R<13>, R<14>, R<15> og R<16> er hver uavhengig utvalgt fra gruppen som består av hydrogen og C1-2 alkyl, eller R9 og R1<0> sammen kan danne et karbonyl, eller R15 og R1<6> sammen danner et karbonyl, hvori R<11> og R13 eller R<9> og R<13> eller R<9> og R<11> eller R11 og R<15> eller R9 og R1<3> kan bindes sammen og kan danne en ring som inkluderer fra 1 til 4 karbonatomer; og R<6>, R<7> and R<8> are each independently selected from the group consisting of hydrogen and methyl; R<9>, R1<0>, R<11>, R<12>, R<13>, R<14>, R<15> and R<16> are each independently selected from the group consisting of hydrogen and C1-2 alkyl, or R9 and R1<0> together may form a carbonyl, or R15 and R1<6> together form a carbonyl, wherein R<11> and R13 or R<9> and R<13> or R< 9> and R<11> or R11 and R<15> or R9 and R1<3> may be linked together and may form a ring including from 1 to 4 carbon atoms; and

R<17>, R<18>, RR<19>, R<2>0 og R2<1> er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, OR23 eller C1.3 alkyl. R<17>, R<18>, RR<19>, R<2>0 and R2<1> are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 or C1.3 alkyl.

I en andre mer foretrukket utførelsesform er m = 1 eller 2; In a second, more preferred embodiment, m = 1 or 2;

R<1>, R<2>, R<3>, R<4> og R<5> hver er uavhengig utvalgt fra gruppen som består av hydrogen metyl; R<1>, R<2>, R<3>, R<4> and R<5> are each independently selected from the group consisting of hydrogen methyl;

R<6>, R<7> og R<8> er hver hydrogen; R<6>, R<7> and R<8> are each hydrogen;

R<9>, R10, R1<1>, R1<2>, R<1>3, R14, R15 og R<16> er hver uavhengig utvalgt fra gruppen som består av hydrogen og Cm alkyl, eller R9 og R<10> sammen kan danne en karbonyl, eller R11 og R<12> kan sammen danne en karbonyl, eller R13 og R<14> kan sammen danne en karbonyl, eller R<1>5 og R1<6> kan sammen danne en karbonyl, hvori R<11> og R<13> eller R<9> og R<13> eller R<9> og R<11> eller R<1>1 og R1<5> eller R<9> og R<13> kan bindes sammen og danne en ring som inkluderer fra 1 til 4 karbonatomer; R<9>, R10, R1<1>, R1<2>, R<1>3, R14, R15 and R<16> are each independently selected from the group consisting of hydrogen and C1 alkyl, or R9 and R< 10> together can form a carbonyl, or R11 and R<12> can together form a carbonyl, or R13 and R<14> can together form a carbonyl, or R<1>5 and R1<6> can together form a carbonyl , in which R<11> and R<13> or R<9> and R<13> or R<9> and R<11> or R<1>1 and R1<5> or R<9> and R< 13> can be linked together to form a ring including from 1 to 4 carbon atoms;

R<17>, R<18>, R19, R20 og R<21> er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, CM alkyl, CF3, og OR23; og R<17>, R<18>, R19, R20 and R<21> are each independently selected from the group consisting of hydrogen, halo, C 1 -C alkyl, CF3, and OR23; and

R<23> er Ci-2 alkyl. R<23> is C1-2 alkyl.

Mest foretrukket er substituerte piperazinforbindelser ifølge foreliggende opprinnelse utvalgt fra Most preferably, substituted piperazine compounds according to the present origin are selected from

N-(2,6-dimetylfenyl)-2-[4-(2-hyddroksy-4-fenylbutyl)piperazinyl]acetamid; N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenyl)propyl]piperazinyl}acetamid; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)propyl]piperazinyl}acetamide;

2-[4-(3-(2H-berizo[d]l,3-dioksolen-5-yl)-2-hydroksypropyl)piperazinyl]-N-(2,6-dimetylfenyl)acetamid; 2-[4-(3-(2H-berizo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide;

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(4-[2-hydroksy-3-fenylpropyl] N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(4-[2-hydroxy-3-phenylpropyl]

piperazinyl} acetamid, piperazinyl} acetamide,

N-(2,6-dimetylfenyl)-2-{4-[4-(4-metoksyfenyl)-2-hydroksybutyl]piperazinyl}acetamid, 2-{4-[4-(2,6-difluorfenyl)-2-hydroksybutyl]piperazinyl}-N-(2,6-dimetylfenyl)-acetamid, N-(2,6-dimethylphenyl)-2-{4-[4-(4-methoxyphenyl)-2-hydroxybutyl]piperazinyl}acetamide, 2-{4-[4-(2,6-difluorophenyl)-2- hydroxybutyl]piperazinyl}-N-(2,6-dimethylphenyl)-acetamide,

N-(2,6-dimetylfenyl)-2-{4-[4-(2-klorfenyl)-2-hydroksybutyl]piperazinyl} acetamid, 2-(4-{4-[4-(tert-butyl)fenyl]fenyl-2-hydroksybutyl}piperazinyl)-N-(2,6-dimtylfenyl)acetamid, N-(2,6-dimethylphenyl)-2-{4-[4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl} acetamide, 2-(4-{4-[4-(tert-butyl)phenyl] phenyl-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide,

N-(2,6-dimetylfenyl)-2-{4-[4-(2-fluorfenyl)-2-hydroksybutyl]piperazinyl}acetamid, N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-4-[4-(trifluormetyl)fenyl]butyl}piperazinyl)acetamid, N-(2,6-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl]piperazinyl}acetamide, N-(2,6-dimethylphenyl)-2-(4-{2- hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide,

2-[4-(3-(2H-benzo[d]l,3-dioksolen-5-yl)-2-hydroksypropyl)piperazinyl]-N-(2,6-dimetylfenyl)-2-metylpropanamid, 2-[4-(3-(2H-benzo[d]l,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-2-methylpropanamide,

N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-3-fenylpropyl)piperazinyl]-2-metylpropanamid, N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(3,4,5-trimetoksyfenyl)propyl]piperazinyl}-2-metylpropanamid, N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-5-fenylpentyl)pipeasinyl]acetamid, N-(2,6-dimetylfenyl)-2-{4-[5-(2-fluorfenyl)-2-hydroksy-pentyl]piperazinyl}acetamid og N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy -3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl}-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)pipeazinyl]acetamide, N -(2,6-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide and

N-(2,6-dimetylfenyl)-2-{4-[5-(2-klorfenyl)-2-hydroksy-pentyl]piperazinyl} acetamid. N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyl)-2-hydroxy-pentyl]piperazinyl} acetamide.

Foreliggende oppfinnelse omfatter ytterligere forbindelser av formel I: The present invention comprises further compounds of formula I:

hvori m= 1,2 eller 3; wherein m= 1,2 or 3;

R<1>, R<2>, R<3>, R<4> og R<5> er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, SR<20>, N(R<20>)2, COR<20>, NR<20>SO2R<22>, Ci-5alkyl, morfolinyl og pyrrolyl, hvori alkylsubstituenten eventuelt er substituert med 1 substituent utvalgt fra gruppen som består av OR<20>; R<1>, R<2>, R<3>, R<4> and R<5> are each independently selected from the group consisting of hydrogen, halo, CF3, SR<20>, N(R<20> )2, COR<20>, NR<20>SO2R<22>, C1-5 alkyl, morpholinyl and pyrrolyl, in which the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of OR<20>;

R<6>, R<7> og R<8> er hver uavhengig utvalgt fra gruppen bestående av hydrogen eller C1-3 alkyl; R<6>, R<7> and R<8> are each independently selected from the group consisting of hydrogen or C1-3 alkyl;

R<9>, R<10>, Ru, R<12>, R1<3>, R<14>, R15 og R<16> er hver uavhengig utvalgt fra gruppen som består av Cm alkyl, hvori R9 og R1<0> sammen kan danne en karbonyl, eller R11 og R12 sammen kan danne en karbonyl, eller R<13> og R14 kan sammen danne en karbonyl, eller R<15> og R<16 >kan sammen danne en karbonyl hvori R<11> og R<13> eller R<9> og R<15> eller R<9> og R<11> eller R<11 >og R<15> eller R<9> og R<13> sammen kan danne en ring som inkluderer fra 1 til 3 karbonatomer; R<9>, R<10>, Ru, R<12>, R1<3>, R<14>, R15 and R<16> are each independently selected from the group consisting of C 1 -C alkyl, wherein R9 and R1< 0> together can form a carbonyl, or R11 and R12 together can form a carbonyl, or R<13> and R14 together can form a carbonyl, or R<15> and R<16> can together form a carbonyl in which R<11 > and R<13> or R<9> and R<15> or R<9> and R<11> or R<11 >and R<15> or R<9> and R<13> together can form a ring including from 1 to 3 carbon atoms;

R<24> er utvalgt fra Ci-C6 alkyl, C3-C8 sykloalkyl og naftyl; R<24> is selected from C1-C6 alkyl, C3-C8 cycloalkyl and naphthyl;

R<20> er utvalgt fra gruppen som består av H eller Ci.6 alkyl; og R<20> is selected from the group consisting of H or C1-6 alkyl; and

R<22>erC,.6alkyl. R<22> is C1-6 alkyl.

I forbindelsene er det foretrukket at R<6>, R<7> og R<8> hver er uavhengig utvalgt fra gruppen som består av hydrogen eller metyl. In the compounds, it is preferred that R<6>, R<7> and R<8> are each independently selected from the group consisting of hydrogen or methyl.

I foretrukne sammensetninger med formel I er m =1; In preferred compositions of formula I, m = 1;

R<1>, R<2>, R<3>, R<4> og R<5> hver uavhengig utvalgt fra gruppen som består av hydrogen eller metyl; R<1>, R<2>, R<3>, R<4> and R<5> each independently selected from the group consisting of hydrogen or methyl;

R<6>, R7 og R<8> er hver hydrogen; R<6>, R7 and R<8> are each hydrogen;

R<1>1 og R1<2> er hver utvalgt fra gruppen som består av hydrogen og metyl, R<9>, R10, R<13>, R14, R15 og R<16> er hver hydrogen og R9 og R1<0> kan sammen danne en karbonyl; R<1>1 and R1<2> are each selected from the group consisting of hydrogen and methyl, R<9>, R10, R<13>, R14, R15 and R<16> are each hydrogen and R9 and R1< 0> can together form a carbonyl;

R<24> er utvalgt fra gruppen som består av C1-C6 alkyl, C3-C8 sykloalkyl og naftyl; og R<20> er <m>etyl eller H. R<24> is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl and naphthyl; and R<20> is <m>ethyl or H.

I andre foretrukne forbindelser er m =1; In other preferred compounds, m = 1;

R<1>, R<2>, R3, R<4> og R<5> hver uavhengig utvalgt fra gruppen som består av hydrogen eller metyl; R<1>, R<2>, R3, R<4> and R<5> each independently selected from the group consisting of hydrogen or methyl;

R<6>, R<7> og R<8> er hver hydrogen; R<6>, R<7> and R<8> are each hydrogen;

R<9>, R1<0>, Ru, R<12>, R<13>, R14, R<1>5 og R1<6> er hver hydrogen; og R<9>, R1<0>, Ru, R<12>, R<13>, R14, R<1>5 and R1<6> are each hydrogen; and

R<24> er utvalgt fra gruppen som består av alkyl som har fra 1 til 6 karbonatomer, sykloalkyl som har fra 4 til 6 karbonatomer og naftyl. R<24> is selected from the group consisting of alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 4 to 6 carbon atoms and naphthyl.

Mest foretrukket er de substituerte piperazinforbindelsene med formel I utvalgt fra gruppen som består av: 2-( {2-[4-(3-isopropoksy-2-hydroksypropyl)piperazinyl]-N-( {2,6-dimetylfenyl)acetamid; N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-3-indan-2-yloksypropyl)piperazinyl]acetamid; N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(fenylmetoksy)propyl]piperazinyl}acetamid; 2-[4-(3-{[4-(tert-butyl)fenyl]metoksy}-2-hydroksypropyl)piperazinyl]-N-(2,6-dimetylfenyl)acetamid; N-(2,6-dimetylfenyl)-2-(4-{3-[(2-fluorfenyl)metoksy]-2-hydroksypropyl}piperazinyl) acetamid; Most preferably, the substituted piperazine compounds of formula I are selected from the group consisting of: 2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide; N -(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]acetamide;N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy -3-(phenylmethoxy)propyl]piperazinyl}acetamide;2-[4-(3-{[4-(tert-butyl)phenyl]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl) N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide;

2-(4-{3-[(2,4-difluorfenyl)metoksy]-2-hydroksypropyl}piperazinyl)-N-(2,6-dimetylfenyl)acetamid; 2-(4-{3-[(2,4-difluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide;

N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-3-{[4-(trifluormetyl)fenyl]metoksy}propyl) piperazinyl] acetamid; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]acetamide;

N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-3-[(2-metoksyfenyl)metoksy]propyl}acetamid; 2-(4-{3-[(2,4-dimetoksyfenyl)metoksyl]-2-hydroksypropyl}piperazinyl)-N-(2,6-dimetylfenyl) acetamid; N-(2,6-dimetylfenyl)-2-(4- {2-hydroksy-3- [(4-metoksyfenyl)metoksy]propyl} piperazin) acetamid; N-(2,6-dimetylfenyl)-2-(4-{3-[(4-fluorfenyl)metoksy]-2-hydroksypropyl}piperazinyl) acetamid; N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-methoxyphenyl)methoxy]propyl}acetamide; 2-(4-{3-[(2,4-dimethoxyphenyl) methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide;N-(2,6-dimethylphenyl)-2-(4- {2-hydroxy-3- [(4-methoxyphenyl)methoxy ]propyl}piperazine)acetamide;N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide;

N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-3-[(4-metoksyfenyl)metoksy}propyl}piperaziriyl) acetamid; N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)methoxy}propyl}piperaziriyl)acetamide;

N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-3-[(4-fenylfenyl)metoksy]propyl}piperazinyl) acetamid; N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylphenyl)methoxy]propyl}piperazinyl)acetamide;

N-(2,6-dimetylfenyl)-2-(4-{3-[(4-butylfenyl)metoksy]-2-hydroksypropyl}piperazinyl) acetamid; N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide;

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-naftylmetoksy)propyl]piperazinyl} acetamid; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-naphthylmethoxy)propyl]piperazinyl} acetamide;

N-(2,6-dimetylfenyl)-2-{4-[3-(sykloheksylmetoksy)-2-hydroksypropyl]piperazinyl} acetamid, og N-(2,6-dimethylphenyl)-2-{4-[3-(cyclohexylmethoxy)-2-hydroxypropyl]piperazinyl} acetamide, and

N-(2,6dimetylfenyl)-2-(4-{3-[(4-fluorfenyl)metoksy]-2-hydroksypropyl}-3,3-dimetyl-piperazinyl)acetamid. N-(2,6dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}-3,3-dimethylpiperazinyl)acetamide.

Følgende definisjoner gjelder for begrepene slik de er anvendt heri: The following definitions apply to the terms as used herein:

"Halo" eller "halogen" - alene eller i kombinasjon betyr alle halogener, dvs. klor (Cl), fluor (F), brom (Br), jod (I). "Halo" or "halogen" - alone or in combination means all halogens, ie chlorine (Cl), fluorine (F), bromine (Br), iodine (I).

"Hydroksyl" referererer til gruppen -OH. "Hydroxyl" refers to the group -OH.

"Tiol" eller "merkapto" refererer til gruppen -SH. "Thiol" or "mercapto" refers to the group -SH.

"Eventuell" og "eventuelt" betyr at det som er den etterfølgende beskrevne hendelsen eller omstendigheten kan eller ikke kan finne sted, og beskrivelsen inkluderer tilfeller hvor begivenheten eller omstendigheten finner sted og tilfeller hvor den ikke gjør det. For eksempel indikerer "eventuelle farmasøytiske eksipienter" at en formulering beskrevet kan eller ikke kan inkludere farmasøytiske eksipienter forskjellig fra de som spesifikt er angitt å være tilstede, og at formuleringen beskrevet på denne måten inkluderer tilfeller hvori de eventuelle eksipientene er tilstede og tilfeller hvori de ikke er det. "Potentially" and "eventually" mean that the event or circumstance subsequently described may or may not occur, and the description includes instances in which the event or circumstance occurs and instances in which it does not. For example, "optional pharmaceutical excipients" indicates that a formulation described may or may not include pharmaceutical excipients other than those specifically stated to be present, and that the formulation thus described includes cases in which the optional excipients are present and cases in which they are not is it.

"Behandle" og "behandling" refererer til en hvilken som helst behandling av en sykdom hos et pattedyr, som inkluderer mennesket, som inkluderer: (i) hindre sykdommen fra å finne sted hos et subjekt som kan være forhåndsdisponert for sykdommen, men ikke ennå er blitt diagnostisert for å ha den; "Treat" and "treatment" refer to any treatment of a disease in a mammal, including man, which includes: (i) preventing the disease from occurring in a subject who may be predisposed to the disease but not yet have been diagnosed as having it;

(ii) inhibere sykdommen, dvs. stoppe dens utvikling; eller (ii) inhibit the disease, i.e. stop its development; or

(iii) oppheve sykdommen, dvs. forårsake tilbakegang av sykdommen. (iii) reverse the disease, i.e. cause regression of the disease.

Sammensetninger ifølge oppfinnelsen er anvendelige for behandling av pattedyr i en behandling av en utvalgt gruppe som består av beskyttelse av skjelettmuskler og skade som resultat av traume, beskytte skjelettmuskler etterfølgende muskel eller systemisk sykdom slik som periodisk klaudikasjon, for å behandle sjokktilstander, for å opprettholde donorvev og organer anvendt i transplantater, og å behandle kardiovaskulære sykdommer som inkluderer atriale og ventrikulære arrytmier, Prinzmetars (variant) angina, stabil angina, og øvelsesindusert angina, kongestiv hjertesykdom og myokardisk infarkt. Behandlingen utføres ved anvendelse av terapeutisk effektiv mengde av en forbindelse ifølge oppfinnelsen og/eller et farmasøytisk akseptabelt syreaddisjonssalt derav i blanding med en farmasøytisk akseptabel eksipient. Compositions according to the invention are useful for the treatment of mammals in a treatment of a selected group consisting of the protection of skeletal muscles and damage as a result of trauma, protecting skeletal muscles following muscle or systemic disease such as periodic claudication, to treat shock states, to maintain donor tissue and organs used in transplants, and to treat cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmet's (variant) angina, stable angina, and exercise-induced angina, congestive heart disease and myocardial infarction. The treatment is carried out by using a therapeutically effective amount of a compound according to the invention and/or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable excipient.

Forbindelser som faller innenfor omfanget av oppfinnelsen inkluderer det optiske isomerene (+) og (-) og R- og S-isomerene av de ovenfor-identifiserte forbindelsene og blandinger derav. Oppfinnelsen inkluderer de enkelte isomerene og alle mulige blandinger derav. Compounds falling within the scope of the invention include the optical isomers (+) and (-) and R and S isomers of the above-identified compounds and mixtures thereof. The invention includes the individual isomers and all possible mixtures thereof.

Alle av de tidligere angitte utførelsesformene inkluderer farmasøytisk akspetable syreaddisjonssalter derav, særlig mono- og dihydroklorider, og blandinger derav. All of the previously stated embodiments include pharmaceutically acceptable acid addition salts thereof, particularly mono- and dihydrochlorides, and mixtures thereof.

Forbindelsene som har den generelle formel I kan fremstilles som angitt i skjemaene IA-7A. En generell syntese av forbindelser ifølge oppfinnelsen er angitt i skjema IA. Forbindelse IV kan fremstilles ved N-acylering av substituert anilin II med 2-substituert kloracetylklorid III. Forbindelse II er kommersielt tilgjengelig og fremstilles enkelt ved reduksjon av det korresponderende nitrobenzenderivåtet (syre/SnCU eller katalytisk hydrogenering, se Advanced Organic Chemistry, (Ed. J. March, (1992) A. Wiley-Interscience. Noen eksempler på kommersielt tilgjengelige substituerte aniliner som korresponderer til generell struktur II inkluderer 2,6-dimetylanilin, 2,3-dimetylanilin, 2-metylanilin, 4-metylanilin, 4-metylanilin, 2,4-dikloranilin, 3,4-dikloranilin, 2,5-dikloranilin, 2,4-dikloranilin, 2-kloranilin, 3-klor-anilin, 2,6-difluoranilin, 2,5-difluoranilin, 3,4-difluoranilin, 2-fluoranilin, 4-fluoranilin, 3-fluoranilin, 2-fluor-6-kloranilin, 4-fluro-3-kloranilin. The compounds of general formula I may be prepared as indicated in Schemes IA-7A. A general synthesis of compounds according to the invention is given in scheme IA. Compound IV can be prepared by N-acylation of substituted aniline II with 2-substituted chloroacetyl chloride III. Compound II is commercially available and is readily prepared by reduction of the corresponding nitrobenzene derivative (acid/SnCU or catalytic hydrogenation, see Advanced Organic Chemistry, (Ed. J. March, (1992) A. Wiley-Interscience. Some examples of commercially available substituted anilines corresponding to general structure II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, 4-methylaniline, 4-methylaniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline, 2 ,4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2,6-difluoroaniline, 2,5-difluoroaniline, 3,4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6 -chloroaniline, 4-fluro-3-chloroaniline.

Forbindelse VI kan oppnås ved å omsette forbindelse IV med N-beskyttet substituert piperazin V gjennom oppvarming i et passende løsemiddel (for eksempel DMF, EtOH). Beskyttelse av nitrogenet i forbindelse V er kun påkrevet når det er nødvendig å kontrollere regiokjemien ved addisjon av forbindelse V med forbindelse IV. I noen tilfeller kan forbindelse V oppnås fra kommersielle kilder. Eksempler på kommersielle tilgjengelige forbindelser som korresponderer til generell struktur V inkluderer 2-metylpiperazin, 2,5-dimetylpiperazin og 2,6-dimetylpiperazin. Avbeskyttelse av forbindelse VI kan utføres ved anvendelse av standard betingelser (for eksempel for Boe gruppe anvend TF A, for CBZ og benzyl anvend hydrogenering). Forbindelse I kan fremstilles ved å omsette en forbindelse VII med epoksid VIII ved oppvarming i et passende løsemiddel (etanol, DMF). Compound VI can be obtained by reacting compound IV with N-protected substituted piperazine V through heating in a suitable solvent (eg DMF, EtOH). Protection of the nitrogen in compound V is only required when it is necessary to control the regiochemistry by addition of compound V with compound IV. In some cases, compound V can be obtained from commercial sources. Examples of commercially available compounds corresponding to general structure V include 2-methylpiperazine, 2,5-dimethylpiperazine and 2,6-dimethylpiperazine. Deprotection of compound VI can be carried out using standard conditions (for example for the Boe group use TF A, for CBZ and benzyl use hydrogenation). Compound I can be prepared by reacting a compound VII with epoxide VIII by heating in a suitable solvent (ethanol, DMF).

Epoksid VIII (hvor m = 1 eller 2) kan fremstilles som angitt i skjema 2. Oppvarming av substituert fenol IX med epiklorhydrin, epibromhydrin, eller 4-brom-l,2-epoksybutan og kalium karbonat i aceton kan gi epoksid VIII. Forbindelse IX kan oppnås fra forskjellige kilder. Eksempler på kommersielt tilgjengelige forbindelser av forbindelse IX inkluderer 2-klorfenol, 2-fluorfenol, 2-metoksyfenol, 2-metylfenol, sesamol, 2,6-diklorfenol, 3,5-diklorfenol, 2,6-difluorfenol, 2,4-difluorfenol5-indanol, 3-klor-4-fluorfenol, 2-klor-4-fluorfenol og 5,6,7,8-tetrahydro-2-naftol. I noen tilfeller kan forbindelse VIII oppnås fra kommersielle kilder. Eksempler på kommersielt tilgjengelige forbindelser som korresponderer til generell struktur VIII inkluderer bensyl, glycidyleter, glycidyl 2-metylfenyleter, glycidyl 4-metoksyfenyleter, glycidyl 4-klorfenyleter, glycidyl 2-klorfenyleter, glycidyl 2-metoksyfenyleter, glycidyl 4-metylfenyleter, glycidyl 3,4-diklorfenyleter og glycidyl 4-fluorfenyleter. Epoxide VIII (where m = 1 or 2) can be prepared as indicated in Scheme 2. Heating substituted phenol IX with epichlorohydrin, epibromohydrin, or 4-bromo-1,2-epoxybutane and potassium carbonate in acetone can give epoxide VIII. Compound IX can be obtained from various sources. Examples of commercially available compounds of compound IX include 2-chlorophenol, 2-fluorophenol, 2-methoxyphenol, 2-methylphenol, sesamol, 2,6-dichlorophenol, 3,5-dichlorophenol, 2,6-difluorophenol, 2,4-difluorophenol5 -indanol, 3-chloro-4-fluorophenol, 2-chloro-4-fluorophenol and 5,6,7,8-tetrahydro-2-naphthol. In some cases, compound VIII can be obtained from commercial sources. Examples of commercially available compounds corresponding to general structure VIII include benzyl, glycidyl ether, glycidyl 2-methylphenyl ether, glycidyl 4-methoxyphenyl ether, glycidyl 4-chlorophenyl ether, glycidyl 2-chlorophenyl ether, glycidyl 2-methoxyphenyl ether, glycidyl 4-methylphenyl ether, glycidyl 3,4 -dichlorophenyl ether and glycidyl 4-fluorophenyl ether.

Forbindelse V kan fremstilles som beskrevet i skjema 3. Alkylering av forbindelse XH med alkylhalogenider ved anvendelse av t-BuLi som base kan gi forbindelse XIII som beskrevet av Pohlman et al. (J. Org. Chem. (1997), 62,1016-1022). Reduksjon av XIV ved anvendelse av diboran kan gi N-benzylbeskyttet versjon av forbindelse V etter N-boc avbeskyttelse med trifluoreddiksyre (TFA) [for diboranreduksjon se Jacobson et al., J. Med. Chem. (1999), 42,1123-1144]. Compound V can be prepared as described in Scheme 3. Alkylation of compound XH with alkyl halides using t-BuLi as a base can give compound XIII as described by Pohlman et al. (J. Org. Chem. (1997), 62, 1016-1022). Reduction of XIV using diborane can give the N-benzyl protected version of compound V after N-boc deprotection with trifluoroacetic acid (TFA) [for diborane reduction see Jacobson et al., J. Med. Chem. (1999), 42,1123-1144].

Forbindelse V kan også fremstilles ved standard kobling (for eksempel EDC eller PyBroP) av D eller L aminosyre og standard avbeskyttelse som angitt i skjema 4. [For fremstilling av diketopiperaziner se P. Cledera et al., Tetrahedron (1998) s. 12349-12360 og R.A. Smith et al., Bioorg. Med. Chem. Lett. (1998) s. 2369-2374]. Reduksjon av diketopiperazinet med diboran kan gi forbindelse XIX den N-benzyl beskyttede versjon av forbindelse V. Compound V can also be prepared by standard coupling (eg EDC or PyBroP) of D or L amino acid and standard deprotection as indicated in scheme 4. [For preparation of diketopiperazines see P. Cledera et al., Tetrahedron (1998) pp. 12349- 12360 and R.A. Smith et al., Bioorg. With. Chem. Easy. (1998) pp. 2369-2374]. Reduction of the diketopiperazine with diborane can give compound XIX the N-benzyl protected version of compound V.

Forbindelse V inkluderer også de bisykliske homologene av piperazin (IS, 4S)-(+)-2,5-diazabisykl[2.2.1]heptan 83,3,8-diazabisyklo[3.2.1] oktan 84, og 2,5-diazabisyklo[2.2.2] oktan 85. Compound V also includes the bicyclic homologues of piperazine (IS, 4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83,3,8-diazabicyclo[3.2.1]octane 84, and 2,5- diazabicyclo[2.2.2] octane 85.

Kommersielt tilgjengelige bisykliske analoger inkluderer (IS, 4S)-(+)-2,5-diazabisyklo[2.2.1]heptan 83. Forbindelsene 84,85 og (1R,4R) isomer av 83 kan fremstilles ved publiserte fremgangsmåter (for 84 og 85, se Sturm, P.A. et al., J. Med. Chem., 1974,17,481-487; for 83 se, Barish, T.F. og Fox, D.E. J. Org. Chem., 1990, 55, 1684-1687. Commercially available bicyclic analogues include (IS,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83. Compounds 84,85 and the (1R,4R) isomer of 83 can be prepared by published procedures (for 84 and 85, see Sturm, P. A. et al., J. Med. Chem., 1974, 17, 481-487; for 83 see, Barish, T. F. and Fox, D. E. J. Org. Chem., 1990, 55, 1684-1687.

Et spesifikt eksempel på fremstilling av en forbindelse med formel I er beskrevet i skjemaene 5A, 6A og 7A for ytterligere å illustrere hvordan forbindelser ifølge oppfinnelsen fremstilles. Spesielt ble 2,6-dikloranilin acylert med 2-kloracetylklorid 2 ved anvendelse av mettet bikarbonat og eter (1:1) som base og ko-løsemiddel, respektivt, for å gi kloracetamidderivatet 3. Ytterligere reaksjon mellom forbindelse 3 og 2,6-dimetylpiperazin ga forbindelse 5 ved oppvarming i etanol. Reaksjon mellom forbindelse 5 og epoksy 6 ved oppvarming av begge komponenter i etanol til refluks ga 2,6-dimetylpiperazinderivat 7. Forbindelse 6 ble i sin tur fremstilt ved oppvarming av epiklorhydrin med 2-metoksyfenol i aceton under nærvær av K2CO3 som beskrevet i skjema 6. A specific example of the preparation of a compound of formula I is described in schemes 5A, 6A and 7A to further illustrate how compounds according to the invention are prepared. Specifically, 2,6-dichloroaniline was acylated with 2-chloroacetyl chloride 2 using saturated bicarbonate and ether (1:1) as base and co-solvent, respectively, to give the chloroacetamide derivative 3. Further reaction between compound 3 and 2,6- dimethylpiperazine gave compound 5 on heating in ethanol. Reaction between compound 5 and epoxy 6 by heating both components in ethanol to reflux gave 2,6-dimethylpiperazine derivative 7. Compound 6 was in turn prepared by heating epichlorohydrin with 2-methoxyphenol in acetone in the presence of K2CO3 as described in scheme 6 .

En spesifikk syntese av forbindelse 14 er beskrevet i skjema 7. Forbindelse 11 ble fremstilt ved åpning av epoksid 6 med Boc-etylendiamin ved oppvarming i EtOH. Acylering av forbindelse 11 ble utført ved anvendelse av kloracetylklorid i diklormetan ved anvendelse av diisopropyletylamin som base. Fjerning av Boe gruppen ved anvendelse av TF A fulgt av ringlukning ved oppvarming i EtOH ga forbindelse 13. Reaksjon mellom forbindelse 13 og 3 slik det er beskrevet ovenfor ga forbindelse 14. Forbindelsene som har generell formel I kan fremstilles som angitt i skjema IB-7B. En generell syntese av forbindelsen ifølge oppfinnelsen er angitt i skjema IB. Forbindelse IV kan fremstilles ved N-acylering av substituerte aniliner med generell struktur II med 2-substituert kloracetylklorid III. Forbindelse II er tilgjengelig kommersielt eller fremstilles enkelt gjennom reduksjon av det korresponderende nitrobenzenderivatet (syre/SnCl2, eller katalytisk hydrogenering, se Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Noen eksempler på kommersielt tilgjengelige aniliner med generell struktur II inkluderer 2,6-dimetylanilin, 2,3-dimetylanilin, 2-metylanilin, 4-metylanilin, 2,4-dikloranilin, 3,4-dikloranilin, 2,5-dikloranilin, 2,4-difluoranilin, 2-fluoranilin, 4-fluroanilin, 3-fluoranilin, 2-fluor-6-kloranilin, 4-fluor-3-kloranilin. A specific synthesis of compound 14 is described in Scheme 7. Compound 11 was prepared by opening epoxide 6 with Boc-ethylenediamine by heating in EtOH. Acylation of compound 11 was carried out using chloroacetyl chloride in dichloromethane using diisopropylethylamine as base. Removal of the Boe group using TF A followed by ring closure by heating in EtOH gave compound 13. Reaction between compound 13 and 3 as described above gave compound 14. The compounds of general formula I can be prepared as shown in Scheme IB-7B . A general synthesis of the compound according to the invention is given in scheme IB. Compound IV can be prepared by N-acylation of substituted anilines of general structure II with 2-substituted chloroacetyl chloride III. Compound II is available commercially or is readily prepared by reduction of the corresponding nitrobenzene derivative (acid/SnCl 2 , or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Some examples of commercially available anilines of general structure II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, 4-methylaniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline, 2 ,4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4-fluoro-3-chloroaniline.

Forbindelse VI kan oppnås ved å reagere forbindelse IV med et N-beskyttet substituert piperazin V ved oppvarming i et passende løsemiddel (for eksempel DMF, EtOH). Beskyttelse av nitrogenet i forbindelse V er kun påkrevet når det er nyttig å kontrollere regiokjemien av tilsettingen av forbindelse V med forbindelse IV. I noen tilfeller kan forbindelse V oppnås fra kommersielle kilder. Eksempler på kommersielt tilgjengelige forbindelser med generell struktur V inkluderer 2-metylpiperazin, 2,5-dimetylpiperazin og 2,6-dimetylpiperazin. Avbeskyttelse av forbindelse VI kan utføres ved anvendelse av standardbetingelser (for eksempel for Boe gruppe anvend TF A, for CBZ og benzyl anvend hydrogenering). Forbindelse I kan fremstilles ved omsette forbindelse VII med epoksid VIII ved oppvarming i passende løsemiddel (etanol, DMF). Compound VI can be obtained by reacting compound IV with an N-protected substituted piperazine V by heating in a suitable solvent (eg DMF, EtOH). Protection of the nitrogen in compound V is only required when it is useful to control the regiochemistry of the addition of compound V with compound IV. In some cases, compound V can be obtained from commercial sources. Examples of commercially available compounds of general structure V include 2-methylpiperazine, 2,5-dimethylpiperazine and 2,6-dimethylpiperazine. Deprotection of compound VI can be carried out using standard conditions (for example for the Boe group use TF A, for CBZ and benzyl use hydrogenation). Compound I can be prepared by reacting compound VII with epoxide VIII by heating in a suitable solvent (ethanol, DMF).

Epoksid VIII kan fremstilles som angitt i skjema 2B. Epoksidering av substituert allylbenzen XI ved anvendelse av mCPB A eller hydrogenperoksid kan gi epoksid VIII (G. Majetich, R. Hicks, G. Sun og P. McGill, (1998), 63,2564-2573). Forbindelse XI kan i sin tur fremstilles ved å omsette aldehyd IX og metylentrifenylfosforan under Wittig-betingelser eller Horner Emmons betingelser [Advanced Organic Chemistry, Eds. J. March, (1992), Wiley-Interscience publication og S. Pine, G. Shen og H. Hoang, Synthesis, (1991), 1]. Forbindelse XI kan også fremstilles enkelt ved å koble et halogenid med den generelle formel X og allylmagnesiumbromid. I noen tilfeller kan forbindelse XI oppnås fra kommersielle kilder. Eksempler på kommersielt tilgjengelige forbindelser som korresponderer til generell struktur XI inkluderer (hvor m = 0) 3-fluorstyren, 4-fluorstyren, 2-klorstyren, 3-klorstyren, 4-klorstyren, 2,6-diklorstyren, 3,4-diklorstyren og 3,4-dimetoksystyren. Andre eksempler på kommersielt tilgjengelige forbindelser med generell struktur XI inkluderer (hvor m = 1) 4-metoksyallylbenzen, 2-hydroksyallylbenzen, 4,5-dimetoksyallylbenzen, 2-metylallylbenzensafrol og 1-allylnaftalen. Epoxide VIII can be prepared as indicated in Scheme 2B. Epoxidation of substituted allylbenzene XI using mCPB A or hydrogen peroxide can give epoxide VIII (G. Majetich, R. Hicks, G. Sun and P. McGill, (1998), 63, 2564-2573). Compound XI can in turn be prepared by reacting aldehyde IX and methylenetriphenylphosphorane under Wittig conditions or Horner Emmons conditions [Advanced Organic Chemistry, Eds. J. March, (1992), Wiley-Interscience publication and S. Pine, G. Shen and H. Hoang, Synthesis, (1991), 1]. Compound XI can also be prepared simply by coupling a halide of the general formula X and allyl magnesium bromide. In some cases, compound XI can be obtained from commercial sources. Examples of commercially available compounds corresponding to general structure XI include (where m = 0) 3-fluorostyrene, 4-fluorostyrene, 2-chlorostyrene, 3-chlorostyrene, 4-chlorostyrene, 2,6-dichlorostyrene, 3,4-dichlorostyrene and 3,4-Dimethoxystyrene. Other examples of commercially available compounds of general structure XI include (where m = 1) 4-methoxyallylbenzene, 2-hydroxyallylbenzene, 4,5-dimethoxyallylbenzene, 2-methylallylbenzenesafrole and 1-allylnaphthalene.

Forbindelse V kan fremstilles som beskrevet i skjema 3B. Alkylering av forbindelse XII med alkylhalogenider ved anvendelse av t-BuLi som base kan gi forbindelse XIII som beskrevet av Pohlman et al. (J. Org. Chem. (1997), 62,1016-1022). Reduksjon av XIII ved anvendelse av diboran kan gi N-benzylbeskyttet versjon av forbindelse V etter N-boc avbeskyttelse med trifluoreddiksyre (TFA, for diboranreduksjon se Jacobson et al., J. Med. Chem., (1999), 42,1123-1144). Compound V can be prepared as described in scheme 3B. Alkylation of compound XII with alkyl halides using t-BuLi as base can give compound XIII as described by Pohlman et al. (J. Org. Chem. (1997), 62, 1016-1022). Reduction of XIII using diborane can give N-benzyl protected version of compound V after N-boc deprotection with trifluoroacetic acid (TFA, for diborane reduction see Jacobson et al., J. Med. Chem., (1999), 42,1123-1144 ).

Forbindelse V kan også fremstilles ved standard kobling (for eksempel EDC eller PyBroP) av D eller L aminosyrer og standard avbeskyttelse (for eksempel Boc-fjerning ved TFA behandling) som angitt i skjema 4. [For fremstilling av diketopiperaziner se P. Cledera et al., Tetrahedron, (1998) s. 12349-12360 og R.A. Smith et al., Bioorg. Med. Chem. Lett. (1998) s. 2369-2374]. Reduksjon av diketopiperazinet med diboran kan gi N-bensyl-beskyttet versjon av forbindelse V. Compound V can also be prepared by standard coupling (for example EDC or PyBroP) of D or L amino acids and standard deprotection (for example Boc removal by TFA treatment) as indicated in scheme 4. [For the preparation of diketopiperazines see P. Cledera et al ., Tetrahedron, (1998) pp. 12349-12360 and R.A. Smith et al., Bioorg. With. Chem. Easy. (1998) pp. 2369-2374]. Reduction of the diketopiperazine with diborane can give the N-benzyl-protected version of compound V.

Forbindelse V kan også inkludere de bisykliske homologene av piperazin (lS,4S)-(+)-2,5-diazabisyklo[2.2.1]heptan 83, 3,8-diazabisyklo[3.2.1]oktan 84, og 2,5-diazabisyklo[2.2.2]oktan 85. Compound V may also include the bicyclic homologues of piperazine (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83, 3,8-diazabicyclo[3.2.1]octane 84, and 2,5 -diazabicyclo[2.2.2]octane 85.

Kommersielt tilgjengelige bisykliske analoger inkluderer (lS,4S)-(+)-2,5-diazabisyklo[2.2.1]heptan 83. Forbindelsene 85,85 og (1R,4R) isomer av 83 kan fremstilles ved publiserte fremgangsmåter (for 84 og 85 se Sturm, P.A. et al., J. Med. Chem., 1974,17,481-487; for 83 se Barish, T.F. og Fox, D.E. J. Org. Chem., 1990, 55, 1684-1687). Commercially available bicyclic analogues include (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane 83. Compounds 85,85 and the (1R,4R) isomer of 83 can be prepared by published procedures (for 84 and 85 see Sturm, P. A. et al., J. Med. Chem., 1974, 17, 481-487; for 83 see Barish, T. F. and Fox, D. E. J. Org. Chem., 1990, 55, 1684-1687).

Et spesifikt eksempel på fremstilling av forbindelsen ifølge oppfinnelsen er beskrevet i skjema 5B for ytterligere å illustrere hvordan forbindelsene ifølge oppfinnelsen fremstilles. Spesielt ble 2,6-dikloranilin acylert med 2-kloractylklorid 2 ved anvendelse av mettet bikarbonat og eter (1:1) som base og ko-løsemiddel, respektivt, for å gi kloracetamidderivatet 3. Ytterligere reaksjon med forbindelse 3 og piperazin ga forbindelse 5 ved oppvarming i etanol. Reaksjon mellom forbindelse 5 og epoksid 6 ved oppvarming av begge komponentene i etanol til refluks ga piperazinderivat 7. Forbindelse 8 er kommersielt tilgjengelig og ble epoksidert ved anvendelse av 3-klorperoksybenzosyre i diklormetan som illustrert i skjema 6B. A specific example of the preparation of the compound according to the invention is described in scheme 5B to further illustrate how the compounds according to the invention are prepared. Specifically, 2,6-dichloroaniline was acylated with 2-chloroactyl chloride 2 using saturated bicarbonate and ether (1:1) as base and cosolvent, respectively, to give the chloroacetamide derivative 3. Further reaction with compound 3 and piperazine gave compound 5 by heating in ethanol. Reaction of compound 5 with epoxide 6 by heating both components in ethanol to reflux afforded piperazine derivative 7. Compound 8 is commercially available and was epoxidized using 3-chloroperoxybenzoic acid in dichloromethane as illustrated in Scheme 6B.

Firekarbon-epoksid 15 kan fremstilles ved å koble kommersielt tilgjengelig 4-metoksybensylklorid og allylmagnesiumbromid fulgt av oksidering med mCPBA som illustrert i skjema 7B. Four-carbon epoxide 15 can be prepared by coupling commercially available 4-methoxybenzyl chloride and allyl magnesium bromide followed by oxidation with mCPBA as illustrated in Scheme 7B.

SKJEMA 7B FORM 7B

Forbindelsene som har generell formel I og IC kan fremstilles som angitt i skjema IC-6C. En generell syntese av forbindelsen ifølge oppfinnelsen er angitt i skjema IC. Forbindelse IV kan fremstilles ved N-acylering av substituert anilin II med 2-substituert kloracetylklorid III. Forbindelse II er kommersielt tilgjengelig eller fremstilles lett ved reduksjon av det korresponderende nitrobenzenderivatet (syre/SnCk eller katalytisk hydrogenering, se Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Noen eksempler på kommersielt tilgjengelig substituert anilin II inkluderer 2,6-dimetylanilin, 2,3-dimetylanilin, 2-metylaniIin, 4-metylanilin, 2,4-dikloranilin, 3,4-dikloranilin, 2,5-dikloranilin, 2,4-dikloranilin, 2-kloranilin, 3-kloranilin, 2,6-difluoranilin, 2,5-difluoranilin, 3,4-difluoranilin, 2-fluoranilin, 4-fluoranilin, 3-fluoranilin, 2-fluor-6-kloranilin, 4-fluor-3-kloranilin. The compounds of general formulas I and IC may be prepared as indicated in Scheme IC-6C. A general synthesis of the compound according to the invention is given in scheme IC. Compound IV can be prepared by N-acylation of substituted aniline II with 2-substituted chloroacetyl chloride III. Compound II is commercially available or readily prepared by reduction of the corresponding nitrobenzene derivative (acid/SnCk or catalytic hydrogenation, see Advanced Organic Chemistry, Ed. J. March, (1992) A. Wiley-Interscience). Some examples of commercially available substituted aniline II include 2,6-dimethylaniline, 2,3-dimethylaniline, 2-methylaniline, 4-methylaniline, 2,4-dichloroaniline, 3,4-dichloroaniline, 2,5-dichloroaniline, 2,4 -dichloroaniline, 2-chloroaniline, 3-chloroaniline, 2,6-difluoroaniline, 2,5-difluoroaniline, 3,4-difluoroaniline, 2-fluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 2-fluoro-6-chloroaniline, 4 -fluoro-3-chloroaniline.

Forbindelse VI kan oppnås ved å omsette forbindelse IV med N-beskyttet substituert piperazin V ved oppvarming i passende løsemiddel (for eksempel DMF, EtOH). Beskyttelse av nitrogen til forbindelse V er kun påkrevet når det er nyttig å kontrollere regiokjemien av addisjonen av forbindelse V med forbindelse IV. I noen tilfeller kan forbindelse V oppnås fra kommersielle kilder. Eksempler på kommersielt tilgjengelige forbindelser som korresponderer til den generelle strukturen V inkluderer 2-metylpiperazin, 2,5-dimetylpiperazin, 2,6-dimetylpiperazin og 4-bensyloksy-karbonylpiperazin-2-on. Avbeskyttelse av forbindelse VI kan utføres ved anvendelse av standardbetingelser (for eksempel Boe gruppe anvend TF A, for CBZ og benzyl anvend hydrogenering). Forbindelse I kan fremstilles ved å omsette forbindelse VII med epoksid VIII ved oppvarming i passende løsemiddel (etanol, DMF). Compound VI can be obtained by reacting compound IV with N-protected substituted piperazine V by heating in a suitable solvent (eg DMF, EtOH). Protection of the nitrogen of compound V is only required when it is useful to control the regiochemistry of the addition of compound V with compound IV. In some cases, compound V can be obtained from commercial sources. Examples of commercially available compounds corresponding to the general structure V include 2-methylpiperazine, 2,5-dimethylpiperazine, 2,6-dimethylpiperazine and 4-benzyloxy-carbonylpiperazin-2-one. Deprotection of compound VI can be carried out using standard conditions (eg Boe group using TF A, for CBZ and benzyl using hydrogenation). Compound I can be prepared by reacting compound VII with epoxide VIII by heating in a suitable solvent (ethanol, DMF).

Epoksid VIII kan fremstilles som angitt i skjema 2C. Oppvarming av alkylalkohol IX med epiklorhydrin eller epibromhydrin og natriurnhydrid i DMF kan gi epoksid VIII. I noen tilfeller kan forbindelse VIII oppnås fra kommersielle kilder. Eksempler på kommersielt tilgjengelige forbindelser med generell struktur VIII inkluderer glycidyl isopropyleter, N butylglycidyleter, T butylglycidyleter og iso-butylglycidyleter. Epoxide VIII can be prepared as indicated in Scheme 2C. Heating alkyl alcohol IX with epichlorohydrin or epibromohydrin and sodium hydride in DMF can give epoxide VIII. In some cases, compound VIII can be obtained from commercial sources. Examples of commercially available compounds of general structure VIII include glycidyl isopropyl ether, N butyl glycidyl ether, T butyl glycidyl ether and iso-butyl glycidyl ether.

Forbindelse V kan fremstilles som beskrevet i skjema 3C. Alkylering av forbindelse XII med alkylhalogenider ved anvendelse av t-BuLi som base kan gi forbindelse XIII som beskrevet av Pohlman et al., (J. Org. Chem., (1997), 62, 1016-1022). Reduksjon av XIV ved anvendelse av diboran kan gi N-benzylbeskyttet versjon av forbindelse V etter N-Boc avbeskyttelse med trifluoreddiksyre (TFA, for diboran reduksjonen se Jacobson et al., J. Med. Chem., (1999), 42, 1123-1144). Compound V can be prepared as described in Scheme 3C. Alkylation of compound XII with alkyl halides using t-BuLi as base can give compound XIII as described by Pohlman et al., (J. Org. Chem., (1997), 62, 1016-1022). Reduction of XIV using diborane can give N-benzyl protected version of compound V after N-Boc deprotection with trifluoroacetic acid (TFA, for the diborane reduction see Jacobson et al., J. Med. Chem., (1999), 42, 1123- 1144).

Forbindelse V kan også fremstilles ved standard kobling (for eksempel EDC eller Compound V can also be prepared by standard coupling (for example EDC or

PyBoP) av D eller L aminosyrer som angitt i skjema 4C. [For fremstillinger av diketo piperaziner se P. Cledera et al., Tetrahedron, (1998), s. 12349-12360 og R.A. Smith et al., Bioorg. Med. Chem. Lett. (1998) s. 2369-2374]. Reduksjon av diketo-piperazinet med diboran kan gi N-benzylbeskyttet versjon av forbindelse V. PyBoP) of D or L amino acids as indicated in Scheme 4C. [For preparations of diketo piperazines see P. Cledera et al., Tetrahedron, (1998), pp. 12349-12360 and R.A. Smith et al., Bioorg. With. Chem. Easy. (1998) pp. 2369-2374]. Reduction of the diketo-piperazine with diborane can give the N-benzyl protected version of compound V.

Et spesifikt eksempel på fremstilling av en forbindelse ifølge oppfinnelsen er beskrevet i skjema 5C og 6C for ytterligere å illustrere hvordan forbindelser ifølge oppfinnelsen fremstilles. A specific example of the preparation of a compound according to the invention is described in schemes 5C and 6C to further illustrate how compounds according to the invention are prepared.

Spesielt ble 2,6-dikloranilin acylert med 2-kloractylklorid 2 ved anvendelse av mettet bikarbonat og eter (1:1) som base og ko-løsemiddel, respektivt, for å gi kloracetamidderivat 3. Videre reaksjon av forbindelse 3 med piperazin ga forbindelse 5 ved oppvarming i etanol. Reaksjon mellom forbindelse 5 og epoksid 6 ved oppvarming av begge komponentene i etanol til refluks ga piperazinderivat 7. Forbindelse 6 ble i sin tur fremstilt ved oppvarming av epibromhydrin med 2-indanol i DMF i nærvær av NaH som beskrevet i skjema 6C. In particular, 2,6-dichloroaniline was acylated with 2-chloroactyl chloride 2 using saturated bicarbonate and ether (1:1) as base and co-solvent, respectively, to give chloroacetamide derivative 3. Further reaction of compound 3 with piperazine gave compound 5 by heating in ethanol. Reaction between compound 5 and epoxide 6 by heating both components in ethanol to reflux gave piperazine derivative 7. Compound 6 was in turn prepared by heating epibromohydrin with 2-indanol in DMF in the presence of NaH as described in Scheme 6C.

Syreaddisjonssaltene av forbindelse ifølge oppfinnelsen kan omdannes til den korresponderende frie basen ved behandling med en egnet base, slik som kalium karbonat eller natrium hydroksid, typisk i nærvær av et vandig løsemiddel, og en temperatur på mellom ca. 0°C og 100°C. Den frie baseformen isoleres ved vanlige fremgangsmåter, slik som ekstraksjon med et organisk løsemiddel. The acid addition salts of compounds according to the invention can be converted to the corresponding free base by treatment with a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of an aqueous solvent, and a temperature of between approx. 0°C and 100°C. The free base form is isolated by usual methods, such as extraction with an organic solvent.

Salter av forbindelsene ifølge oppfinnelsen kan skiftes ut ved å dra fordel av forskjellige løseligheter og flyktigheter, eller ved behandling av passende ladet jonebytterharpiks. Denne omdannelsen blir utført ved en temperatur mellom ca. 0°C og kokepunkt til løsemidlet som anvendes som medium for fremgangsmåten. Administrasjon av de aktive forbindelsene og saltene beskrevet heri kan være via en hvilken som helst av de aksepterte administrasjonsmodusene for terapeutiske midler. Disse metodene inkluderer oral, parenteral, transdermal, subkutan og andre systemiske moduser. Den foretrukne administrasjonsfremgangsmåten er oral, unntatt i de tilfeller der subjektet er ute av stand til å ta inn, ved seg selv, eventuell medisinering. I disse tilfeller vil det være nødvendig å administrere sammensetningen parenteralt. Salts of the compounds of the invention can be replaced by taking advantage of different solubilities and volatilities, or by treatment with suitably charged ion exchange resin. This conversion is carried out at a temperature between approx. 0°C and boiling point of the solvent used as medium for the method. Administration of the active compounds and salts described herein may be via any of the accepted modes of administration for therapeutic agents. These methods include oral, parenteral, transdermal, subcutaneous and other systemic modes. The preferred method of administration is oral, except in cases where the subject is unable to ingest, by himself, any medication. In these cases, it will be necessary to administer the composition parenterally.

Foreliggende oppfinnelse omfatter videre anvendelse av en forbindelse som omtalt ovenfor for fremstilling av et preparat for behandling av et pattedyr som trenger behandling valgt fra gruppen som består av å beskytte skjelettmuskelatur mot skade som resultat av traumer, beskytte skjelettmuskler etterfølgende muskel- eller systemiske sykdommer, å behandle sjokktilstander, å bevare donorvev og organer anvendt ved transplantasjon og å behandle kardiovaskulære sykdommer. The present invention further comprises the use of a compound as mentioned above for the preparation of a preparation for the treatment of a mammal in need of treatment selected from the group consisting of protecting skeletal muscle from damage as a result of trauma, protecting skeletal muscle following muscular or systemic diseases, to treating shock conditions, preserving donor tissue and organs used in transplantation and treating cardiovascular diseases.

Foreliggende oppfinnelse omfatter videre en farmasøytisk sammensetning, kjennetegnet ved at den innbefatter forbindelse som omtalt ovenfor og en eller flere farmasøytiske eksipienter. The present invention further comprises a pharmaceutical composition, characterized in that it includes a compound as mentioned above and one or more pharmaceutical excipients.

Avhengig av tiltenkt modus kan sammensetningene være i form av faste, delvis faste, eller flytende doseringsformer, slike som for eksempel tabletter, stikkpiller, piller, kapsler, pulvere, væsker, suspensjoner eller lignende, foretrukket i enhetsdoserings-former egnet for enkel administrasjon av presise doseringer. Sammensetningene kan inkludere en eller flere vanlige farmasøytiske eksipienter og minst en aktiv forbindelse ifølge oppfinnelsen eller de farmasøytisk akseptable saltene derav, og, i tillegg, kan inkludere andre medisinske midler, farmasøytiske midler, bærere, adjuvanser, fortynningsmidler, etc. Depending on the intended mode, the compositions may be in the form of solid, semi-solid or liquid dosage forms, such as for example tablets, suppositories, pills, capsules, powders, liquids, suspensions or the like, preferably in unit dosage forms suitable for easy administration of precise dosages. The compositions may include one or more common pharmaceutical excipients and at least one active compound of the invention or its pharmaceutically acceptable salts, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.

Mengden aktiv forbindelse administrert vil selvfølgelig avhenge av subjektet som behandles, subjektets vekt, alvorligheten av lidelsen, administrasjonsmåten og vurderinger til legen. Imidlertid er en effektiv dosering i området fra 0,1 - 30 mg/kg/dag, foretrukket 0,5 - 20 mg/kg/dag. For et gjennomsnittlig 70 kg menneske vil denne mengden utgjøre 7 - 2100 mg pr. dag, eller foretrukket 35 - 1400 mg/dag. Siden mange av effektene til forbindelsene heri (beskytte skjelettmuskler mot skade som resultat av traume; beskytte skjelettmuskler etterfølgende muskel- eller systemiske sykdommer slik som periodisk klaudikasjon; behandle sjokktilstander; bevare donorvev og organer anvendt ved transplantater; behandle kardiovaskulære sykdommer slik som artial og ventrikulær arrytmier, Prinzmetars (variant) angina, stabil angina, øvelsesindusert angina, kongestiv hjertesykdom og myokardisk infarkt) oppnås ved en tilsvarende mekanisme (delvis fettsyreoksidasjoninhibering) er dosene (og administrasjonsformene) alle generelt innenfor samme generelle og foretrukne områder for alle disse anvendelsene. The amount of active compound administered will of course depend on the subject being treated, the subject's weight, the severity of the disorder, the method of administration and assessments of the physician. However, an effective dosage is in the range from 0.1 - 30 mg/kg/day, preferably 0.5 - 20 mg/kg/day. For an average 70 kg person, this amount will amount to 7 - 2100 mg per day, or preferably 35 - 1400 mg/day. Since many of the effects of the compounds herein (protecting skeletal muscles from injury as a result of trauma; protecting skeletal muscles following muscular or systemic diseases such as periodic claudication; treating shock states; preserving donor tissues and organs used in transplants; treating cardiovascular diseases such as arterial and ventricular arrhythmias , Prinzmetar's (variant) angina, stable angina, exercise-induced angina, congestive heart disease and myocardial infarction) are achieved by a similar mechanism (partial fatty acid oxidation inhibition), the doses (and forms of administration) are all generally within the same general and preferred ranges for all these applications.

For faste sammensetninger kan vanlige ikke-toksiske faste stoffer for eksempel inneholde farmasøytiske kvaliteter av mannitol, laktose, stivelse, magnesiumstearat, natriumsakkarid, talkum, cellulose, glukose, sukrose, magnesiumkarbonat, og lignende anvendes. Den aktive forbindelsen som definert ovenfor kan formuleres som stikkpiller, for eksempel ved anvendelse av polyalkylenglykoler, for eksempel propylenglykol, som bærer. Flytende farmasøytisk administrerbare sammensetninger kan for eksempel fremstilles ved å løse opp, dispergere etc, en aktiv forbindelse som definert ovenfor og eventuelt farmasøytiske adjuvanser i en eksipient, slik som for eksempel vann, saltvann, vandig dekstrose, glyserol, etanol og lignende, og dermed danne en løsning eller suspensjon. Hvis det er ønskelig kan den farmasøytiske sammensetningen som skal administreres også inneholde mindre mengder ikke-toksiske hjelpesubstanser slik som fuktemiddel eller emulgeringsmidler, pH-buffere og lignende, for eksempel natriumacetat, sorbitanmonolaurat, trietanolamin, natriumacetat, trietanolamin oleat, etc. Fremgangsmåter for fremstilling av slike doseringsformer er kjente, og vil være klart for fagmannen; se for eksempel Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975. Sammensetningen eller formuleringen som skal administreres vil uansett inneholde en mengde aktiv forbindelse, en terapeutisk effektiv mengde, dvs. en mengde effektiv til å lindre symptomene til subjektet som behandles. For oral administrasjon blir en farmasøytisk akseptabel ikke-toksisk sammensetning dannet ved inkorporering av en hvilken som helst av de vanligvis anvendte eksipientene, slik som for eksempel farmasøytiske kvaliteter av mannitol, laktose, stivelse, magnesium stearat, natrium sakkarin, talkum, cellulose, glukose, sukrose, magnesium, karbonat og lignende. Slike sammensetninger kan ha form av løsninger, suspensjoner, tabletter, piller, kapsler, pulvere, vedvarende frigivelsesformuleringer og lignende. Slike sammensetninger kan inneholde 10%-95% aktiv ingrediens, foretrukket 1-70%. For solid compositions, common non-toxic solids containing, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharide, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like can be used. The active compound as defined above can be formulated as suppositories, for example using polyalkylene glycols, for example propylene glycol, as a carrier. Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as defined above and possibly pharmaceutical adjuvants in an excipient, such as for example water, saline, aqueous dextrose, glycerol, ethanol and the like, thereby forming a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain smaller amounts of non-toxic excipients such as wetting agents or emulsifiers, pH buffers and the like, for example sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, etc. such dosage forms are known, and will be clear to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975. The composition or formulation to be administered will in any case contain an amount of active compound, a therapeutically effective amount, i.e., an amount effective to relieve the symptoms of the subject which is processed. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by incorporating any of the commonly used excipients such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium, carbonate and the like. Such compositions may take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. Such compositions may contain 10%-95% active ingredient, preferably 1-70%.

Parenteral administrasjon er generelt karakterisert ved injeksjon, enten subkutant, intramuskulært eller intravenøst. Injiserbare formuleringer kan fremstilles i vanlige former, enten som flytende løsninger eller suspensjoner, faste former egnet for løsning eller suspensjon i væske før injeksjon eller som emulsjoner. Egnede eksipienter er for eksempel vann, saltvann, dekstrose, glyceserol, etanol eller lignende. I tillegg, hvis ønskelig, kan de farmasøytiske sammensetningene som administreres også inneholde mindre mengder ikke-toksiske hjelpesubstanser slike som fuktemidler eller emulgeringsmidler, pH-buffere og lignende, slik som for eksempel natriumacetat, sorbitanmonolaurat, trietanolaminoleat, etc. Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectable formulations can be prepared in common forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid before injection or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions administered may also contain smaller amounts of non-toxic excipients such as wetting agents or emulsifiers, pH buffers and the like, such as for example sodium acetate, sorbitan monolaurate, triethanolamino oleate, etc.

En nylig anvist fremgangsmåte for parenteral administrasjon anvender implantering av et sakte frigivelses- eller vedvarende frigivelsessystem, slik at et konstant nivå av dosen opprettholdes. Se for eksempel US patent nr. 3,710,795.1 en annen nylig utviklet fremgangsmåte kan sammensetninger ifølge oppfinnelsen administreres oralt i en vedvarende frigivelsesdoseringsform ved anvendelse av sammensetningene og/eller fremgangsmåtene beskrevet i US patent søknad serie nr. 09/321,522 inngitt 27. Mai 1999. A recently indicated method of parenteral administration utilizes the implantation of a slow release or sustained release system so that a constant level of dose is maintained. See for example US patent no. 3,710,795.1 another recently developed method, compositions according to the invention can be administered orally in a sustained release dosage form using the compositions and/or methods described in US patent application series no. 09/321,522 filed 27 May 1999.

Følgende eksempler er representative for oppfinnelsen, men er ikke konstruert som begrensning av oppfinnelsens omfang. The following examples are representative of the invention, but are not intended to limit the scope of the invention.

Eksempel 1 Example 1

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksy)propyl]-3,5-dimetylpiperazinyl} acetamid (7). N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxy)propyl]-3,5-dimethylpiperazinyl} acetamide (7).

Del A. Part A.

Syntese av N-(2,6-dimetylfenyl)-2-kloracetamid (3). Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3).

2,6-dimetylanilin (9,8 g, 81,2 mmol) ble oppløst i eter (100 ml) og mettet vandig NaHC03 (100 ml) og reaksjonsblandingen ble avkjølt på isvann/vannbad. Til den kalde løsningen ble det tilsatt kloractylklorid 2 (9,17 g, 81,2 mmol) dråpevis i løpet av 2 timer. Blandingen ble avkjølt til romtemperatur i løpet av 14 timer. Blandingen ble ekstrahert med EtOAc (3 x 50). De kombinerte organiske sjiktene ble tørket over MgSCu, filtrert og konsentrert. Residuet ble triturert i eter og filtrert som ga forbindelse 3 som et hvitt faststoff. 2,6-Dimethylaniline (9.8 g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO 3 (100 mL) and the reaction mixture was cooled on an ice/water bath. To the cold solution was added chloroactyl chloride 2 (9.17 g, 81.2 mmol) dropwise over 2 hours. The mixture was cooled to room temperature over 14 hours. The mixture was extracted with EtOAc (3 x 50). The combined organic layers were dried over MgSCu, filtered and concentrated. The residue was triturated in ether and filtered to give compound 3 as a white solid.

Del B. Part B.

Syntese av N-(2,6-dimetyIfenyl)-2-(3,5-dimetylpiperazinyl)acetamid (5). Synthesis of N-(2,6-dimethylphenyl)-2-(3,5-dimethylpiperazinyl)acetamide (5).

Til en løsning av forbindelse 3 (5 g, 25,2 mmol) i etanol (100 ml) ble det tilsatt 2,6-dimetylpiperazin 4 (2,1 g, 25,0 mmol) og N,N-diisopropylamin (3,2 g, 25,2 mmol). Reaksjonsblandingen ble refluksert i 24 timer. Blandingen ble konsentrert i vakuum og residuet ble renset med kolonne kromatografi (10:1, DCM:MeOH) som ga forbindelse 5. To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added 2,6-dimethylpiperazine 4 (2.1 g, 25.0 mmol) and N,N-diisopropylamine (3, 2 g, 25.2 mmol). The reaction mixture was refluxed for 24 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1, DCM:MeOH) to give compound 5.

Del C. Part C.

Syntese av glycidyl 4-metoksyfenyleter (6). Synthesis of glycidyl 4-methoxyphenyl ether (6).

2-metoksyfenol (1,0 g, 8,0 mmol) og epiklorhydrin (3,7 g, 40,0 mmol) ble løst i aceton (20 ml). K2C03 (2,2 g, 16,0 mmol) ble tilsatt og blandingen ble varmet til 70°C i 24 timer. Reaksjonsblandingen ble konsentrert i vakuum. Residuet ble løst i 100 ml EtOAc, vasket med 100 ml vann, tørket over MgSC>4, og filtrert. Blandingen ble fordampet til tørrhet og residuet renset ved anvendelse av kolonne kromatografi (2:1, heksan:etylacetat) som ga forbindelse 6. 2-Methoxyphenol (1.0 g, 8.0 mmol) and epichlorohydrin (3.7 g, 40.0 mmol) were dissolved in acetone (20 mL). K 2 CO 3 (2.2 g, 16.0 mmol) was added and the mixture was heated to 70 °C for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in 100 mL EtOAc, washed with 100 mL water, dried over MgSO 4 , and filtered. The mixture was evaporated to dryness and the residue purified using column chromatography (2:1, hexane:ethyl acetate) to give compound 6.

Del D. Part D.

Syntese avN-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksy)propyl]-3,5-dimetylpiperazinyl} acetamid (7). Synthesis of N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxy)propyl]-3,5-dimethylpiperazinyl} acetamide (7).

Til en løsning av forbindelse 5 i 10 ml EtOH (0,4 g, 1,4 mmol) ble det tilsatt forbindelse 6 (0,27 g, 1,5 mmol). Reaksjonsblandingen ble refluksert i 24 timer. Blandingen ble konsentrert i vakuum og residuet ble renset ved anvendelse av prep. TLC (10:1, DCM:MeOH) som ga forbindelse 7. To a solution of compound 5 in 10 mL of EtOH (0.4 g, 1.4 mmol) was added compound 6 (0.27 g, 1.5 mmol). The reaction mixture was refluxed for 24 hours. The mixture was concentrated in vacuo and the residue was purified using prep. TLC (10:1, DCM:MeOH) which gave compound 7.

2-{(5S,2R)-4-[2-hydroksy-3-(2-metoksyfenoksy)propyl]-2,5-dimetylpiperazinyl}-N-(2,6-dimetylfenyl)acetamid (15) 2-{(5S,2R)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-2,5-dimethylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide (15)

Forbindelse 15 ble fremstilt på samme måte som forbindelse 7 ved å anvende (2R,5S)-dimetylpiperazin istedenfor 2,6-dimetylpiperazin 4 i del B som ga forbindelse 15: massespektrum (M+l) = 456,5. Compound 15 was prepared in the same manner as compound 7 by using (2R,5S)-dimethylpiperazine instead of 2,6-dimethylpiperazine 4 in part B to give compound 15: mass spectrum (M+1) = 456.5.

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)propyl]-2-oksopiperazinyl} acetamid (16) N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-2-oxopiperazinyl} acetamide (16)

Forbindelse 16 ble fremstilt ved å anvende 4-bensyloksykarbonyl-2-okso-piperazin istedenfor 2,6-dimetylpiperazin 4 i del B for forbindelse 7 som ble utført til det endelige målet på samme måte som forbindelse 7 etter fjerning av den CBZ-beskyttende gruppen (hydrogenering - 20 psi, 10% palladium på karbon) som ga forbindelse 16: massespektrum (M+l) = 442,41. Compound 16 was prepared by using 4-benzyloxycarbonyl-2-oxo-piperazine instead of 2,6-dimethylpiperazine 4 in part B for compound 7 which was carried to the final target in the same manner as compound 7 after removal of the CBZ protecting group (hydrogenation - 20 psi, 10% palladium on carbon) which gave compound 16: mass spectrum (M+1) = 442.41.

2,5-diasa-5- [2-hydroksy-3-(2-metoksyfenoksy)propyl] bisyklo [4.4.0] des-2-yl}-N-(2,6-dimetylfenyI)acetamid (17) 2,5-diaza-5-[2-hydroxy-3-(2-methoxyphenoxy)propyl]bicyclo[4.4.0]des-2-yl}-N-(2,6-dimethylphenyl)acetamide (17)

Forbindelse 17 ble fremstilt på samme måte som forbindelse 7 ved å anvende perhydroquinoksalin istedenfor 2,6-dimetylpiperazin 4 i del B som ga forbindelse 17: massespektrum (M+l) = 482,4. Compound 17 was prepared in the same manner as compound 7 by using perhydroquinoxaline instead of 2,6-dimethylpiperazine 4 in part B to give compound 17: mass spectrum (M+1) = 482.4.

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)propyl]-3,3-dimetylpiperazinyl} acetamid (18) N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3,3-dimethylpiperazinyl} acetamide (18)

Forbindelse 18 ble fremstilt på samme måte som forbindelse 7 ved å anvende 2,2-dimetylpiperazin istedenfor 2,6-dimetylpiperazin 4 i del B som ga forbindelse 18: massespektrum (M+l) = 456,51. Compound 18 was prepared in the same manner as compound 7 by using 2,2-dimethylpiperazine instead of 2,6-dimethylpiperazine 4 in part B to give compound 18: mass spectrum (M+1) = 456.51.

2-{5-[(2S)-2-hydroksy-3-(2-metoksyfenoksy)propyl](lS,4S)-2,5-diazabisyklo[2.2.1]hept-2-yl}-N-(2,6-dimetylfenyl)acetamid (19) 2-{5-[(2S)-2-hydroxy-3-(2-methoxyphenoxy)propyl](1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-(2 ,6-dimethylphenyl)acetamide (19)

Forbindelse 19 ble fremstilt på samme måte som forbindelse 7 ved å anvende (1S,4S)-(+)-2,5-diazabisyklo[2.2.1]heptan istedenfor 2,6-dimetylpiperazin 4 i del B som ga forbindelse 19: massespektrum (M+l) = 481,5. Compound 19 was prepared in the same manner as compound 7 by using (1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane instead of 2,6-dimethylpiperazine 4 in part B to give compound 19: mass spectrum (M+1) = 481.5.

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-4-(2-metoksyfenoksy)butyl]-piperazinyl} acetamid (20) N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(2-methoxyphenoxy)butyl]-piperazinyl} acetamide (20)

Forbindelse 20 ble fremstilt på samme måte som forbindelse 7 ved å anvende 4-brom-1,2-epoksybutan 6b istedenfor epiklorhydrin 6a i del B som ga forbindelse 20: massespektrum (M+l) = 442,37. Compound 20 was prepared in the same manner as compound 7 by using 4-bromo-1,2-epoxybutane 6b instead of epichlorohydrin 6a in part B to give compound 20: mass spectrum (M+1) = 442.37.

N-(2,6-dimetylfenyl)-2-{4-[4-(4-fluorfenoksy)-2-hydroksybutyl]-piperazinyl} acetamid (21) N-(2,6-dimethylphenyl)-2-{4-[4-(4-fluorophenoxy)-2-hydroxybutyl]-piperazinyl} acetamide (21)

Forbindelse 21 ble fremstilt på samme måte som forbindelse 7 ved å anvende 4-brom-1,2-epoksybutan 6b istedenfor epiklorhydrin 6a i del B som ga forbindelse 21: massespektrum (M+l) = 430,35. Compound 21 was prepared in the same manner as compound 7 by using 4-bromo-1,2-epoxybutane 6b instead of epichlorohydrin 6a in part B to give compound 21: mass spectrum (M+1) = 430.35.

2-(4-{4-[4-(tert-butyl)fenoksy]-2-hydroksybutyl}piperazin)-N-(2,6-dimetylfenyl)-acetamid (22) 2-(4-{4-[4-(tert-butyl)phenoxy]-2-hydroxybutyl}piperazine)-N-(2,6-dimethylphenyl)-acetamide (22)

Forbindelse 22 ble fremstilt på samme måte som forbindelse 7 ved å anvende 4-brom-1,2-epoksybutan 6b istedenfor epiklorhydrin 6a i del B som ga forbindelse 22: massespektrum (M+l) = 468,32. Compound 22 was prepared in the same manner as compound 7 by using 4-bromo-1,2-epoxybutane 6b instead of epichlorohydrin 6a in part B to give compound 22: mass spectrum (M+1) = 468.32.

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-4-(4-fenylfenoksy)butyl] piper azinyl} acetamid (23) N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(4-phenylphenoxy)butyl] piper azinyl} acetamide (23)

Forbindelse 23 ble fremstilt på samme måte som forbindelse 7 ved å anvende 4-brom-1,2-epoksybutan 6b istedenfor epiklorhydrin 6a i del B som ga forbindelse 23: massespektrum (M+l) = 488,41. Compound 23 was prepared in the same manner as compound 7 by using 4-bromo-1,2-epoxybutane 6b instead of epichlorohydrin 6a in part B to give compound 23: mass spectrum (M+1) = 488.41.

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-4-(4-metoksyfenoksy)butyl]-piperazinyl} acetamid (24) N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-4-(4-methoxyphenoxy)butyl]-piperazinyl} acetamide (24)

Forbindelse 24 ble fremstilt på samme måte som forbindelse 7 ved å anvende 4-brom-1,2-epoksybutan 6b istedenfor epiklorhydrin i del B som ga forbindelse 24: massespektrum (M+l) = 442,37. Compound 24 was prepared in the same manner as compound 7 by using 4-bromo-1,2-epoxybutane 6b instead of epichlorohydrin in part B to give compound 24: mass spectrum (M+1) = 442.37.

Eksempel 2 Example 2

N-(2,6-dimetyIfenyI)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)propyI]-3-oksopiperazinyl} acetamid (14) N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-oxopiperazinyl} acetamide (14)

Del E. Part E.

Syntese av (tert-butoksy)-N-(2- {[2-hydroksy-3-(2-metoksyfenoksy)propyl] amino} etyl)karboksamid (11) Synthesis of (tert-butoxy)-N-(2-{[2-hydroxy-3-(2-methoxyphenoxy)propyl]amino}ethyl)carboxamide (11)

Epoksid 6 (1,0 g, 5,5 mmol) og boc-etylendiamin (0,88 g, 5,5 mmol) ble løst i 20 ml EtOH og blandingen ble varmet ved refluks i 24 timer. Løsemidlet ble fordampet og residuet ble renset ved anvendelse av kolonnekromatografi (1:1, Heks:EtOAc) som ga forbindelse 11. Epoxide 6 (1.0 g, 5.5 mmol) and boc-ethylenediamine (0.88 g, 5.5 mmol) were dissolved in 20 mL of EtOH and the mixture was heated at reflux for 24 h. The solvent was evaporated and the residue was purified using column chromatography (1:1, Hex:EtOAc) to give compound 11.

Syntese avN-{2-[(tert-butoksy)karbonylamino]etyl}-2-klor-N[2-hydroksy-3-(2-metoksyfenoksy)propyl] acetamid (12) Synthesis of N-{2-[(tert-butoxy)carbonylamino]ethyl}-2-chloro-N[2-hydroxy-3-(2-methoxyphenoxy)propyl] acetamide (12)

Forbindelse 11 (1,0 g, 3,0 mmol) ble løst i 20 ml DCM og behandlet med diisopropyletylamin (0,76 g, 4,5 mmol). Blandingen ble avkjølt ved 0°C. Til den kalde blandingen ble det dråpevis tilsatt kloractylklorid i 5 ml DCM. Reaksjonsblandingen ble rørt ved romtemperatur i 24 timer. Blandingen ble fortynnet med 50 ml DCM og vasket med 50 ml vann og 10% sitronsyre. Det organiske sjikt ble tørket over MgS04 og filtrert. Løsemidlet ble fordampet under redusert trykk og residuet ble rekrystallisert fra etyleter som ga forbindelse 12. Compound 11 (1.0 g, 3.0 mmol) was dissolved in 20 mL of DCM and treated with diisopropylethylamine (0.76 g, 4.5 mmol). The mixture was cooled at 0°C. To the cold mixture was added dropwise chloroactyl chloride in 5 ml of DCM. The reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with 50 ml of DCM and washed with 50 ml of water and 10% citric acid. The organic layer was dried over MgSO 4 and filtered. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl ether to give compound 12.

Syntese av l-[2-hydroksy-3-(2-metoksyfenoksy)propyl]piperazin-2-on (13). Forbindelse 12 (0,5 g, 1,5 mmol) ble løst i 10 ml TFA. Blandingen ble rørt ved romtemperatur i 2 timer. TFA ble fjernet under redusert trykk. Residuet ble løst i 20 ml EtOH og behandlet med diisopropyletylamin (0,76 g, 4,5 mmol). Blandingen ble varmet til refluks i 24 timer. Løsemidlet ble fjernet under redusert trykk som ga forbindelse 13 som ble anvendt uten ytterligere rensing. Synthesis of l-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-2-one (13). Compound 12 (0.5 g, 1.5 mmol) was dissolved in 10 mL of TFA. The mixture was stirred at room temperature for 2 hours. TFA was removed under reduced pressure. The residue was dissolved in 20 mL of EtOH and treated with diisopropylethylamine (0.76 g, 4.5 mmol). The mixture was heated to reflux for 24 hours. The solvent was removed under reduced pressure to give compound 13 which was used without further purification.

Del F. Part F.

Syntese av N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)propyl]-3-oksopiperazinyl} acetamid (14) Synthesis of N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-oxopiperazinyl} acetamide (14)

Til en løsning av forbindelse 13 i 10 ml EtOH (0,1 g, 0,30 mmol) ble det dråpevis tilsatt forbindelse 3 (0,7 g, 0,36 mmol) og diisopropyletylamin (0,76 g, 0,36 mmol). Reaksjonsblandingen ble varmet til refluks i 24 timer. Blandingen ble konsentrert i vakuum, residuet ble renset for anvendelse av prep. TLC (10:1, DCM:MeOH) som ga forbindelse 14: Massespektrum (M+l) = 442,34. To a solution of compound 13 in 10 mL EtOH (0.1 g, 0.30 mmol) was added dropwise compound 3 (0.7 g, 0.36 mmol) and diisopropylethylamine (0.76 g, 0.36 mmol ). The reaction mixture was heated to reflux for 24 hours. The mixture was concentrated in vacuo, the residue was purified for use in prep. TLC (10:1, DCM:MeOH) which gave compound 14: Mass spectrum (M+1) = 442.34.

Eksempel 3 Example 3

Forbindelsene som er listet opp i tabell 1 nedenfor ble fremstilt på samme måte som forbindelse 14 i eksempel 2. The compounds listed in Table 1 below were prepared in the same manner as compound 14 in Example 2.

Eksempel 4 2-[4-(3-(2H-benzo[d]l,3-dioksolen-5-yl)-2-hydroksypropyl)piperazinyl]-N-(2,6-dimetylfenyl)acetamid (7B). Example 4 2-[4-(3-(2H-benzo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide (7B).

Del A. Part A.

Syntese av N-(2,6-dimtylfenyl)-2-kloracetamid (3B). Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3B).

2,6-dimetylanilin (9,8 g, 81,2 mmol) ble løst i eter (100 ml) og mettet vandig NaHC03 (100 ml) og reaksjonsblandingen ble avkjølt i isvann/vannbad. Til den kalde løsningen ble det tilsatt kloractylklorid 2B (9,17 g, 81,2 mmol) dråpevis i løpet av 2 timer. Blandingen ble varmet til romtemperatur i løpet av 14 timer. Blandingen ble ekstrahert med EtOAc (3 x 50). De kombinerte organiske lagene ble tørket over MgS04, filtrert og konsentrert. Residuet ble triturert i eter og filtrert hvilket ga forbindelse 3B som et hvitt faststoff. 2,6-Dimethylaniline (9.8 g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO 3 (100 mL) and the reaction mixture was cooled in an ice water/water bath. To the cold solution was added chloroactyl chloride 2B (9.17 g, 81.2 mmol) dropwise over 2 hours. The mixture was warmed to room temperature over 14 hours. The mixture was extracted with EtOAc (3 x 50). The combined organic layers were dried over MgSO 4 , filtered and concentrated. The residue was triturated in ether and filtered to give compound 3B as a white solid.

DelB. Part B.

Syntese av N-(2,6-dimetylfenyI)-2-piperazinylacetamid (5B). Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (5B).

Til en løsning av forbindelse 3 (5 g, 25,2 mmol) i etanol (100 ml) ble tilsatt forbindelse 4B (2,1 g, 25,0 mmol) og N,N-diisopropylamin (3,2 g, 25,2 mmol). Reaksjonsblandingen ble refluksert i 24 timer. Blandingen ble konsentrert i vakuum og residuet ble renset med kolonne kromatografi (10:1 diklormetan:metanol) som ga forbindelse 5B. To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added compound 4B (2.1 g, 25.0 mmol) and N,N-diisopropylamine (3.2 g, 25, 2 mmol). The reaction mixture was refluxed for 24 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1 dichloromethane:methanol) to give compound 5B.

Del C. Part C.

Syntese av 5-(oksiran-2-ylmetyl)-2H-benzo[d]l,3-dioksan (6B). Synthesis of 5-(oxiran-2-ylmethyl)-2H-benzo[d]l,3-dioxane (6B).

Til en iskald løsning av 8 (1,0 g, 6,17 mmol) i diklormetan ble dråpevis tilsatt en løsning av 3-klorperoksybenzosyre (1,8 g, 10,43 mmol) i 20 ml diklormetan i løpet av 1 time. Reaksjonsblandingen ble rørt ved romtemperatur i 12 timer. Reaksjonsblandingen ble filtrert for å fjerne eventuelle faste stoffer og konsentrert i vakuum. Til residuet ble det tilsatt dietyleter (200 ml), og løsningen ble vasket med mettet natriumbikarbonat (3 x 100 ml). Det organiske sjiktet ble tørket over MgS04, og konsentrert i vakuum. Residuet ble renset ved anvendelse av prep. TLC (2:1 heksametylacetat) som ga 6B. To an ice-cold solution of 8 (1.0 g, 6.17 mmol) in dichloromethane was added dropwise a solution of 3-chloroperoxybenzoic acid (1.8 g, 10.43 mmol) in 20 ml of dichloromethane over 1 hour. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered to remove any solids and concentrated in vacuo. To the residue was added diethyl ether (200 ml), and the solution was washed with saturated sodium bicarbonate (3 x 100 ml). The organic layer was dried over MgSO 4 and concentrated in vacuo. The residue was purified using prep. TLC (2:1 hexamethyl acetate) which gave 6B.

DelD. Part D.

2-[4-(3-(2H-benzo[d]l,3-dioksolen-5-yl)-2-hydroksypropyl)piperazinyl]-N-(2,6-dimetylfenyl)acetamid (7B) 2-[4-(3-(2H-benzo[d]l,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide (7B)

Til en løsning av forbindelse 5B (0,4 g, 1,64 mmol) i etanol (100 ml) ble det tilsatt To a solution of compound 5B (0.4 g, 1.64 mmol) in ethanol (100 mL) was added

forbindelse 6B (0,38 g, 2,14 mmol) i 10 ml EtOH. Reaksjonsblandingen ble refluksert i 24 timer. Blandingen ble konsenrert i vakuum, og residuet ble renset ved anvendelse av prep. TLC (10:1 diklormetan:metanol) som ga forbindelse 7B: massespektrum (MH+1) = 426,34. compound 6B (0.38 g, 2.14 mmol) in 10 mL of EtOH. The reaction mixture was refluxed for 24 hours. The mixture was concentrated in vacuo and the residue was purified using prep. TLC (10:1 dichloromethane:methanol) which gave compound 7B: mass spectrum (MH+1) = 426.34.

N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-4-fenylbutyl)piperazinyl]acetamid(9B). N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide (9B).

Forbindelse 9B ble fremstilt på samme måte som forbindelse 7B ved å anvende 4-fenyl-buten istedenfor 3-(3,4-metylendioksyfenyl)-l-propen i del C som ga forbindelse 9B: massespektrum (MH+1) = 396,32. Compound 9B was prepared in the same manner as compound 7B by using 4-phenyl-butene instead of 3-(3,4-methylenedioxyphenyl)-1-propene in part C to give compound 9B: mass spectrum (MH+1) = 396.32 .

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenyl)-propyl]piperazinyl} acetamid (10B) N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)-propyl]piperazinyl} acetamide (10B)

Forbindelse 10B ble fremstilt på samme måte som forbindelse 7B ved å anvende 3-(2-metoksyfenyl)-l-propen i stedet for 3-(3,4-metylendioksyfenyl)-l-propen i del C som ga forbindelse 10B: massespektrum (MH+1) = 412,35. Compound 10B was prepared in the same manner as compound 7B by using 3-(2-methoxyphenyl)-1-propene in place of 3-(3,4-methylenedioxyphenyl)-1-propene in part C to give compound 10B: mass spectrum ( MH+1) = 412.35.

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(4-metoksyfenyl)-propyl]piperazinyl} acetamid (11B) N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)-propyl]piperazinyl} acetamide (11B)

Forbindelse 1 IB ble fremstilt på samme måte som forbindelse 7B ved å anvende 3-(4-metoksyfenyl)-l-propen i stedet for 3-(3,4-metylendioksyfenyl)-l-propen i del C som ga forbindelse 11B: massespektrum (MH+1) = 412,35. Compound 1 IB was prepared in the same manner as compound 7B by using 3-(4-methoxyphenyl)-1-propene in place of 3-(3,4-methylenedioxyphenyl)-1-propene in part C to give compound 11B: mass spectrum (MH+1) = 412.35.

N-(2,6-dimetyIfenyl)-2- {4-[2-hydroksy-3-fenylpropyl] piperazinyl} acetamid (12B) N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-phenylpropyl] piperazinyl} acetamide (12B)

Forbindelse 12B ble fremstilt på samme måte som forbindelse 7B ved å anvende 3-fenyl-l-propen i stedet for 3-(3,4-metylendioksyfenyl)-l-propen i del C som ga forbindelse 12B: massespektrum (MH+1) = 382. Compound 12B was prepared in the same manner as compound 7B by using 3-phenyl-l-propene in place of 3-(3,4-methylenedioxyphenyl)-l-propene in part C to give compound 12B: mass spectrum (MH+1) = 382.

N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-3-naftylpropyl)piperazinyl]acetamid (13B) N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-naphthylpropyl)piperazinyl]acetamide (13B)

Forbindelse 13B ble fremstilt på samme måte som forbindelse 7B ved å anvende 3-(l-naftyl)-l-propen i stedet for 3-(3,4-metylendioksyfenyl)-l-propen i del C som ga forbindelse 13: massespektrum (MH+1) = 432,55. Compound 13B was prepared in the same manner as compound 7B by using 3-(1-naphthyl)-1-propene in place of 3-(3,4-methylenedioxyphenyl)-1-propene in part C to give compound 13: mass spectrum ( MH+1) = 432.55.

EKSEMPEL 5 EXAMPLE 5

Del A Part A

Intermediat (14B): Til en løsning av 4-metoksybenzylklorid (2 mmol) i vannfri eter (10 ml) ble det tilsatt allylmagnesiumbromid (4 ml, IM løsning i THF) og reaksjonsblandingen ble rørt i 16 timer ved romtemperatur. Mettet ammoniumklorid løsning (91 ml) ble tilsatt og eterlaget ble separert, vasket med vann og tørket. Fordampning av eter under redusert trykk ga olefin 14B som en olje. Den ble anvendt i neste reaksjon uten rensning. Intermediate (14B): To a solution of 4-methoxybenzyl chloride (2 mmol) in anhydrous ether (10 mL) was added allylmagnesium bromide (4 mL, 1M solution in THF) and the reaction mixture was stirred for 16 h at room temperature. Saturated ammonium chloride solution (91 ml) was added and the ether layer was separated, washed with water and dried. Evaporation of ether under reduced pressure gave olefin 14B as an oil. It was used in the next reaction without purification.

Del B Part B

Intermediat (15B): Til en iskald løsning av 15B (2 mmol) i diklormetan ble det dråpevis tilsatt en løsning 3-klorperoksybenzosyre (4 mmol) i 20 ml diklormetan i løpet av 1 time. Reaksjonsblandingen ble rørt ved romtemperatur i 12 timer. Reaksjonsblandingen ble filtrert for å fjerne eventuelle faste stoffer og konsentrert i vakuum. Til residuet ble det tilsatt dietyleter (200 ml) og blandingen ble vasket med mettet natriumbikarbonat (3 x 100 ml). Det organiske laget ble tørket over MgSC>4 og konsentrert i vakuum. Residuet ble renset ved anvendelse av prep. TLC (2:1 heksan: etyl acetat) som ga 15B. Intermediate (15B): To an ice-cold solution of 15B (2 mmol) in dichloromethane, a solution of 3-chloroperoxybenzoic acid (4 mmol) in 20 ml of dichloromethane was added dropwise over the course of 1 hour. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered to remove any solids and concentrated in vacuo. To the residue was added diethyl ether (200 mL) and the mixture was washed with saturated sodium bicarbonate (3 x 100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified using prep. TLC (2:1 hexane:ethyl acetate) which gave 15B.

DelC Part C

Syntese avN-(2,6-dimetylfenyl)-2-{4-[4-(4-metoksyfenyl)-2-hydroksybutyl] piperazinyl} acetamid (16B) Synthesis of N-(2,6-dimethylphenyl)-2-{4-[4-(4-methoxyphenyl)-2-hydroxybutyl] piperazinyl} acetamide (16B)

Til en løsning av forbindelse 5B (0,4 g, 1,64 mmol) i etanol (100 ml) ble det tilsatt forbindelse 15B (2,14 mmol) i 10 ml EtOH. Reaksjonsblandingen ble refluksert i 24 timer. Blandingen ble konsentrert i vakuum, og residuet ble renset ved anvendelse av prep. TLC (10:1 diklormetammetanol) som ga forbindelse 16. (M+l) = 426,3. To a solution of compound 5B (0.4 g, 1.64 mmol) in ethanol (100 mL) was added compound 15B (2.14 mmol) in 10 mL of EtOH. The reaction mixture was refluxed for 24 hours. The mixture was concentrated in vacuo and the residue was purified using prep. TLC (10:1 dichlorometammethanol) which gave compound 16. (M+1) = 426.3.

2-{4-[4-(2,6-dilfuorfenyl)-2-hydroksybut>l]piperazinyl}-N-(2,6-dimetylfenyl)acetamid (17B) 2-{4-[4-(2,6-Difluorophenyl)-2-hydroxybutyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide (17B)

Forbindelse 17B ble fremstilt på samme måte som forbindelse 16B ved å anvende 2,6-difluorbensylklorid i stedet for 4-metoksybensylklorid. (M+l) 432,2. Compound 17B was prepared in the same manner as compound 16B by using 2,6-difluorobenzyl chloride instead of 4-methoxybenzyl chloride. (M+1) 432.2.

N-(2,6-difluorfenyl)-{4-[4-(2-klorfenyl)-2-hydroksybutyl]piperazinyl}acetamid N-(2,6-difluorophenyl)-{4-[4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl}acetamide

(18B) (18B)

Forbindelse 18B ble fremstilt på samme måte som forbindelse 16B ved å anvende 2-klorbensylklorid i stedet for 4-metoksybensylklorid. (M+l) 430,2. Compound 18B was prepared in the same manner as compound 16B by using 2-chlorobenzyl chloride instead of 4-methoxybenzyl chloride. (M+1) 430.2.

2-(4-{4-[4-(tert-butyl)fenyl]-2-hydroksybutyl}piperazinyl)-N-(2,6-dimetylfenyl)acetamid (19B) 2-(4-{4-[4-(tert-butyl)phenyl]-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide (19B)

Forbindelse 19B ble fremstilt på samme måte som forbindelse 16B ved å anvende 4-t-butylbensylklorid i stedet for 4-metoksybensylklorid. (M+l) 452,3. Compound 19B was prepared in the same manner as compound 16B by using 4-t-butylbenzyl chloride instead of 4-methoxybenzyl chloride. (M+1) 452.3.

N-(2,6-dimerylfenyl)-2-{4-[4-(2-fluorfenyl)-2-hydroksybutyl]piperazin}acetamid N-(2,6-dimerylphenyl)-2-{4-[4-(2-fluorophenyl)-2-hydroxybutyl]piperazine}acetamide

(20B) (20B)

Forbindelse 20B ble fremstilt på samme måte som forbindelse 16B ved å anvende 2-fluorbensylklorid i stedet for 4-metoksybensylklorid. (M+l) = 414,2. Compound 20B was prepared in the same manner as compound 16B by using 2-fluorobenzyl chloride instead of 4-methoxybenzyl chloride. (M+1) = 414.2.

N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-4-[4-(trifluormetyl)fenyl]butyl}piperazinyl) acetamid (21) N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide (21)

Forbindelse 21B ble fremstilt på samme måte som forbindelse 16B ved å anvende 4-trifluormetylbensylklorid i stedet for 4-metoksybensylklorid. (M+l) = 464,2. Compound 21B was prepared in the same manner as compound 16B by using 4-trifluoromethylbenzyl chloride instead of 4-methoxybenzyl chloride. (M+1) = 464.2.

2-I4-(3-(2H-benzo[d]l,3-dioksen-5-yl)-2-hydroksypropyl)piperazinyl]-N-(2,6-dimetylfenyl)-2-metylpropanamid (22B) 2-14-(3-(2H-benzo[d]1,3-dioxen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-2-methylpropanamide (22B)

Denne forbindelsen ble fremstilt på samme måte som forbindelse 7B ved å anvende 2-klor-2-metylpropionylklorid i stedet for kloractylklorid i del A. (M+l) = 454,54. This compound was prepared in the same manner as compound 7B by using 2-chloro-2-methylpropionyl chloride in place of chloroactyl chloride in part A. (M+1) = 454.54.

N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-3-fenylpropyl)piperazinyl]-2-metylpropanamid (23B) N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide (23B)

Denne forbindelsen ble fremstilt på samme måte som forbindelse 7B ved å anvende 2-klor-2-metylpropionylklorid i stedet for kloractylklorid i del A og allylbenzen for 8B. This compound was prepared in the same manner as compound 7B by using 2-chloro-2-methylpropionyl chloride in place of chloroactyl chloride in part A and allylbenzene for 8B.

(M+l) = 410,34. (M+l) = 410.34.

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(3,4,5-trimetoksyfenyl)propyl] piperazinyl}-2-metylpropanamid (24B) N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5-trimethoxyphenyl)propyl]piperazinyl}-2-methylpropanamide (24B)

Denne forbindelsen ble fremstilt på samme måte som forbindelse 7B ved å anvende 2-klor-2-metylpropionylklorid i stedet for kloractylklorid i del A og 3,4,5-trimetoksy-alkylbenzen for 8B. (M+l) = 472,54. This compound was prepared in the same manner as compound 7B by using 2-chloro-2-methylpropionyl chloride in place of chloroactyl chloride in part A and 3,4,5-trimethoxyalkylbenzene for 8B. (M+l) = 472.54.

N-(2,6-dimetylfenyl)-2- [4-(2-hydroksy-5-fenylpentyl)piperazinyl] acetamid (25B) N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)piperazinyl]acetamide (25B)

Denne forbindelsen ble fremstilt på samme måte som forbindelse 16B ved å anvende fenetyl klorid i stedet for 4-metoksybensylklorid i del A. (M+l) = 410,4. This compound was prepared in the same manner as compound 16B by using phenethyl chloride in place of 4-methoxybenzyl chloride in part A. (M+1) = 410.4.

N-(2,6-dimetylfenyl)-2-{4-[5-(2-fluorfenyl)-2-hydroksy-pentyl]piperazinyl}acetamid (26B) N-(2,6-dimethylphenyl)-2-{4-[5-(2-fluorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide (26B)

Denne forbindelsen ble fremstilt på samme måte som forbindelse 16B ved å anvende 2-fluorfenetyl klorid i stedet for 4-metoksybensylklorid i del A. (M+l) = 428,1. This compound was prepared in the same manner as compound 16B by using 2-fluorophenethyl chloride in place of 4-methoxybenzyl chloride in part A. (M+1) = 428.1.

N-(2,6-dimet>'lfenyl)-2-{4-[5-(2-klorfenyl)-pentyl]piperazinyl}acetamid (27B) N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyl)-pentyl]piperazinyl}acetamide (27B)

Denne forbindelsen ble fremstilt på samme måte som forbindelse 16B ved å anvende 2-klorfenetyl klorid i stedet for 4-metoksybensylklorid i del A. (M+l) = 444,3. This compound was prepared in the same manner as compound 16B by using 2-chlorophenethyl chloride in place of 4-methoxybenzyl chloride in part A. (M+1) = 444.3.

EKSEMPEL 6 EXAMPLE 6

N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-3-indan-2-y loksypropyl)piperazinyl] acetamid (7C) N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl] acetamide (7C)

Del A. Part A.

Syntese av N-(2,6-dimetylfenyl)-2-kloracetamid (3C). Synthesis of N-(2,6-dimethylphenyl)-2-chloroacetamide (3C).

2,6-dimetylanilin (9,8 g, 81,2 mmol) ble løst i eter (100 ml) og mettet vandig NaHC03, (100 ml) og reaksjonsblandingen ble avkjølt i isvann/vannbad. Til den kalde løsningen ble det tilsatt kloractylklorid 2C (9,17 g, 81,2 mmol) dråpevis i løpet av 2 timer. 2,6-Dimethylaniline (9.8 g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO 3 (100 mL) and the reaction mixture was cooled in an ice water/water bath. To the cold solution was added chloroactyl chloride 2C (9.17 g, 81.2 mmol) dropwise over 2 hours.

Blandingen ble oppvarmet til romtemperatur i 14 timer. Blandingen ble fortynnet med 100 ml eter og det organiske laget ble tørket over MgSCv, filtrert og konsentrert, hvilket ga forbindelse 3C som et hvitt faststoff. The mixture was warmed to room temperature for 14 hours. The mixture was diluted with 100 mL of ether and the organic layer was dried over MgSO4, filtered and concentrated to give compound 3C as a white solid.

Del B. Part B.

Syntese av N-(2,6-dimetylfenyl)-2-piperazinylacetamid (5C). Synthesis of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (5C).

Til en løsning av forbindelse 3C i 100 ml EtOH (5 g, 25,2 mmol) ble det tilsatt forbindelse 4C (2,1 g, 25,0 mmol) og N,N-diisopropyletylamin (3,2 g, 25,2 mmol). Reaksjonsblandingen ble refluksert i 24 timer. Blandingen ble konsentrert i vakuum og residuet ble renset ved kolonnekromatografi (10:1, DCM:MeOH) som ga forbindelse 5C. To a solution of compound 3C in 100 mL EtOH (5 g, 25.2 mmol) was added compound 4C (2.1 g, 25.0 mmol) and N,N-diisopropylethylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1, DCM:MeOH) to give compound 5C.

Del C. Part C.

Syntese av 2-(oksiran-2-ylmetoksy)propan (6C). Synthesis of 2-(oxiran-2-ylmethoxy)propane (6C).

Til en løsning av 60% NaH (0,18 g, 4,5 mmol) i DMF (10 ml) avkjølt til 0 grader ble det tilsatt 2 propanol (0,5 g, 3,73 mmol) i DMF (2 ml) dråpevis. Etter røring i 30 minutter ble epibromhydrin (1,11 g, 8,18 mmol) i DMF (1 ml) tilsatt dråpevis. Reaksjonen ble varmet til romtemperatur og rørt i 48 timer. Løsemidlet ble fjernet i vakuum og residuet ble renset ved anvendelse av prep. TLC (30:1, DCM:MeOH) som ga forbindelse 6C. To a solution of 60% NaH (0.18 g, 4.5 mmol) in DMF (10 ml) cooled to 0 degrees was added 2 propanol (0.5 g, 3.73 mmol) in DMF (2 ml) drop by drop. After stirring for 30 min, epibromohydrin (1.11 g, 8.18 mmol) in DMF (1 mL) was added dropwise. The reaction was warmed to room temperature and stirred for 48 hours. The solvent was removed in vacuo and the residue was purified using prep. TLC (30:1, DCM:MeOH) which gave compound 6C.

Del D. Part D.

Syntese av N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-3-indan-2-yloksypropyl) piperazinyl] acetamid (7C) Synthesis of N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]acetamide (7C)

Til en løsning av 6C (0,43 g, 2,3 mmol) i etanol (4 ml) ble det tilsatt 5C (0,405 g, 1,64 mmol). Løsningen ble oppvarmet til refluks og rørt i 24 timer. Etter ferdig reaksjon ble løsningen konsentrert i vakuum og renset ved anvendelse av prep. TLC (10:1, DCM:MeOH) som ga 7C. Massespektrum (M+l) = 438,36. To a solution of 6C (0.43 g, 2.3 mmol) in ethanol (4 mL) was added 5C (0.405 g, 1.64 mmol). The solution was heated to reflux and stirred for 24 hours. After the reaction was complete, the solution was concentrated in vacuo and purified using prep. TLC (10:1, DCM:MeOH) which gave 7C. Mass spectrum (M+1) = 438.36.

2-({2-[4-(3-isopropoksy-2-hydroksypropyl)piperazinyl]-N-({2,6-dimetylfenyl)acetamid (10C) 2-({2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide (10C)

Forbindelse 10C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige glycidyl isopropyleter med 2-(oksiran-2-ylmetoksy)indan i del D som ga 10C: Massespektrum MS (MH+) = 364,37. Compound 10C was prepared in the same manner as compound 7C by replacing the commercially available glycidyl isopropyl ether with 2-(oxiran-2-ylmethoxy)indane in part D to give 10C: Mass spectrum MS (MH + ) = 364.37.

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(fenylmetoksy)propyl] N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(phenylmethoxy)propyl]

piperazinyl} acetamid (11C) piperazinyl} acetamide (11C)

Forbindelse 11C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige benzylglycidyleter med 2-(oksiran-2-ylmetoksy)indan i del D som ga 11C: Massespektrum MS (MH+) = 412,36. Compound 11C was prepared in the same manner as compound 7C by replacing the commercially available benzyl glycidyl ether with 2-(oxiran-2-ylmethoxy)indane in part D to give 11C: Mass spectrum MS (MH + ) = 412.36.

2-({2-[4-(3-syklopentyloksy-2-hydroksypropyl)piperazinyl]-dimetylfenyl)acetamid 2-({2-[4-(3-cyclopentyloxy-2-hydroxypropyl)piperazinyl]-dimethylphenyl)acetamide

(12C) (12C)

Forbindelse 12C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige syklopentanol med 2-indanol i del C som ga 12C: MS (MH+) = 390. Compound 12C was prepared in the same manner as compound 7C by replacing the commercially available cyclopentanol with 2-indanol in part C to give 12C: MS (MH + ) = 390.

2-({2-[4-(3-sykloheksyloksy-2-hydroksypropyl)piperazinyl]-dimetylfenyl)acetamid 2-({2-[4-(3-cyclohexyloxy-2-hydroxypropyl)piperazinyl]-dimethylphenyl)acetamide

(13C) (13C)

Forbindelse 13C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige sykloheksenol med 2-indanol i del C som ga 13C: MS (MH+) = 404. Compound 13C was prepared in the same manner as compound 7C by replacing the commercially available cyclohexenol with 2-indanol in part C to give 13C: MS (MH + ) = 404.

2-[4-(3-{[4-(tert-butyl)fenyl]metoksy}-2-hydroksypropyl)piperazinyl]-N-(2,6-dimetylfenyl)acetamid (14C): Forbindelse 14C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 4-t-bu-bensylalkohol med 2-propanol i del C. MS (M+l) = 468,44. 2-[4-(3-{[4-(tert-butyl)phenyl]methoxy}-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide (14C): Compound 14C was prepared in the same manner as compound 7C by replacing the commercially available 4-t-bu-benzyl alcohol with 2-propanol in part C. MS (M+1) = 468.44.

N-(2,6-dimetylfenyl)-2-(4-{3-[(2-fluorfenyl)metoksy]-2-hydroksypropyl} piperazinyl) acetamid (15C): Forbindelse 15C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 2-fluorbensylalkohol med 2-propanol i del C. MS (M+l) = 430,39. 2-(4-{3-[(2,4-difluorfenyl)metoksy]-2-hydroksypropyl}piperazinyl)-N-(2,6-dimetylfenyl) acetamid (16C): Forbindelse 16C ble fremstilt på samme måte som forbindelse 7 ved å erstatte den kommersielt tilgjengelige 2,4-difluorbensylalkohol med 2-propanol i del C. MS (M+l) = 448,38. N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide (15C): Compound 15C was prepared in the same manner as compound 7C by replace the commercially available 2-fluorobenzyl alcohol with 2-propanol in part C. MS (M+1) = 430.39. 2-(4-{3-[(2,4-difluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide (16C): Compound 16C was prepared in the same manner as compound 7 by replacing the commercially available 2,4-difluorobenzyl alcohol with 2-propanol in part C. MS (M+1) = 448.38.

N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-3-{[4-(trifluormetyl)fenyl]metoksy}propyl) piperazinyl] acetamid (17C): N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]acetamide (17C):

Forbindelse 17C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 4-trifluormetyl-bensylalkohol med 2-propanol i del C. MS (M+l) = 480,37. Compound 17C was prepared in the same manner as compound 7C by replacing the commercially available 4-trifluoromethylbenzyl alcohol with 2-propanol in part C. MS (M+1) = 480.37.

N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-3-[(2-metoksyfenyl)metoksy]propyl} piperazinyl) acetamid (18C): Forbindelse 18C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 2-metoksy-bensylalkohol med 2-propanol i del C. MS (M+l) = 442,41. 2-(4-{3-[(2,4-dimetoksyfenyl)-metoksy]-2-hydroksypropyl}piperazinyl)-N-(2,6-dimetylfenyl)acetamid (19C): Forbindelse 19C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 2,4-dimetoksy-bensylalkohol med 2-propanol i del C. MS (M+l) = 472,42. N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide (18C): Compound 18C was prepared in the same manner as compound 7C by replacing the commercially available 2-methoxy-benzyl alcohol with 2-propanol in part C. MS (M+1) = 442.41. 2-(4-{3-[(2,4-dimethoxyphenyl)-methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide (19C): Compound 19C was prepared in the same manner as compound 7C by replacing the commercially available 2,4-dimethoxy-benzyl alcohol with 2-propanol in part C. MS (M+1) = 472.42.

N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-3-[(4-metoksyfenyl)metoksy]propyl} piperazinyl) acetamid (20 C): Forbindelse 20C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 4-metoksy-bensylalkohol med 2-propanol i del C. MS (M+l) = 442,42. N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide (20C): Compound 20C was prepared in the same manner as compound 7C by replacing the commercially available 4-methoxy-benzyl alcohol with 2-propanol in part C. MS (M+1) = 442.42.

N-(2,6-dimetylfenyl)-2-(4-{3-[(4-nuorfenyl)metoksy]-2-hydroksypropyl}piperazinyl) acetamid (21C): N-(2,6-dimethylphenyl)-2-(4-{3-[(4-nuorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide (21C):

Forbindelse 21C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 4-fluor-bensylalkohol med 2-propanol i del C. MS (M+l) = 430,40. Compound 21C was prepared in the same manner as compound 7C by replacing the commercially available 4-fluorobenzyl alcohol with 2-propanol in part C. MS (M+1) = 430.40.

N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-3-[(4-metylfenyl)metoksy]propyl}piperazinyl) acetamid (22C): N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methylphenyl)methoxy]propyl}piperazinyl)acetamide (22C):

Forbindelse 22C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 4-metyl-bensylalkohol med 2-propanol i del C. MS (M+l) = 426,41. Compound 22C was prepared in the same manner as compound 7C by replacing the commercially available 4-methylbenzyl alcohol with 2-propanol in part C. MS (M+1) = 426.41.

N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-3-[(4-fenylmetyl)metoksy]propyl} piperazinyl) acetamid (23 C): N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylmethyl)methoxy]propyl}piperazinyl)acetamide (23 C):

Forbindelse 23C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 4-fenyl-bensylalkohol med 2-propanol i del C. MS (M+l) = 488,42. Compound 23C was prepared in the same manner as compound 7C by replacing the commercially available 4-phenyl-benzyl alcohol with 2-propanol in part C. MS (M+1) = 488.42.

N-(2,6-dimetylfenyl)-2-(4-{3-[(4-butylfenyl)metoksy]-2-hydroksypropyl} piperazinyl) acetamid (24C): Forbindelse 24C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 4-n-bu-bensylalkohol med 2-propanol i del C. MS (M+l) = 468,45. N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide (24C): Compound 24C was prepared in the same manner as compound 7C by replace the commercially available 4-n-bu-benzyl alcohol with 2-propanol in part C. MS (M+1) = 468.45.

N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-naftylmetoksy)propyl]piperazinyl} acetamid (25 C): N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-naphthylmethoxy)propyl]piperazinyl} acetamide (25 C):

Forbindelse 25C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 2-naftylmetanol med 2-propanol i del C. MS (M+l) = 462,41. Compound 25C was prepared in the same manner as compound 7C by replacing the commercially available 2-naphthylmethanol with 2-propanol in part C. MS (M+1) = 462.41.

N-(2,6-dimetylfenyl)-2-{4-[3-(sykloheksylmetoksy)-2-hydroksypropyl]piperazinyl} acetamid (26 C): N-(2,6-dimethylphenyl)-2-{4-[3-(cyclohexylmethoxy)-2-hydroxypropyl]piperazinyl} acetamide (26 C):

Forbindelse 26C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige sykloheksylmetanol med 2-propanol i del C. MS (M+l) = 418,55. Compound 26C was prepared in the same manner as compound 7C by replacing the commercially available cyclohexylmethanol with 2-propanol in part C. MS (M+1) = 418.55.

N-(2,6-dimetylfenyl)-2-(4-{3-[(4-fluorfenyl)-metoksy]-2-hydroksypropyl}-3,3-dimetylpiperazinyl)acetamid (27 C): Forbindelse 27C ble fremstilt på samme måte som forbindelse 7C ved å erstatte den kommersielt tilgjengelige 4-fluorbensylalkohol med 2-propanol i del C. MS (M+l) = 458,5. N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)-methoxy]-2-hydroxypropyl}-3,3-dimethylpiperazinyl)acetamide (27 C): Compound 27C was prepared on same way as compound 7C by replacing the commercially available 4-fluorobenzyl alcohol with 2-propanol in part C. MS (M+1) = 458.5.

Eksempel 7 Example 7

Mitokondrie undersøkelser Mitochondrial investigations

Rottehjerte mitokondrier ble isolert ved fremgangsmåten til Nedergard og Cannon (Methods in Enzymol. 55,3,1979). Rat heart mitochondria were isolated by the method of Nedergard and Cannon (Methods in Enzymol. 55,3,1979).

Palmitoyl CoA oksidasjon - The Palmitoyl CoA oksidasjonen ble utført i et totalt volum på 100 mikroliter som inneholder de følgende midler: 110 mM KC1,33 mM tris buffer ved pH 8,2 mM Kpi, 2 mM MgCl2,0,1 mM EDTA, 14,7 mikroM avfettet BSA, 0,5 mM malinsyre, 13 mM karnitin, 1 mM ADP, 52 mikrogram mitokondrie protein, og 16 mkroM 1-C14 palmitoyl CoA (Sp. aktivitet 60 mCi/mmol; 20 mikroCi/ml, ved anvendelse av 5 mikroliter pr. undersøkelse). Forbindelsene ifølge oppfinnelsen ble tilsatt i DMSO løsning ved de følgende konsentrasjoner: 100 mikroM, 30 mikroM, og 3 mikroM. I hver analyse ble en DMSO kontroll benyttet. Etter 15 minutter ved 30°C ble den enzymatiske reaksjonen sentrifugert (20.000 g i 1 minutt), og 70 mikroliter av supernatanten ble tilsatt til en aktivert reversfase kieselsyre kolonne (ca. 0,5 ml av kieselsyre). Kolonnen ble eluert med 2 ml vann, og 0,5 ml av elueringsmidlet ble anvendt for scintillasjonstelling for å bestemme mengden av C14 fanget som C<14 >bikarbonatjon. Palmitoyl CoA oxidation - The Palmitoyl CoA oxidation was performed in a total volume of 100 microliters containing the following agents: 110 mM KC1, 33 mM Tris buffer at pH 8.2 mM Kpi, 2 mM MgCl2, 0.1 mM EDTA, 14 .7 microM defatted BSA, 0.5 mM malic acid, 13 mM carnitine, 1 mM ADP, 52 micrograms mitochondrial protein, and 16 µM 1-C14 palmitoyl CoA (Sp. activity 60 mCi/mmol; 20 microCi/ml, using 5 microliters per examination). The compounds according to the invention were added in DMSO solution at the following concentrations: 100 microM, 30 microM, and 3 microM. In each analysis, a DMSO control was used. After 15 minutes at 30°C, the enzymatic reaction was centrifuged (20,000 g for 1 minute), and 70 microliters of the supernatant was added to an activated reverse phase silicic acid column (about 0.5 ml of silicic acid). The column was eluted with 2 ml of water, and 0.5 ml of the eluent was used for scintillation counting to determine the amount of C 14 trapped as C < 14 >bicarbonate ion.

Eksempel 8 Example 8

Palmitoyl karnitinoksidasjon Palmitoyl carnitine oxidation

Palmitoyl karnitinoksidasjonen ble utført i et totalt volum på 100 ul som inneholdt følgende midler: 110 mM KC1,33 mM tris buffer ved pH 8,2 mM Kpi, 2 mM MgCl2, 0,1 mM EDTA, 0,1 mg/ml avfettet BSA, 0,5 mM malinsyre, 3 mM ADP, 52 mikrogram mitokondrie protein, og 43 mikroM 1-C14 palmitoyl karnitin (Sp. aktivitet 60 mCi/mmol; 20 mikroCi/ml, ved anvendelse av 5 mikroliter pr. undersøkelse). Forbindelsene ifølge oppfinnelsen ble tilsatt i DMSO løsning ved de følgende konsentrasjoner: 100 mikroM, 30 mikroM, og 3 mikroM. I hver analyse ble en DMSO kontroll benyttet. Etter 15 minutter ved 30°C ble den enzymatiske reaksjonen sentrifugert (20.000 gil minutt), og 70 mikroliter av supernatanten ble tilsatt til en aktivert revers fase kieselsyrekolonne (ca. 0,5 ml av kieselsyre). Kolonnen ble eluert med 2 ml vann, og 0,5 ml av elueringsmidlet ble anvendt for scintillasjonstelling for å bestemme mengden av C<14> fanget som C<14> bikarbonatjon. Dataene er presentert som % aktivitet av kontroll. The palmitoyl carnitine oxidation was carried out in a total volume of 100 µl containing the following agents: 110 mM KCl, 33 mM Tris buffer at pH 8.2 mM Kpi, 2 mM MgCl2, 0.1 mM EDTA, 0.1 mg/ml defatted BSA , 0.5 mM malic acid, 3 mM ADP, 52 micrograms mitochondrial protein, and 43 microM 1-C14 palmitoyl carnitine (Sp. activity 60 mCi/mmol; 20 microCi/ml, using 5 microliters per examination). The compounds according to the invention were added in DMSO solution at the following concentrations: 100 microM, 30 microM, and 3 microM. In each analysis, a DMSO control was used. After 15 minutes at 30°C, the enzymatic reaction was centrifuged (20,000 g/min), and 70 microliters of the supernatant was added to an activated reverse phase silicic acid column (about 0.5 ml of silicic acid). The column was eluted with 2 mL of water, and 0.5 mL of the eluent was used for scintillation counting to determine the amount of C<14> trapped as C<14> bicarbonate ion. The data are presented as % activity of control.

Eksempel 9 Example 9

Metabolitisk stabilitet: Metabolic stability:

Som et mål på metabolitisk stabilitet ble forbindelsene ifølge oppfinnelsen inkubert med human lever S-9 mikrosomale fraksjoner. Etter 30 minutter ved 37°C ble mengden morlegemiddel igjen bestemt ved anvendelse av LC-masse spek. Responsfaktoren for hver forbindelse ble bestemt ved å etablere en standardkurve og å anvende en indre standard i løpet av analysen av prøvene. Et gjennomsnitt av fem eksperimenter for prosent ranolasin gjenværende ved 30 minutters tidspunktet er 57%. Forbindelsene ifølge oppfinnelsen ble undersøkt som beskrevet i protokollen nedenfor og prosentandel morforbindelse ble dividert med gjennomsnittlig prosent ranolasin gjenværende (57%) som ga en metabolitisk stabilitetsfaktor. En forbindelse med et stabilitetstall større enn 1,2 har en bedre stabilitet enn ranolasin i lever S-9 undersøkelsen. En forbindelse med et stabilitetstall mellom 1,2 og 0,8 har en ekvivalentstabilitet i lever S-9 undersøkelsen. En forbindelse med stabilitetstall mindre enn 0,8 er mindre stabil enn ranolasin i lever S-9 undersøkelsen. As a measure of metabolic stability, the compounds of the invention were incubated with human liver S-9 microsomal fractions. After 30 minutes at 37°C, the amount of parent drug was again determined using LC mass spec. The response factor for each compound was determined by establishing a standard curve and using an internal standard during the analysis of the samples. An average of five experiments for percent ranolazine remaining at the 30 minute time point is 57%. The compounds according to the invention were examined as described in the protocol below and the percentage of parent compound was divided by the average percentage of ranolazine remaining (57%) which gave a metabolic stability factor. A compound with a stability number greater than 1.2 has a better stability than ranolazine in the liver S-9 study. A compound with a stability number between 1.2 and 0.8 has an equivalent stability in the liver S-9 examination. A compound with a stability number less than 0.8 is less stable than ranolazine in the liver S-9 study.

Formålet med dette eksperimentet er å sammenligne prosentandel gjenværende for forbindelsene ifølge oppfinnelsen med prosentandel gjenværende for ranolasin etter 30 minutter inkubering med humane lever S-9 fraksjoner. The purpose of this experiment is to compare the percentage remaining for the compounds according to the invention with the percentage remaining for ranolazine after 30 minutes of incubation with human liver S-9 fractions.

Reagenser: Reagents:

Følgende reagenser ble anvendt: Kaliumfosfat, 0,5M pH 7,4 (inkuberingsbuffer), holdt ved romtemperatur; 0,05M MgCl2 holdt ved 4°C; P-nikotinamid adenin dinukleotidfosfat, tetranatirumsalt, redusert form (NADPH), 0,02M løsning i vann (~16,6 mg/ml) fra Sigma Lot # 79H7044 fremstilt på bruksdagen. 1 mM ranolasin eller forbindelsene 43,45,47, 52, 70, 74,76, 78 og 80 i CAN ytterligere fortynnet for å oppnå 100 uM i 10% CAN; Human S9 forråd; 20 mg/ml fra Gentest. The following reagents were used: Potassium phosphate, 0.5M pH 7.4 (incubation buffer), kept at room temperature; 0.05M MgCl2 kept at 4°C; P-nicotinamide adenine dinucleotide phosphate, tetrasodium salt, reduced form (NADPH), 0.02M solution in water (~16.6 mg/ml) from Sigma Lot # 79H7044 prepared on the day of use. 1 mM ranolazine or compounds 43,45,47, 52, 70, 74,76, 78 and 80 in CAN further diluted to obtain 100 µM in 10% CAN; Human S9 Repository; 20 mg/ml from Gentest.

Fremgangsmåte: Approach:

Inkuberingsblandingen ble fremstilt som følger: The incubation mixture was prepared as follows:

• 1% av organisk løsemiddel (acetonitril) ble anvendt i inkuberingsblanding. Generelt ble 30 inkubater fremstilt samtidig ved forhåndsblanding av 0,75 ml MgCl2,0,75 ml inkuberingsbuffer, 0,75 ml NADPH, 3,75 ml vann. Deretter ble 200 ul/inkubat pipettert, 25 ul forbindelse som skulle testes tilsatt, blandet og reaksjonen ble initiert ved tilsetting av S-9. • 1% of organic solvent (acetonitrile) was used in the incubation mixture. In general, 30 incubates were prepared simultaneously by premixing 0.75 ml MgCl 2 , 0.75 ml incubation buffer, 0.75 ml NADPH, 3.75 ml water. Then 200 µl/incubate was pipetted, 25 µl of compound to be tested was added, mixed and the reaction was initiated by addition of S-9.

Alle komponentene ble kombinert med inkubasjonsbuffer og det ble repipettert 200 Hl/rør pluss 25 ul av forbindelsen som ble testet sammen med 25 ul S-9. All components were combined with incubation buffer and 200 µl/tube plus 25 µl of the compound being tested was re-pipetted along with 25 µl of S-9.

Etter 5 minutter med pre-inkubasjon ved 37°C, ved 0 og 30 minutter etter oppstart av reaksjonen, ble en 50 ul alikvot av inkubasjonsblandingen fjernet og tilsatt til 100 ul av 9:1 acetonitrilmetanol som inneholdt indre standard. After 5 min of pre-incubation at 37°C, at 0 and 30 min after initiation of the reaction, a 50 µl aliquot of the incubation mixture was removed and added to 100 µl of 9:1 acetonitrile methanol containing internal standard.

Blandingen ble sentrifugert og en 100 ul alikvot av supernatanten ble fortynnet i 1 ml løsemiddel C (0,1% maursyre i vann). Deretter ble prøvene anlysert for forhold mellom forbindelse og indre standard ved tid null og 30 minutter ved LC/MS (injisert 10 The mixture was centrifuged and a 100 µl aliquot of the supernatant was diluted in 1 ml of solvent C (0.1% formic acid in water). The samples were then analyzed for the ratio between compound and internal standard at time zero and 30 minutes by LC/MS (injected 10

Analyse og databeregninger: Analysis and data calculations:

Prøvene ble analysert for utgangsforbindelser og potentielle metabolitter ved LC/MS ved anvendelse av indre standard og en ODS-C18 kolonne med en strømningshastighet på 0,25 ml/min. Fremgangsmåten ovenfor resulterte i følgende relative stabilitetsfaktorer sammenlignet med ranolasin for forbindelsene ifølge oppfinnelsen som er illustrert i tabell 4. Hvis en forbindelse er mer stabil enn ranolasin i lever S-9 undersøkelsen da vil stabilitetsfaktoren være større enn 1,0. Hvis en forbindelse er mindre stabil enn ranolasin, da vil stabiliseringsfaktoren være mindre enn 1,0. The samples were analyzed for parent compounds and potential metabolites by LC/MS using an internal standard and an ODS-C18 column with a flow rate of 0.25 mL/min. The above procedure resulted in the following relative stability factors compared to ranolazine for the compounds of the invention which are illustrated in Table 4. If a compound is more stable than ranolazine in the liver S-9 study then the stability factor will be greater than 1.0. If a compound is less stable than ranolazine, then the stabilization factor will be less than 1.0.

Claims (16)

1. Substituerte piperazinforbindelser, karakterisert ved at de har følgende formel: hvori X er utvalgt fra gruppen som består av: hvori m = 1 eller 2 eller 3; Ri, R2, R3, R4 og R5 er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, SR23, N(R23)2, COR23, NR23SO2R22, Ci.5alkyl, morfolinyl og pyrrolyl, hvori alkylsubstituenten eventuelt er substituert med 1 substituent utvalgt fra OR23, hvori R2 og R3 kan bindes sammen og danne et sammensmeltet ringsystem som har fra tre til fire karbonatomer, hvori R4 og R5 kan bindes sammen og danne -CH=CH-CH=CH-; R6, R7 og Rg er hver uavhengig utvalgt fra gruppen som består av hydrogen og Q.6 alkyl; R9, Rio, Rn, R12, R13, R14, R15 og Ri6 er hver uavhengig utvalgt fra gruppen som består av hydrogen, Cm alkyl, hvori R9 og Rio sammen kan danne et karbonyl, eller Rn og R12 kan sammen danne et karbonyl, eller Ri 3 og Ri 4 kan sammen danne et karbonyl, eller Ri 5 og Ri 6 kan sammen danne et karbonyl hvori Rn og Ri 3 eller R9 og Ri 5 og Rn eller Rn og Ri 5 eller R9 og Ri 3 kan binde sammen og danne et brodannet ringsystem som har fra 1 til 4 karbonatomer hvori R9 og Rio eller Rn eller R]2 eller Ri3 og Rh eller Ri5 og Ri 6 kan binde sammen og danne et brodannende ringsystem som har fra 1 til 5 karbonatomer med den betingelsen at R9, Rio, Rn, R12, R13, R14, R15 og Ri6 ikke alle er hydrogen når R24 er fenyl og når X er R22 er C1-6 alkyl; R23 er utvalgt fra gruppen som består av H og Ci.6; og R24 er utvalgt fra gruppen som består av C1-6 alkyl, C3-8 sykloalkyl, naftyl og hvori Rn, Ri8, R19, R23 og R2i hver er uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, OR23, Ci-salkyl eller to av R17-R21 danner en Ci-2 alkylendioksyfenyl.1. Substituted piperazine compounds, characterized in that they have the following formula: wherein X is selected from the group consisting of: wherein m = 1 or 2 or 3; R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 , SR 23 , N(R 23 ) 2 , COR 23 , NR 23 SO 2 R 22 , C 1-5 alkyl, morpholinyl and pyrrolyl, wherein the alkyl substituent is optionally substituted with 1 substituent selected from OR 23 , wherein R 2 and R 3 may be bonded together to form a fused ring system having from three to four carbon atoms, wherein R 4 and R 5 may be bonded to form -CH=CH-CH=CH-; R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; R 9 , R 10 , R n , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, C 1 to C 6 alkyl, wherein R 9 and R 10 may together form a carbonyl, or R n and R 12 may together form a carbonyl, or Ri 3 and Ri 4 can together form a carbonyl, or Ri 5 and Ri 6 can together form a carbonyl in which Rn and Ri 3 or R9 and Ri 5 and Rn or Rn and Ri 5 or R9 and Ri 3 can bond together and form a bridged ring system having from 1 to 4 carbon atoms in which R9 and Rio or Rn or R]2 or Ri3 and Rh or Ri5 and Ri 6 can bond together to form a bridged ring system having from 1 to 5 carbon atoms with the condition that R9, Rio , Rn, R12, R13, R14, R15 and R16 are not all hydrogen when R24 is phenyl and when X is R 22 is C 1-6 alkyl; R23 is selected from the group consisting of H and C1.6; and R24 is selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, naphthyl and wherein Rn, R18, R19, R23 and R21 are each independently selected from the group consisting of hydrogen, halo, CF3, OR23, C1-6 alkyl or two of R17-R21 form a C1-2 alkylenedioxyphenyl. 2. Substituerte piperazinforbindelser ifølge krav 1, karakterisert v e d at den har følgende formel: hvori m = 1 eller 2 eller 3; Ri, R2, R3, R4 og R5 er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, SR23, N(R23)2, NR23S02R22, Ci.5alkyl, morfolinyl, pyrrolyl, hvori alkylsubstituenten eventuelt er substituert med 1 substituent, hvori R2 og R3 kan bindes sammen og danne et sammensmeltet ringsystem som har fra tre til fire karbonatomer, hvori R4 og R5 kan bindes sammen og danne CH=CH-CH=CH-; R6, R7 og R8 er hver uavhengig utvalgt fra gruppen som består av hydrogen og Ci.6 alkyl; R9, Rio, Rn, R12, R13, R14, R15 og Ri6 er hver uavhengig utvalgt fra gruppen som består av hydrogen og Cm alkyl, hvori R9 og Rio sammen kan danne et karbonyl, eller Rn og Ri2 kan sammen danne et karbonyl, eller R13 og R14 kan sammen danne et karbonyl, eller Ri 5 og Ri 6 kan sammen danne et karbonyl hvori Ri 1 og Ri 3 eller R9 og Ri 5 og R9 eller Ri 1 og Ri 5 eller R9 og Ri 3 kan binde sammen og danne et brodannende ringsystem som har fra 1 til 4 karbonatomer hvori R9 og Rio eller Ri 1 eller Ri2 eller R]3 og Ri4 eller Ri 5 og Ri 6 sammen kan danne et brodannende ringsystem som har fra 1 til 5 karbonatomer med den betingelsen at R9, Rio, Ri 1, Ri2, R13, R14, Ris og Ri6 ikke alle er hydrogen når R17, R]8, R19, R2o og R2i alle er hydrogen; R22 er C1-6 alkyl; Rn, Ri<g>, R19, R2o og R2i hver er uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, OR23, Ci-salkyl, to av R17-R20 danner Ci.2alkendioksyfenyl; R23 er utvalgt fra gruppen som består av H og C1-6 alkyl.2. Substituted piperazine compounds according to claim 1, characterized in that it has the following formula: wherein m = 1 or 2 or 3; R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halo, CF 3 , SR 23 , N(R 23 ) 2 , NR 23 SO 2 R 22 , C 1-5 alkyl, morpholinyl, pyrrolyl, wherein the alkyl substituent is optionally substituted with 1 substituent , wherein R 2 and R 3 may be bonded to form a fused ring system having from three to four carbon atoms, wherein R 4 and R 5 may be bonded to form CH=CH-CH=CH-; R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; R 9 , R 10 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen and C 1 -C 1 alkyl, wherein R 9 and R 10 can together form a carbonyl, or R 1 and R 12 can together form a carbonyl, or R13 and R14 may together form a carbonyl, or Ri 5 and Ri 6 may together form a carbonyl in which Ri 1 and Ri 3 or R9 and Ri 5 and R9 or Ri 1 and Ri 5 or R9 and Ri 3 may bond together and form a bridging ring system having from 1 to 4 carbon atoms in which R9 and Rio or Ri 1 or Ri2 or R]3 and Ri4 or Ri 5 and Ri 6 together can form a bridging ring system having from 1 to 5 carbon atoms with the proviso that R9, Rio , R 1 , R 1 , R 13 , R 14 , R 11 and R 16 are not all hydrogen when R 17 , R 18 , R 19 , R 20 and R 21 are all hydrogen; R 22 is C 1-6 alkyl; Rn, R1<g>, R19, R20 and R2i are each independently selected from the group consisting of hydrogen, halo, CF3, OR23, C1-6alkyl, two of R17-R20 form C1-2alkenedioxyphenyl; R 23 is selected from the group consisting of H and C 1-6 alkyl. 3. Forbindelse ifølge krav 2, karakterisert ved atm=l; Ri, R2, R3, R4 og R5 er hver uavhengig utvalgt fra gruppen som består av hydrogen og metyl; Ré, R7 og R8 er hver hydrogen; R9, Rio, Rn, Ri2, R13, R14, Ris og Ri6 er hver uavhengig utvalgt fra gruppen som består av hydrogen og C1-2 alkyl, eller R9 og Rio sammen kan danne et karbonyl eller Ri 1 og Ri 2 sammen kan danne et karbonyl, eller Ri 3 og Rh sammen kan danne et karbonyl, eller Ri5 og Ri6 sammen kan danne et karbonyl med den betingelsen at R9, Rio, Ri 1, Ri2, Ri 3, Rh, Ri 5 og Ri 6 ikke alle samtidig er hydrogen og hvori Ri eller R9 og Ri 5 eller R9 og Rn eller Rn og Ri 5 eller R9 og Rn kan bindes sammen og danne en ring som har fra 1 til 4 karbonatomer; Rn, Ri<g>, R19, R20 og R21 hver er uavhengig utvalgt fra gruppen som består av hydrogen, halo, CM alkyl og OR23; og R<23>erC,.2alkyl.3. Compound according to claim 2, characterized by atm=1; R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen and methyl; R 8 , R 7 and R 8 are each hydrogen; R9, Rio, Rn, Ri2, R13, R14, Ris and Ri6 are each independently selected from the group consisting of hydrogen and C1-2 alkyl, or R9 and Rio together can form a carbonyl or Ri1 and Ri2 together can form a carbonyl, or Ri 3 and Rh together can form a carbonyl, or Ri5 and Ri6 together can form a carbonyl with the proviso that R9, Rio, Ri 1, Ri2, Ri 3, Rh, Ri 5 and Ri 6 are not all simultaneously hydrogen and wherein Ri or R9 and Ri5 or R9 and Rn or Rn and Ri5 or R9 and Rn can be linked together to form a ring having from 1 to 4 carbon atoms; Rn, Ri<g>, R19, R20 and R21 are each independently selected from the group consisting of hydrogen, halo, C1-C alkyl and OR23; and R<23> is C1-2alkyl. 4. Forbindelse ifølge krav 2, karakterisert ved at den er utvalgt fra gruppen som består av: N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)propyl]-3-oksopiperazinyl} acetamid, N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)propyl]-3,5-dimetylpiperazinyl} acetamid, 2-{(5S,2R)-4-[-hydroksy-3-(2-metoksyfenoksy)propyl]-2,5-dimetylpiperazinyl}-N-(2,6-dimetylfenyl)acetamid, 2-{2,5-diasa-5-[2-hydroksy-3-(2-metoksyfenoksy)propyl]bisyklo[4.4.0]des-2-yl}-N-(2,6-dimetylfenyl)acetamid, N-(2,6-dimetylfenyl)-2- {4- [2-hydroksy-3 -(2-metoksyfenoksy)propyl] -3 - oksopiperazinyl} acetamid, N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)propyl]-3,3-dimetylpiperazinyl} acetamid,4. Compound according to claim 2, characterized in that it is selected from the group consisting of: N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-oxopiperazinyl } acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3,5-dimethylpiperazinyl} acetamide, 2-{(5S,2R)- 4-[-hydroxy-3-(2-methoxyphenoxy)propyl]-2,5-dimethylpiperazinyl}-N-(2,6-dimethylphenyl)acetamide, 2-{2,5-diaza-5-[2-hydroxy- 3-(2-Methoxyphenoxy)propyl]bicyclo[4.4.0]des-2-yl}-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2- {4- [2 -hydroxy-3-(2-methoxyphenoxy)propyl]-3-oxopiperazinyl}acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3 ,3-dimethylpiperazinyl} acetamide, 2- {5-[(2S)-2-hydroksy-3-(2-metoksyfenoksy)propyl](l S,4S)-2,5-diazabisyklo[2.2.1 ]hept-2-yl} -N-(2,6-dimetylfenyl)acetamid, N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-metoksyfenoksy)butyl]-piperazinyl} acetamid, N-(2,6-dimetylfenyl)-2-{4-[4-(4-fluorfenoksy)-2-hydroksybutyl]-piperazinyl}acetamid, 2-(4-{4-[4-(tert-butyl)fenoksy]-2-hydroksybutyl}piperazinyl)-N-(2,6-dimetylfenyl)acetamid, N-(2,6-dimetylfenyl)-2- {4- [2-hydroksy-3 -(2-metoksyfenoksy)butyl] - piperazinyl} acetamid, N-(2,6-dimetylfenyl)-2-piperazinyl} acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2,6-dimetylfenyl)-acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2,6-diklorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-sulfamoyl-fenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(5-metoksy-3-(trifluormetyl)fenyl]acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-indan-5-ylacetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-naftylacetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-klornaftyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2-pyrrolylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazin}-N-fenylacetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-N-(2-klorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2-k^ 4-metylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-[2-(l-metylvinyl)fenyl] acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2-metylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-[6-metyl-2-(metyletyl)fenyl] acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(3-metyltiofenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-klor-2-metoksy-5 -metylfenyl) acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-[4-(dimetylamino)fenyl] acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2,4-dimetoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-lfuorfenoksy)-2-hyfr^ diklorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-klorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(3-klorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}^ diklorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-^ metoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-metylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(3-metylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-fluorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hy^ syanofenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-84 asetylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(2-metoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-[4-(trifiuormetyl)fenyl] acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-[4-klor-3 -(trifluormetyl)fenyl] acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpipérazinyl}-N-(3,5-dimetoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(4-morfolin-4-ylfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-ty^ 4-metoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(3,4,5-trimetoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}-N-(3,4-dimetoksyfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazin 2-fluorfenyl)acetamid, 2-{(3S)-4-[(2S)-3-(2-fluorfenoksy)-2-hydroksypropyl]-3-metylpiperazinyl}^ (hydroksy-rnetyl-6-metylfenyl]acetarnid.2- {5-[(2S)-2-hydroxy-3-(2-methoxyphenoxy)propyl](1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-( 2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenoxy)butyl]-piperazinyl} acetamide, N-(2,6-dimethylphenyl) )-2-{4-[4-(4-fluorophenoxy)-2-hydroxybutyl]-piperazinyl}acetamide, 2-(4-{4-[4-(tert-butyl)phenoxy]-2-hydroxybutyl}piperazinyl) -N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2- {4- [2-hydroxy-3 -(2-methoxyphenoxy)butyl]-piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2-piperazinyl}acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (2,6-dimethylphenyl)-acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2,6-dichlorophenyl) )acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-sulfamoyl-phenyl)acetamide, 2-{( 3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(5-methoxy-3-(trifluoromethyl)phenyl]acetamide, 2-{(3S) -4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-indan-5-ylacetamide, 2-{(3S)-4-[(2S)-3- (2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-naphthylacetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl }-N-(4-chloronaphthyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-pyrrolylphenyl) acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine}-N-phenylacetamide, 2-{(3S)-4-[(2S )-3-(2-fluorophenoxy)-2-hydroxypropyl 1]-N-(2-chlorophenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-k ^ 4-Methylphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[2-(1-methylvinyl)phenyl ] acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-methylphenyl)acetamide, 2-{(3S) -4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[6-methyl-2-(methylethyl)phenyl] acetamide, 2-{(3S)-4 -[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-methylthiophenyl)acetamide, 2-{(3S)-4-[(2S)-3-( 2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-chloro-2-methoxy-5-methylphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2 -fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4-(dimethylamino)phenyl] acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2- hydroxypropyl]-3-methylpiperazinyl}-N-(2,4-dimethoxyphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxydichlorophenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy )-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-chlorophenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3- methylpiperazinyl}-N-(3-chlorophenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}^ dichlorophenyl)acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-^ methoxyphenyl)acetamide, 2-{(3S)-4-[(2S) -3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-methylphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)- 2-hydroxypropyl]-3-methylpiperazinyl}-N-(3-methylphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl} -N-(4-fluorophenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hy^cyanophenyl)acetamide, 2-{(3S)-4-[ (2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-84 acetylphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy) -2-hydroxypropyl]-3-methylpiperazinyl}-N-(2-methoxy yphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4-(trifluoromethyl)phenyl] acetamide, 2- {(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-[4-chloro-3-(trifluoromethyl)phenyl] acetamide, 2-{( 3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,5-dimethoxyphenyl)acetamide, 2-{(3S)-4-[( 2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(4-morpholin-4-ylphenyl)acetamide, 2-{(3S)-4-[(2S)-3- (2-fluorophenoxy)-2-thy^4-methoxyphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N- (3,4,5-trimethoxyphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}-N-(3,4- dimethoxyphenyl)acetamide, 2-{(3S)-4-[(2S)-3-(2-fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazine 2-fluorophenyl)acetamide, 2-{(3S)-4-[(2S)- 3-(2-Fluorophenoxy)-2-hydroxypropyl]-3-methylpiperazinyl}^(hydroxymethyl-6-methylphenyl]acetarnide. 5. Substituert piperazinforbindelse, karakterisert ved at den har følgende formel: hvori m = 0,1 eller 2 eller 3; R<1>, R<2>, R<3>, R<4> og R<5> er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, SR23, N(R23)2, COR23, NR23S02R22, Ci-5 alkyl, morfolinyl, pyrrolyl, hvori alkylsubstituenten eventuelt er substituert med 1 substituent OR23; R<6>, R<7> og R<8> er uavhengig utvalgt fra gruppen som består av hydrogen og Ci-6 alkyl; R<9>, R1<0>, R", R<12>, R1<3>, R14, R<1>5 og R1<6> er hver uavhengig utvalgt fra gruppen som består av hydrogen og Cm alkyl, hvori R<9> og R<10> sammen kan danne en karbonyl, eller R11 og R<12> kan sammen danne en karbonyl, eller R13 og R<14> kan sammen danne en karbonyl, eller R<1>5 og R1<6> kan sammen danne en karbonyl, hvori R11 og R<13> eller R<9> og R13 eller R<9> og R<11> eller R11 og R<15> eller R9 og R<13> sammen kan danne et brodannet ringsystem hvori de to R gruppene sammen omfatter fra 1 til 4 karbonatomer og hvori R<9> og R<10 >eller R<11> og R<12> eller R<13> og R<14> eller R15 og R<16> sammen kan danne et spiro ringsystem hvori de to R gruppene sammen omfatter fra 1 til 5 karbonatomer; R<17>, R<18>, R19, R20 og R<21> har betydningen angitt i krav 1; R22 er d-s alkyl; og R23 er utvalgt fra gruppen som består av H og Ci-6 alkyl.5. Substituted piperazine compound, characterized in that it has the following formula: where m = 0.1 or 2 or 3; R<1>, R<2>, R<3>, R<4> and R<5> are each independently selected from the group consisting of hydrogen, halo, CF3, SR23, N(R23)2, COR23, NR23S02R22 , C1-5 alkyl, morpholinyl, pyrrolyl, in which the alkyl substituent is optionally substituted with 1 substituent OR23; R<6>, R<7> and R<8> are independently selected from the group consisting of hydrogen and C1-6 alkyl; R<9>, R1<0>, R", R<12>, R1<3>, R14, R<1>5 and R1<6> are each independently selected from the group consisting of hydrogen and C 1 -C alkyl, wherein R<9> and R<10> together can form a carbonyl, or R11 and R<12> can together form a carbonyl, or R13 and R<14> can together form a carbonyl, or R<1>5 and R1< 6> can together form a carbonyl, in which R11 and R<13> or R<9> and R13 or R<9> and R<11> or R11 and R<15> or R9 and R<13> can together form a bridged ring system in which the two R groups together comprise from 1 to 4 carbon atoms and in which R<9> and R<10 >or R<11> and R<12> or R<13> and R<14> or R15 and R< 16> together can form a spiro ring system in which the two R groups together comprise from 1 to 5 carbon atoms; R<17>, R<18>, R19, R20 and R<21> have the meaning stated in claim 1; R 22 is C 1-6 alkyl; and R 23 is selected from the group consisting of H and C 1-6 alkyl. 6. Forbindelse ifølge krav 5, karakterisert vedatm=l eller 2; R<1>, R<2>, R<3>, R<4> og R<5> hver er uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, OR<23> og CU2 alkyl, hvori R<23> er Ci-2 alkyl; R<6>, R<7> og R<8> er hver uavhengig utvalgt fra gruppen som består av hydrogen og metyl; R<9>, R1<0>, R<11>, R<12>, R<13>, R<14>, R<15> og R<16> er hver uavhengig utvalgt fra gruppen som består av hydrogen og Ci.2 alkyl, eller R<9>bg R<10> sammen kan danne et karbonyl, eller R15 og R1<6> sammen danner et karbonyl, hvori R<11> og R<13> eller R<9> og R<13> eller R<9> og R<11> eller R1<1> og R<15> eller R9 og R1<3> kan bindes sammen og kan danne en ring som inkluderer fra 1 til 4 karbonatomer; og R<1>7, R1<8>, RR<19>, R<2>0 og R2<1> er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, OR23 eller C1-3 alkyl.6. Compound according to claim 5, characterized by atm=1 or 2; R<1>, R<2>, R<3>, R<4> and R<5> are each independently selected from the group consisting of hydrogen, halo, CF3, OR<23> and CU2 alkyl, wherein R< 23 > is C 1-2 alkyl; R<6>, R<7> and R<8> are each independently selected from the group consisting of hydrogen and methyl; R<9>, R1<0>, R<11>, R<12>, R<13>, R<14>, R<15> and R<16> are each independently selected from the group consisting of hydrogen and Ci.2 alkyl, or R<9>bg R<10> together can form a carbonyl, or R15 and R1<6> together form a carbonyl, in which R<11> and R<13> or R<9> and R <13> or R<9> and R<11> or R1<1> and R<15> or R9 and R1<3> may be linked together and may form a ring including from 1 to 4 carbon atoms; and R<1>7, R1<8>, RR<19>, R<2>0 and R2<1> are each independently selected from the group consisting of hydrogen, halo, CF3, OR23 or C1-3 alkyl. 7. Forbindelse ifølge krav 5, karakterisert vedatm=l eller 2; R<1>, R<2>, R<3>, R<4> og R<5> hver er uavhengig utvalgt fra gruppen som består av hydrogen metyl; R<6>, R<7> og R<8> er hver hydrogen; R<9>, R1<0>, R1<1>, R12, R<13>, R<14>, R<15> og R<16> er hver uavhengig utvalgt fra gruppen som består av hydrogen og Cm alkyl, eller R<9> og R<10> sammen kan danne en karbonyl, eller R11 og R1<2> kan sammen danne en karbonyl, eller R13 og R<14> kan sammen danne en karbonyl, eller R15 og R<16> kan sammen danne en karbonyl, hvori R<11> og R<13> eller R<9> og R<13> eller R<9> og R<11> eller R11 og R<15> eller R9 og R1<3> kan bindes sammen og danne en ring som inkluderer fra 1 til 4 karbonatomer; R<17>, R<18>, R19, R<2>0 og R2<1> er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, Cm alkyl, CF3, og OR23; og R<23> er Ci-2 alkyl.7. Compound according to claim 5, characterized by atm=1 or 2; R<1>, R<2>, R<3>, R<4> and R<5> are each independently selected from the group consisting of hydrogen methyl; R<6>, R<7> and R<8> are each hydrogen; R<9>, R1<0>, R1<1>, R12, R<13>, R<14>, R<15> and R<16> are each independently selected from the group consisting of hydrogen and C 1 -C alkyl, or R<9> and R<10> together can form a carbonyl, or R11 and R1<2> can together form a carbonyl, or R13 and R<14> can together form a carbonyl, or R15 and R<16> can together form a carbonyl, in which R<11> and R<13> or R<9> and R<13> or R<9> and R<11> or R11 and R<15> or R9 and R1<3> can bond together to form a ring that includes from 1 to 4 carbon atoms; R<17>, R<18>, R19, R<2>0 and R2<1> are each independently selected from the group consisting of hydrogen, halo, C 1 -C alkyl, CF 3 , and OR 23 ; and R<23> is C1-2 alkyl. 8. Substituert piperazinforbindelse ifølge krav 5, karakterisert ved at den er utvalgt fra gruppen som består av: N-(2,6-dimetylfenyl)-2-[4-(2-hyddroksy-4-fenylbutyl)piperazinyl]acetamid; N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2- metoksyfenyl)propyl]piperazinyl}acetamid; 2-[4-(3-(2H-benzo[d]l,3-dioksolen-5-yl)-2-hydroksypropyl)piperazinyl]-N-(2,6-dimetylfenyl)acetamid; N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(4-[2-hydroksy-3-fenylpropyl] piperazinyl} acetamid, N-(2,6-dimetylfenyl)-2-{4-[4-(4-metoksyfenyl)-2-hydroksybutyl]piperazinyl}acetamid, 2-{4-[4-(2,6-difluorfenyl)-2-hydroksybutyl]piperazinyl}-N-(2,6-dimetylfenyl)-acetamid, N-(2,6-dimetylfenyl)-2-{4-[4-(2-klorfenyl)-2-hydroksybutyl]piperazinyl}acetamid, 2-(4-{4-[4-(tert-butyl)fenyl]fenyl-2-hydroksybutyl}piperazinyl)-N-(2,6-dimtylfenyl)acetamid, N-(2,6-dimetylfenyl)-2-{4-[4-(2-fluorfenyl)-2-hydroksybutyl]piperazinyl}acetamid, N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-4-[4- (trifluormetyl)fenyl]butyl} piperazinyl)acetamid, 2-[4-(3-(2H-benzo[d]l,3-dioksolen-5-yl)-2-hydroksypropyl)piperazinyl]-N-(2,6-dimetylfenyl)-2-metylpropanamid, N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-3-fenylpropyl)piperazinyl]-2-metylpropanamid, N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(3,4,5-trimetoksyfenyl)propyl]piperazinyl}-2-metylpropanamid, N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-5-fenylpentyl)pipeasinyl]acetamid, N-(2,6-dimetylfenyl)-2-{4-[5-(2-fluorfenyl)-2-hydroksy-pentyl]piperazinyl}acetamid og N-(2,6-dimetylfenyl)-2-{4-[5-(2-klorfenyl)-2-hydroksy-pentyl]piperazinyl} acetamid.8. Substituted piperazine compound according to claim 5, characterized in that it is selected from the group consisting of: N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-4-phenylbutyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-methoxyphenyl)propyl]piperazinyl}acetamide; 2-[4-(3-(2H-benzo[d]1,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(4-[2-hydroxy-3-phenylpropyl] piperazinyl} acetamide, N-(2,6-dimethylphenyl)-2- {4-[4-(4-Methoxyphenyl)-2-hydroxybutyl]piperazinyl}acetamide, 2-{4-[4-(2,6-difluorophenyl)-2-hydroxybutyl]piperazinyl}-N-(2,6- dimethylphenyl)-acetamide, N-(2,6-dimethylphenyl)-2-{4-[4-(2-chlorophenyl)-2-hydroxybutyl]piperazinyl}acetamide, 2-(4-{4-[4-(tert -butyl)phenyl]phenyl-2-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide, N-(2,6-dimethylphenyl)-2-{4-[4-(2-fluorophenyl)-2 -hydroxybutyl]piperazinyl}acetamide, N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-4-[4-(trifluoromethyl)phenyl]butyl}piperazinyl)acetamide, 2-[4-(3 -(2H-benzo[d]l,3-dioxolen-5-yl)-2-hydroxypropyl)piperazinyl]-N-(2,6-dimethylphenyl)-2-methylpropanamide, N-(2,6-dimethylphenyl)- 2-[4-(2-hydroxy-3-phenylpropyl)piperazinyl]-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(3,4,5- trimethoxyphenyl)propyl]piperazinyl}-2-methylpropanamide, N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-5-phenylpentyl)pipeasinyl]acetamide, N-(2,6-dimethylphen yl)-2-{4-[5-(2-fluorophenyl)-2-hydroxy-pentyl]piperazinyl}acetamide and N-(2,6-dimethylphenyl)-2-{4-[5-(2-chlorophenyl) -2-Hydroxy-pentyl]piperazinyl} acetamide. 9. Substituert piperazinforbindelse, karakterisert ved at den har følgende formel: hvori m= 1,2 eller 3; R<1>, R<2>, R<3>, R<4> og R<5> er hver uavhengig utvalgt fra gruppen som består av hydrogen, halo, CF3, SR<20>, N(R<20>)2, COR<20>, NR<20>S<O>2R<22>, Ci.5alkyl, morfolinyl og pyrrolyl, hvori alkylsubstituenten eventuelt er substituert med 1 substituent utvalgt fra gruppen som består av OR<20>; R<6>, R<7> og R<8> er hver uavhengig utvalgt fra gruppen bestående av hydrogen eller Ci.3 alkyl; R<9>, R1<0>, R<11>, R<12>, R<13>, R<14>, R<15> og R<16> er hver uavhengig utvalgt fra gruppen som består av Cm alkyl, hvori R<9> og R<10> sammen kan danne en karbonyl, eller R<11> og R<12> sammen kan danne en karbonyl, eller R<13> og R1<4> kan sammen danne en karbonyl, eller R<15> og R<16 >kan sammen danne en karbonyl hvori <Rn> og R<13> eller R<9> og R<15> eller R<9> og R<11> eller R<11 >og R<15> eller R<9> og R<13> sammen kan danne en ring som inkluderer fra 1 til 3 karbonatomer; R<24> er utvalgt fra Ci-C6 alkyl, C3-C8 sykloalkyl og naftyl; R<20> er utvalgt fra gruppen som består av H eller C1-6 alkyl; og R<22> er C1.6 alkyl.9. Substituted piperazine compound, characterized in that it has the following formula: wherein m= 1,2 or 3; R<1>, R<2>, R<3>, R<4> and R<5> are each independently selected from the group consisting of hydrogen, halo, CF3, SR<20>, N(R<20> )2, COR<20>, NR<20>S<O>2R<22>, C1-5 alkyl, morpholinyl and pyrrolyl, in which the alkyl substituent is optionally substituted with 1 substituent selected from the group consisting of OR<20>; R<6>, R<7> and R<8> are each independently selected from the group consisting of hydrogen or C1-3 alkyl; R<9>, R1<0>, R<11>, R<12>, R<13>, R<14>, R<15> and R<16> are each independently selected from the group consisting of C 1 -C alkyl , wherein R<9> and R<10> together may form a carbonyl, or R<11> and R<12> together may form a carbonyl, or R<13> and R1<4> may together form a carbonyl, or R<15> and R<16 >can together form a carbonyl in which <Rn> and R<13> or R<9> and R<15> or R<9> and R<11> or R<11 >and R <15> or R<9> and R<13> together may form a ring including from 1 to 3 carbon atoms; R<24> is selected from C1-C6 alkyl, C3-C8 cycloalkyl and naphthyl; R<20> is selected from the group consisting of H or C1-6 alkyl; and R<22> is C1.6 alkyl. 10. Forbindelse ifølge krav 9, karakterisert ved at R<6>, R<7 >og R<8> hver er uavhengig utvalgt fra gruppen som består av hydrogen eller metyl.10. Compound according to claim 9, characterized in that R<6>, R<7> and R<8> are each independently selected from the group consisting of hydrogen or methyl. 11. Forbindelse ifølge krav 10, karakterisert ved atm=l; R<1>, R<2>, R<3>, R<4> og R<5> hver uavhengig utvalgt fra gruppen som består av hydrogen eller metyl; R<6>, R<7> og R<8> er hver hydrogen; R<1>1 og R1<2> er hver utvalgt fra gruppen som består av hydrogen og metyl, R<9>, R10, R13, R14, R15 og R<16> er hver hydrogen og R9 og R1<0> kan sammen danne en karbonyl; R<24> er utvalgt fra gruppen som består av C1-C6 alkyl, C3-C8 sykloalkyl og naftyl; og R<20> er metyl eller H.11. Compound according to claim 10, characterized by atm=1; R<1>, R<2>, R<3>, R<4> and R<5> each independently selected from the group consisting of hydrogen or methyl; R<6>, R<7> and R<8> are each hydrogen; R<1>1 and R1<2> are each selected from the group consisting of hydrogen and methyl, R<9>, R10, R13, R14, R15 and R<16> are each hydrogen and R9 and R1<0> may together form a carbonyl; R<24> is selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl and naphthyl; and R<20> is methyl or H. 12. Forbindelse ifølge krav 9, karakterisert ved atm=l; R<1>, R<2>, R<3>, R<4> og R<5> hver uavhengig utvalgt fra gruppen som består av hydrogen eller metyl; R<6>, R<7> og R<8> er hver hydrogen; R<9>, R1<0>, R<11>, R<12>, R<13>, R<14>, R<15> og R<16> er hver hydrogen; og R<24> er utvalgt fra gruppen som består av alkyl som har fra 1 til 6 karbonatomer, sykloalkyl som har fra 4 til 6 karbonatomer og naftyl.12. Compound according to claim 9, characterized by atm=1; R<1>, R<2>, R<3>, R<4> and R<5> each independently selected from the group consisting of hydrogen or methyl; R<6>, R<7> and R<8> are each hydrogen; R<9>, R1<0>, R<11>, R<12>, R<13>, R<14>, R<15> and R<16> are each hydrogen; and R<24> is selected from the group consisting of alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 4 to 6 carbon atoms and naphthyl. 13. Forbindelse ifølge krav 9, karakterisert ved at den er valgt fra gruppen som består av substituerte piperazinforbindelser utvalgt fra gruppen som består av:13. Compound according to claim 9, characterized in that it is selected from the group consisting of substituted piperazine compounds selected from the group consisting of: 2-( {2-[4-(3-isopropoksy-2-hydroksypropyl)piperazinyl]-N-( {2,6-dimetylfenyl)acetamid; N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-3-indan-2-yloksypropyl)piperazinyl]acetamid; N-(2,6-dimetylfenyl)-2- {4-[2-hydroksy-3 -(fenylmetoksy)propyl]piperazinyl} acetamid:2-( {2-[4-(3-isopropoxy-2-hydroxypropyl)piperazinyl]-N-({2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-indan-2-yloxypropyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(phenylmethoxy)propyl]piperazinyl} acetamide: 2-( {2-[4-(3-sykloheksyloksy-2-hydroksypropyl)piperazinyl]-N- {2,6-dimetylfenyl)acetamid; N-(2,6-dimetylfenyl)-2-(-{3-[2-fluorfenyl)metoksy]-2-hydroksypropyl} piperazinyl)acetamid; 2-(4-{3-[(2,4-difluorfenyl)metoksy]-2-hydroksypropyl}piperazinyl)-N-(2,6-dimetylfenyl)acetamid; N-(2,6-dimetylfenyl)-2-[4-(2-hydroksy-3-{[4-(trifluormetyl)fenyl]metoksy}propyl) piperazinyl] acetamid; N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-3-[(2-metoksyfenyl)metoksy]propyl} piperazinyl)acetamid; 2-(4-{3-[(2,4-dimetokysfenyl)-metoksy]-2-hydroksypropyl}piperazinyl)-N-(2,6-dimetylfenyl)acetamid; N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-3-[(4-metoksyfenyl)-metoksy]propyl} piperazinyl)acetamid; N-(2,6-dimetylfenyl)-2-(4-{3-[(4-fluorfenyl)metoksy]-2-hydroksypropyl}piperazinyl)acetamid; N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-3-[(4-metylfenyl)metoksy]propyl}piperazinyl) acetamid; N-(2,6-dimetylfenyl)-2-(4-{2-hydroksy-3-[(4-fenylfenyl)metoksy]propyl}piperazinyl) acetamid; N-(2,6-dimetylfenyl)-2-(4-{3-[(4-butylfenyl)metoksy^ acetamid; N-(2,6-dimetylfenyl)-2-{4-[2-hydroksy-3-(2-naftylmetoksy)propyl]piperazinyl} acetamid; N-(2,6-dimetylfenyl)-2-{4-[3-(sykloheksylmetoksy)-2-hydroksypropyl]piperazinyl} acetamid; og N-(2,6-dimetylfenyl)-2-(4-{3-[(4-fluorfenyl)metoksy]-2-hydroksypropyl}-3,3-dimetylpiperazinyl)acetamid.2-({2-[4-(3-cyclohexyloxy-2-hydroxypropyl)piperazinyl]-N-{2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-(-{3-[2-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide; 2-(4-{3-[(2,4-difluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-{[4-(trifluoromethyl)phenyl]methoxy}propyl)piperazinyl]acetamide; N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-methoxyphenyl)methoxy]propyl}piperazinyl)acetamide; 2-(4-{3-[(2,4-dimethoxyphenyl)-methoxy]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide; N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)-methoxy]propyl}piperazinyl)acetamide; N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}piperazinyl)acetamide; N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methylphenyl)methoxy]propyl}piperazinyl)acetamide; N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-phenylphenyl)methoxy]propyl}piperazinyl)acetamide; N-(2,6-dimethylphenyl)-2-(4-{3-[(4-butylphenyl)methoxy)acetamide; N-(2,6-dimethylphenyl)-2-{4-[2-hydroxy-3-(2-naphthylmethoxy)propyl]piperazinyl} acetamide; N-(2,6-dimethylphenyl)-2-{4-[3-(cyclohexylmethoxy)-2-hydroxypropyl]piperazinyl} acetamide; and N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)methoxy]-2-hydroxypropyl}-3,3-dimethylpiperazinyl)acetamide. 14. Anvendelse av en forbindelse ifølge krav 1 eller 5 eller 9 for fremstilling av et preparat for behandling av et pattedyr som trenger behandling valgt fra gruppen som består av å beskytte skjelettmuskelatur mot skade som resultat av traumer, beskytte skjelettmuskler etterfølgende muskel- eller systemiske sykdommer, å behandle sjokktilstander, å bevare donorvev og organer anvendt ved transplantasjon og å behandle kardiovaskulære sykdommer.14. Use of a compound according to claim 1 or 5 or 9 for the preparation of a preparation for the treatment of a mammal in need of treatment selected from the group consisting of protecting skeletal muscle from damage as a result of trauma, protecting skeletal muscle following muscular or systemic diseases, to treating shock conditions, preserving donor tissue and organs used in transplantation and treating cardiovascular diseases. 15. Anvendelse ifølge krav 14, hvori den kardiovaskulære sykdommen er utvalgt fra gruppen som inkluderer atriale og ventrikulære arytmier, Prinzmetal's (variant) angina, stabil angina og arbeidsindusert angina, kongestiv hjertesykdom og myokardisk infarkt.15. Use according to claim 14, wherein the cardiovascular disease is selected from the group including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina and work-induced angina, congestive heart disease and myocardial infarction. 16. Farmasøytisk sammensetning, karakterisert ved at den innbefatter forbindelse ifølge krav 1 eller 5 eller 9 og en eller flere farmasøytiske eksipienter.16. Pharmaceutical composition, characterized in that it includes a compound according to claim 1 or 5 or 9 and one or more pharmaceutical excipients.
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