NO972898L - 4,4- (Disubstituted) Cyclohexan-1-One Monomers and Related Compounds - Google Patents

4,4- (Disubstituted) Cyclohexan-1-One Monomers and Related Compounds

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Publication number
NO972898L
NO972898L NO972898A NO972898A NO972898L NO 972898 L NO972898 L NO 972898L NO 972898 A NO972898 A NO 972898A NO 972898 A NO972898 A NO 972898A NO 972898 L NO972898 L NO 972898L
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Norway
Prior art keywords
cyclopentyloxy
methoxyphenyl
cyclohexan
substituted
methyl
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NO972898A
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Norwegian (no)
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NO972898D0 (en
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Iv Siegfried Benja Christensen
Joseph M Karpinski
M Dominic Ryan
Paul Elliot Bender
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Smithkline Beecham Corp
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Publication of NO972898D0 publication Critical patent/NO972898D0/en
Publication of NO972898L publication Critical patent/NO972898L/en

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Description

4,4-(Disubstituerte)cykloheksan-1-on-monomere og beslektede forbindelser 4,4-(Disubstituted)cyclohexan-1-one monomers and related compounds

Oppfinnelsens områdeField of the invention

Foreliggende oppfinnelse vedrører nye 4,4-(disubstituerte)cykloheksan-1-oner og beslektede forbindelser, farmasøytiske preparater inneholdende disse forbindelsene, og anvendelsen av disse ved behandling av allergiske og inflammatoriske sykdommer og for hemming av produksjonen av Tumor-Nekrose-Faktor (TNF). The present invention relates to new 4,4-(disubstituted)cyclohexan-1-ones and related compounds, pharmaceutical preparations containing these compounds, and their use in the treatment of allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF ).

Bakgrunn for oppfinnelsenBackground for the invention

Bronkial astma er en kompleks, flerfaktoriell sykdomkarakterisert vedreversibel innsnevring av luftveiene og hyper-reaktivitet av luftrøret overfor ytre stimuli. Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airways and hyper-reactivity of the trachea to external stimuli.

Identifiseringen av nye terapeutiske midler for astma vanskeliggjøres av at flere mediatorer er årsaken til utviklingen av sykdommen. Det er således usannsynlig at elimineringen av virkningen av en enkelt mediator vil ha en vesentlig virkning på alle de tre komponentene av kronisk astma. Et alternativ til "mediator-fremgangsmåten" er å regulere aktiviteten av cellene som er årsaken til patofysiologi til sykdommen. The identification of new therapeutic agents for asthma is made difficult by the fact that several mediators are the cause of the development of the disease. Thus, it is unlikely that the elimination of the effect of a single mediator will have a significant effect on all three components of chronic asthma. An alternative to the "mediator approach" is to regulate the activity of the cells that are the cause of the pathophysiology of the disease.

En slik måte er å forhøye nivåene av cAMP (adenosin-cyklisk-3',5'-monofosfat). Cyklisk AMP har vist seg å være en "second messenger" som medierer den biologiske reaksjonen på en rekke hormoner, neurotransmittere og legemidler; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973] når den egnede agonisten binder seg til bestemte celleoverflate-reseptorer, blir adenylatcyklase aktivert, og dette overfører Mg<+2->ATP til cAMP med akselererende hastighet. One such way is to increase the levels of cAMP (adenosine-cyclic-3',5'-monophosphate). Cyclic AMP has been shown to be a "second messenger" that mediates the biological response to a variety of hormones, neurotransmitters and drugs; [Cancer Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973] when the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, and this transfers Mg<+2->ATP to cAMP at an accelerating rate.

Cyklisk AMP modulerer aktiviteten av de fleste, om ikke alle, av cellene som bidrar til psykopatologien av ytre (allergisk) astma. En forhøyelse av cAMP vil således gi gunstige virkninger, som omfatter: 1) avslapning av glatt muskulatur i luftveiene, 2) hemming av frigjøring av mast-celle-mediator, 3) undertrykkelse av neutrofil degranulering, 4) hemming av basofil degranulering og 5) hemming av monocytt og makrofag aktivering. Forbindelser som aktiverer adenylatcyklase eller hemmer fosfodiesterase bør således være effektive for undertrykkelse av uønsket aktivering av glatt muskulatur i luftveiene og en rekke betennelsesceller. Den viktigste cellulære mekanisme for inaktivering av cAMP er hydrolyse av 3'-fosfodiester-bindingen ved hjelp av én eller flere av en familie av isozymer som betegnes som cyklisk nukleotid-fosfodiesteraser (PDE'er). Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the psychopathology of extrinsic (allergic) asthma. An increase in cAMP will thus produce beneficial effects, which include: 1) relaxation of airway smooth muscle, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation and 5) inhibition of monocyte and macrophage activation. Thus, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing unwanted activation of airway smooth muscle and a variety of inflammatory cells. The major cellular mechanism for inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes termed cyclic nucleotide phosphodiesterases (PDEs).

Det har nå vist seg ved en særskilt cyklisk nukleotid-fosfodiesterase-(PDE)-isozym, PDE IV, er årsaken til nedbrytningen av cAMP i den glatte muskulaturen i luftveiene og betennelsescellene. [Torphy, "Fosfodiesterase Isozymes: Potential Targets for Novel Anti-astmatic Agents" i New Drugs for Astma, Barnes, ed. IBC Technical Services Ltd., 1989]. Forskning viser at hemmingen av dette enzymet ikke bare gir avslapning av glatt muskulatur i luftveiene, men også undertrykker degranuleringen av mastceller, basofiler og neutrofiler og hemmer dessuten aktiveringen av monocytter og neutrofiler. De gunstige virkningene av PDE IV-inhibitorer øker dessuten vesentlig når adenylatcyklase-aktiviteten av målcellene forhøyes ved hjelp av egnede hormoner eller autokoider, noe som vil være tilfelle in vivo. PDE IV-inhibitorer vil således være effektive i en astmatisk lunge når nivåene av prostaglandin-E2og prostacyklin (aktivatorer for adenylat-cyklase) er forhøyet. Slike forbindelser vil gi en enestående angrepsvinkel når det gjelder farmakoterapien av bronkial astma og har vesentlige terapeutiske fordeler fremfor midler som nå er på markedet. It has now been shown that a particular cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is the cause of the breakdown of cAMP in the smooth muscles of the airways and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research shows that the inhibition of this enzyme not only relaxes airway smooth muscle, but also suppresses the degranulation of mast cells, basophils and neutrophils and also inhibits the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors increase substantially when the adenylate cyclase activity of the target cells is increased by means of suitable hormones or autocoids, which would be the case in vivo. Thus, PDE IV inhibitors will be effective in an asthmatic lung when the levels of prostaglandin-E2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would provide a unique angle of attack in the pharmacotherapy of bronchial asthma and have significant therapeutic advantages over agents currently on the market.

Forbindelsene ifølge foreliggende oppfinnelse hemmer også produksjonen av Tumor-Nekrose-Faktor (TNF), et serumglykoprotein. Rikelig og ikke regulert TNF-produksjon er implisert ved mediering og forverring av en rekke sykdommer, og omfatter reumatoid artritt, reumatoid spondylitis, osteoartritt, podagra artritt og andre artrittiske tilstander; sepsis, septisk sjokk, endotoksisk sjokk, gramnegativ sepsis, toksisk sjokk syndrom, voksen respirasjons-"distress syndrom", cerebral malaria, kronisk pulmonar betennelsessykdom, silikose, pulmonar sarkoidosis, knokkel-resorpsjons-sykdommer, reperfusjons-skade, transplant- henholdsvis verts-reaksjon, allograft-avstøtninger, feber og myalgi som skyldes infeksjon, slik som influensa, kakeksi sekundært til infeksjon eller malignitet, kakeksi sekundært til "menneske-ervervet immunsviktsyndrom" (AIDS), AIDS, ARC (AIDS-beslektet kompleks), arrsvulst, arrdannelse, CrohrTs sykdom, ulcerøs kolitt eller pyresis i tillegg til en rekke autoimmune sykdommer, slik som multippel sklerose, autoimmun diabetes og systemisk lupus erytematosus. The compounds according to the present invention also inhibit the production of Tumor Necrosis Factor (TNF), a serum glycoprotein. Abundant and unregulated TNF production has been implicated in mediating and aggravating a number of diseases, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, transplant or host reaction, allograft rejection, fever and myalgia due to infection such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to "human acquired immunodeficiency syndrome" (AIDS), AIDS, ARC (AIDS-related complex), cicatricial tumor, scarring , Crohr's disease, ulcerative colitis or pyresis in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosus.

AIDS skyldes infeksjon av T-lymfocytter med "Human Immunsvikt-virus" AIDS is caused by infection of T-lymphocytes with "Human Immunodeficiency Virus"

(HIV). Det er blitt identifisert minst tre typer eller stammer av HIV, det vil si HIV-1, HIV-2 og HIV-3. Som en følge av HIV-infeksjon, blir T-celle-mediert immunitet svekket og smittede individer viser alvorlige, opportunistiske infeksjoner og/eller uvanlige neoplasmer. HIV-inntrengen i T-lymfocytten krever T-lymfocytt-aktivering. Vira slik som HIV-1 eller HIV-2 infiserer T-lymfocytter etter T-celleaktivering og slik virusprotein-ekspresjon og/eller -formering er mediert eller holdt ved like av en slik T-celleaktivering. Straks en aktivert T-lymfocytt er infisert med HIV, må T-lymfocytten fortsette å holdes ved like i en aktivert tilstand for å tillate HIV-gene-ekspresjon og/eller HIV-formering. (HIV). At least three types or strains of HIV have been identified, ie HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T cell-mediated immunity is impaired and infected individuals exhibit severe, opportunistic infections and/or unusual neoplasms. HIV entry into the T-lymphocyte requires T-lymphocyte activation. Viruses such as HIV-1 or HIV-2 infect T-lymphocytes following T-cell activation and such viral protein expression and/or propagation is mediated or maintained by such T-cell activation. Once an activated T-lymphocyte is infected with HIV, the T-lymphocyte must continue to be maintained in an activated state to allow HIV gene expression and/or HIV propagation.

Cytokiner, særlig TNF, er implisert i aktivert T-celle-mediert HlV-protein-ekspresjon og/eller virusformering ved å spille en rolle i å holde ved like T-lymfocytt-aktiveringen. Påvirkningen av cytokinaktiviteten slik som ved hemmingen av cytokinproduksjonen, særlig TNF, i et HIV-infisert individ hjelper derfor til å begrense opprettholdelsen av T-celleaktiveringen, og reduserer derved progresjonen av HIV-smitte til tidligere ikke-infiserte celler og resulterer i en nedsettelse eller eliminering av progresjonen av immunsvikt på grunn av HIV-infeksjon. Monocytter, makrofager og beslektede celler, slik som kupffer- og glial-celler er også implisert i å opprettholde HIV-infeksjonen. Disse cellene, slik som T-cellene, er mål for virusformering og nivået av virusformeringen er avhengig av aktiveringstilstanden til cellene. [Se Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, 1989]. Monokiner, slik som TNF, har vist seg å aktivere HIV-formeringen i monocytter og/eller makrofager [Se Poli et al., Proe. Nati. Acad. Sei., 87:782-784, 1990], og hemming av monokin-produksjon eller -aktivitet hjelper derfor til å begrense HIV-progresjonen som angitt ovenfor for T-cellene. Cytokines, particularly TNF, are implicated in activated T-cell-mediated HIV protein expression and/or virus propagation by playing a role in maintaining T-lymphocyte activation. The influence of cytokine activity such as by the inhibition of cytokine production, particularly TNF, in an HIV-infected individual therefore helps to limit the maintenance of T-cell activation, thereby reducing the progression of HIV infection to previously uninfected cells and resulting in a reduction or elimination of the progression of immunodeficiency due to HIV infection. Monocytes, macrophages and related cells, such as Kupffer and glial cells are also implicated in maintaining the HIV infection. These cells, like the T-cells, are targets for viral replication and the level of viral replication is dependent on the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al., Proe. Nati. Acad. Sei., 87:782-784, 1990], and inhibition of monokine production or activity therefore helps to limit HIV progression as noted above for the T cells.

TNF er også implisert i forskjellige roller med andre virusinfeksjoner, slik som cytomegalovirus (CMV), influensavirus, adenovirus og herpesvirus av lignende årsaker som nevnt ovenfor. TNF is also implicated in various roles with other viral infections, such as cytomegalovirus (CMV), influenza virus, adenovirus and herpes virus for similar reasons as mentioned above.

TNF er også knyttet til gjær- og soppinfeksjoner, spesielt Candida albicans har vist seg å forårsake TNF-produksjon in vitro i humane monocytter og naturlige dreperceller. [Se Riipi et al., Infection and Immunity, 58(9):2750-54, 1990; og Jafari et al., Journal of Infectious Diseases, 164:389-95, 1991. Se også Wasan et al., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; og Luke et al., Journal of Infectious Diseases, 162:211-214,1990]. TNF is also linked to yeast and fungal infections, in particular Candida albicans has been shown to cause TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al., Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke et al., Journal of Infectious Diseases, 162:211-214,1990].

Evnen til å regulere skadelige virkninger av TNF er fremmet ved anvendelsen av forbindelser som hemmer TNF i pattedyr som har dette behovet. Det er et behov for forbindelser som er nyttige for behandling av TNF-medierte sykdomstilstander som er forverret eller som skyldes rikelig og/eller uregulert produksjon av TNF. The ability to regulate deleterious effects of TNF has been advanced by the use of compounds that inhibit TNF in mammals in need. There is a need for compounds useful in the treatment of TNF-mediated disease states that are exacerbated or that result from excessive and/or dysregulated production of TNF.

Sammenfatning av oppfinnelsenSummary of the Invention

Foreliggende oppfinnelse tilveiebringer nye forbindelser ifølge formelen (I): The present invention provides new compounds according to the formula (I):

hvor: where:

Ri er-(CR4R5)nC(0)0(CR4R5)mR6. -(CR4R5)nC(0)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6 eller -(CR4R5)rR6hvor alkylgruppene kan være usubstituert eller substituert med én eller flere fluoratomer; R 1 is-(CR 4 R 5 )nC(O)O(CR 4 R 5 )m R 6 . -(CR4R5)nC(0)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6 or -(CR4R5)rR6where the alkyl groups may be unsubstituted or substituted with one or more fluorine atoms;

m er 0 til 2; m is 0 to 2;

n er 0 til 4; n is 0 to 4;

r er 0 til 6; r is 0 to 6;

R4og R5er uavhengig hydrogen eller Ci-2-alkyl; R 4 and R 5 are independently hydrogen or C 1-2 alkyl;

R6er hydrogen, metyl, hydroksyl, aryl, halogensubstituert aryl, aryloksyCi-3-alkyl, halogensubstiuert aryloksyCi-3-alkyl, indanyl, indenyl, C7-H-polycykloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrotienyl, tienyl, tetrahydrotiopyranyl, tiopyranyl, C3-6-cykloalkyl, eller en C4-6-cykloalkyl inneholdende én eller to umettede bindinger, hvor cykloalkyl- eller heterocyklisk gruppe kan være usubstituert eller substituert med 1 til 3 metylgrupper, én etylgruppe eller én hydroksylgruppe; R6 is hydrogen, methyl, hydroxyl, aryl, halogen-substituted aryl, aryloxyC1-3-alkyl, halogen-substituted aryloxyC1-3-alkyl, indanyl, indenyl, C7-H-polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl , C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, where the cycloalkyl or heterocyclic group may be unsubstituted or substituted with 1 to 3 methyl groups, one ethyl group or one hydroxyl group;

forutsatt at:presumed that:

a) når R6er hydroksyl, er m 2; ellera) when R6 is hydroxyl, m is 2; or

b) når R6er hydroksyl, er r 2 til 6; ellerb) when R 6 is hydroxyl, r is 2 to 6; or

c) når R6er 2-tetrahydropyranyl, 2-tetrahydrotiopyranyl, 2-tetrahydrofuranyl eller 2-tetrahydrotienyl, er m 1 eller 2; eller d) når R6er 2-tetrahydropyranyl, 2-tetrahydrotiopyranyl, 2-tetrahydrofuranyl eller 2-tetrahydrotienyl, er r 1 til 6; e) når n er 1 og m er 0, er R6forskjellig fra H i -(CR4R5)nO(CR4R5)mR6; c) when R 6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, m is 1 or 2; or d) when R 6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, r is 1 to 6; e) when n is 1 and m is 0, R6 is different from H in -(CR4R5)nO(CR4R5)mR6;

X er YR2, fluor, NR4R5, eller formylamin; X is YR 2 , fluorine, NR 4 R 5 , or formylamine;

Y er O eller S(0)m'; Y is O or S(0)m';

rn' er 0, 1 eller 2; rn' is 0, 1 or 2;

X2er O eller NRs; X 2 is O or NR s ;

X3er hydrogen eller X; X 3 is hydrogen or X;

R2er -CH3eller -CH2CH3usubstituert eller substituert med 1 eller flere fluoratomer; R 2 is -CH 3 or -CH 2 CH 3 unsubstituted or substituted with 1 or more fluorine atoms;

s er 0 til 4; s is 0 to 4;

R3er COOR14, C(0)NR4R14eller R7; R 3 is COOR 14 , C(O)NR 4 R 14 or R 7 ;

W er alkyl med 2 til 6 karbonatomer, alkenyl med 2 til 6 karbonatomer eller alkynyl med 2 til 6 karbonatomer; W is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;

ZerO, NR7, NCR4R5C2-6-alkenyl, NOR14, NOR15, NOCR4R5C2-6-alkenyl, NNR4R14, NNR4R15, NCN, NNRsC(0)NR8Rl4, NNR8C(S)NR8R14, eller =Z er 2-(1,3-ditian), 2-(1,3-ditiolan), dimetyltioketal, dietyltioketal, 2-(1,3-dioksolan), 2-(1,3-dioksan), 2-(1,3-oksatiolan), dimetylketal eller dietylketal; ZerO, NR7, NCR4R5C2-6-alkenyl, NOR14, NOR15, NOCR4R5C2-6-alkenyl, NNR4R14, NNR4R15, NCN, NNRsC(0)NR8Rl4, NNR8C(S)NR8R14, or =Z is 2-(1,3-dithiane ), 2-(1,3-dithiolane), dimethylthioketal, diethylthioketal, 2-(1,3-dioxolane), 2-(1,3-dioxane), 2-(1,3-oxathiolane), dimethyl ketal or diethyl ketal;

R7er -(CR4R5)qRi2eller C<|_6-alkyl hvor R12eller C<|_6-alkylgruppen er usubstituert eller substituert én eller flere ganger med metyl eller etyl som er usubstituert eller substituert med 1 til 3 fluoratomer, -F, -Br, -Cl, -NO2, -NR-|rjRl1. -C(0)R8, -C02R8, -0(CH2)2^0R8, -0(CH2)qR8, -CN, -C(0)NRioRl1, -O(CH2)qC(O)NRi0Rl1, -0(CH2)qC(0)R9, -NRioC(0)NRi0Rl1, -NR10C(0)R11, -NRl0C(O)ORg, -NRi0C(O)Ri3, -C(NRlo)NRioRl1, -C(NCN)NR10R11, -C(NCN)SRg, -NRioC(NCN)SRg , -NRioC(NCN)NRioR11, -NRioS(0)2R9, -SCOWRg, -NRioC(0)C(0)NRioRl 1, -NRinC(0)C(0)Rio eller Rl3<i>R7 is -(CR4R5)qRi2or C<|_6-alkyl where R12 or the C<|_6-alkyl group is unsubstituted or substituted one or more times with methyl or ethyl which is unsubstituted or substituted with 1 to 3 fluorine atoms, -F, -Br, - Cl, -NO2, -NR-|rjRl1. -C(0)R8, -C02R8, -0(CH2)2^0R8, -0(CH2)qR8, -CN, -C(0)NRioRl1, -O(CH2)qC(O)NRi0Rl1, -0( CH2)qC(0)R9, -NRioC(0)NRi0Rl1, -NR10C(0)R11, -NRl0C(O)ORg, -NRi0C(O)Ri3, -C(NRlo)NRioRl1, -C(NCN)NR10R11, -C(NCN)SRg, -NRioC(NCN)SRg , -NRioC(NCN)NRioR11, -NRioS(0)2R9, -SCOWRg, -NRioC(0)C(0)NRioRl 1, -NRinC(0)C( 0)Rio or Rl3<i>

q erO, 1 eller 2; q is 0, 1 or 2;

R12er R-|3 C3-C7-cykloalkyl, (2-, 3- eller 4-pyridyl), pyrimidyl, pyrazolyl, (1- eller 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morfolinyl, furanyl, (2- eller 3-tienyl), kinolinyl, naftyl eller fenyl; R12 is R-|3 C3-C7-cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl or phenyl;

Rq er hydrogen eller Rg; Rq is hydrogen or Rg;

Rg er C-|_4-alkyl usubstituert eller substituert med én til tre fluoratomer; R 8 is C 1-4 alkyl unsubstituted or substituted with one to three fluorine atoms;

RlOer OR8eller R-n; R10 is OR8 or R-n;

R-| 1 er hydrogen, eller C^-alkyl usubstituert eller substituert med én til tre fluoratomer; eller når R10og R11er lik NR10R11kan de sammen med nitrogenatomet danne en 5- til 7-leddet ring som bare inneholder karbonatomer eller karbonatomer og minst et heteroatom valgt fra O, N eller S; R-| 1 is hydrogen, or C 1 -alkyl unsubstituted or substituted with one to three fluorine atoms; or when R 10 and R 11 are equal to NR 10 R 11 they may together with the nitrogen atom form a 5- to 7-membered ring containing only carbon atoms or carbon atoms and at least one heteroatom selected from O, N or S;

R13er en substituert eller usubstituert heteroarylgruppe valgt fra gruppen bestående av oksazolidinyl, oksazolyl, tiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, tiazolidinyl, isoksazolyl, oksadiazolyl og tiadiazolyl og hvor R13er substituert på R12eller Ri3-ringene er bundet ved et karbonatom og hver annen Ri3-ring kan være usubstituert eller substituert med én eller to C-|_2-alkylgrupper som kan være usubstituert eller substituert på metylgruppen med 1 til 3 fluoratomer; R 13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl and thiadiazolyl and where R 13 is substituted on the R 12 or R 13 rings are bound by a carbon atom and each other R 13 ring may be unsubstituted or substituted with one or two C 1-2 alkyl groups which may be unsubstituted or substituted on the methyl group with 1 to 3 fluorine atoms;

R14er hydrogen eller R7; eller når Rs og R14er lik NR8R14kan de sammen med nitrogenatomet danne en 5- til 7-leddet ring som består av bare karbonatomer eller karbonatomer og minst et heteroatom valgt fra O, N eller S; R 14 is hydrogen or R 7 ; or when R 5 and R 14 are equal to NR 8 R 14 they may together with the nitrogen atom form a 5- to 7-membered ring consisting of only carbon atoms or carbon atoms and at least one heteroatom selected from O, N or S;

forutsatt at:presumed that:

f) R7er ikke lik C-|_4-alkyl usubstituert eller substituert med én til tre fluoratomer; eller f) R 7 is not equal to C 1-4 alkyl unsubstituted or substituted with one to three fluorine atoms; or

farmasøytisk akseptable salter derav.pharmaceutically acceptable salts thereof.

En annen gruppe av forbindelser ifølge foreliggende oppfinnelse er representert ved formelen (II) Another group of compounds according to the present invention is represented by the formula (II)

hvor: where:

R1er-(CR4R5)nC(0)0(CR4R5)mR6. -(CR4R5)nC(0)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6 eller (CR4R5)rR6nvor alkylgruppene kan være usubstituerte eller substituerte med én eller flere fluoratomer; R 1 is-(CR 4 R 5 )nC(O)O(CR 4 R 5 )m R 6 . -(CR4R5)nC(0)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6 or (CR4R5)rR6nwhere the alkyl groups may be unsubstituted or substituted with one or more fluorine atoms;

m er 0 til 2; m is 0 to 2;

n er 0 til 4; n is 0 to 4;

r er 0 til 6; r is 0 to 6;

R4og R5er uavhengig valgt fra hydrogen eller Ci-2-alkyl; R 4 and R 5 are independently selected from hydrogen or C 1-2 alkyl;

R6er hydrogen, metyl, hydroksyl, aryl, halogensubstiuert aryl, aryloksyCi-3-alkyl, halogensubstiuert aryloksyC-|-3-alkyl, indanyl, indenyl, C7-11-polycykloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrotienyl, tienyl, tetrahydrotiopyranyl, tiopyranyl, C3-6-cykloalkyl eller en C4_6-cykloalkyl inneholdende én eller to umettede bindinger, hvor cykloalkyl- og heterocykliske grupper er usubstituert eller substituert med 1 til 3 metylgrupper, en etylgruppe eller en hydroksylgruppe; R6 is hydrogen, methyl, hydroxyl, aryl, halogen-substituted aryl, aryloxyC1-3-alkyl, halogen-substituted aryloxyC-1-3-alkyl, indanyl, indenyl, C7-11-polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl , thiopyranyl, C3-6-cycloalkyl or a C4-6-cycloalkyl containing one or two unsaturated bonds, wherein cycloalkyl and heterocyclic groups are unsubstituted or substituted with 1 to 3 methyl groups, an ethyl group or a hydroxyl group;

forutsatt at:presumed that:

a) når R6er hydroksyl, er m 2; ellera) when R6 is hydroxyl, m is 2; or

b) når R6er hydroksyl, er r 2 til 6; ellerb) when R 6 is hydroxyl, r is 2 to 6; or

c) når R6er 2-tetrahydropyranyl, 2-tetrahydrotiopyranyl, 2-tetrahydrofuranyl eller 2-tetrahydrotienyl, er m 1 eller 2; eller d) når R6er 2-tetrahydropyranyl, 2-tetrahydrotiopyranyl, 2-tetrahydrofuranyl eller 2-tetrahydrotienyl, er r 1 til 6; e) når n er 1 og m er 0, er R6forskjellig fra H i -(CR4R5)nO(CR4R5)mR6; c) when R 6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, m is 1 or 2; or d) when R 6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, r is 1 to 6; e) when n is 1 and m is 0, R6 is different from H in -(CR4R5)nO(CR4R5)mR6;

X er YR2, fluor, NR4R5eller formylamin; X is YR 2 , fluorine, NR 4 R 5 or formylamine;

Y er O eller S(0)rry; Y is O or S(O)rry;

rn' er 0, 1 eller 2; rn' is 0, 1 or 2;

X2er O eller NR8; X 2 is O or NR 8 ;

X3er hydrogen eller X; X 3 is hydrogen or X;

F*2er uavhengig valgt fra -CH3eller -CH2CH3som kan være usubstituert eller substituert med 1 eller flere fluoratomer; F*2 is independently selected from -CH3 or -CH2CH3 which may be unsubstituted or substituted with 1 or more fluorine atoms;

s er 0 til 4; s is 0 to 4;

R3er COOR14, C(0)NR4R14eller R7; R 3 is COOR 14 , C(O)NR 4 R 14 or R 7 ;

W er alkyl med 2 til 6 karbonatomer, alkenyl med 2 til 6 karbonatomer eller alkynyl med 2 til 6 karbonatomer; W is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;

T er C(Y')R14, C(0)0R14, C(Y')NRiqR14, C(NRio)NRioR14, CN, C(N0R8)R14-C(0)NR8NR8C(0)R8, C(0)NR8NRioR14. C(NORi4)R8, C(NR8)NRioR14, C(NRi4)NRsR8C(NCN)NRioRl4, C(NCN)SR9, (2-, 4- eller 5-imidazolyl), (3-, 4- eller 5-pyrazolyl), (4- eller 5-triazolyl[1,2,3]), (3- eller 5-triazolyl[1,2,4]), (5-tetrazolyl), (2-, 4- eller 5-oksazolyl), (3-, 4- eller 5-isoksazolyl), (3- eller 5-oksadiazolyl[1,2,4]), (2-oksadiazolyl[1,3,4]), (2-tiadiazolyl[1.3.4]). (2-, 4-eller 5-tiazolyl), (2-, 4- eller 5-oksazolidinyl), (2-, 4- eller 5-tiazolidinyl), eller (2-, 4-eller 5-imidazolidinyl); hvor alle de heterocykliske ringsystemene eventuelt kan være substituert én eller flere ganger med R14; T is C(Y')R14, C(0)0R14, C(Y')NRiqR14, C(NRio)NRioR14, CN, C(N0R8)R14-C(0)NR8NR8C(0)R8, C(0) NR8NRioR14. C(NORi4)R8, C(NR8)NRioR14, C(NRi4)NRsR8C(NCN)NRioRl4, C(NCN)SR9, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl ), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl ), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1.3. 4]). (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); where all the heterocyclic ring systems may optionally be substituted one or more times with R 14 ;

Y' er O eller S; Y' is O or S;

R7er -(CR4R5)qRi2eller C-|_e-alkyl hvor R12eller Ci_6-alkylgruppen er usubstituert eller substituert én eller flere ganger med metyl eller etyl som er usubstituert eller substituert med 1 til 3 fluoratomer, -F, -Br, -Cl, -NO2, -NR-|rjRl1. -C(0)R8, -C02R8. -0(CH2)2-40R8. -0(CH2)qR8, -CN, -C(0)NRirjRl1, -0(CH2)qC(0)NRioRl1. -0(CH2)qC(0)R9, -NRioC(0)NRioRl1. -NR10C(0)R11, -NRioC(0)OR9. -NRioC(0)Rl3. -C(NRio)NRioRl 1, -C(NCN)NR10R11, -C(NCN)SR9, -NRioC(NCN)SR9 , -NRioC(NCN)NRioRl1. -NRioS(0)2R9. -S(0)m'R9, -NRioC(0)C(0)NRioRl1. -NRioC(0)C(0)Rio eller<R>13; R7 is -(CR4R5)qRi2or C-|_e-alkyl where R12 or the C1_6-alkyl group is unsubstituted or substituted one or more times by methyl or ethyl which is unsubstituted or substituted by 1 to 3 fluorine atoms, -F, -Br, -Cl, - NO2, -NR-|rjRl1. -C(O)R8, -CO2R8. -O(CH2)2-40R8. -O(CH2)qR8, -CN, -C(0)NRirjR1, -O(CH2)qC(0)NRioR1. -O(CH 2 )qC(O)R 9 , -NR 10 C(O)NR 10 R 1 . -NR10C(0)R11, -NR10C(0)OR9. -NR 10 C(0)R 13 . -C(NR 10 )NR 10 R 1 , -C(NCN)NR 10 R 11 , -C(NCN)SR 9 , -NR 10 C(NCN)SR 9 , -NR 10 C(NCN)NR 10 R 1 . -NR io S(0) 2 R 9 . -S(O)m'R 9 , -NR io C(O)C(O)NR io R 1 . -NR io C(O)C(O) R io or<R>13;

q er 0, 1, eller 2; q is 0, 1, or 2;

R12er R13. C3-C7-cykloalkyl, eller en usubstituert eller substituert aryl-eller heteroarylgruppe valgt fra gruppen bestående av (2-, 3- eller 4-pyridyl), pyrimidyl, pyrazolyl, (1- eller 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morfolinyl, furanyl, (2- eller 3-tienyl), kinolinyl, naftyl og fenyl; R12 is R13. C3-C7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl , morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl and phenyl;

R8er uavhengig valgt fra hydrogen eller Rg; R 8 is independently selected from hydrogen or R 8 ;

Rg er C-|_4-alkyl usubstituert eller substituert med én til tre fluoratomer; R 8 is C 1-4 alkyl unsubstituted or substituted with one to three fluorine atoms;

RlO er OR8 eller Rn; R10 is OR8 or Rn;

Rl1er hydrogen eller C-|_4-alkyl usubstituert eller substituert med én til tre fluoratomer; eller når R10og Ri 1 er lik NR10R11kan de sammen med nitrogenatomet danne en 5- til 7-leddet ring som bare består av karbonatomer eller karbonatomer og minst et heteroatom valgt fra O, N, eller S; R 11 is hydrogen or C 1-4 alkyl unsubstituted or substituted with one to three fluorine atoms; or when R 10 and Ri 1 are equal to NR 10 R 11 , they together with the nitrogen atom may form a 5- to 7-membered ring consisting only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S;

R13er en substituert eller usubstituert heteroarylgruppe valgt fra gruppen bestående av oksazolidinyl, oksazolyl, tiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, tiazolidinyl, isoksazolyl, oksadiazolyl og tiadiazolyl og hvor Ri 3 er substituert på Ri 2 eller Ri 3 er ringene bundet til et karbonatom og hver annen Ri3-ring kan være usubstituert eller substituert med én eller to alkylgrupper, som kan være usubstituert eller substituert på metylgruppen med 1 til 3 fluoratomer; R 13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl and thiadiazolyl and where Ri 3 is substituted on Ri 2 or Ri 3 the rings are bound to a carbon atom and every other R 13 ring may be unsubstituted or substituted with one or two alkyl groups, which may be unsubstituted or substituted on the methyl group with 1 to 3 fluorine atoms;

R-I4er hydrogen eller R7; eller når Rs og R14er lik NR8R14kan de sammen med nitrogenatomet danne en 5- til 7-leddet ring som bare består av karbonatomer eller karbonatomer og minst et heteroatom valgt fra O, N eller S; R-14 is hydrogen or R7; or when R 5 and R 14 are equal to NR 8 R 14 they may together with the nitrogen atom form a 5- to 7-membered ring consisting only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N or S;

forutsatt at:presumed that:

f) R7er ikke Ci_4-alkyl, som kan være usubstituert eller substituert med én til tre fluoratomer; f) R 7 is not C 1-4 alkyl, which may be unsubstituted or substituted with one to three fluorine atoms;

eller farmasøytisk akseptable salter derav.or pharmaceutically acceptable salts thereof.

Foreliggende oppfinnelse vedrører også farmasøytiske preparater som består av en forbindelse med formel (I) og (II) og en farmasøytisk akseptabel bærer eller fortynningsmiddel. The present invention also relates to pharmaceutical preparations which consist of a compound of formula (I) and (II) and a pharmaceutically acceptable carrier or diluent.

Foreliggende oppfinnelse vedrører også en fremgangsmåte for å mediere eller hemme den enzymatiske aktiviteten (eller katalytiske aktiviteten) av PDE IV i pattedyr, omfattende mennesker, og som omfatter administeringen til et pattedyr som har behov for dette av en effektiv mengde av en forbindelse med formel (I) og (II) som vist nedenfor. The present invention also relates to a method for mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, and which comprises the administration to a mammal in need thereof of an effective amount of a compound of formula ( I) and (II) as shown below.

Foreliggende oppfinnelse tilveiebringer dessuten en fremgangsmåte for behandling av allergiske og inflammatoriske sykdommer som består i administeringen til et pattedyr, omfattende mennesker, som har behov for dette av en effektiv mengde av en forbindelse med formel (I) og (II). The present invention also provides a method for the treatment of allergic and inflammatory diseases which consists in the administration to a mammal, including humans, in need thereof of an effective amount of a compound of formula (I) and (II).

Foreliggende oppfinnelse tilveiebringer også en fremgangsmåte for behandling av astma som omfatter administering til et pattedyr, omfattende mennesker, som har behov for dette av en effektiv mengde av en forbindelse med formel (I) og (II). The present invention also provides a method of treating asthma which comprises administering to a mammal, including humans, in need thereof an effective amount of a compound of formula (I) and (II).

Foreliggende oppfinnelse vedrører også en fremgangsmåte for å hemme TNF-produksjonen i et pattedyr, omfattende mennesker, som omfatter administering til et pattedyr som har behov for slik behandling, av en effektiv TNF-hemmende mengde av en forbindelse med formel (I) og (II). Denne fremgangsmåten kan også anvendes for profylaktisk behandling eller forhindring av visse TNF-medierte sykdomstilstander som er mottakelige for dette. The present invention also relates to a method for inhibiting TNF production in a mammal, including humans, which comprises administering to a mammal in need of such treatment, an effective TNF-inhibiting amount of a compound of formula (I) and (II ). This method can also be used for prophylactic treatment or prevention of certain TNF-mediated disease states which are susceptible to this.

Foreliggende oppfinnelse vedrører også en fremgangsmåte for å behandle et menneske som lider av human-immunsvikt-virus (HIV) og som omfatter administering til et slikt menneske en effektiv TNF-hemmende mengde av en forbindelse med formel (I) og (II). The present invention also relates to a method for treating a human suffering from human immunodeficiency virus (HIV) and which comprises administering to such a human an effective TNF-inhibiting amount of a compound of formula (I) and (II).

Forbindelser med formel (I) og (II) er også nyttige ved behandlingen av ytterligere virale infeksjoner, hvor slike vira er sensitive for oppregulering av TNF eller vil fremkalle TNF-produksjon in vivo. Compounds of formula (I) and (II) are also useful in the treatment of additional viral infections, where such viruses are sensitive to up-regulation of TNF or will induce TNF production in vivo.

Forbindelser med formel (I) og (II) er dessuten nyttige ved behandling av gjær- eller soppinfeksjoner, hvor en slik gjær eller sopp er sensitiv for oppregulering av TNF eller vil fremkalle TNF-produksjon in vivo. Compounds of formula (I) and (II) are also useful in the treatment of yeast or fungal infections, where such yeast or fungus is sensitive to up-regulation of TNF or will induce TNF production in vivo.

Detaljert beskrivelse av oppfinnelsenDetailed description of the invention

Foreliggende oppfinnelse vedrører også en fremgangsmåte for å mediere eller hemme den enzymatiske aktiviteten (eller katalytiske aktiviteten) av PDE IV i et pattedyr som har behov for dette og å hemme produksjon av TNF i et pattedyr som har behov for dette, og som omfatter administering til pattedyret av en effektiv mengde av en forbindelse med formel (I) og (II). The present invention also relates to a method for mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal in need of this and for inhibiting the production of TNF in a mammal in need of this, and which comprises administration to the mammal of an effective amount of a compound of formula (I) and (II).

Fosfodiesterase IV-inhibitorer er nyttige ved behandlingen av en rekke allergiske og inflammatoriske sykdommer omfattende: astma, kronisk bronkitt, atopisk dermatitt, urticaria, allergisk rhinitis, allergisk konjunktivitt, vernal konjunktivitt, eosinofil granulom, psoriasis, reumatoid artritt, septisk sjokk, ulcerøs kolitt, Crohn's sykdom, reperfusjonsskade av myokardet og hjernen, kronisk glomerulonefritt, endotoksisk sjokk og respirasjons-"distress syndrom" hos voksne. I tillegg er PDE IV-inhibitorer nyttige ved behandlingen av diabetes insipidus og sykdommer i sentralnervesystemet, slik som depresjon og multi-infarkt demens. Phosphodiesterase IV inhibitors are useful in the treatment of a number of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and respiratory distress syndrome in adults. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus and diseases of the central nervous system, such as depression and multi-infarct dementia.

Vira som er beregnet for behandling her er de som produserer TNF som en følge av infeksjon, eller de som er sensitive for hemming, slik som ved redusert formering, direkte eller indirekte, av TNF-inhibitorer med formel (I) og (II). Slike vira omfatter, men er ikke begrenset til HIV-1, HIV-2 og HIV-3, cytomegalovirus (CMV), influensa, adenovirus og herpesgruppen av vira, slik som, men ikke begrenset til Herpes zoster og Herpes simplex. Viruses intended for treatment herein are those that produce TNF as a consequence of infection, or those that are sensitive to inhibition, such as by reduced propagation, directly or indirectly, by TNF inhibitors of formula (I) and (II). Such viruses include, but are not limited to, HIV-1, HIV-2, and HIV-3, cytomegalovirus (CMV), influenza, adenovirus, and the herpes family of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.

Mer spesielt vedrører foreliggende oppfinnelse en fremgangsmåte for å behandle et pattedyr som er angrepet av et human-immunsvikt-virus (HIV), som omfatter administeringen til et slikt pattedyr en effektiv TNF-hemmende mengde av en forbindelse med formel (I) og (II). More particularly, the present invention relates to a method of treating a mammal which has been attacked by a human immunodeficiency virus (HIV), comprising administering to such a mammal an effective TNF-inhibiting amount of a compound of formula (I) and (II ).

Forbindelsene ifølge foreliggende oppfinnelse kan også anvendes i forbindelse med veterinærbehandling av dyr, bortsett fra mennesker, som har behov for hemming av TNF-produksjon. TNF-medierte sykdommer for behandling, terapeutisk eller profylaktisk, i dyr omfatter sykdomstilstander slik som de som er nevnt ovenfor, men særlig virale infeksjoner. Eksempler på slike vira omfatter, men er ikke begrenset til immunsviktvirus hos katt (FIV) eller annen retroviral infeksjon, slik som ekin smittsom anemivirus, caprinartrittvirus, visnavirus, maedivirus og andre lentivira. The compounds according to the present invention can also be used in connection with veterinary treatment of animals, apart from humans, which need inhibition of TNF production. TNF-mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those mentioned above, but especially viral infections. Examples of such viruses include, but are not limited to, feline immunodeficiency virus (FIV) or other retroviral infection, such as equine infectious anemia virus, caprine arthritis virus, visnavirus, maedivirus and other lentiviruses.

Forbindelsene ifølge foreliggende oppfinnelse er også nyttige ved behandling av gjær- og soppinfeksjoner, hvor slik gjær og sopp er sensitiv overfor oppregulering av TNF eller vil fremkalle TNF-produksjon in vivo. En foretrukket sykdomstilstand for behandling er sopp-meningitis. Forbindelsene med formel (I) og (II) kan dessuten administreres i forbindelse med andre valgte legemidler for systemiske gjær- og soppinfeksjoner. Legemiddelvalg for soppinfeksjoner omfatter, men er ikke begrenset til klassen av forbindelser som betegnes som polymixiner, slik som polymycin B, klassen av forbindelser som betegnes som imidazoler, slik som clotrimazol, econazol, miconazol og ketoconazol; klassen av forbindelser som betegnes som triazoler, slik som fluconazol og itranazol, og klassen av forbindelser som betegnes som amfotericiner, særlig amfotericin B og liposomal amfotericin B. The compounds according to the present invention are also useful in the treatment of yeast and fungal infections, where such yeast and fungi are sensitive to up-regulation of TNF or will induce TNF production in vivo. A preferred disease state for treatment is fungal meningitis. The compounds of formula (I) and (II) can also be administered in conjunction with other selected drugs for systemic yeast and fungal infections. Drug choices for fungal infections include, but are not limited to, the class of compounds termed polymyxins, such as polymycin B, the class of compounds termed imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; the class of compounds referred to as triazoles, such as fluconazole and itranazole, and the class of compounds referred to as amphotericins, particularly amphotericin B and liposomal amphotericin B.

Forbindelsene med formel (I) og (II) kan også anvendes for å hemme og/eller redusere giftigheten av et antisopp, antibakterielt eller antiviralt middel ved administering av en effektiv mengde av en forbindelse med formel (I) og (II) til et pattedyr som har behov for slik behandling. En forbindelse med formel (I) og (II) administreres fortrinnsvis for å hemme eller redusere giftigheten av amfotericin-klassen av forbindelser, særlig amfotericin B. The compounds of formula (I) and (II) can also be used to inhibit and/or reduce the toxicity of an antifungal, antibacterial or antiviral agent by administering an effective amount of a compound of formula (I) and (II) to a mammal who are in need of such treatment. A compound of formula (I) and (II) is preferably administered to inhibit or reduce the toxicity of the amphotericin class of compounds, particularly amphotericin B.

Betegnelsen ,,C1_3-alkyl-"1 "C^-alkyl-", "C<|_6-alkyl-" eller "alkyl<M->grupper er ment å omfatte både rette og forgrenete kjederadikaler med 1 til 10, dersom kjedelengden ikke er begrenset, og omfatter, men er ikke begrenset til metyl, etyl, n-propyl, isopropyl, n-butyl, sek-butyl, isobutyl, fert-butyl og lignende. The designation "C1_3-alkyl-"1 "C^-alkyl-", "C<|_6-alkyl-" or "alkyl<M->groups is intended to include both straight and branched chain radicals of 1 to 10, if the chain length is not limited, and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and the like.

Med "alkenyl" menes både rette og forgrenete kjederadikaler med 1 til 6 karbonlengder, dersom kjedelengden ikke er begrenset, og omfatter, men er ikke begrenset til vinyl, 1-propenyl, 2-propenyl eller 3-metyl-2-propenyl. By "alkenyl" is meant both straight and branched chain radicals of 1 to 6 carbon lengths, if the chain length is not limited, and includes, but is not limited to vinyl, 1-propenyl, 2-propenyl or 3-methyl-2-propenyl.

Med betegnelsen "cykloalkyl" eller "cykloalkyl-alkyl" menes grupper av 3-7 karbonatomer, slik som cyklopropyl, cyklopropylmetyl, cyklopentyl, eller cykloheksyl. The term "cycloalkyl" or "cycloalkyl-alkyl" means groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.

Med "aryl" eller "aralkyl", dersom intet annet er angitt, menes en aromatisk ring eller et ringsystem med 6-10 karbonatomer, slik som fenyl, benzyl, fenetyl eller naftyl. Fortrinnsvis er aryl monocyklisk, det vil si fenyl. Alkylkjeden er ment å omfatte både rette og forgrenete kjederadikaler med 1 til 4 karbonatomer. Med "heteroaryl" menes et aromatisk ringsystem inneholdende én eller flere heteroatomer. By "aryl" or "aralkyl", if nothing else is indicated, is meant an aromatic ring or a ring system with 6-10 carbon atoms, such as phenyl, benzyl, phenethyl or naphthyl. Preferably, aryl is monocyclic, ie phenyl. The alkyl chain is intended to include both straight and branched chain radicals with 1 to 4 carbon atoms. By "heteroaryl" is meant an aromatic ring system containing one or more heteroatoms.

Med "halogen" menes alle halogener, det vil si klor, fluor, brom, eller jod. By "halogen" is meant all halogens, i.e. chlorine, fluorine, bromine or iodine.

Med "hemming av produksjonen av IL-1" eller "hemming av produksjonen av TNF" menes: a) et fall av usedvanlig høye nivåer av henholdsvis in vivo IL-1 eller TNF i et menneske til normale nivåer eller under normale nivåer ved hemming av in wVo-frigjøring av IL-1 av alle cellene, og omfatter, men er ikke begrenset til monocytter eller makrofager; b) en nedregulering, ved et translasjonelt eller transkripsjonelt nivå, av usedvanlig høye nivåer av henholdsvis in vivo- IL-1- eller -TNF-nivåer i et By "inhibition of the production of IL-1" or "inhibition of the production of TNF" is meant: a) a fall of abnormally high levels of in vivo IL-1 or TNF respectively in a human to normal levels or below normal levels by inhibition of in wVo release of IL-1 by all cells, and includes but is not limited to monocytes or macrophages; b) a downregulation, at a translational or transcriptional level, of unusually high levels of in vivo IL-1 or TNF levels, respectively, in a

menneske til normale nivåer eller under normale nivåer; ellerhuman to normal levels or below normal levels; or

c) en nedregulering ved hemming av den direkte syntesen av IL-1- eller TNF-nivåer som et post-translasjonelt resultat. c) a down-regulation by inhibiting the direct synthesis of IL-1 or TNF levels as a post-translational result.

Uttrykket "TNF-mediert sykdom eller sykdomstilstand" betyr en hvilken som helst eller alle sykdomstilstander hvor TNF spiller en rolle, enten ved produksjon av TNF alene, eller ved at TNF forårsaker at et annet cytokin blir frigjort, slik som, men ikke begrenset til IL-1 eller IL-6. En sykdomstilstand hvor IL-1 for eksempel er en hovedkomponent, og hvis produksjon eller virkning blir akutt forverret eller utsondret som reaksjon på TNF, vil derfor bli betraktet som en sykdomstilstand som er mediert av TNF. Idet TNF-& (også kjent som lymfotoksin) har en nær beslektet strukturell homologi med TNF-a (også kjent som kakektin), og siden begge induserer lignende, biologiske reaksjoner og binder seg til samme cellulære reseptor, er både TNF-a og TNF-B hemmet av forbindelsene ifølge foreliggende oppfinnelse, og begge betegnes her som "TNF" dersom intet annet er angitt. Fortrinnsvis er det TNF-a som hemmes. The term "TNF-mediated disease or disease state" means any or all disease states in which TNF plays a role, either by production of TNF alone, or by TNF causing another cytokine to be released, such as, but not limited to, IL -1 or IL-6. A disease state where IL-1 is, for example, a main component, and whose production or effect is acutely worsened or secreted in response to TNF, will therefore be considered a disease state that is mediated by TNF. Since TNF-α (also known as lymphotoxin) has a closely related structural homology with TNF-α (also known as cachectin), and since both induce similar biological responses and bind to the same cellular receptor, both TNF-α and TNF -B inhibited by the compounds of the present invention, and both are referred to herein as "TNF" unless otherwise indicated. Preferably, it is TNF-α that is inhibited.

"Cytokin" betyr ethvert utskilt polypeptid som påvirker funksjonen av cellene, og er et molekyl som modulerer gjensidige påvirkninger mellom cellene i immune, inflammatoriske eller hematopoietiske reaksjoner. Et cytokin omfatter, men er ikke begrenset til, monokiner og lymfokiner uten hensyn til hvilke celler som produserer disse. Det hemmede cytokinet ifølge foreliggende oppfinnelse som skal anvendes ved behandlingen av et HIV-smittet menneske, må være et cytokin som er implisert i (a) initieringen og/eller vedlikeholdelse av T-celleaktiveringen og/eller aktivert T-cellemediert HIV-gene-ekspresjon og/eller -formering og/eller (b) ethvert problem som er assosiert til cytokinmediert sykdom, slik som kakeksi eller muskelsvinn. Fortrinnsvis er cytokinet TNF-a. "Cytokine" means any secreted polypeptide that affects the function of cells, and is a molecule that modulates interactions between cells in immune, inflammatory or hematopoietic reactions. A cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce these. The inhibited cytokine according to the present invention to be used in the treatment of an HIV-infected human must be a cytokine that is implicated in (a) the initiation and/or maintenance of T-cell activation and/or activated T-cell-mediated HIV gene expression and/or proliferation and/or (b) any problem associated with cytokine-mediated disease, such as cachexia or muscle wasting. Preferably, the cytokine is TNF-α.

Alle forbindelsene med formel (I) og (II) er nyttige ved fremgangsmåten for hemming av produksjonen av TNF, fortrinnsvis makrofager, monocytter eller makrofager og monocytter, i et pattedyr, omfattende mennesket, som har behov for dette. Alle forbindelsene med formel (I) og (II) er nyttige ved fremgangsmåten for hemming eller mediering av den enzymatiske eller katalytiske aktiviteten av PDE IV og ved behandling av sykdomstilstander som er mediert av disse. All the compounds of formula (I) and (II) are useful in the method of inhibiting the production of TNF, preferably macrophages, monocytes or macrophages and monocytes, in a mammal, including man, in need thereof. All of the compounds of formula (I) and (II) are useful in the method of inhibiting or mediating the enzymatic or catalytic activity of PDE IV and in the treatment of disease states mediated by these.

Følgende forbindelser er foretrukne:The following compounds are preferred:

Når Ri for forbindelsene med formel (I) og (II) er et alkyl substituert med 1 eller flere halogener, idet halogenene fortrinnsvis er fluor og klor, særlig foretrukket er et Ci-4-alkyl substituert med 1 eller flere fluoratomer. Den foretrukne halogensubstituerte alkylkjede-lengde inneholder én eller to karbonatomer, og særlig foretrukket er gruppene -CF3, -CH2F, -CHF2, -CF2CHF2, -CH2CF3og -CH2CHF2. Foretrukne Ri-substitutenterfor forbindelsene med formel (I) og (II) er CH2-cyklopropyl, CH2-C5-6-cykloalkyl, C4-6-cykloalkyl, usubstituert eller substituert med OH, C7-H-polycykloalkyl, (3-eller 4-cyklopentenyl), fenyl, tetrahydrofuran-3-yl, benzyl eller Ci-2-alkyl som er usubstituert eller substituert med 1 eller flere fluoratomer, -(CH2)1-3C(0)0(CH2)0-2CH3, -(CH2)1-30(CH2)0-2CH3og -(CH2)2-40H. When Ri for the compounds of formula (I) and (II) is an alkyl substituted with 1 or more halogens, the halogens preferably being fluorine and chlorine, particularly preferred is a C 1-4 alkyl substituted with 1 or more fluorine atoms. The preferred halogen-substituted alkyl chain length contains one or two carbon atoms, and particularly preferred are the groups -CF3, -CH2F, -CHF2, -CF2CHF2, -CH2CF3 and -CH2CHF2. Preferred Ri substituents for the compounds of formula (I) and (II) are CH2-cyclopropyl, CH2-C5-6-cycloalkyl, C4-6-cycloalkyl, unsubstituted or substituted with OH, C7-H-polycycloalkyl, (3-or 4 -cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C1-2-alkyl which is unsubstituted or substituted by 1 or more fluorine atoms, -(CH2)1-3C(0)0(CH2)0-2CH3, -( CH2)1-30(CH2)0-2CH3 and -(CH2)2-40H.

Når Ri er (CR4R5), er R4og R5uavhengig hydrogen eller alkyl. Dette tillater forgrening av de individuelle metylen-enhetene som (CR4R5)neller (CR4R5)m; hver gjentatte metylen-enhet er uavhengig av den andre, f.eks., (CR4R5)nhvor n er 2 kan f.eks. være -CH2CH(-CH3)-. De individuelle hydrogen-atomene i den gjentatte metylen-enheten eller det forgrenede hydrokarbonet kan være usubstituert eller substituert med fluoratomer uavhengig av hverandre, og gir f.eks. de foretrukne Ri -substitusjonene som angitt ovenfor. When R 1 is (CR 4 R 5 ), R 4 and R 5 are independently hydrogen or alkyl. This allows branching of the individual methylene units as (CR4R5)nell or (CR4R5)m; each repeating methylene unit is independent of the other, e.g., (CR4R5)where n is 2 can e.g. be -CH2CH(-CH3)-. The individual hydrogen atoms in the repeating methylene unit or the branched hydrocarbon can be unsubstituted or substituted with fluorine atoms independently of each other, giving e.g. the preferred R 1 -substitutions as indicated above.

Når Ri er et C7-11-polycykloalkyl, eksempler er bicyklo[2,2,1]-heptyl, When R 1 is a C7-11 polycycloalkyl, examples are bicyclo[2,2,1]-heptyl,

bicyklo[2,2,2]oktyl, bicyklo[3,2,1]oktyl, tricyklo[5,2,1,0<2.6>]decyl etc, ytterligere eksempler er beskrevet i Saccamano et al., WO 87/06576, publisert 5. november 1987, og som her er referert til i sin helhet. bicyclo[2,2,2]octyl, bicyclo[3,2,1]octyl, tricyclo[5,2,1,0<2.6>]decyl etc, further examples are described in Saccamano et al., WO 87/06576 , published on 5 November 1987, and to which reference is made here in its entirety.

Foretrukket for Z er O, NCN, NR7, NOR14, NOR15, NNR4R14, NNR4R15, 2- (1,3-ditian), dimetyltio ketal, 2-(1,3-dioksolan) eller dimetylketal. Mer foretrukket erO, NR7, NOR14, NORisog 2-(1,3-dioksolan). Preferred for Z is O, NCN, NR7, NOR14, NOR15, NNR4R14, NNR4R15, 2-(1,3-dithiane), dimethylthio ketal, 2-(1,3-dioxolane) or dimethyl ketal. More preferred are O, NR7, NOR14, NORis and 2-(1,3-dioxolane).

Foretrukne grupper for X i formel (I) og (II) er de hvor X er YR2og Y er oksygen. Den foretrukne X2-gruppen i formel (I) og (II) er den hvor X2er oksygen. Den foretrukne X3-gruppen i formel (I) og (II) er den hvor X3er hydrogen. Foretrukne R2-grupper, hvor mulig, er C"|-2-alkyl, usubstituert eller substituert med 1 eller flere halogenatomer. Halogenatomene er fortrinnsvis fluor og klor og særlig foretrukket er fluor. Mer foretrukne R2-grupper er de hvor R2er metyl eller fluorsubstituerte alkyler, særlig Ci-2-alkyl, slik som -CF3-, -CHF2- eller Preferred groups for X in formula (I) and (II) are those where X is YR 2 and Y is oxygen. The preferred X 2 group in formulas (I) and (II) is that where X 2 is oxygen. The preferred X 3 group in formula (I) and (II) is that where X 3 is hydrogen. Preferred R2 groups, where possible, are C"|-2-alkyl, unsubstituted or substituted with 1 or more halogen atoms. The halogen atoms are preferably fluorine and chlorine and particularly preferred is fluorine. More preferred R2 groups are those where R2 is methyl or fluorine-substituted alkyls, especially C1-2 alkyl, such as -CF3-, -CHF2- or

-CH2CHF2-grupper. Mest foretrukket er -CHF2-og -CH3-grupper.-CH2CHF2 groups. Most preferred are -CHF2 and -CH3 groups.

Foretrukne R7-grupper omfatter R13, usubstituert eller substituert -(CH2)o-2(2-, 3- eller 4-pyridyl), (CH2)l-2(2-imidazolyl), (CH2)2(4-morfolinyl), (CH2)2(4-piperazinyl), (CH2)i-2(2-tienyl), (CH2)i-2(4-tiazolyl), usubstituert eller substituert pyrimidinyl og substituert eller usubstituert (CH2)o-2fenyl. Preferred R7 groups include R13, unsubstituted or substituted -(CH2)o-2(2-, 3- or 4-pyridyl), (CH2)1-2(2-imidazolyl), (CH2)2(4-morpholinyl) , (CH2)2(4-piperazinyl), (CH2)i-2(2-thienyl), (CH2)i-2(4-thiazolyl), unsubstituted or substituted pyrimidinyl and substituted or unsubstituted (CH2)o-2phenyl.

Foretrukne ringer når R10og R11i -NR10R11sammen med nitrogenet som de er bundet til danner en 5- til 7-leddet ring er de som består bare av karbonatomer eller karbonatomer og minst et heteroatom valgt fra O, N, eller S og omfatter, men er ikke begrenset til 1-imidazolyl, 2-(R8)-1-imidazolyl, 1-pyrazolyl, 3- (R8)-1 -pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)-1-triazolyl, 5-(R8)-2-triazolyl, 5-(R8)-1-tetrazolyl, 5-(R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morfolinyl, piperazinyl, 4-(Rs)-1-piperazinyl eller pyrrolylring. Preferred rings when R 10 and R 11 i -NR 10 R 11 together with the nitrogen to which they are attached form a 5- to 7-membered ring are those consisting only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S and include, but are not limited to 1-imidazolyl, 2-(R8)-1-imidazolyl, 1-pyrazolyl, 3-(R8)-1-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)-1-triazolyl, 5- (R8)-2-triazolyl, 5-(R8)-1-tetrazolyl, 5-(R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(Rs)-1-piperazinyl or pyrrolyl ring.

Foretrukne ringer når Rs og R14i -NR8R14sammen med nitrogenet som de er bundet til kan danne en 5- til 7-leddet ring er de som bare består av karbonatomer eller karbonatomer og minst et heteroatom valgt fra O, N, eller S og omfatter, men er ikke begrenset til 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morfolinyl, piperazinyl og pyrrolyl. De respektive ringene kan være ytterligere substituert, når det er mulig, på et tilgjengelig nitrogen- eller karbonatom med gruppen R7som beskrevet for formel (I) og (II). Eksempler på slike karbon-substitusjoner omfatter, men er ikke begrenset til, 2-(R7)-1-imidazolyl, 4- (R7)-1-imidazolyl, 5-(R7)-1-imidazolyl, 3-(R7)-1-pyrazolyl, 4-(R7)-1-pyrazolyl, 5- (R7)-1-pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-1-triazolyl, 5-(R7)-1-triazolyl, 5-(R7)-1-tetrazolyl og 5-(R7)-2-tetrazolyl. Anvendbare nitrogen-substitusjoner med R7omfatter, men er ikke begrenset til, 1-(R7)-2-tetrazolyl, 2-(R7)-1-tetrazolyl, 4-(R7)-1-piperazinyl. Når mulig, kan ringen være substituert én eller flere ganger med R7. Preferred rings when R s and R 14 i -NR 8 R 14 together with the nitrogen to which they are attached can form a 5- to 7-membered ring are those consisting only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N, or S and include, but is not limited to 1-imidazolyl, 1-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, and pyrrolyl. The respective rings may be further substituted, when possible, on an available nitrogen or carbon atom with the group R 7 as described for formula (I) and (II). Examples of such carbon substitutions include, but are not limited to, 2-(R7)-1-imidazolyl, 4-(R7)-1-imidazolyl, 5-(R7)-1-imidazolyl, 3-(R7)- 1-pyrazolyl, 4-(R7)-1-pyrazolyl, 5-(R7)-1-pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)- 1-triazolyl, 5-(R7)-1-triazolyl, 5-(R7)-1-tetrazolyl and 5-(R7)-2-tetrazolyl. Useful nitrogen substitutions with R 7 include, but are not limited to, 1-(R 7 )-2-tetrazolyl, 2-(R 7 )-1-tetrazolyl, 4-(R 7 )-1-piperazinyl. Whenever possible, the ring may be substituted one or more times with R7.

Foretrukne grupper for NR8R14som inneholder en heterocyklisk ring er 5-(Ri4)-1-tetrazolyl, 2-(Ri4)-1-imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(R-|4)-1-piperazinyl eller 4-(Ri5)-1-piperazinyl. Preferred groups for NR8R14 containing a heterocyclic ring are 5-(Ri4)-1-tetrazolyl, 2-(Ri4)-1-imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(R-|4)-1- piperazinyl or 4-(R 15 )-1-piperazinyl.

Foretrukne ringer for R13omfatter (2-, 4- eller 5-imidazolyl), (3-, 4- eller 5-pyrazolyl), (4- eller 5-triazolyl[1,2,3]), (3- eller 5-triazolyl[1,2,4]), (5-tetrazolyl), Preferred rings for R 13 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5- triazolyl[1,2,4]), (5-tetrazolyl),

(2-, 4- eller 5-oksazolyl), (3-, 4- eller 5-isoksazolyl), (3- eller 5-oksadiazolyl[1,2,4]), (2-oksadiazolyl[1,3,4]), (2-tiadiazolyl[1,3,4]), (2-, 4-, eller 5-tiazolyl), (2-, 4-, 5-oksazolidinyl), (2-, 4- eller 5-tiazolidinyl) eller (2-, 4- eller 5-imidazolidinyl). (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4 ]), (2-thiadiazolyl[1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, 5-oxazolidinyl), (2-, 4- or 5- thiazolidinyl) or (2-, 4- or 5-imidazolidinyl).

Når R7-gruppen er usubstituert eller substituert med en heterocyklisk ring slik som imidazolyl, pyrazolyl, pyrimidinyl, triazolyl, tetrazolyl eller tiazolyl kan den heterocykliske ringen selv være usubstituert eller substituert med Rs enten på et tilgjengelig nitrogenatom eller karbonatom, slik som 1-(R8)-2-imidazolyl, 1-(R8)-4-imidazolyl, 1-(R8)-5-imidazolyl, 1-(R8)-3-pyrazolyl, 1-(R8)-4-pyrazolyl, 1-(R8)-5-pyrazolyl, 1-(Rs)-4-triazolyl eller 1-(R8)-5-triazolyl. Når det er mulig kan ringen være substituert én eller flere ganger med Rs. When the R7 group is unsubstituted or substituted with a heterocyclic ring such as imidazolyl, pyrazolyl, pyrimidinyl, triazolyl, tetrazolyl or thiazolyl, the heterocyclic ring itself may be unsubstituted or substituted with Rs either on an available nitrogen atom or carbon atom, such as 1-(R8 )-2-imidazolyl, 1-(R8)-4-imidazolyl, 1-(R8)-5-imidazolyl, 1-(R8)-3-pyrazolyl, 1-(R8)-4-pyrazolyl, 1-(R8 )-5-pyrazolyl, 1-(Rs)-4-triazolyl or 1-(R8)-5-triazolyl. Whenever possible the ring may be substituted one or more times by Rs.

W er fortrinnsvis alkyl, alkenyl eller alkynyl med 3 til 5 karbonatomer, og i alkenyl eller alkynyl kan inneholde én eller to dobbelt- eller trippelbindinger. Det er særlig foretrukket at W er etynyl eller 1,3-butadiynyl. W is preferably alkyl, alkenyl or alkynyl with 3 to 5 carbon atoms, and i alkenyl or alkynyl may contain one or two double or triple bonds. It is particularly preferred that W is ethynyl or 1,3-butadiynyl.

Foretrukne er forbindelsene med formel (I) og (II) hvor R-| er -CH2-cyklopropyl, -CH2-C5-6-cykloalkyl, -C4_6-cykloalkyl som kan være usubstituert eller substituert med OH, tetrahydrofuran-3-yl, (3- eller 4-cyklopentenyl), benzyl eller -C-|-2-alkyl som kan være usubstituert eller substituert med 1 eller flere fluoratomer, og -(CH2)2-4OH; R2er metyl eller fluorsubstituert alkyl, R3er lik R7 hvor R7er en usubstituert eller substituert aryl- eller heteroarylring, X er YR2og Z erO, NR7 Preferred are the compounds of formula (I) and (II) where R-| is -CH2-cyclopropyl, -CH2-C5-6-cycloalkyl, -C4_6-cycloalkyl which may be unsubstituted or substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -C-|- 2-alkyl which may be unsubstituted or substituted with 1 or more fluorine atoms, and -(CH2)2-4OH; R2 is methyl or fluoro-substituted alkyl, R3 is equal to R7 where R7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2 and Z is O, NR7

Z' er fortrinnsvis COOR14.Z' is preferably COOR14.

Mest foretrukket er de forbindelsene hvor Ri er -CH2-cyklopropyl, cyklopentyl, 3-hydroksycyklopentyl, metyl eller CF2H; X er YR2; Y er oksygen; X2er oksygen; X3er hydrogen; og R2er CF2H eller metyl, W er etynyl eller 1,3-butadiynyl, R3er en substituert eller usubstituert pyrimidinylring, og Z er O, NR7. Most preferred are those compounds where R 1 is -CH 2 -cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF 2 H; X is YR 2 ; Y is oxygen; X2 is oxygen; X 3 is hydrogen; and R 2 is CF 2 H or methyl, W is ethynyl or 1,3-butadiynyl, R 3 is a substituted or unsubstituted pyrimidinyl ring, and Z is O, NR 7 .

Når de kan fremstilles omfatter foreliggende oppfinnelse også farmasøytisk akseptable salter av forbindelsene ifølge foreliggende oppfinnelse. Disse saltene vil være de som er akseptable for anvendelse til farmasøytisk bruk. Med dette er ment ved saltet bibeholder den biologiske aktiviteten til moderforbindelsen og saltet ikke har uheldige eller skadelige virkninger når det benyttes og anvendes ved behandling av sykdommer. When they can be prepared, the present invention also includes pharmaceutically acceptable salts of the compounds according to the present invention. These salts will be those acceptable for use in pharmaceutical applications. By this is meant that the salt retains the biological activity of the parent compound and the salt does not have adverse or harmful effects when it is used and used in the treatment of diseases.

Farmasøytisk akseptable salter fremstilles etter vanlige metoder. Moderforbindelsen, oppløst i et egnet løsningsmiddel, behandles med et overskudd av en organisk eller uorganisk syre, i tilfelle av syreaddisjon salter av en base, eller et overskudd av organisk eller uorganisk base når molekylet inneholder f.eks. Pharmaceutically acceptable salts are prepared by conventional methods. The parent compound, dissolved in a suitable solvent, is treated with an excess of an organic or inorganic acid, in the case of acid addition salts of a base, or an excess of organic or inorganic base when the molecule contains e.g.

COOH.COOH.

Farmasøytiske blandinger ifølge foreliggende oppfinnelse omfatter en farmasøytisk bærer eller et fortynningsmiddel og en viss mengde av en forbindelse med formel (I) og (II). Forbindelsen kan være tilstede i en mengde som gir en fysiologisk respons, eller den kan være tilstede i en mindre mengde slik at brukeren vil ha behov for å innta to eller flere enheter av preparatet for å gi den tilsiktede virkning. Disse preparatene kan være fremstilt som et fast stoff, en væske eller være i gassform. Eller én av disse tre formene kan overføres til en annen ved administreringstidspunktet slik som når et fast stoff leveres som en aerosol, eller når en væske leveres som en spray eller aerosol. Pharmaceutical compositions according to the present invention comprise a pharmaceutical carrier or a diluent and a certain amount of a compound of formula (I) and (II). The compound may be present in an amount that produces a physiological response, or it may be present in a smaller amount so that the user will need to consume two or more units of the preparation to produce the intended effect. These preparations can be produced as a solid, a liquid or in gaseous form. Or one of these three forms may be transferred to another at the time of administration such as when a solid is delivered as an aerosol, or when a liquid is delivered as a spray or aerosol.

Preparattype og farmasøytisk bærer eller fortynningsmiddel vil selvfølgelig være avhengig av den tilsiktede administreringsmåten, f. eks. parenteral, topisk, oral eller ved inhalering. Preparation type and pharmaceutical carrier or diluent will of course depend on the intended method of administration, e.g. parenterally, topically, orally or by inhalation.

For topisk administrering vil det farmasøytiske preparatet være i form av en krem, salve, liniment, lotion, pasta, aerosol og dråper som er egnet for administrering til hud, øye, øre eller nese. For topical administration, the pharmaceutical preparation will be in the form of a cream, ointment, liniment, lotion, paste, aerosol and drops suitable for administration to the skin, eye, ear or nose.

For parenteral administrering vil det farmasøytiske preparatet være i form av en steril injiserbar væske, slik som en ampulle eller en vandig eller ikke-vandig, flytende suspensjon. For parenteral administration, the pharmaceutical preparation will be in the form of a sterile injectable liquid, such as an ampoule or an aqueous or non-aqueous liquid suspension.

For oral administrering vil det farmasøytiske preparatet være i form av en For oral administration, the pharmaceutical preparation will be in the form of a

tablett, kapsel, pulver, pille, "atroche", sugetablett, sirup, væske eller emulsjon. tablet, capsule, powder, pill, "atroche", lozenge, syrup, liquid or emulsion.

Når det farmasøytiske preparatet anvendes i form av en løsning eller suspensjon omfatter eksempelvis egnete bærere eller fortynningsmidler: for vandige løsninger, vann; for ikke-vandige løsninger, etanol, glyserin, propylen-glykol, maisolje, bomullsfrøolje, peanøttolje, sesamolje, flytende parafiner og blandinger derav med vann; for faste systemer, laktose, kaolin og mannitol; og for aerosolsystemer, diklordifluormetan, klortrifluoretan og komprimert karbondioksyd. Preparatene kan også i tillegg til den farmasøytiske bæreren eller fortynningsmiddelet omfatte andre bestanddeler slik som stabilisatorer, antioksydasjons-midler, konserveringsmidler, smøremidler, suspensjonsmidler, viskositets-regulerende midler og lignende, forutsatt at de ytterligere bestanddelene ikke har en skadelig virkning på den terapeutiske virkningen av preparatene. When the pharmaceutical preparation is used in the form of a solution or suspension, suitable carriers or diluents include, for example: for aqueous solutions, water; for non-aqueous solutions, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. The preparations may also, in addition to the pharmaceutical carrier or diluent, include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity-regulating agents and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic effect of the preparations.

De omtalte farmasøytiske preparatene fremstilles ved å følge vanlige teknikker innen farmasien og tilpasset det ønskede sluttproduktet. The mentioned pharmaceutical preparations are produced by following common techniques in pharmacy and adapted to the desired end product.

Mengden av bærer eller fotynningsmiddel i disse preparatene vil variere, men vil fortrinnsvis utgjøre hoveddelen av en suspensjon eller løsning av den aktive bestanddelen. Når fortynningsmiddelet er et fast stoff kan det være tilstede i en mindre, lik eller større mengde en den faste, aktive bestanddelen. The amount of carrier or diluent in these preparations will vary, but will preferably constitute the main part of a suspension or solution of the active ingredient. When the diluent is a solid, it may be present in a smaller, equal or larger amount than the solid, active ingredient.

Vanligvis administreres en forbindelse med formel I til et individ i et preparat som består av en tilstrekkelig, ikke-giftig mengde for å frembringe en hemming av sykdomssymptomene hvori leukotriener er en faktor. Topiske formuleringer vil inneholde mellom ca. 0,01 til 5,0 vekt% av den aktive bestanddelen og vil påføres, alt etter behov, som et forebyggende eller helbredende middel til det angrepne området. Når den anvendes som en oral eller en annen inntatt eller injisert kur, er dose-enheten av preparatet valgt fra området fra 50 mg til 1.000 mg av aktiv bestanddel i hver administrering. For enkelthets skyld vil like store doser administreres 1 til 5 ganger daglig slik at det daglige dosenivået er valgt fra ca. 50 mg til ca. 5.000 mg. Generally, a compound of formula I is administered to a subject in a preparation consisting of a sufficient, non-toxic amount to produce an inhibition of the disease symptoms in which leukotrienes are a factor. Topical formulations will contain between approx. 0.01 to 5.0% by weight of the active ingredient and will be applied, as needed, as a preventive or curative agent to the affected area. When used as an oral or other ingested or injected regimen, the dosage unit of the preparation is selected from the range of 50 mg to 1,000 mg of active ingredient in each administration. For the sake of simplicity, equal doses will be administered 1 to 5 times a day so that the daily dose level is chosen from approx. 50 mg to approx. 5,000 mg.

Det vil forstås ved noen av forbindelsene med formel (I) og (II) kan eksistere både i racemisk- og optiskaktive former; noen kan også eksistere i forskjellige diastereomere former som har forskjellige fysikalske og biologiske egenskaper. Alle disse forbindelsene ligger innenfor rammen av foreliggende oppfinnelse. It will be understood that some of the compounds of formula (I) and (II) can exist in both racemic and optically active forms; some may also exist in different diastereomeric forms that have different physical and biological properties. All these compounds are within the scope of the present invention.

Forbindelser med formel (I) hvor Z er O eller (II) kan forekomme i en tautomer form, slik som enolformen. Dette kan forklares med ved =0 er Compounds of formula (I) where Z is O or (II) may occur in a tautomeric form, such as the enol form. This can be explained by at =0 is

eksocyklisk til cykloheksanringen (ellei exocyclic to the cyclohexane ring (otherwise

i motsetning til den endocykliske eller -C(-OH)=C(-R)-gruppenhvor cykloheksanringen nå er umettet i 1-2 stillingen, d.v.s. cykloheks-1-en , eller in contrast to the endocyclic or -C(-OH)=C(-R) group where the cyclohexane ring is now unsaturated in the 1-2 position, i.e. cyclohex-1-ene, or

ig R er Z i formel (II). Det and R is Z in formula (II). The

er nå også erkjent at 2-stillingen i ringen i den eksocykliske formen kan være substituert (R), slik som i forbindelsene med formel (I) eller (II). is now also recognized that the 2-position in the ring in the exocyclic form can be substituted (R), as in the compounds of formula (I) or (II).

De følgende eksemplene er gitt for ytterligere å illustrere foreliggende oppfinnelse. Disse eksemplene er ment bare å illustrere foreliggende oppfinnelse og ikke å begrense oppfinnelsen på noen måte. Når det gjelder hva som er forbeholdt oppfinnerne vises det til kravene. The following examples are given to further illustrate the present invention. These examples are intended only to illustrate the present invention and not to limit the invention in any way. As regards what is reserved for the inventors, reference is made to the requirements.

Det er ikke forventet noen uakseptable, toksiologiske virkninger når disse forbindelsene administreres i henhold til foreliggende oppfinnelse. No unacceptable toxicological effects are expected when these compounds are administered according to the present invention.

FremstillingsmetoderManufacturing methods

Synteseskjema(er) med tekstbeskrivelseSynthesis form(s) with text description

Forbindelser med formel (I) kan fremstilles ifølge de fremgangsmåtene som er beskrevet her og som omfatter å omsette en endestående acetylen som, f. eks., forbindelse 1- skjema 1 med et arylhalogenid, slik som fenyljodid, i nærvær av en egnet katalysator, slik som et kobber-(l)-halogenid og en toverdig eller nullverdig palladiumforbindelse i nærvær av, f. eks., trifenylfosfin i et egnet løsningsmiddel, slik som et amin, som i fremgangsmåten til Brandsma et al. (Syn. Comm., 1990, 20, 1889), etterfulgt av hydrolyse av den ketalbeskyttende gruppen under vanlige betingelser, og man får en forbindelse med formelen 2- skjema 1. Forbindelser med formelen 1- skjema 1 kan fremstilles etter fremgangsmåter som er analoge til de som er beskrevet i tidligere inngitte "co-pending" U.S. patentsøknader 07/862,083, 07/968,753 og PCT/US93/01990 hvor U.S. er utpekt og inngitt 5. mars 1993 (WIPO publikasjonsnr. WO 93/19748) eller PCT patentsøknad PCT/US93/02325 publisert som WO 93/19750. Compounds of formula (I) can be prepared according to the methods described herein which comprise reacting a terminal acetylene such as, for example, compound 1- Scheme 1 with an aryl halide, such as phenyl iodide, in the presence of a suitable catalyst, such as a copper-(1)-halide and a divalent or null palladium compound in the presence of, for example, triphenylphosphine in a suitable solvent, such as an amine, as in the method of Brandsma et al. (Syn. Comm., 1990, 20, 1889), followed by hydrolysis of the ketal protecting group under usual conditions, and one obtains a compound of the formula 2- scheme 1. Compounds of the formula 1- scheme 1 can be prepared by methods which are analogous to those described in previously filed "co-pending" U.S. patent applications 07/862,083, 07/968,753 and PCT/US93/01990 where U.S. is designated and filed March 5, 1993 (WIPO Publication No. WO 93/19748) or PCT Patent Application PCT/US93/02325 published as WO 93/19750.

a) PdfPPHj), PPhj, Cul, C8H5I, piperidin; b) pyridin p-toluensulfonat, (H3C)2CO/H20 a) PdfPPHj), PPhj, Cul, C8H5I, piperidine; b) pyridine p-toluenesulfonate, (H3C)2CO/H2O

Forbindelser med formel (I) kan alternativt fremstilles ved omsetning av en Compounds of formula (I) can alternatively be prepared by reacting a

endestående acetylen, som f. eks., forbindelse 1 - skjema 2 med et egnet halogenid, R3X, hvor R3betyr R3som angitt i formel (I) eller en gruppe som er overførbar til R3, i nærvær av en egnet katalysator, slik som et kobber-(l)-halogenid og en toverdig eller nullverdig palladiumforbindelse i nærvær av f. eks. terminal acetylene, such as, for example, compound 1 - scheme 2 with a suitable halide, R3X, where R3 is R3 as indicated in formula (I) or a group transferable to R3, in the presence of a suitable catalyst, such as a copper -(l)-halide and a divalent or zero-valent palladium compound in the presence of e.g.

trifenylfosfin, i et egnet løsningsmiddel, slik som et amin, som i fremgangsmåten til Brandsma et al. (Syn. Comm., 1990, 20, 1889), for å gi en forbindelse med formelen 2- skiema 2: slike forbindelser med formelen (I) kan deretter overføres til andre forbindelser med formelen (I) ved vanlige manipulasjoner av de funksjonelle gruppene på R3-delen. Forbindelser med formelen 1- skjema 2 kan fremstilles etter fremgangsmåter som er analoge til de som er beskrevet i tidligere inngitte "co-pending" U.S. patentsøknader 07/862,083, 07/968,753 og PCT/US93/01990, hvor U.S. er utpekt og inngitt 5. mars 1993 (WIPO publikasjonsnr. WO 93/19748) eller PCT patentsøknad PCT/US93/02325 publisert som WO 93/19750. triphenylphosphine, in a suitable solvent, such as an amine, as in the method of Brandsma et al. (Syn. Comm., 1990, 20, 1889), to give a compound of the formula 2- scheme 2: such compounds of the formula (I) can then be transferred to other compounds of the formula (I) by usual manipulations of the functional groups on the R3 part. Compounds of Formula 1-Scheme 2 may be prepared by methods analogous to those described in previously filed co-pending U.S. Pat. patent applications 07/862,083, 07/968,753 and PCT/US93/01990, where U.S. is designated and filed March 5, 1993 (WIPO Publication No. WO 93/19748) or PCT Patent Application PCT/US93/02325 published as WO 93/19750.

a) Pd(PPhj)4, PPh3, Cul, RjX, piperidin a) Pd(PPhj)4, PPh3, Cul, RjX, piperidine

Alternativt gir oksydativ karbonylering av en endestående acetylen, som Alternatively, oxidative carbonylation of a terminal acetylene gives, as

f. eks. forbindelse 1- skjema 3. ved å anvende et egnet metallsalt, slik som et kobbersalt med en katalytisk mengde av et palladiumsalt, i nærvær av en egnet base som en syrefelle, slik som natriumacetat, i en egnet alkohol, slik som metanol, som i fremgangsmåten til Tsuji et al. (Tet. Lett., 1980, 21, 849), etterfulgt av hydrolyse av metylesteren under vanlige betingelser, og dette gir en forbindelse med formelen (I) ( 2- skiema 3V. slike forbindelser med formel (I) kan deretter overføres til andre forbindelser med formelen (I) ved vanlig manipulering av karboksylestergruppen. e.g. compound 1- scheme 3. by using a suitable metal salt, such as a copper salt with a catalytic amount of a palladium salt, in the presence of a suitable base as an acid trap, such as sodium acetate, in a suitable alcohol, such as methanol, as in the method of Tsuji et al. (Tet. Lett., 1980, 21, 849), followed by hydrolysis of the methyl ester under usual conditions, and this gives a compound of formula (I) ( 2-scheema 3V. such compounds of formula (I) can then be transferred to other compounds of the formula (I) by usual manipulation of the carboxyl ester group.

a) PdCI2, CuCI2, Na02CCH3, CO, CH3OH a) PdCl2, CuCl2, NaO2CCH3, CO, CH3OH

Forbindelser med formel (II) kan fremstilles etter fremgangsmåter som er Compounds of formula (II) can be prepared by methods which are

analoge med de i skjemaene 1, 2 og 3 ovenfor som illustrert i skjema 4. Avhengig av typen av Z'-gruppene av forbindelsene med formel (II), kan =0-gruppene ha behov for beskyttelse under koblingstrinnene som her er beskrevet, f. eks. en forbindelse med formel (II) hvor =0 er et dimetylketal eller 2-(1,3-dioksolan), etterfulgt av fjerning av beskyttelsesgruppen og deretter omsetning etter syntesemetodene som er beskrevet i tidligere inngitte "co-pending" U.S. patentsøknader 07/862,083, 07/968,753 og PCT/US93/01990, hvor U.S. er utpekt og inngitt 5. mars 1993 (WIPO publikasjonsnr. WO 93/19748) eller PCT patentsøknad PCT/US93/02325 publisert som WO 93/19750, og dette gir forbindelsen med formelen (II); Z'-gruppen kan på samme måte ha behov for beskyttelse under koblingstrinnene, etterfulgt av fjerning av beskyttelsesgruppen, og man får forbindelsen med formelen (II), og slike beskyttende grupper er velkjent for fagmannen på området. (Se: Green, T. og Wuts, P.G.M., Protecting Groups in Organic Synthesis, 2. utg., John Wiley og Sons, New York, 1991.) analogous to those in Schemes 1, 2 and 3 above as illustrated in Scheme 4. Depending on the nature of the Z' groups of the compounds of formula (II), the =0 groups may require protection during the coupling steps described herein, f e.g. a compound of formula (II) wherein =0 is a dimethyl ketal or 2-(1,3-dioxolane), followed by removal of the protecting group and then reaction according to the synthetic methods described in previously filed co-pending U.S. patent applications 07/862,083, 07/968,753 and PCT/US93/01990, where U.S. is designated and filed March 5, 1993 (WIPO Publication No. WO 93/19748) or PCT Patent Application PCT/US93/02325 published as WO 93/19750, and this provides the compound of formula (II); The Z' group may similarly require protection during the coupling steps, followed by removal of the protecting group, and the compound of formula (II) is obtained, and such protecting groups are well known to those skilled in the art. (See: Green, T. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 2nd ed., John Wiley and Sons, New York, 1991.)

a) Pd(PPh3)4, PPh3. Cul, RjX, piperidin a) Pd(PPh3)4, PPh3. Cul, RjX, piperidine

Fremstilling av de gjenværende forbindelsene med formlene (I) og (II) kan Preparation of the remaining compounds of formulas (I) and (II) can

oppnås ved fremgangsmåter som er analoge til de som er beskrevet ovenfor og i eksemplene nedenfor. achieved by methods analogous to those described above and in the examples below.

Det vil forstås at forbindelser med formlene (I) og (II) kan være i forskjellige diastereomere former som har forskjellige fysikalske og biologiske egenskaper; slike isomerer kan adskilles etter vanlige kromatografiske metoder. It will be understood that compounds of formulas (I) and (II) may be in different diastereomeric forms which have different physical and biological properties; such isomers can be separated by usual chromatographic methods.

De følgende eksemplene er gitt for ytterligere å illustrere foreliggende oppfinnelse. Disse eksemplene er bare gitt for å illustrere oppfinnelsen og er ikke ment å begrense oppfinnelsen på noen måte. Hva som er forbeholdt oppfinnerne fremgår av kravene nedenfor. The following examples are given to further illustrate the present invention. These examples are given to illustrate the invention only and are not intended to limit the invention in any way. What is reserved for the inventors appears from the requirements below.

FremstillingseksemplerManufacturing examples

Eksempel 1Example 1

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(2-pyridyletynyl)cykloheksan Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(2-pyridylethynyl)cyclohexane

1a) 4-cyano-4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)cykloheksan 1a) 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)cyclohexane

En løsning av 4-cyano-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on (1,0 g, 3,19 mmol, beskrevet i PCT-patentsøknadene PCT/US3/01990 (WIPO publikasjonsnr. WO 93/19748) og PCT-patentsøknad PCT/US93/02325 publisert som WIPO nr. WO 93/19750) i benzen (25 ml) ble behandlet med p-toluen-sulfonsyre (5 mg) og etylenglykol (0,18 ml, 3,19 mmol) og ble deretter oppvarmet under tilbakeløp i en argonatmosfære; vann ble fjernet fra blandingen via en Dean-Stark-felle. Etter 1,5 timer ble det tilsatt eter (200 ml), løsningen ble vasket med vandig 5% natriumbikarbonat og saltløsning, ble tørket (kaliumkarbonat) og ble fordampet og man fikk en klar, fargeløs olje (1,16 g, 100%). A solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (1.0 g, 3.19 mmol, described in PCT patent applications PCT/US3/01990 (WIPO Publication No. WO 93 /19748) and PCT Patent Application PCT/US93/02325 published as WIPO No. WO 93/19750) in benzene (25 mL) was treated with p-toluenesulfonic acid (5 mg) and ethylene glycol (0.18 mL, 3, 19 mmol) and was then heated under reflux in an argon atmosphere; water was removed from the mixture via a Dean-Stark trap. After 1.5 h, ether (200 mL) was added, the solution was washed with aqueous 5% sodium bicarbonate and brine, dried (potassium carbonate) and evaporated to give a clear, colorless oil (1.16 g, 100%) .

<1>H NMR(250 MHz, CDCI3) 5 7,0 (m, 2H), 6,85 (d, J=7 Hz, 1H), 4,8 (m, 1H), 4,0 (m, 4H), 3,85 (s, 3H), 1,58-2,20 (m, 16H). <1>H NMR(250 MHz, CDCl3) δ 7.0 (m, 2H), 6.85 (d, J=7 Hz, 1H), 4.8 (m, 1H), 4.0 (m, 4H), 3.85 (s, 3H), 1.58-2.20 (m, 16H).

1 b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1 -(etylendioksy)-4-formylcykloheksan 1 b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-formylcyclohexane

Diisobutylaluminumhydrid (1,0 M i toluen, 8,13 ml, 8,13 mmol) ble tilsatt dråpevis til en løsning av 4-cyano-4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)cykloheksan (1,16 g, 3,19 mmol) oppløst i toluen (20 ml) under en argonatmosfære. Etter 18 timer ved romtemperatur ble det tilsatt mettet, vandig natriumbisulfitt (100 ml) og blandingen ble ekstrahert tre ganger med diklormetan. De samlede, organiske ekstraktene ble vasket med saltløsning, ble tørket (kaliumkarbonat) og ble fordampet. Rensning med flash-kromatografi, eluering med 4:1 heksaner/etylacetat, ga en klar, fargeløs olje (0,62 g, 53%). Diisobutylaluminum hydride (1.0 M in toluene, 8.13 mL, 8.13 mmol) was added dropwise to a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)cyclohexane (1.16 g, 3.19 mmol) dissolved in toluene (20 mL) under an argon atmosphere. After 18 hours at room temperature, saturated aqueous sodium bisulfite (100 mL) was added and the mixture was extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 4:1 hexanes/ethyl acetate, gave a clear, colorless oil (0.62 g, 53%).

<1>H NMR(400 MHz, CDCI3) 5 9,35 (s, 1H), 6,88 (br s, 2H), 6,80 (s, 1H), 4,73 (m, 1H), 3,95 (m, 4H), 3,85 (s, 3H), 2,33 (m, 2H), 2,10 (m, 2H), 1,57-1,99 (m, 12H). <1>H NMR(400 MHz, CDCl3) δ 9.35 (s, 1H), 6.88 (br s, 2H), 6.80 (s, 1H), 4.73 (m, 1H), 3 .95 (m, 4H), 3.85 (s, 3H), 2.33 (m, 2H), 2.10 (m, 2H), 1.57-1.99 (m, 12H).

1 c) 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1 -(etylendioksy)-4-etynylcykloheksan 1 c) 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane

En løsning av dimetyl(diazometyl)fosfonat (0,516 g, 3,44 mmole, fremstilt som i Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36(10), 1379-1386) oppløst i tørr tetrahydrofuran (10 ml) ble tilsatt ved hjelp av en kanyle til en løsning av kalium-t-butoksyd (0,386 g, 3,4 mmol) oppløst i tørr tetrahydrofuran (10 ml) ved -78°C under en argonatmosfære. Til dette ble det hurtig tilsatt en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-formylcykloheksan (0,62 g, 1,72 mmol) i tørr tetrahydrofuran (10 ml). Etter 2 timer ble reaksjonsblandingen oppvarmet til romtemperatur, vann ble tilsatt og blandingen ble ekstrahert tre ganger med etylacetat. De samlede, organiske ekstraktene ble vasket med saltløsning, ble tørket (natriumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 3:1 heksaner/etylacetat ga et hvitt, fast stoff ( 0,5 g, 81%). Sm.p. 53,5-55°C. A solution of dimethyl (diazomethyl)phosphonate (0.516 g, 3.44 mmol, prepared as in Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36(10), 1379-1386) dissolved in dry tetrahydrofuran (10 mL) was added by cannula to a solution of potassium t-butoxide (0.386 g, 3.4 mmol) dissolved in dry tetrahydrofuran (10 mL) at -78°C under an argon atmosphere. To this was quickly added a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-formylcyclohexane (0.62 g, 1.72 mmol) in dry tetrahydrofuran (10 ml) . After 2 hours, the reaction mixture was warmed to room temperature, water was added and the mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate gave a white solid (0.5 g, 81%). Sm.p. 53.5-55°C.

1 d) 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1 -(etylendioksy)-4-(2-pyridyletynyl)-cykloheksan 1 d) 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(2-pyridylethynyl)-cyclohexane

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-etynylcykloheksan (0,15 g, 0,42 mmol) og 2-brompyridin (0,040 ml, 0,42 mmol) i piperidin (2 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)-palladium(O) (0,02 g, 4%), kobber-(l)-jodid (0,005 g, 6%) og en liten krystall av trifenylfosfin, og blandingen ble oppvarmet til 80°C i 0,5 timer. Vann ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ekstraktet ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 35:65 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(2-pyridyletynyl)cykloheksan som et hvitt skum (0,17 g, 95%). Sm.p. 41-42°C. To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.15 g, 0.42 mmol) and 2-bromopyridine (0.040 mL, 0.42 mmol ) in piperidine (2 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)-palladium(O) (0.02 g, 4%), copper (l)-iodide (0.005 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated to 80°C for 0.5 hr. Water was added and the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(2-pyridylethynyl)cyclohexane as a white foam (0 .17 g, 95%). Sm.p. 41-42°C.

<1>H-NMR (400 MHz, CDCI3) 5 8,58 (d, J=4,6Hz, 1H), 7,65 (t, J=7,7 Hz, 1H), 7,43 (d, J=8,0Hz, 1H), 7,21 (m, 2H), 7,17 (d, J=8,5Hz, 1H), 6,84 (d, J=8,5 Hz, 1H), 4,81 (m, 1H), 3,99 (s, 4H), 3,84 (s, 3H), 2,25 (m, 2H), 2,15 (m, 4H), 1,8-2,0 (m, 8H), 1,59 (m, 2H). <1>H-NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.6Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.0Hz, 1H), 7.21 (m, 2H), 7.17 (d, J=8.5Hz, 1H), 6.84 (d, J=8.5Hz, 1H), 4 .81 (m, 1H), 3.99 (s, 4H), 3.84 (s, 3H), 2.25 (m, 2H), 2.15 (m, 4H), 1.8-2, 0 (m, 8H), 1.59 (m, 2H).

Eksempel 2Example 2

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(fenyletynyl)cykloheksan-l -on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(phenylethynyl)cyclohexan-1-one

En prøve av 1,1-(etylendioksy)-4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan (0,15 g, 0,42 mmol) ble behandlet med spormengder av trifenylfosfin, tetrakis(trifenylofsfin)palladium(0) og kobber-(l)-jodid. Jodbenzen (0,47 ml, 4,2 mmol) og piperidin (2 ml) ble deretter tilsatt og blandingen ble oppvarmet under en argonatmosfære. Etter 3 timer, ble blandingen fortynnet med etylacetat (50 ml), ble vasket én gang med fortynnet, vandig HCI, ble tørket (magnesiumsulfat) og fordampet. Rensning med flash-kromatografi (4:1 heksaner/etylacetat) ga en klar, fargeløs olje (0,18 g, 100%). A sample of 1,1-(ethylenedioxy)-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexane (0.15 g, 0.42 mmol) was treated with trace amounts of triphenylphosphine, tetrakis(triphenylphosphine)palladium( 0) and copper (l)-iodide. Iodobenzene (0.47 mL, 4.2 mmol) and piperidine (2 mL) were then added and the mixture was heated under an argon atmosphere. After 3 hours, the mixture was diluted with ethyl acetate (50 mL), washed once with dilute aqueous HCl, dried (magnesium sulfate) and evaporated. Purification by flash chromatography (4:1 hexanes/ethyl acetate) gave a clear, colorless oil (0.18 g, 100%).

<1>H NMR(400 MHz, CDCI3) 8 7,44 (m, 2H), 7,3 (m, 3H), 7,23 (d, J=2 Hz, 1H), 7,12 (dd, J=2 og 8 Hz, 1H), 6,81 (d, J=8 Hz, 1H), 4,8 (m, 1H), 4,0 (s, 4H), 3,85 (s, 3H), 2,25 (m, 2H), 2,10 (m, 2H), 1,78-2,03 (m, 10H), 1,6 (m, 2H). <1>H NMR(400 MHz, CDCl3) δ 7.44 (m, 2H), 7.3 (m, 3H), 7.23 (d, J=2 Hz, 1H), 7.12 (dd, J=2 and 8 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 4.8 (m, 1H), 4.0 (s, 4H), 3.85 (s, 3H) , 2.25 (m, 2H), 2.10 (m, 2H), 1.78-2.03 (m, 10H), 1.6 (m, 2H).

Eksempel 3Example 3

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(fenyletynyl)cykloheksan-1 - on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(phenylethynyl)cyclohexan-1-one

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(fenyletynyl)cykloheksan-l-on (0,18 g, 0,42 mmol) oppløst i 4:1 aceton/vann (5 ml) ble det tilsatt pyridin-p-toluensulfonat (5 mg). Blandingen ble oppvarmet under tilbakeløp under en argonatmosfære. Etter 6 timer ble det tilsatt vann (15 ml) og blandingen ble ekstrahert tre ganger med etylacetat. De samlede, organiske ekstraktene ble tørket (magnesiumsulfat) og ble fordampet. Rensning med triturering fra eter/heksaner ga et hvitt, fast stoff (0,08 g, 49%). Sm.p. 99-100°C. To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(phenylethynyl)cyclohexan-1-one (0.18 g, 0.42 mmol) dissolved in 4:1 acetone/water (5 ml) was added pyridine-p-toluenesulfonate (5 mg). The mixture was heated under reflux under an argon atmosphere. After 6 hours, water (15 ml) was added and the mixture was extracted three times with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and evaporated. Purification by trituration from ether/hexanes gave a white solid (0.08 g, 49%). Sm.p. 99-100°C.

Eksempel 4Example 4

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-pyridyletynyl)-cykloheksan-1-on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)-cyclohexan-1-one

En blanding av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(2-pyridyletynyl)cykloheksan (0,17 g, 0,39 mmol) og pyridin-p-toluensulfonat (0,10 g, 0,39 mmol) i aceton (4 ml) og vann (1 ml) ble tilbakeløpskokt i tre dager og ble deretter fordampet. Vann ble tilsatt, blandingen ble ekstrahert tre ganger med diklormetan, ekstraktet ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 25:75 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-pyridyletynyl)cykloheksan-1-on som en voks (0,12 g, 78%). A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(2-pyridylethynyl)cyclohexane (0.17 g, 0.39 mmol) and pyridine p-toluenesulfonate (0 .10 g, 0.39 mmol) in acetone (4 mL) and water (1 mL) was refluxed for three days and then evaporated. Water was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexan-1-one as a wax (0.12 g, 78 %).

<1>H-NMR (400 MHz, CDCI3) 6 8,61 (d, J=4,8 Hz, 1H), 7,68 (dt, J=7,8, 1,8 Hz, 1H), 7,47 (d, J=7,8 Hz, 1H), 7,27 (m, 1H), 7,20 (d, J=2,3 Hz, 1H), 7,15 (dd, J=8,5, 2,4 Hz, 1H), 6,87 (d, J=8,5 Hz, 1H), 4,81 (m, 1H), 3,85 (s, 3H), 3,07 (dt, J=14,4, 5,8 Hz, 2H), 2,49 (d, J=14,8 Hz, 2H), 2,41 (m, 2H), 2,27 (dt, J=13,4, 3,9 Hz, 2H), 1,8-2,0 (m, 6H), 1,61 (m, 2H). <1>H-NMR (400 MHz, CDCl3) 6 8.61 (d, J=4.8 Hz, 1H), 7.68 (dt, J=7.8, 1.8 Hz, 1H), 7 .47 (d, J=7.8 Hz, 1H), 7.27 (m, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.15 (dd, J=8, 5, 2.4 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.81 (m, 1H), 3.85 (s, 3H), 3.07 (dt, J=14.4, 5.8 Hz, 2H), 2.49 (d, J=14.8 Hz, 2H), 2.41 (m, 2H), 2.27 (dt, J=13.4 , 3.9 Hz, 2H), 1.8-2.0 (m, 6H), 1.61 (m, 2H).

Anal. (C25H27NO3-0.65 H2O) beregnet: C, 74,84; H, 7,11; N, 3,49; funnet: C, 75,00; H, 6,83; N, 3,52. Anal. (C25H27NO3-0.65 H2O) calcd: C, 74.84; H, 7.11; N, 3.49; found: C, 75.00; H, 6.83; N, 3.52.

Eksempel 5Example 5

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(4-nitrofenyletynyl)cykloheksan Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(4-nitrophenylethynyl)cyclohexane

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-etynylcykloheksan (0,15 g, 0,42 mmol) og 4-jodnitrofenol (0,11 g, 0,42 mmol) i piperidin (2 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)-palladium(O) (0,02 g, 4%), kobber-(l)-jodid (0,005 g, 6%) og en liten krystall av trifenylfosfin. Etter oppvarming ved 80°C i 0,5 timer, ble vann og 1N saltsyre tilsatt. Blandingen ble ekstrahert tre ganger med diklormetan, ekstraktet ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 2:8 etylacetat.heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(4-nitrofenyletynyl)cykloheksan som en rød-oransje voks (0,2 g, 97%). Sm.p. 58-59°C. To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.15 g, 0.42 mmol) and 4-iodonitrophenol (0.11 g, 0, 42 mmol) in piperidine (2 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)-palladium(O) (0.02 g, 4%), copper (l)-iodide (0.005 g, 6%) and a small crystal of triphenylphosphine. After heating at 80°C for 0.5 hours, water and 1N hydrochloric acid were added. The mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(4-nitrophenylethynyl)cyclohexane as a red-orange wax (0.2 g, 97%). Sm.p. 58-59°C.

<1>H-NMR (400 MHz, CDCI3) 8 8,18 (d, J=8,7Hz, 2H), 7,58 (d, J=8,7Hz, 2H), 7,16 (d, J=2,5 Hz, 1H), 7,12 (dd, J=8,4, 2,5 Hz, 1H), 6,86 (d, J=8,4Hz, 1H), 4,80 (m, 1H), 4,01 (s, 4H), 3,85 (s, 3H), 1,8-2,3 (m, 14H), 1,6 (m, 2H). <1>H-NMR (400 MHz, CDCl3) 8 8.18 (d, J=8.7Hz, 2H), 7.58 (d, J=8.7Hz, 2H), 7.16 (d, J =2.5 Hz, 1H), 7.12 (dd, J=8.4, 2.5 Hz, 1H), 6.86 (d, J=8.4Hz, 1H), 4.80 (m, 1H), 4.01 (s, 4H), 3.85 (s, 3H), 1.8-2.3 (m, 14H), 1.6 (m, 2H).

Eksempel 6Example 6

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-aminofenyletynyl)-cykloheksan-1-on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-aminophenylethynyl)-cyclohexan-1-one

Til 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(4-nitrofenyletynyl)cykloheksan (0,19 g, 0,40 mmol) i metanol (1 ml), eddiksyre (1,2 ml) og vann (1,2 ml) under en argonatmosfære ble det tilsatt titantriklorid (0,3 g, 2 mmol). Etter omrøring i 1,5 timer ved romtemperatur ble vann (1,2 ml) og ammoniumhydroksyd (2,5 ml) tilsatt. Etter omrøring i ytterligere 1 time, ble metanol (17,5 ml), 5% natriumkarbonat (17,5 ml) og diklormetan (35 ml) tilsatt og omrøring ble fortsatt i 3 dager. Suspensjonen ble filtrert gjennom Celite<®>, ble vasket godt med diklormetan og fordampet. Vann ble tilsatt, blandingen ble ekstrahert tre ganger med diklormetan, ekstraktet ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 3:7 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-aminofenyl-etynyl)cykloheksan-1-on som en fargeløs olje (0,12 g, 73%). To 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(4-nitrophenylethynyl)cyclohexane (0.19 g, 0.40 mmol) in methanol (1 mL), acetic acid (1 .2 ml) and water (1.2 ml) under an argon atmosphere was added titanium trichloride (0.3 g, 2 mmol). After stirring for 1.5 hours at room temperature, water (1.2 ml) and ammonium hydroxide (2.5 ml) were added. After stirring for an additional 1 hour, methanol (17.5 mL), 5% sodium carbonate (17.5 mL) and dichloromethane (35 mL) were added and stirring was continued for 3 days. The suspension was filtered through Celite®, washed well with dichloromethane and evaporated. Water was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-aminophenyl-ethynyl)cyclohexan-1-one as a colorless oil (0.12 g, 73%).

<1>H-NMR (400 MHz, CDCI3) 6 7,28 (d, J=8,4 Hz, 2H), 7,24 (d, J=2,1 Hz, 1H), 7,12 (d, J=8,5 Hz, 1H), 6,85 (d, J=8,5 Hz, 1H), 6,64 (d, J=8,1 Hz, 2H), 4,80 (m, 1H), 3,85 (s, 3H), 3,05 (dt, J=14,3, 4,1 Hz, 2H), 2,45 (br d, J=14,6 Hz, 2H), 2,29 (m, 4H), 1,8-2,0 (m,6H), 1,61 (m, 2H). <1>H-NMR (400 MHz, CDCl3) 6 7.28 (d, J=8.4 Hz, 2H), 7.24 (d, J=2.1 Hz, 1H), 7.12 (d , J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.64 (d, J=8.1 Hz, 2H), 4.80 (m, 1H ), 3.85 (s, 3H), 3.05 (dt, J=14.3, 4.1 Hz, 2H), 2.45 (br d, J=14.6 Hz, 2H), 2, 29 (m, 4H), 1.8-2.0 (m, 6H), 1.61 (m, 2H).

Eksempel 7Example 7

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-acetamidofenyletynyl)-cykloheksan-1-on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-acetamidophenylethynyl)-cyclohexan-1-one

Til 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-aminofenyletynyl)-cykloheksan-1-on (0,12 g, 0,29 mmol) i diklormetan (3 ml) under en argonatmosfære ble det tilsatt pyridin (fem dråper) og eddiksyreanhydrid (0,081 ml, 0,86 mmol) og reaksjonsblandingen ble omrørt ved romtemperatur i 2 timer. Saltsyre (1N) ble tilsatt, blandingen ble ekstrahert tre ganger med diklormetan, ekstraktet ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 1:1 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-acetamidofenyletynyl)cykloheksan-1-on som et hvitt, fast stoff (0,11 g, 87%). Sm.p. 79-80°C; To 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-aminophenylethynyl)-cyclohexan-1-one (0.12 g, 0.29 mmol) in dichloromethane (3 mL) under an argon atmosphere was added pyridine (five drops) and acetic anhydride (0.081 mL, 0.86 mmol) and the reaction mixture was stirred at room temperature for 2 h. Hydrochloric acid (1N) was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 1:1 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-acetamidophenylethynyl)cyclohexan-1-one as a white solid (0.11 g, 87%). Sm.p. 79-80°C;

Anal. (C28H31NO40.5 H2O) beregnet: C, 73,98; H, 7,10; N, 3,08; funnet: C, 74,11; H, 7,24; N, 3,03. Anal. (C28H31NO40.5H2O) calcd: C, 73.98; H, 7.10; N, 3.08; found: C, 74.11; H, 7.24; N, 3.03.

Eksempel 8Example 8

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(3-nitrofenyletynyl)cykloheksan Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-nitrophenylethynyl)cyclohexane

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-etynylcykloheksan (0,14 g, 0,38 mmol) og 3-jodnitrofenol (0,10 g, 0,38 mmol) i piperidin (2 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)-palladium(O) (0,02 g, 4%), kobber-(l)-jodid (0,005 g, 6%) og en liten krystall av trifenylfosfin. Etter oppvarming ved 70°C i 0,33 timer, ble blandingen fortynnet med diklormetan, ble vasket med 1N saltsyre, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 2:8 etylacetat:heksaner, ga 1,1-(etylendioksy)-4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-nitrofenyletynyl)cykloheksan som en oransje voks (0,17 g, 94%). To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.14 g, 0.38 mmol) and 3-iodonitrophenol (0.10 g, 0, 38 mmol) in piperidine (2 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)-palladium(O) (0.02 g, 4%), copper (l)-iodide (0.005 g, 6%) and a small crystal of triphenylphosphine. After heating at 70°C for 0.33 hours, the mixture was diluted with dichloromethane, washed with 1N hydrochloric acid, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, gave 1,1-(ethylenedioxy)-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-nitrophenylethynyl)cyclohexane as an orange wax (0 .17 g, 94%).

<1>H-NMR (400MHz, CDCI3) 6 8,29 (s, 1H), 8,16 (d, J=9,0Hz, 1H), 7,75 (d, J=7,9 Hz, 1H), 7,50 (t, J=8,0 Hz, 1H), 7,26 (d, J=2Hz, 1H), 7,14 (dd, J=8,3, 2 Hz, 1H), 6,86 (d, J=8,3 Hz, 1H), 4,82 (m, 1H), 4,01 (s, 4H), 3,85 (s, 3H), 2,18 (m, 4H), 2,07 (m, 2H), 1,93 (m, 4H), 1,85 (m, 4H), 1,6 (m, 2H). <1>H-NMR (400MHz, CDCl3) 6 8.29 (s, 1H), 8.16 (d, J=9.0Hz, 1H), 7.75 (d, J=7.9 Hz, 1H ), 7.50 (t, J=8.0 Hz, 1H), 7.26 (d, J=2Hz, 1H), 7.14 (dd, J=8.3, 2 Hz, 1H), 6 .86 (d, J=8.3 Hz, 1H), 4.82 (m, 1H), 4.01 (s, 4H), 3.85 (s, 3H), 2.18 (m, 4H) , 2.07 (m, 2H), 1.93 (m, 4H), 1.85 (m, 4H), 1.6 (m, 2H).

Eksempel 9Example 9

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-aminofenyletynyl)-cykloheksan-1-on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-aminophenylethynyl)-cyclohexan-1-one

Til 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(3-nitrofenyletynyl)cykloheksan (0,17 g, 0,35 mmol) i metanol (1 ml), eddiksyre (1,2 ml) og vann (1,2 ml) under en argonatmosfære ble det tilsatt titantriklorid (0,3 g, 2 mmol). Etter omrøring i 1,5 timer ved romtemperatur, ble det tilsatt titantriklorid (0,3g, 2 mmol) og vann (1,2 ml) og blandingen ble omrørt i 0,5 timer ved romtemperatur og i 0,5 timer ved 45-50°C og deretter avkjølt til romtemperatur. Vann (1,2 ml) og ammoniumhydroksyd (2,5 ml) ble tilsatt. Etter omrøring i ytterligere 1 time, ble metanol (17,5 ml), 5% natriumkarbonat (17,5 ml) og diklormetan (35 ml) tilsatt og omrøring ble fortsatt i 2 timer. Suspensjonen ble filtrert gjennom Celite<®>, ble vasket godt med diklormetan og ekstraktet ble fordampet. Resten ble fortynnet med diklormetan, det organiske sjiktet ble vasket med 5:95 ammoniumhydroksyd:vann, ble tørket (kaliumkarbonat) og ble fordampet. Rensning med flash-kromatografi, eluering med 3:7 etylacetat.heksaner, ga en blanding av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-aminofenyletynyl)-cykloheksan-1-on og 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(3-aminofenyletynyl)cykloheksan (0,07 g). Denne blandingen og en spatel-tipp av pyridinin-p-toluensulfonat i aceton (4 ml) og vann (1 ml) ble tilbakeløpskokt i 3 dager og deretter fordampet. Vann ble tilsatt, blandingen ble ekstrahert tre ganger med diklormetan, ekstraktet ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 35:65 etylacetatheksaner ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-aminofenyl-etynyl)cykloheksan-1-on som en fargeløs olje (0,07 g, 50%). To 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-nitrophenylethynyl)cyclohexane (0.17 g, 0.35 mmol) in methanol (1 mL), acetic acid (1 .2 ml) and water (1.2 ml) under an argon atmosphere was added titanium trichloride (0.3 g, 2 mmol). After stirring for 1.5 h at room temperature, titanium trichloride (0.3 g, 2 mmol) and water (1.2 mL) were added and the mixture was stirred for 0.5 h at room temperature and for 0.5 h at 45- 50°C and then cooled to room temperature. Water (1.2 mL) and ammonium hydroxide (2.5 mL) were added. After stirring for an additional 1 hour, methanol (17.5 mL), 5% sodium carbonate (17.5 mL) and dichloromethane (35 mL) were added and stirring was continued for 2 hours. The suspension was filtered through Celite<®>, was washed well with dichloromethane and the extract was evaporated. The residue was diluted with dichloromethane, the organic layer was washed with 5:95 ammonium hydroxide:water, dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate.hexanes, gave a mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-aminophenylethynyl)-cyclohexan-1-one and 4-(3- cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-aminophenylethynyl)cyclohexane (0.07 g). This mixture and a spatula tip of pyridine p-toluenesulfonate in acetone (4 mL) and water (1 mL) were refluxed for 3 days and then evaporated. Water was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate-hexanes gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-aminophenyl-ethynyl)cyclohexan-1-one as a colorless oil (0.07 g, 50 %).

<1>H-NMR (400 MHz, CDCI3) 5 7,22 (d, J=2,2 Hz, 1H), 7,14 (m, 2H), 6,87 (m, 2H), 6,82 (d, J=2,8 Hz, 1H), 6,66 (dd, J=9,0, 2,4 Hz, 1H), 4,81 m, 1H), 3,85 (s, 3H), 3,7 (br, 2H), 3,04 (dt, J=14,3, 6,0 Hz, 2H), 2,47 (br d, J=14,6 Hz, 2H), 2,2-2,3 (m, 4H), 1,8-2,0 (m, 6H), 1,61 (m, 2H). <1>H-NMR (400 MHz, CDCl3) δ 7.22 (d, J=2.2 Hz, 1H), 7.14 (m, 2H), 6.87 (m, 2H), 6.82 (d, J=2.8 Hz, 1H), 6.66 (dd, J=9.0, 2.4 Hz, 1H), 4.81 m, 1H), 3.85 (s, 3H), 3.7 (br, 2H), 3.04 (dt, J=14.3, 6.0 Hz, 2H), 2.47 (br d, J=14.6 Hz, 2H), 2.2- 2.3 (m, 4H), 1.8-2.0 (m, 6H), 1.61 (m, 2H).

Eksempel 10Example 10

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-acetamidofenyletynyl)-cykloheksan-1-on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-acetamidophenylethynyl)-cyclohexan-1-one

Til 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-aminofenyletynyl)-cykloheksan-1-on (0,07 g, 0,18 mmol) i diklormetan (2 ml) under en argonatmosfære ble det tilsatt pyridin (tre dråper) og eddiksyreanhydrid (0,05 ml, 0,53 mmol) og reaksjonsblandingen ble omrørt ved romtemperatur i 2 timer. Saltsyre (1N) ble tilsatt, blandingen ble ekstrahert tre ganger med diklormetan, ekstraktet ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 45:55 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-acetamidofenyletynyl)cykloheksanon som et hvitt, fast stoff (0,05 g, 61%). Sm.p. 63 -640C; To 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-aminophenylethynyl)-cyclohexan-1-one (0.07 g, 0.18 mmol) in dichloromethane (2 mL) under an argon atmosphere was added pyridine (three drops) and acetic anhydride (0.05 mL, 0.53 mmol) and the reaction mixture was stirred at room temperature for 2 hours. Hydrochloric acid (1N) was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 45:55 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-acetamidophenylethynyl)cyclohexanone as a white solid (0.05 g, 61% ). Sm.p. 63 - 640C;

Anal. (C28H31N04-1.75 H2O) beregnet: C, 70,49; H, 7,29; N, 2,94; funnet: C, 70,09; H, 6,94; N, 2,83. Anal. (C28H31N04-1.75 H2O) calcd: C, 70.49; H, 7.29; N, 2.94; found: C, 70.09; H, 6.94; N, 2.83.

Eksempel 11Example 11

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(3-karbometoksyfenyletynyl)cykloheksan Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-carbomethoxyphenylethynyl)cyclohexane

En blanding av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-etynylcykloheksan (0,150 g, 0,421 mmol) og metyl-3-jodbenzoat (0,110 g, 0,421 mmol) i piperidin (2,1 ml, tørr) under en argonatmosfære ble behandlet med en blanding av tetrakis(trifenylfosfin)palladium(0) (0,020 g, 0,017 mmol), kobber-(l)- jodid (0,010 g, 0,053 mmol) og trifenylfosfin (krystall) og blandingen ble oppvarmet ved 80°C i 40 minutter. Reaksjonsblandingen ble avkjølt til 0°C, ble helt ned på is-vann, ble surgjort med 3N saltsyre og ble ekstrahert fem ganger med metylenklorid. Den organiske fasen ble vasket med fortynnet saltsyre, vann, mettet saltløsning, ble tørket over magnesiumsulfat, ble filtrert og konsentrert/vakuum. Resten ble pre-adsorbert og kromatografert på silikagel, eluert med 15 til 20% etylacetat i heksaner, og man fikk en svakt gul olje (0,20 g, 97%). A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.150 g, 0.421 mmol) and methyl 3-iodobenzoate (0.110 g, 0.421 mmol) in piperidine (2 .1 mL, dry) under an argon atmosphere was treated with a mixture of tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol), copper (l)-iodide (0.010 g, 0.053 mmol) and triphenylphosphine (cryst.) and the mixture was heated at 80°C for 40 minutes. The reaction mixture was cooled to 0°C, poured onto ice-water, acidified with 3N hydrochloric acid and extracted five times with methylene chloride. The organic phase was washed with dilute hydrochloric acid, water, brine, dried over magnesium sulfate, filtered and concentrated/vacuum. The residue was pre-adsorbed and chromatographed on silica gel, eluting with 15 to 20% ethyl acetate in hexanes, to give a pale yellow oil (0.20 g, 97%).

<1>H-NMR (250 MHz, CDCI3) 6 8,11 (t, J=1,4Hz, 1H), 7,97 (d-d, J=1,3 Hz;J=7,9 Hz, 1H), 7,63 (d-d, J=7,8 Hz;J=1,3 Hz, 1H), 7,39 (t, J=7,8 Hz, 1H), 7,23 (d, J=2,2, 1H), 7,15 (d-d, J=8,4 Hz;J=2,3Hz, 1H), 6,89 (d, J=8,4Hz,1H), 4,80 (m, 1H), 4,00 (s, br, 4 H), 3,92 (s, 3H), 3,84 (s, 3H), 2,4 til 1,75 (m, 18H). <1>H-NMR (250 MHz, CDCl3) 6 8.11 (t, J=1.4Hz, 1H), 7.97 (d-d, J=1.3 Hz; J=7.9 Hz, 1H) , 7.63 (d-d, J=7.8 Hz;J=1.3 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.23 (d, J=2, 2, 1H), 7.15 (d-d, J=8.4 Hz;J=2.3Hz, 1H), 6.89 (d, J=8.4Hz,1H), 4.80 (m, 1H) , 4.00 (s, br, 4H), 3.92 (s, 3H), 3.84 (s, 3H), 2.4 to 1.75 (m, 18H).

Eksempel 12Example 12

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-karbometoksyfenyl-etynyl)cykloheksan-1 -on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-carbomethoxyphenyl-ethynyl)cyclohexan-1-one

En løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(3-karbometoksyfenyletynyl)cykloheksan (0,060 g, 0,12 mmol) i tetrahydrofuran (5 ml) som inneholdt 3N saltsyre (0,60 ml) under en argonatmosfære ble oppvarmet ved 55-60 °C i 2 timer. Den avkjølte reaksjonsblandingen ble fordelt mellom iskald, fortynnet, vandig natriumkarbonatløsning og etylacetat. Den organiske fasen ble vasket med vann, mettet saltløsning, ble tørket over natriumsulfat.og ble konsentrert /' vakuum. Resten ble kromatografert (silikagel), eluert med 15% etylacetat/heksaner, og man fikk en harpiks (0,052 g, 95%). A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-carbomethoxyphenylethynyl)cyclohexane (0.060 g, 0.12 mmol) in tetrahydrofuran (5 mL) containing 3N hydrochloric acid (0.60 mL) under an argon atmosphere was heated at 55-60 °C for 2 h. The cooled reaction mixture was partitioned between ice-cold dilute aqueous sodium carbonate solution and ethyl acetate. The organic phase was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo. The residue was chromatographed (silica gel), eluted with 15% ethyl acetate/hexanes, and a resin was obtained (0.052 g, 95%).

Anal. (C28H30O5-1/4 H2O) beregnet: C 74,56, H 6,82, funnet: C 74,43, H 6,80. Anal. (C28H30O5-1/4 H2O) calcd: C 74.56, H 6.82, found: C 74.43, H 6.80.

<1>H-NMR (400 MHz, CDCI3) 6 8,15 (s , 1H), 8,00 (d-d, J=1,5 Hz;J=6,6 Hz, 1H), 7,65 (d-d, J=1,3 Hz, J=7,7 Hz, 1H), 7,43 (t, J=7,7 Hz, 1H), 7,21 (d, J=2,1, 1H), 7,12 (d-d, J=2,0 Hz, J=8,5Hz, 1H), 6,87 (d, J=8,5 Hz,1H), 4,81 (m, 1H), 3,94 (s, 3 H), 3,86 (s, 3H), 3,04 (d-t, J=6,0Hz, J=14,2, 2H), 2,50 (d,br, J=14,8, 2H), 2,4-2,2 (m,4H), 2,0-1,5 (m). <1>H-NMR (400 MHz, CDCl3) 6 8.15 (s , 1H), 8.00 (d-d, J=1.5 Hz; J=6.6 Hz, 1H), 7.65 (d-d , J=1.3 Hz, J=7.7 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.21 (d, J=2.1, 1H), 7 .12 (d-d, J=2.0 Hz, J=8.5Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.81 (m, 1H), 3.94 ( s, 3H), 3.86 (s, 3H), 3.04 (d-t, J=6.0Hz, J=14.2, 2H), 2.50 (d,br, J=14.8, 2H), 2.4-2.2 (m, 4H), 2.0-1.5 (m).

Eksempel 13Example 13

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(3-karboksyfenyletynyl)cykloheksan Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-carboxyphenylethynyl)cyclohexane

En løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(3-karbometoksyfenyletynyl)cykloheksan (0,12 g, 0,245 mmol) i metanol (5 ml) ble behandlet med 10% vandig natriumhydroksyd (0,3 ml, 0,734 mmol) under en argonatmosfære og ble oppvarmet ved 55-60°C i 2,5 timer. Den avkjølte reaksjonsblandingen ble konsentrert i en argonstrøm og resten ble fordelt mellom kaldt vann surgjort med fortynnet saltsyre og metylenklorid. Den vandige fasen ble ekstrahert ytterligere to ganger med metylenklorid og den samlede, organiske fasen ble tørket over magnesiumsulfat, og man fikk sluttproduktet som en olje (0,11 g, 94%). A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-carbomethoxyphenylethynyl)cyclohexane (0.12 g, 0.245 mmol) in methanol (5 mL) was treated with 10 % aqueous sodium hydroxide (0.3 mL, 0.734 mmol) under an argon atmosphere and was heated at 55-60°C for 2.5 hours. The cooled reaction mixture was concentrated in a stream of argon and the residue was partitioned between cold water acidified with dilute hydrochloric acid and methylene chloride. The aqueous phase was extracted twice more with methylene chloride and the combined organic phase was dried over magnesium sulfate to give the final product as an oil (0.11 g, 94%).

<1>H-NMR (400 MHz, CDCI3) 8 8,18 (s, 1H), 8,02 (d, J=7,9 Hz, 1H), 7,68 (d, J=7,8 Hz,1H), 7,42 (t, J=7,8 Hz, 1H), 7,23 (d, J=2,2, 1H), 7,14 (d-d, J=8,4Hz;J=2,3 Hz, 1H), 6,85 (d, J=8,4 Hz,1H), 4,82 (p, 1H), 4,01 (t, 4,2 H), 3,85 (s, 3,2H), 2,4 til 1,5 (m, 17H). <1>H-NMR (400 MHz, CDCl3) 8 8.18 (s, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.68 (d, J=7.8 Hz ,1H), 7.42 (t, J=7.8 Hz, 1H), 7.23 (d, J=2.2, 1H), 7.14 (d-d, J=8.4Hz; J=2 ,3 Hz, 1H), 6.85 (d, J=8.4 Hz,1H), 4.82 (p, 1H), 4.01 (t, 4.2 H), 3.85 (s, 3.2H), 2.4 to 1.5 (m, 17H).

Eksempel 14Example 14

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-karboksyfenyl-etynyl)cykloheksan-1 -on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-carboxyphenyl-ethynyl)cyclohexan-1-one

En løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(3-karboksyfenyletynyl)cykloheksan (0,11 g, 0,23 mmol) i tetrahydrofuran (6 ml) som inneholdt 3N saltsyre (0,7 ml) ble oppvarmet under en argonatmosfære ved 55-70°C i 2 timer. Den avkjølte reaksjonsblandingen ble konsentrert /' vakuum og resten ble fordelt mellom kaldt vann og metylenklorid. Den organiske fasen ble vasket med mettet saltløsning, ble tørket over magnesiumsulfat og ble fordampet. Resten ble kromatografert (silika), eluert med metylenklorid/metanol/vann (90/5/0,25 til 90/10/0,5) og ble konsentrert /' vakuum. Resten ble oppløst i metanol og ble skummet /' vakuum, og man fikk hvite glassbiter (0,082 g, 81% utbytte). Anal. (C27H2805-1/4 H20-1/4 CH3OH) beregnet: C 73,55, H 6,68, funnet: C 73,51, H 6,66. A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-carboxyphenylethynyl)cyclohexane (0.11 g, 0.23 mmol) in tetrahydrofuran (6 mL) containing 3N hydrochloric acid (0.7 mL) was heated under an argon atmosphere at 55-70°C for 2 hours. The cooled reaction mixture was concentrated in vacuo and the residue partitioned between cold water and methylene chloride. The organic phase was washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed (silica), eluted with methylene chloride/methanol/water (90/5/0.25 to 90/10/0.5) and concentrated in vacuo. The residue was dissolved in methanol and skimmed /' vacuum, and white glass pieces were obtained (0.082 g, 81% yield). Anal. (C27H2805-1/4 H20-1/4 CH3OH) calcd: C 73.55, H 6.68, found: C 73.51, H 6.66.

<1>H-NMR (400 MHz, CDCI3) 5 8,22 (t, J=1,5Hz, 1H), 8,09 (d-d, J=1,3 Hz;J=7,9 Hz, 1H), 7,72 (d-d, J=1,3Hz, J=7,8Hz, 1H), 7,47 (t, J=7,8 Hz, 1H), 7,22 (d, J=2,2, 1H), 7,13 (d-d, J=2,3 Hz, J=8,4Hz, 1H), 6,88 (d, J=8,5Hz,1H), 4,82 (p, 1H), 3,86 (s, 3H), 3,25 (d, J=20 Hz, CH3OH, 0.55H), 3,04 (d-t, J=5,8 Hz, J=14,5, 1,7H), 2,50 (d.br, J=14,8, 1.8H), 2,4-2,2 (m, 4 H), 2,0-1,5 (m). <1>H-NMR (400 MHz, CDCl3) δ 8.22 (t, J=1.5Hz, 1H), 8.09 (d-d, J=1.3 Hz; J=7.9 Hz, 1H) , 7.72 (d-d, J=1.3Hz, J=7.8Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.22 (d, J=2.2, 1H), 7.13 (d-d, J=2.3 Hz, J=8.4Hz, 1H), 6.88 (d, J=8.5Hz, 1H), 4.82 (p, 1H), 3 .86 (s, 3H), 3.25 (d, J=20 Hz, CH3OH, 0.55H), 3.04 (d-t, J=5.8 Hz, J=14.5, 1.7H), 2 .50 (d.br, J=14.8, 1.8H), 2.4-2.2 (m, 4H), 2.0-1.5 (m).

Eksempel 15 Example 15

4-(3-Cyklopentyloksy-4-metoksyfenyl)-4-(4-pyridyletynyl)cykloheksan-1-on 15a) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-pyridyletynyl)-1,1 - (etylendioksy)-cykloheksan 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-1-one 15a) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)-1,1 - (ethylenedioxy)cyclohexane

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynyl-1,1-(etylendioksy)cykloheksan (0,10 g, 0,28 mmol) og 4-brompyridin (0,54 g, 2,8 mmol) i piperidin (1,5 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)palladium(O) (0,013 g, 4%), kobber-(l)-jodid (0,004 g, 6%) og en liten krystall av trifenylfosfin, og blandingen ble oppvarmet ved 80-85°C i 0,5 timer. Vann ble tilsatt, blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 35:65 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-pyridyletynyl)-1,1- (etylendioksy)cykloheksan som en svakt gul olje (0,11 g, 93%).<1>H-NMR (400 MHz, CDCI3) 5 8,56 (d, J=5,3Hz, 2H), 7,33 (d, J=5,3 Hz, 2H), 7,16 (d, J=2,2 Hz, 1H), 7,09 (dd, J=8,5, 2,2 Hz, 1H), 6,85 (d, J=8,5Hz, 1H), 4,80 (m, 1H), 4,00 (m, 4H), 3,85 (s, 3H), 2,0 - 2,2 (m, 6 H), 1,8 - 2,0 (m, 8H), 1,59 (m, 2H). To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-1,1-(ethylenedioxy)cyclohexane (0.10 g, 0.28 mmol) and 4-bromopyridine (0.54 g, 2 .8 mmol) in piperidine (1.5 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(O) (0.013 g, 4%), copper (l)-iodide (0.004 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80-85°C for 0.5 hours. Water was added, the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)-1,1-(ethylenedioxy)cyclohexane as a pale yellow oil ( 0.11 g, 93%).<1>H-NMR (400 MHz, CDCl3) δ 8.56 (d, J=5.3Hz, 2H), 7.33 (d, J=5.3 Hz, 2H), 7.16 (d, J=2.2 Hz, 1H), 7.09 (dd, J=8.5, 2.2 Hz, 1H), 6.85 (d, J=8.5Hz , 1H), 4.80 (m, 1H), 4.00 (m, 4H), 3.85 (s, 3H), 2.0 - 2.2 (m, 6H), 1.8 - 2 .0 (m, 8H), 1.59 (m, 2H).

15b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-pyridyletynyl)cykloheksan-1 -on 15b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-1-one

En blanding av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-pyridyletynyl)-1,1-(etylendioksy)cykloheksan (0,10 g, 0,24 mmol) og pyridin-p-toluensulfonat (0,06g, 0,24 mmol) i aceton (4ml_) og vann (1 ml) ble tilbakeløpskokt i 20 timer og deretter fordampet. Vann ble tilsatt, blandingen ble ekstrahert tre ganger med A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)-1,1-(ethylenedioxy)cyclohexane (0.10 g, 0.24 mmol) and pyridine p-toluenesulfonate (0 .06g, 0.24mmol) in acetone (4ml) and water (1ml) was refluxed for 20h and then evaporated. Water was added, the mixture was extracted three times with

diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 35:65 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-pyridyletynyl)cykloheksan-1-on (0,08 g, 91%) som et hvitt, fast stoff, Sm.p. 148-149<0>C. dichloromethane, was dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-1-one (0.08 g, 91%) as a white solid, Sm.p. 148-149<0>C.

Anal. (C25H27NO3-0,5 H2O) beregnet: C, 75,29; H, 7,08; N, 3,51; funnet: C, 75,51; H,6,95; N, 3,42. Anal. (C 25 H 27 NO 3 -0.5 H 2 O) calcd: C, 75.29; H, 7.08; N, 3.51; found: C, 75.51; H, 6.95; N, 3.42.

Eksempel 16 Example 16

4-(3-Cyklopentyloksy-4-metoksyfenyl)-4-(3-pyridyletynyl)cykloheksan-1-on4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(3-pyridylethynyl)cyclohexan-1-one

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcyklo-heksan-1-on (0,22 g, 0,70 mmol) og 3-brompyridin (0,70 ml, 7,0 mmol) i piperidin (2 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)palladium(0) To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.22 g, 0.70 mmol) and 3-bromopyridine (0.70 mL, 7.0 mmol) ) in piperidine (2 ml) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(0)

(0,034 g, 4%), kobber-(l)-jodid (0,009 g, 6%) og en liten krystall av trifenylfosfin og blandingen ble oppvarmet ved 80-85°C i 0,5 timer. Ammoniumklorid ble tilsatt, blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 35:65 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-pyridyletynyl)cykloheksan-1-on som et gråhvitt, fast stoff (0,22 g, 80%). Produktet ble ytterligere triturert fra eter-heksaner, Sm.p. 88-89°C. (0.034 g, 4%), copper (1)-iodide (0.009 g, 6%) and a small crystal of triphenylphosphine and the mixture was heated at 80-85°C for 0.5 hours. Ammonium chloride was added, the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-1-one as an off-white solid (0.22 g, 80%). The product was further triturated from ether-hexanes, m.p. 88-89°C.

Anal. (C25H27NO3-0.375 H2O) beregnet: C, 75,78; H, 7,03; N, 3,53; funnet: C, 75,77; H, 6,89; N, 3,40. Anal. (C25H27NO3-0.375 H2O) calcd: C, 75.78; H, 7.03; N, 3.53; found: C, 75.77; H, 6.89; N, 3.40.

Eksempel 17 Example 17

4-(2-Karbometoksytien-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on 4-(2-Carbomethoxythien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one

17a) 2-brom-5-karboksymetyltiofen17a) 2-bromo-5-carboxymethylthiophene

2-Brom-5-karboksymetyltiofen ble fremstilt etter standard metode som er velkjent for fagmannen på området og var et hvitt, fast stoff, Sm.p. 59-60°C. 2-Bromo-5-carboxymethylthiophene was prepared by standard methods well known to those skilled in the art and was a white solid, mp. 59-60°C.

17b) 4-(2-karbometoksytien-5-ylefynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on 17b) 4-(2-carbomethoxythien-5-ylphenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcyklo-heksan-1-on (0,21 g, 0,7 mmol) og 2-brom-5-karboksymetyltiofen (0,18 g, 1,2 mmol) i trietylamin (2 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)palladium(O) (0,031 g, 4%) og kobber-(l)-jodid (0,008 g, 6%) og blandingen ble oppvarmet ved 80-85°C i 4,5 timer. Ammoniumklorid ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 2:8 etylacetat:heksaner, ga 4-(2-karbometoksytien-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on som en gul olje (0,25 g, 82%). To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.21 g, 0.7 mmol) and 2-bromo-5-carboxymethylthiophene (0.18 g, 1.2 mmol) in triethylamine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(O) (0.031 g, 4%) and copper-(1)-iodide (0.008 g, 6%) and the mixture was heated at 80-85°C for 4.5 hours. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, gave 4-(2-carbomethoxythien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one as a yellow oil (0 .25 g, 82%).

<1>H-NMR (400 MHz, CDCI3) 5 7,67 (d, J=4,0Hz, 1 H), 7,16 (d, J=4,0 Hz, 1 H), 7,15 (d, J=2,2Hz, 1 H), 7,07 ( dd, J=8,4, 2,2 Hz, 1H), 6,87 (d, J=8,4 Hz, 1 H), 4,80 (m, 1 H), 3,89 (s, 3 H), 3,85 (s, 3 H), 2,95 (dt, J=14,5, 5,9 Hz, 2 H), 2,49 (brd, J=14,5 Hz, 2 H), 2,36 (m, 2 H), 2,26 ( dt, J=13,4, 4,0 Hz, 2 H), 1,8 - 2,0 (m, 6 H), 1,6 (m, 2H) ppm. <1>H-NMR (400 MHz, CDCl3) δ 7.67 (d, J=4.0Hz, 1 H), 7.16 (d, J=4.0 Hz, 1 H), 7.15 ( d, J=2.2Hz, 1H), 7.07 ( dd, J=8.4, 2.2Hz, 1H), 6.87 (d, J=8.4Hz, 1H), 4 .80 (m, 1 H), 3.89 (s, 3 H), 3.85 (s, 3 H), 2.95 (dt, J=14.5, 5.9 Hz, 2 H), 2.49 (brd, J=14.5 Hz, 2 H), 2.36 (m, 2 H), 2.26 ( dt, J=13.4, 4.0 Hz, 2 H), 1, 8 - 2.0 (m, 6H), 1.6 (m, 2H) ppm.

Anal. (C26H28O5S 0.25 H2O) beregnet: C, 68,32; H, 6,28; funnet: C, 68,25; H, 6,12. Anal. (C26H28O5S 0.25 H2O) calcd: C, 68.32; H, 6.28; found: C, 68.25; H, 6.12.

Eksempel 18 Example 18

4-(2-Karboksytien-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on, natriumsalt 4-(2-Carboxythien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one, sodium salt

En løsning av 4-(2-karbometoksytien-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on (0,13 g, 0,30 mmol) og grovmalt kaliumhydroksyd (0,025 g, 0,45 mmol) i tetrahydrofuran (5mL), metanol (5mL) og vann (2mL) ble omrørt ved romtemperatur under en argonatmosfære i 24 timer. Reaksjonsblandingen ble surgjort (10% HCI), ble ekstrahert tre ganger med 5:95 metanol:diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Råproduktet ble behandlet med 10% natriumhydroksyd for å danne saltet. Omvendt fase-kromatografi, eluering med 1:1 metanol:vann, ga 4-(2-karboksytien-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on, natrium salt, ga et hvitt, fast stoff (0,070 g, 55%), Sm.p. 194-195°C. A solution of 4-(2-carbomethoxythien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.13 g, 0.30 mmol) and coarse potassium hydroxide (0.025 g, 0 .45 mmol) in tetrahydrofuran (5mL), methanol (5mL) and water (2mL) was stirred at room temperature under an argon atmosphere for 24 hours. The reaction mixture was acidified (10% HCl), extracted three times with 5:95 methanol:dichloromethane, dried (magnesium sulfate) and evaporated. The crude product was treated with 10% sodium hydroxide to form the salt. Reverse phase chromatography, eluting with 1:1 methanol:water, gave 4-(2-carboxythien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one, sodium salt, gave a white , solid (0.070 g, 55%), m.p. 194-195°C.

Anal. (C25H2505SNa-1,25 H2O) beregnet: C, 62,16; H, 5,74; funnet: C, 61,90; H, 5,49. Anal. (C 25 H 25 O 5 SNa-1.25 H 2 O) calcd: C, 62.16; H, 5.74; found: C, 61.90; H, 5.49.

Eksempel 19 Example 19

4-(2-Cyanotien-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on 19a) 2-brom-5-cyanotiofen 4-(2-Cyanothien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one 19a) 2-bromo-5-cyanothiophene

2-Brom-5-cyanotiofen ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var en fargeløs olje, 2-Bromo-5-cyanothiophene was prepared by conventional methods well known to those skilled in the art and was a colorless oil,

<1>H-NMR (400 MHz, CDCI3): 5 7,40 (d, J=4Hz, 1 H), 7,10 (d, J=4 Hz, 1H) ppm. <1>H-NMR (400 MHz, CDCl 3 ): δ 7.40 (d, J=4Hz, 1H), 7.10 (d, J=4Hz, 1H) ppm.

19b) 4-(2-cyanotien-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on 19b) 4-(2-cyanothien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynyl-cykloheksan-1-on (0,22 g, 0,7 mmol) og 2-brom-5-cyanotiofen (0,13 g, 0,7 mmol) i trietylamin (5 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)palladium(O) (0,034 g, 4%) og kobber-(l)-jodid (0,007 g, 6%) og blandingen ble oppvarmet ved 85-90°C i 2 timer. Ammoniumklorid ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 2:8 etylacetat:heksaner, ga 4-(2-cyanotien-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on (0,06 g, 18%). Dette ble slått sammen med produktet (0,017g) oppnådd i en annen, lignende omsetning og ble triturert fra diklormetan-heksaner, og man fikk et hvitt, fast stoff, Sm.p. 106-107°C. To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-one (0.22 g, 0.7 mmol) and 2-bromo-5-cyanothiophene (0.13 g, 0.7 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(O) (0.034 g, 4%) and copper-(1)-iodide (0.007 g, 6%) and the mixture was heated at 85-90°C for 2 hours. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, gave 4-(2-cyanothien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.06 g, 18%). This was combined with the product (0.017g) obtained in another similar reaction and triturated from dichloromethane-hexanes to give a white solid, m.p. 106-107°C.

Anal. (C25H25NO3S 0.5 H2O) beregnet: C, 70,07; H, 6,11; N, 3,27; funnet: C, 70,15; H, 5,84; N, 3,32. Anal. (C25H25NO3S 0.5 H2O) calcd: C, 70.07; H, 6.11; N, 3.27; found: C, 70.15; H, 5.84; N, 3.32.

Eksempel 20 Example 20

4-(3-Cyklopentyloksy-4-metoksyfenyl)-4-[5-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-2-yletynyl]cykloheksan-1 -on 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-one

20a) 2-brom-5-(5-metyl-[1,2,4]oksadiazol-2-yl)tiofen 20a) 2-bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene

2-Brom-5-(5-metyl-[1,2,4]oksadiazol-2-yl)tiofen ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var et hvitt, fast stoff, Sm.p. 48-49°C. 2-Bromo-5-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene was prepared by conventional methods well known to those skilled in the art and was a white solid, m.p. 48-49°C.

20b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[5-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-2-yletynyl]cykloheksan-1-on 20b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-one

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynyl-cykloheksan-1-on (0,17 g, 0,88 mmol) og 2-brom-5-(5-metyl-[1,2,4]oksadiazol-2-yl)tiofen (0,18 g, 1,2 mmol) i trietylamin (5 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)palladium(0) (0,037 g, 4%) og kobber-(l)-jodid (0,010 g, 6%) og blandingen ble oppvarmet ved 85-90°C i 2 timer. Ammoniumklorid ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 25:75 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[5-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-2-yletynyl]cykloheksan-1-on som en hvit voks (0,17 g, 45%), Sm.p. 94-95°C. To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-one (0.17 g, 0.88 mmol) and 2-bromo-5-(5-methyl-[1 ,2,4]oxadiazol-2-yl)thiophene (0.18 g, 1.2 mmol) in triethylamine (5 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(0) (0.037 g, 4%) and copper-(1)-iodide (0.010 g, 6%) and the mixture was heated at 85-90°C for 2 hours. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl )thien-2-ylethynyl]cyclohexan-1-one as a white wax (0.17 g, 45%), m.p. 94-95°C.

Anal. (C27H28N2O4S) beregnet: C, 68,04; H, 5,92; N, 5,88; funnet: C, 67,83; H, 5,89; N, 5,92. Anal. (C27H28N2O4S) calcd: C, 68.04; H, 5.92; N, 5.88; found: C, 67.83; H, 5.89; N, 5.92.

Eksempel 21 Example 21

4-(2-Karbometoksytien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on 4-(2-Carbomethoxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

21a) 4-brom-2-karboksymetyltiofen21a) 4-bromo-2-carboxymethylthiophene

4-Brom-2-karboksymetyltiofen ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var en brun olje. 4-Bromo-2-carboxymethylthiophene was prepared by conventional methods well known to those skilled in the art and was a brown oil.

<1>H-NMR (400 MHz, CDCI3) 5 7,69 (d, J=1,5Hz, 1 H), 7,45 (d, J=1,5 Hz, 1 H), 3,90 (s, 3 H) ppm. <1>H-NMR (400 MHz, CDCl3) δ 7.69 (d, J=1.5Hz, 1 H), 7.45 (d, J=1.5 Hz, 1 H), 3.90 ( s, 3 H) ppm.

21b) 4-(2-karbometoksytien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on. 21b) 4-(2-carbomethoxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one.

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcyklo-heksan-1-on (0,25 g, 0,8 mmol) og 4-brom-2-karboksymetyltiofen (0,27 g, 1,2 mmol) i trietylamin (3,5 ml) under en argonatmosfære ble det tilsatt tetrakis-(trifenylfosfin)palladium(O) (0,038 g, 4%) og kobber-(l)-jodid (0,010 g, 6%) og blandingen ble oppvarmet ved 80-85°C i 0,5 timer. Ammoniumklorid ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 2:8 etylacetat:heksaner, ga 4-(2-karbometoksytien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on som et gult glass (0,15 g, 42%). To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.25 g, 0.8 mmol) and 4-bromo-2-carboxymethylthiophene (0.27 g, 1.2 mmol) in triethylamine (3.5 mL) under an argon atmosphere were added tetrakis-(triphenylphosphine)palladium(O) (0.038 g, 4%) and copper (l)-iodide (0.010 g, 6%) and the mixture was heated at 80-85°C for 0.5 hours. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, gave 4-(2-carbomethoxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one as a yellow glass (0 .15 g, 42%).

<1>H-NMR (400 MHz, CDCI3) 6 7,81 (d, J=1,3 Hz, 1 H), 7,60 (d, J=1,3 Hz, 1 H), 7,16 (d, J=2,2 Hz, 1H), 7,10 (dd, J=8,5, 2,2 Hz, 1 H), 6,86 (d, J=8,5 Hz, 1 H), 4,80 (m, 1 H), 3,90 (s, 3 H), 3,84 (s, 3 H), 2,98 (dt, J=14,8, 5,7 Hz, 2 H), 2,48 (br d, J=14,8 Hz, 2 H), 3,33 (m, 2 H), 2,26 (dt, J=13,6, 4 Hz, 2 H), 1,9 - 2,0 (m, 6 H), 1,6 (m, 2 H) ppm. <1>H-NMR (400 MHz, CDCl3) 6 7.81 (d, J=1.3 Hz, 1 H), 7.60 (d, J=1.3 Hz, 1 H), 7.16 (d, J=2.2 Hz, 1H), 7.10 (dd, J=8.5, 2.2 Hz, 1 H), 6.86 (d, J=8.5 Hz, 1 H) , 4.80 (m, 1 H), 3.90 (s, 3 H), 3.84 (s, 3 H), 2.98 (dt, J=14.8, 5.7 Hz, 2 H ), 2.48 (br d, J=14.8 Hz, 2 H), 3.33 (m, 2 H), 2.26 (dt, J=13.6, 4 Hz, 2 H), 1 .9 - 2.0 (m, 6H), 1.6 (m, 2H) ppm.

Anal. (C26H28O5S) beregnet: C, 69,00; H, 6,24; funnet: C, 68,82; H, 6,04. Anal. (C26H28O5S) calcd: C, 69.00; H, 6.24; found: C, 68.82; H, 6.04.

Eksempel 22 Example 22

4-(2-Karboksytien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on 4-(2-Carboxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

En løsning av 4-(2-karbometoksytien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on (0,19 g, 0,43 mmol) og grovmalt kaliumhydroksyd (0,036 g, 0,64 mmol) i tetrahydrofuran (2mL), metanol (2mL) og vann (0,4mL) ble omrørt ved romtemperatur under en argonatmosfære i 24 timer. Reaksjonsblandingen ble surgjort (10% HCI), ble ekstrahert tre ganger med 5:95 metanokdiklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 0,1: 3:97 eddiksyre:metanol:diklormetan, ga 4-(2-karboksytien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on som et gråhvitt, fast stoff (0,18 g, 95%), Sm.p. 80-82°C. A solution of 4-(2-carbomethoxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.19 g, 0.43 mmol) and coarse potassium hydroxide (0.036 g, 0 .64 mmol) in tetrahydrofuran (2mL), methanol (2mL) and water (0.4mL) was stirred at room temperature under an argon atmosphere for 24 hours. The reaction mixture was acidified (10% HCl), extracted three times with 5:95 methanolic dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 0.1:3:97 acetic acid:methanol:dichloromethane, gave 4-(2-carboxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one as an off-white solid (0.18 g, 95%), m.p. 80-82°C.

Anal. (C25H26O5S-0.25 H2O) beregnet: C, 67,78; H, 6,03; funnet: C, 67,72; H, 6,02. Anal. (C25H26O5S-0.25 H2O) calcd: C, 67.78; H, 6.03; found: C, 67.72; H, 6.02.

Eksempel 23 Example 23

4-(2-Cyanotien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on 23a) 4-brom-2-cyanotiofen 4-(2-Cyanothien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one 23a) 4-bromo-2-cyanothiophene

4-Brom-2-cyanotiofen ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var et lyserødt, fast stoff, Sm.p. 43-44°C. 4-Bromo-2-cyanothiophene was prepared by conventional methods well known to those skilled in the art and was a pale pink solid, mp. 43-44°C.

23b) 4-(2-cyanotien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on. 23b) 4-(2-cyanothien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one.

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcyklo-heksan-1-on (0,25 g, 0,8 mmol) og 4-brom-2-cyanotiofen (0,15 g, 0,8 mmol) i trietylamin (5 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)palladium(O) (0,038 g, 4%) og kobber-(l)-jodid (0,008 g, 6%) og blandingen ble oppvarmet ved 85-90°C i 24 timer. Vann ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 2:8 etylacetat:heksaner, ga 4-(2-cyanotien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on som ble ytterligere triturert fra diklormetan-heksaner som et hvitt, fast stoff (0,08 g, 24%), Sm.p. 112-113°C. To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.25 g, 0.8 mmol) and 4-bromo-2-cyanothiophene (0.15 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(O) (0.038 g, 4%) and copper-(1)-iodide (0.008 g, 6%) and the mixture was heated at 85-90°C for 24 hours. Water was added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, gave 4-(2-cyanothien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one which was further triturated from dichloromethane -hexanes as a white solid (0.08 g, 24%), m.p. 112-113°C.

Anal. (C25H25NO3S 0.375 H2O) beregnet: C, 70,44; H, 6,09; N, 3,29; funnet: C, 70,38; H, 5,94; N, 3,20. Anal. (C25H25NO3S 0.375 H2O) calcd: C, 70.44; H, 6.09; N, 3.29; found: C, 70.38; H, 5.94; N, 3.20.

Eksempel 24 Example 24

4-(3-Cyklopentyloksy-4-metoksyfenyl)-4-[2-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-4-yletynyl] cykloheksan-1-on 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-[2-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-4-ylethynyl]cyclohexan-1-one

24a) 4-brom-2-{5-metyl-[1,2,4]oksadiazol-2-yl)tiofen 24a) 4-bromo-2-{5-methyl-[1,2,4]oxadiazol-2-yl)thiophene

4-Brom-2-{5-metyl-[1,2,4]oksadiazol-2-yl)tiofen ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var et hvitt, fast stoff, Sm.p. 66-67°C. 4-Bromo-2-{5-methyl-[1,2,4]oxadiazol-2-yl)thiophene was prepared by conventional methods well known to those skilled in the art and was a white solid, m.p. 66-67°C.

24b) c/s-[4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[2-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-4-yletynyl]cykloheksan-1-ol] 24b) c/s-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[2-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-4-ylethynyl]cyclohexane- 1-ol]

Til en løsning av frans-[4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynyl-cykloheksan-1-ol] (0,25 g, 0,8 mmol, fremstilt som beskrevet i "co-pending" patentsøknad P50287 og således innlevert på samme dag) og 4-brom-2-(5-metyl-[1,2,4]oksadiazol-2-yl)tiofen (0,20 g, 0,8 mmol) i trietylamin (5 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)palladium(0) (0,038 g, 4%), kobber-(l)-jodid (0,009 g, 6%) og en liten krystall av trifenylfosfin og blandingen ble oppvarmet ved 70-75°C i 0,5 timer. Saltsyre (5%) ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 1:1 etylacetat: heksaner, ga c/s-[4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[2-(5-metyI-[1,2,4]oksadiazol-2-yl)tien-4-yletynyl] cykloheksan-1-ol] (0,20 g, 53%) som ble ytterligere triturert fra diklormetan-heksaner og man fikk et hvitt, fast stoff, To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-ol] (0.25 g, 0.8 mmol, prepared as described in "co-pending" patent application P50287 and thus submitted on the same day) and 4-bromo-2-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene (0.20 g, 0.8 mmol) in triethylamine (5 mL ) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(0) (0.038 g, 4%), copper (l)-iodide (0.009 g, 6%) and a small crystal of triphenylphosphine and the mixture was heated at 70- 75°C for 0.5 hours. Hydrochloric acid (5%) was added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 1:1 ethyl acetate:hexanes, gave c/s-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[2-(5-methyl-[1,2,4] oxadiazol-2-yl)thien-4-ylethynyl]cyclohexan-1-ol] (0.20 g, 53%) which was further triturated from dichloromethane-hexanes to give a white solid,

Sm.p. 142-143°C. Sm.p. 142-143°C.

Anal. (C27H30N2O4S) beregnet: C, 67,76; H, 6,32; N, 5,85; funnet: C, 67,85; H, 6,42; N, 5,54. Anal. (C27H30N2O4S) calcd: C, 67.76; H, 6.32; N, 5.85; found: C, 67.85; H, 6.42; N, 5.54.

24c) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[2-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-4-yletynyl]cykloheksan-1-on 24c) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[2-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-4-ylethynyl]cyclohexan-1-one

Til en suspensjon av pyridinklorkromat (0,04 g, 0,20 mmol) i diklormetan (1 ml) ved romtemperatur under en argonatmosfære ble det hurtig tilsatt en løsning av c/'s-[4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[2-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-4-yletynyl]cykloheksan-1-ol] (0,06 g, 0,13 mmol) i diklormetan (2 ml) og blandingen ble omrørt i 1 time. Eter (20 ml) ble tilsatt og omrøring ble fortsatt i 0,25 timer. Blandingen ble filtrert gjennom Celite<®>og ble fordampet. Rensning med flash-kromatografi, eluering med 25:75 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[2-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-4-yletynyl]cykloheksan-1-on som en fargeløs olje. Omkrystallisering fra diklormetan-heksaner ga et hvitt, fast stoff (0,033 g, 53%), Sm.p. 94-95°C. To a suspension of pyridine chlorochromate (0.04 g, 0.20 mmol) in dichloromethane (1 mL) at room temperature under an argon atmosphere was rapidly added a solution of c/'s-[4-(3-cyclopentyloxy-4-methoxyphenyl )-4-[2-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-4-ylethynyl]cyclohexan-1-ol] (0.06 g, 0.13 mmol) in dichloromethane (2 ml) and the mixture was stirred for 1 hour. Ether (20 mL) was added and stirring was continued for 0.25 h. The mixture was filtered through Celite<®> and evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[2-(5-methyl-[1,2,4]oxadiazol-2-yl )thien-4-ylethynyl]cyclohexan-1-one as a colorless oil. Recrystallization from dichloromethane-hexanes gave a white solid (0.033 g, 53%), m.p. 94-95°C.

Anal. (C27H28N2O4S-1.0 H20) beregnet: C, 65,57; H, 6,11; N, 5,66; funnet: C, 65,46; H, 5,74; N, 5,60. Anal. (C 27 H 28 N 2 O 4 S-1.0 H 2 O) calcd: C, 65.57; H, 6.11; N, 5.66; found: C, 65.46; H, 5.74; N, 5.60.

Eksempel 25 Example 25

4-(4-Karbometoksytien-2yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on 4-(4-Carbomethoxythien-2ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

25a) 2-brom-4-karboksymetyltiofen25a) 2-bromo-4-carboxymethylthiophene

2-Brom-4-karboksymetyltiofen ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var en brun olje. 2-Bromo-4-carboxymethylthiophene was prepared by conventional methods well known to those skilled in the art and was a brown oil.

<1>H-NMR (400 MHz, CDCI3) 8 7,99 (s, 1H), 7,47 (s, 1 H), 3,86 (s, 3H) ppm. <1>H-NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.47 (s, 1H), 3.86 (s, 3H) ppm.

25b) 4-(4-karbometoksytien-2-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on 25b) 4-(4-carbomethoxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynyl-cykloheksan-1-on (0,35 g, 1,12 mmol) og 2-brom-4-karboksymetyltiofen (0,25 g, 1,13 mmol) i trietylamin (5 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenyl-fosfin)palladium(0) (0,044 g, 4%), kobber-(l)-jodid (0,011 g, 6%) og en liten krystall av trifenylfosfin og blandingen ble oppvarmet ved 80-85°C i 0,5 timer. Vann og saltsyre (10%) ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 2:8 etylacetat.heksaner, ga 4-(4-karbometoksy-tien-2-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on som en gul gummi (0,29 g, 58%). To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-one (0.35 g, 1.12 mmol) and 2-bromo-4-carboxymethylthiophene (0.25 g, 1.13 mmol) in triethylamine (5 mL) under an argon atmosphere was added tetrakis(triphenyl-phosphine)palladium(0) (0.044 g, 4%), copper (l)-iodide (0.011 g, 6%) and a small crystal of triphenylphosphine and the mixture was heated at 80-85°C for 0.5 hours. Water and hydrochloric acid (10%) were added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, gave 4-(4-carbomethoxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one as a yellow gum (0.29 g, 58%).

<1>H-NMR (400 MHz, CDCI3) 8 8,00 (d, J=1,1 Hz, 1 H), 7,61 (d, J=1,1 Hz, 1 H), 7,16 (d, J=2,2 Hz, 1 H), 7,07 (dd, J=8,4, 2,2 Hz, 1 H), 6,87 (d, J=8,4 Hz, 1 H), 4,81 (m, 1 H), 3,88 (s, 3 H), 3,86 (s, 3 H), 2,97 (dt, J=14,4, 5,7 Hz, 2 H), 2,49 (br d, J=13,5 Hz, 2 H), 2,35 (m, 2 H), 2,29 (m, 2 H), 1,9 - 2,0 (m, 6 H), 1,6 (m, 2 H) ppm. Anal. (C26H28O5S) beregnet: C, 69,00; H, 6,24; funnet: C, 68,76; H, 6,46. <1>H-NMR (400 MHz, CDCl3) 8 8.00 (d, J=1.1 Hz, 1 H), 7.61 (d, J=1.1 Hz, 1 H), 7.16 (d, J=2.2 Hz, 1 H), 7.07 (dd, J=8.4, 2.2 Hz, 1 H), 6.87 (d, J=8.4 Hz, 1 H ), 4.81 (m, 1 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 2.97 (dt, J=14.4, 5.7 Hz, 2 H), 2.49 (br d, J=13.5 Hz, 2 H), 2.35 (m, 2 H), 2.29 (m, 2 H), 1.9 - 2.0 (m , 6H), 1.6 (m, 2H) ppm. Anal. (C26H28O5S) calcd: C, 69.00; H, 6.24; found: C, 68.76; H, 6.46.

Eksempel 26 Example 26

4-(4-Karboksytien-2-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on 4-(4-Carboxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

En løsning av 4-(4-karbometoksytien-2-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on (0,12 g, 0,427 mmol) og grovmalt kaliumhydroksyd (0,045 g, 0,81 mmol) i tetrahydrofuran (2,5mL), metanol (2,5mL) og vann (0,5mL) ble omrørt ved romtemperatur under en argonatmosfære i tre dager. Reaksjonsblandingen ble surgjort (10% HCI), ble ekstrahert tre ganger med 5:95 metanol.diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 0,25:2,5:97,5 eddiksyre:metanol: diklormetan, ga 4-(4-karboksytien-2-yletynyl)-4-(3-cyklopentyloksy-4-metoksy-fenyl)cykloheksan-1-on som et gråhvitt skum (0,11 g, 94%), Sm.p. 75-76°C. Anal. (C25H26O5S 0.25 htøO) beregnet: C, 67,78; H, 6,03; funnet: C, 67,73; H, 5,80. A solution of 4-(4-carbomethoxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.12 g, 0.427 mmol) and coarse potassium hydroxide (0.045 g, 0.81 mmol) in tetrahydrofuran (2.5mL), methanol (2.5mL) and water (0.5mL) was stirred at room temperature under an argon atmosphere for three days. The reaction mixture was acidified (10% HCl), extracted three times with 5:95 methanol:dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 0.25:2.5:97.5 acetic acid:methanol:dichloromethane, gave 4-(4-carboxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxy-phenyl) )cyclohexan-1-one as an off-white foam (0.11 g, 94%), m.p. 75-76°C. Anal. (C25H26O5S 0.25 htøO) calcd: C, 67.78; H, 6.03; found: C, 67.73; Height, 5.80.

Eksempel 27 Example 27

4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[4-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-2-yletynyl]cykloheksan-1 -on 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-one

27a) 2-brom-4-{5-metyl-[1,2,4]oksadiazol-2-yl)tiofen 27a) 2-bromo-4-{5-methyl-[1,2,4]oxadiazol-2-yl)thiophene

2-Brom-4-{5-metyl-[1,2,4]oksadiazol-2-yl)tiofen ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var et hvitt, fast stoff, Sm.p. 72-730C. 2-Bromo-4-{5-methyl-[1,2,4]oxadiazol-2-yl)thiophene was prepared by conventional methods well known to those skilled in the art and was a white solid, m.p. 72-730C.

27b) c/'s-[4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[4-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-2-yletynyl] cykloheksan-1 -ol] 27b) c/'s-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl] cyclohexane -1 -ol]

Til en løsning av frans-[4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynyl-cykloheksan-1-ol (0,25 g, 0,8 mmol, fremstilt som beskrevet i "co-pending" patentsøknad inngitt av de samme oppfinnerne, identifisert som P50287 og inngitt på samme dag) og 2-brom-4-{5-metyl-[1,2,4]oksadiazol-2-yl)tiofen (0,20 g, 0,8 mmol) i trietylamin (5 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)palladium(O) (0,038 g, 4%), kobber-(l)-jodid (0,009 g, 6%) og en liten krystall av trifenylfosfin og blandingen ble oppvarmet ved 70-75°C i 0,5 timer. Saltsyre To a solution of trans-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-ol (0.25 g, 0.8 mmol, prepared as described in "co-pending" patent application filed by the same inventors, identified as P50287 and submitted on the same day) and 2-bromo-4-{5-methyl-[1,2,4]oxadiazol-2-yl)thiophene (0.20 g, 0.8 mmol ) in triethylamine (5 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(O) (0.038 g, 4%), copper (l)-iodide (0.009 g, 6%) and a small crystal of triphenylphosphine and the mixture was heated at 70-75°C for 0.5 hours. Hydrochloric acid

(5%) ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 1:1 etylacetat:heksaner, ga c/s-[4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[4-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-2-yletynyl] cykloheksan-1-ol] som ble ytterligere triturert fra diklormetan-heksaner, og man fikk et hvitt, fast stoff (0,20 g, 53%), Sm.p. 142-1430C. (5%) was added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 1:1 ethyl acetate:hexanes, gave c/s-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4] oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-ol] which was further triturated from dichloromethane-hexanes to give a white solid (0.20 g, 53%), m.p. 142-1430C.

Anal. (C27H30N2O4S 0.75 H2O) beregnet: C, 65,90; H, 6,45; N, 5,69; funnet: C, 66,06; N, 6,42; N, 5,50. Anal. (C27H30N2O4S 0.75 H2O) calcd: C, 65.90; H, 6.45; N, 5.69; found: C, 66.06; N, 6.42; N, 5.50.

27c) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[4-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-2-yletynyl]cykloheksan-1-on. 27c) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-one.

Til en suspensjon av pyridinklorkromat (0,07 g, 0,31 mmol) i diklormetan (1 ml) ved romtemperatur under en argonatmosfære ble det hurtig tilsatt en oppløsning av c/'s-[4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[4-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-2-yletynyl]cykloheksan-1-ol] (0,10 g, 0,21 mmol) i diklormetan (2 ml) og omrørt 0,5 timer. Eter (20 ml) ble tilsatt og omrøring fortsatt i 0,5 timer. Blandingen ble filtrert gjennom Celite<®>og ble fordampet. Rensning med flash-kromatografi, eluering med 25:75 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[4-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-2-yletynyl]cykloheksan-1-on som et hvitt, fast stoff, Sm.p. 90-91 °C. To a suspension of pyridine chlorochromate (0.07 g, 0.31 mmol) in dichloromethane (1 mL) at room temperature under an argon atmosphere was rapidly added a solution of c/'s-[4-(3-cyclopentyloxy-4-methoxyphenyl )-4-[4-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-ol] (0.10 g, 0.21 mmol) in dichloromethane (2 ml) and stirred for 0.5 hours. Ether (20 mL) was added and stirring continued for 0.5 h. The mixture was filtered through Celite<®> and evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl-[1,2,4]oxadiazol-2-yl )thien-2-ylethynyl]cyclohexan-1-one as a white solid, m.p. 90-91 °C.

Anal. (C27H28N2O4S 0.25 H2O) beregnet: C, 67,41; H, 5,97; N, 5,82; funnet: C, 67,43; H, 5,87; N, 5,80. Anal. (C27H28N2O4S 0.25 H2O) calcd: C, 67.41; H, 5.97; N, 5.82; found: C, 67.43; H, 5.87; N, 5.80.

Eksempel 28 Example 28

4-(3-Cyklopentyloksy-4-metoksyfenyl)-4-(2-metylsulfonylpyrimidin-4-yletynyl) cykloheksan-1-on 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl)cyclohexan-1-one

28a) 4-jod-2-tiometylpyrimidin28a) 4-iodo-2-thiomethylpyrimidine

4-Jod-2-tiometylpyrimidin ble fremstilt ved å følge en fremgangsmåte i litteraturen (A.J. Majeed, 0. Antonsen, T. Benneche, K. Undheim. Tetrahedron 1989, 45, 993-1006). 4-Iodo-2-thiomethylpyrimidine was prepared by following a procedure in the literature (A.J. Majeed, 0. Antonsen, T. Benneche, K. Undheim. Tetrahedron 1989, 45, 993-1006).

28b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-metyltiopyrimidin-4-yletynyl) cykloheksan-1-on 28b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylthiopyrimidin-4-ylethynyl)cyclohexan-1-one

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynyl-cykloheksan-1-on (0,35 g, 1,12 mmol) og og 4-jod-2-tiometylpyrimidin(0,56 g, 2,4 mmol, som en blanding av 4-jod-2-tiometylpyrimidin og 4-klor-2-tiometylpyrimidin) i trietylamin (5 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)palladium(O) (0,051 g, 4%) og kobber-(l)-jodid (0,014 g, 6%) og blandingen ble oppvarmet ved 85-90°C i 0,5 timer. Ammoniumklorid ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 25:75 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-metyltiopyrimidin-4-yletynyl) cykloheksan-1-on som en gul harpiks (0,35 g, 72%).<1>H-NMR (400 MHz, CDCI3) 6 8,50 (d, J=5,3 Hz, 1 H), 7,17 (d, J=2,3 Hz, 1 H), 7,08 (dd, J=8,5, 2,3 Hz, 1 H), 7,03 (d, J=5,3 Hz, 1 H), 6,87 (d, J=8,5 Hz, 1 H), 4,81 (m, 1 H), 3,86 (s, 3 H), 2,99 (dt, J=14,7, 8,7 Hz, 2 H), 2,58 (s, 3 H), 2,46 (br d, J= 18,7 Hz, 2 H), 2,40 (m, 2 H), 2,29 (m, 2 H), 1,8 - 2,0 (m, 6 H), 1,6 (m, 2 H) ppm. To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexan-1-one (0.35 g, 1.12 mmol) and and 4-iodo-2-thiomethylpyrimidine (0.56 g , 2.4 mmol, as a mixture of 4-iodo-2-thiomethylpyrimidine and 4-chloro-2-thiomethylpyrimidine) in triethylamine (5 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(O) (0.051 g, 4%) and copper-(1)-iodide (0.014 g, 6%) and the mixture was heated at 85-90°C for 0.5 hours. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylthiopyrimidin-4-ylethynyl)cyclohexan-1-one as a yellow resin (0 .35 g, 72%).<1>H-NMR (400 MHz, CDCl3) 6 8.50 (d, J=5.3 Hz, 1 H), 7.17 (d, J=2.3 Hz , 1 H), 7.08 (dd, J=8.5, 2.3 Hz, 1 H), 7.03 (d, J=5.3 Hz, 1 H), 6.87 (d, J =8.5 Hz, 1 H), 4.81 (m, 1 H), 3.86 (s, 3 H), 2.99 (dt, J=14.7, 8.7 Hz, 2 H) , 2.58 (s, 3 H), 2.46 (br d, J= 18.7 Hz, 2 H), 2.40 (m, 2 H), 2.29 (m, 2 H), 1 .8 - 2.0 (m, 6H), 1.6 (m, 2H) ppm.

28c) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-metylsulfonylpyrimidin-4-yletynyl)cykloheksan-1-on 28c) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl)cyclohexan-1-one

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-metyltio-pyrimidin-4-yletynyl)cykloheksan-1-on (0,35 g, 0,81 mmol) i kloroform (5mL) ved To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylthio-pyrimidin-4-ylethynyl)cyclohexan-1-one (0.35 g, 0.81 mmol) in chloroform (5 mL) by

-10°C under en argonatmosfære ble det dråpevis tilsatt i løpet av 20 minutter en løsning av 3-klorperoksybenzosyre (0,31 g, 1,78 mmol) i kloroform. Reaksjonsblandingen ble omrørt i 1 time ved -10°C, og deretter i 1 time ved romtemperatur, deretter behandlet med 5% natriumkarbonat, ble ekstrahert tre ganger med diklormetan, ble tørket (kaliumkarbonat) og ble fordampet. Rensning med flash-kromatografi, eluering med 1:99 metanol.diklormetan, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-metylsulfonylpyrimidin-4-yletynyl)cykloheksan-1-on som et hvitt -10°C under an argon atmosphere, a solution of 3-chloroperoxybenzoic acid (0.31 g, 1.78 mmol) in chloroform was added dropwise over 20 minutes. The reaction mixture was stirred for 1 hour at -10°C, and then for 1 hour at room temperature, then treated with 5% sodium carbonate, extracted three times with dichloromethane, dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 1:99 methanol:dichloromethane, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl)cyclohexan-1-one as a white

skum (0,27 g, 72%), Sm.p. 60-64°C. En annen sats ble skaffet tilveie ved oksydasjon av sulfoksydet som et hvitt skum, Sm.p. 71-73°C. foam (0.27 g, 72%), Sm.p. 60-64°C. Another charge was obtained by oxidation of the sulphoxide as a white foam, Sm.p. 71-73°C.

Anal. (C25H28N2O5S-0.25 H20) beregnet: C, 63,47; H, 6,07; N, 5,92; funnet: C, 63,43; H, 6,07; N, 5,58. Anal. (C 25 H 28 N 2 O 5 S-0.25 H 2 O) calcd: C, 63.47; H, 6.07; N, 5.92; found: C, 63.43; H, 6.07; N, 5.58.

Eksempel 29 Example 29

4-(2-Aminopyrimidin-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on 4-(2-Aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

Inn i en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-metylsulfonyl-pyrimidin-4-yletynyl)cykloheksan-1-on (0,26 g, 0,56 mmol) i metanol (4ml_) ved - 78°C ble det kondensert flytende ammoniakk (4 ml) og trykkrøret ble forseglet og reaksjonsblandingen ble omrørt ved romtemperatur i 2,5 timer, Etter avkjøling ble løsningsmidlene fordampet. Rensningen nødvendiggjorde to flash-kromografier, eluering først med 2:98 metanol:diklormetan og deretter med 4:6 etylacetat:heksaner, og man fikk 4-(2-aminopyrimidin-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on som et hvitt, fast stoff (0,18 g, 73%), Sm.p. 68-70°C Into a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonyl-pyrimidin-4-ylethynyl)cyclohexan-1-one (0.26 g, 0.56 mmol) in methanol (4 ml_ ) at -78°C, liquid ammonia (4 ml) was condensed and the pressure tube was sealed and the reaction mixture was stirred at room temperature for 2.5 hours. After cooling, the solvents were evaporated. The purification necessitated two flash chromatographies, eluting first with 2:98 methanol:dichloromethane and then with 4:6 ethyl acetate:hexanes, to give 4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-one as a white solid (0.18 g, 73%), m.p. 68-70°C

Anal. (C24H27N3O3-0.2 H2O) beregnet: C, 70,46; H, 6,75; N, 10,27; funnet: C, 70,73; H, 6,79; N, 9,87. Anal. (C 24 H 27 N 3 O 3 -0.2 H 2 O) calcd: C, 70.46; H, 6.75; N, 10.27; found: C, 70.73; H, 6.79; N, 9.87.

Eksempel 30 Example 30

4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(1-metylimidazol-2-yletynyl)cykloheksan-1-on 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(1-methylimidazol-2-ylethynyl)cyclohexan-1-one

30a) 1-metyl-2-jodimidazol30a) 1-methyl-2-iodimidazole

1-Metyl-2-jodimidazol ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var et hvitt, fast stoff, Sm.p. 58-59°C. 1-Methyl-2-iodimidazole was prepared by conventional methods well known to those skilled in the art and was a white solid, m.p. 58-59°C.

30b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(1-metylimidazol-2-yletynyl) cykloheksan-1-on 30b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(1-methylimidazol-2-ylethynyl)cyclohexan-1-one

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcyklo-heksan-1-on (0,50 g, 1,6 mmol) og 1-metyl-2-jodimidazol (0,35 g, 1,6 mmol) i trietylamin (50 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)-paliadium(O) (0,074 g, 4%), kobber-(l)-jodid (0,018 g, 6%) og en liten krystall av trifenylfosfin og blandingen ble oppvarmet ved 80-85°C i 1 time. Vann ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesiumsulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 3:1 etylacetat:heksaner, ga uren 4-(4-karbometoksytien-2-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on (0,16 g, 26%), som ble slått sammen med produktet fra den andre omsetningen (0,16 g, 43%) og renset med flash-kromatografi, eluering med 1:99 metanol:diklormetan, etterfulgt av omkrystallisering fra diklormetan-heksaner, og man fikk ren 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(1-metylimidazol-2-yletynyl)cykloheksan-1-on (0,12 g) som et gråhvitt, faststoff, Sm.p. 137-138°C. To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.50 g, 1.6 mmol) and 1-methyl-2-iodimidazole (0.35 g, 1.6 mmol) in triethylamine (50 mL) under an argon atmosphere was added tetrakis(triphenylphosphine) palladium(O) (0.074 g, 4%), copper (l)-iodide (0.018 g, 6%) and a small crystal of triphenylphosphine and the mixture was heated at 80-85°C for 1 hour. Water was added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 3:1 ethyl acetate:hexanes, gave impure 4-(4-carbomethoxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.16 g , 26%), which was combined with the product of the second reaction (0.16 g, 43%) and purified by flash chromatography, eluting with 1:99 methanol:dichloromethane, followed by recrystallization from dichloromethane-hexanes, and gave pure 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(1-methylimidazol-2-ylethynyl)cyclohexan-1-one (0.12 g) as an off-white solid, m.p. 137-138°C.

Anal. (C24H28N2O3-0,2 H2O) beregnet: C, 72,77; H, 7,23; N, 7,07; funnet: C, 72,82; H, 7,99; N, 6,97. Anal. (C 24 H 28 N 2 O 3 -0.2 H 2 O) calcd: C, 72.77; H, 7.23; N, 7.07; found: C, 72.82; H, 7.99; N, 6.97.

Eksempel 31 Example 31

4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(imidazol-2-yletynyl)cykloheksan-1-on, hydrokloridsalt 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(imidazol-2-ylethynyl)cyclohexan-1-one, hydrochloride salt

31a) 1-te/f-butylkarbonyl-2-jodimidazol31a) 1-tert-Butylcarbonyl-2-iodimidazole

1-te/f-Butylkarbonyl-2-jodimidazol ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var et hvitt, fast stoff, Sm.p. 77-78°C. 1-te/f-Butylcarbonyl-2-iodimidazole was prepared by conventional methods well known to those skilled in the art and was a white solid, m.p. 77-78°C.

31b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(1 -fefr-butylkarboksyimidazol-2-yletynyl) cykloheksan-1-on 31b) 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(1-fefr-butylcarboxyimidazol-2-ylethynyl)cyclohexan-1-one

Til en løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcyklo-heksan-1-on (0,28g, 0,9 mmol) og 1-te/t-butylkarbonyl-2-jodimidazol (0,29 g, 0,97 mmol) i trietylamin (5 ml) under en argonatmosfære ble det tilsatt tetrakis(trifenylfosfin)palladium(O) (0,042 g, 4%), kobber-(l)-jodid (0,005g, 6%) og en liten krystall av trifenylfosfin og blandingen ble oppvarmet ved 80-85°C i 1 time. Vann ble tilsatt og blandingen ble ekstrahert tre ganger med diklormetan, ble tørket (magnesium sulfat) og ble fordampet. Rensning med flash-kromatografi, eluering med 3:7 etylacetat:heksaner, ga 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(1-rert-butyl-karbonylimidazol-2-yletynyl)cykloheksan-1-on (0,18 g, 4%) som en fargeløs olje.<1>H-NMR (400 MHz, CDCI3) 5 7,36 (s, 1 H), 7,20 (d, J=2,1Hz, 1 H), 7,17 (dd, J=8,5, 2,1 Hz, 1 H), 7,01 (s, 1 H), 6,85 (d, J=8,5Hz, 1 H), 4,85 (m, 1 H), 3,84 (s, 3 H), 3,18 (m, 2 H), 2,44 (m, 4 H), 2,22 (m, 2 H), 1,8-2,0 (m, 6 H), 1,6 (m, 11 H) ppm. To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.28g, 0.9 mmol) and 1-te/t-butylcarbonyl-2-iodimidazole (0, 29 g, 0.97 mmol) in triethylamine (5 mL) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(O) (0.042 g, 4%), copper (l)-iodide (0.005g, 6%) and a small crystal of triphenylphosphine and the mixture was heated at 80-85°C for 1 hour. Water was added and the mixture was extracted three times with dichloromethane, dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes, gave 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(1-tert-butylcarbonylimidazol-2-ylethynyl)cyclohexan-1-one (0 .18 g, 4%) as a colorless oil.<1>H-NMR (400 MHz, CDCl3) δ 7.36 (s, 1 H), 7.20 (d, J=2.1Hz, 1 H) , 7.17 (dd, J=8.5, 2.1 Hz, 1 H), 7.01 (s, 1 H), 6.85 (d, J=8.5Hz, 1 H), 4, 85 (m, 1 H), 3.84 (s, 3 H), 3.18 (m, 2 H), 2.44 (m, 4 H), 2.22 (m, 2 H), 1, 8-2.0 (m, 6 H), 1.6 (m, 11 H) ppm.

31c) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(imidazol-2-yletynyl)cykloheksan-1-on, hydroklorid salt 31c) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(imidazol-2-ylethynyl)cyclohexan-1-one, hydrochloride salt

En løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(1-terf-butyl-karbonylimidazol-2-yletynyl)cykloheksan-1-on (0,18 g, 0,37 mmol) og hydrogenklorid-mettet etylacetat (40 dråper) i etylacetat (10 ml) ble omrørt under en argonatmosfære ved romtemperatur i 24 timer. Suspensjonen ble avkjølt til 0°C og filtrert, og man fikk 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(imidazol-2-yletynyl)cykloheksan-1-on, hydrokloridsalt (0,12 g, 76%) som et hvitt, fast stoff, Sm.p. 183-184°C. A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(1-tert-butyl-carbonylimidazol-2-ylethynyl)cyclohexan-1-one (0.18 g, 0.37 mmol) and hydrogen chloride-saturated ethyl acetate (40 drops) in ethyl acetate (10 mL) was stirred under an argon atmosphere at room temperature for 24 h. The suspension was cooled to 0°C and filtered to give 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(imidazol-2-ylethynyl)cyclohexan-1-one, hydrochloride salt (0.12 g, 76%) as a white solid, Sm.p. 183-184°C.

Anal. (C23H26N2O3-HCI 0,25 H2O) beregnet: C, 65,70; H, 6,83; N, 6,66; funnet: C, 65,46; H, 6,65; N, 6,44. Anal. (C 23 H 26 N 2 O 3 -HCl 0.25 H 2 O) calcd: C, 65.70; H, 6.83; N, 6.66; found: C, 65.46; H, 6.65; N, 6.44.

Eksempel 32Example 32

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[4-(2-hydroksyetan-1-oksy)fenyl]etynyl)cykloheksan-1-on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-(2-hydroxyethan-1-oxy)phenyl]ethynyl)cyclohexan-1-one

32a) 4-(2-hydroksyetoksy)fenyljodid32a) 4-(2-hydroxyethoxy)phenyl iodide

En smelte av etylenkarbonat (6,5 g, 74 mmol) i en liten kolbe under argon ble behandlet med 4-jodfenol (0,400 g, 1,82 mmol) og pulverisert kaliumkarbonat (1,26 g, 9,1 mmol) og ble omrørt ved 90°C i 3 timer. Blandingen ble behandlet med kald, fortynnet saltsyre for å spalte overskuddet av kaliumkarbonat, og et overskudd av vandig natriumhydroksydløsning ble langsomt tilsatt og blandingen ble omrørt natten over. Suspensjonen ble ekstrahert med metylenklorid, ble vasket med vann og saltløsning, ble tørket over natriumsulfat og ble strippet, og man fikk et hvitt, fast stoff som ble renset med flash-kromatografi på silikagel (20 ml) med metylenklorid, og man fikk (0,128 g, 27%) av mellomproduktet som et hvitt, fast stoff, Sm.p. 76-77,5°C. A melt of ethylene carbonate (6.5 g, 74 mmol) in a small flask under argon was treated with 4-iodophenol (0.400 g, 1.82 mmol) and powdered potassium carbonate (1.26 g, 9.1 mmol) and was stirred at 90°C for 3 hours. The mixture was treated with cold dilute hydrochloric acid to decompose the excess potassium carbonate, and an excess of aqueous sodium hydroxide solution was slowly added and the mixture was stirred overnight. The suspension was extracted with methylene chloride, washed with water and brine, dried over sodium sulfate and stripped to give a white solid which was purified by flash chromatography on silica gel (20 mL) with methylene chloride to give (0.128 g, 27%) of the intermediate as a white solid, m.p. 76-77.5°C.

32b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[4-(2-hydroksyetan-1-oksy)fenyl]etynyl)-1,1 -(etylendioksy)cykloheksan 32b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-(2-hydroxyethane-1-oxy)phenyl]ethynyl)-1,1-(ethylenedioxy)cyclohexane

En løsning av 4-(2-hydroksyetoksy)fenyl jodid (0,059 g, 0,22 mmol) og 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-etynylcykloheksan (0,080 g, 0,22 mmol) i tørr piperidin (1 ml) ble behandlet med en blanding av tetrakis-(trifenylfosfin)palladium (0,013 g, 0,011 mmol), kobber-(l)-jodid (0,0025 g, 0,013 mmol) og trifenylfosfin (krystall) som beskrevet ovenfor i eksempel 11. Rensning av råproduktet med kromatografi (silikagel, 1 til 2% metanol i metylenklorid) etterfulgt av pumping / vakuum, ga mellomproduktet som en viskøs olje. A solution of 4-(2-hydroxyethoxy)phenyl iodide (0.059 g, 0.22 mmol) and 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.080 g, 0 .22 mmol) in dry piperidine (1 mL) was treated with a mixture of tetrakis-(triphenylphosphine)palladium (0.013 g, 0.011 mmol), copper (l)-iodide (0.0025 g, 0.013 mmol) and triphenylphosphine ( crystal) as described above in Example 11. Purification of the crude product by chromatography (silica gel, 1 to 2% methanol in methylene chloride) followed by pumping/vacuum gave the intermediate as a viscous oil.

<1>H-NMR (400 MHz, CDCI3) 8 7,39 (d, J=9,0Hz, 2H), 7,24 (d, J=2,1 Hz, 1H), 7,13 (d-d, J=8,3 Hz, J=2,1 Hz, 1H), 6,85 (d, J=8,7, 2H), 6,84 (d, J=8,3 Hz, 1H), 4,81 (p, J=2,0 Hz, 1H), 4,09 (t, J=4,4 Hz, 2 H), 4,00 (s, 4H), 3,97 (t, J=4,4Hz, 2H), 3,84 (s, 3H), 2,3 til 1,5 (m, 21H med H2O). <1>H-NMR (400 MHz, CDCl3) 8 7.39 (d, J=9.0Hz, 2H), 7.24 (d, J=2.1 Hz, 1H), 7.13 (d-d, J=8.3 Hz, J=2.1 Hz, 1H), 6.85 (d, J=8.7, 2H), 6.84 (d, J=8.3 Hz, 1H), 4, 81 (p, J=2.0 Hz, 1H), 4.09 (t, J=4.4 Hz, 2 H), 4.00 (s, 4H), 3.97 (t, J=4, 4Hz, 2H), 3.84 (s, 3H), 2.3 to 1.5 (m, 21H with H2O).

32c) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[4-(2-hydroksyetan-1-oksy)fenyl]etynyl)cykloheksan-1-on 32c) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-(2-hydroxyethan-1-oxy)phenyl]ethynyl)cyclohexan-1-one

En løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[4-(2-hydroksyetan-1-oksy)fenyl]etynyl)-1,1-(etylendioksy)cykloheksan (0,090 g, 0,18 mmol) i tetrahydrofuran (8 ml) ble behandlet med 3N saltsyre (0,9 ml) som i eksempel 12. Rensning med kromatografi (silikagel, 40 til 50% etylacetat i heksaner) etterfulgt av tørking / vakuum ved 60° C ga sluttproduktet som et glass. Anal. (C28H3205-1/4 H2O) beregnet: C 74,23, H 7,23, funnet: C 74,31, H 7,24. A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-(2-hydroxyethane-1-oxy)phenyl]ethynyl)-1,1-(ethylenedioxy)cyclohexane (0.090 g, 0 .18 mmol) in tetrahydrofuran (8 ml) was treated with 3N hydrochloric acid (0.9 ml) as in Example 12. Purification by chromatography (silica gel, 40 to 50% ethyl acetate in hexanes) followed by drying / vacuum at 60° C gave the final product as a glass. Anal. (C28H3205-1/4 H2O) calcd: C 74.23, H 7.23, found: C 74.31, H 7.24.

<1>H-NMR (400 MHz, CDCI3) 8 7,41 (d, J=8,9 Hz, 2H), 7,23 (d, J=2,3 Hz, 1H), 7,13 (d-d, J=8,5 Hz, J=2,3 Hz, 1H), 6,89 (d, J=8,7, 2H), 6,86 (d, J=8,3 Hz, 1H), 4,80 (p, 1H), 4,11 (t, J=4,5 Hz, 2 H), 3,98 (t, J=4,4Hz, 2H), 3,85 (s, 3H), 3,04 (d-t, J=14,1 Hz, J=6,1Hz, 2H), 2,47 (d.br, J=13,0, 2H), 2,4 til 1,5 (m, 19H med H2O). <1>H-NMR (400 MHz, CDCl3) 8 7.41 (d, J=8.9 Hz, 2H), 7.23 (d, J=2.3 Hz, 1H), 7.13 (d-d , J=8.5 Hz, J=2.3 Hz, 1H), 6.89 (d, J=8.7, 2H), 6.86 (d, J=8.3 Hz, 1H), 4 .80 (p, 1H), 4.11 (t, J=4.5 Hz, 2 H), 3.98 (t, J=4.4Hz, 2H), 3.85 (s, 3H), 3 .04 (d-t, J=14.1 Hz, J=6.1Hz, 2H), 2.47 (d.br, J=13.0, 2H), 2.4 to 1.5 (m, 19H with H2O).

Eksempel 33Example 33

Fremstilling av 4-(4-karbometoksyfenyletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1 -on Preparation of 4-(4-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

33a) 4-(4-karbometoksyfenyletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1 - 33a) 4-(4-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1 -

(etylendioksy)cykloheksan(ethylenedioxy)cyclohexane

En omrørt blanding av 4-(4-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-etynylcykloheksan (0,200 g, 0,56 mmol) og metyl-4-jodbenzoat (0,147 g, 0,56 mmol) i trietylamin (2,5 ml, tørr) ble behandlet med en blanding av tetrakis(trifenylfosfin)palladium (0,032 g, 0,028 mmol), kobber-(l)-jodid (0,0064 g, 0,034 mmol) og trifenylfosfin (krystall) etter fremgangsmåten i eksempel 1d. Reaksjonsblandingen ble ekstrahert og kromatografert som beskrevet i eksempel 1d og strippet /' vakuum, og man fikk en svakt gul olje (0,25 g, 91%). A stirred mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.200 g, 0.56 mmol) and methyl 4-iodobenzoate (0.147 g, 0.56 mmol) ) in triethylamine (2.5 mL, dry) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.032 g, 0.028 mmol), copper (l)-iodide (0.0064 g, 0.034 mmol) and triphenylphosphine (cryst. ) following the procedure in example 1d. The reaction mixture was extracted and chromatographed as described in Example 1d and stripped /' vacuum, and a pale yellow oil was obtained (0.25 g, 91%).

<1>H-NMR (400 MHz, CDCI3) 5 7,98 (d, 9,4 Hz, 2H), 7,50 (d, J=9,4 Hz, 2H), 7,20 (d, J=1,9 Hz, 1H), 7,12 (d-d, J=1,9 Hz, J=8,6Hz, 1H), 6,84 (d, J=8,6, 1H), 4,80 (p, J=3,8 Hz, 1H), 4,00 (s, br, 4H), 3,92 (s, 3H), 3,85 (s, 3H), 2,3 til 1,5 (m, 17H med H20). <1>H-NMR (400 MHz, CDCl3) δ 7.98 (d, 9.4 Hz, 2H), 7.50 (d, J=9.4 Hz, 2H), 7.20 (d, J =1.9 Hz, 1H), 7.12 (d-d, J=1.9 Hz, J=8.6Hz, 1H), 6.84 (d, J=8.6, 1H), 4.80 ( p, J=3.8 Hz, 1H), 4.00 (s, br, 4H), 3.92 (s, 3H), 3.85 (s, 3H), 2.3 to 1.5 (m , 17H with H2O).

33b) 4-(4-karbometoksyfenyletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan 33b) 4-(4-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexane

En omrørt løsning av 4-(4-karbometoksyfenyletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)cykloheksan (0,150 g, 0,12 mmol) i tetrahydrofuran (7 ml) ble behandlet med 3N saltsyre (0,70 ml) som beskrevet i eksempel 14 ovenfor. Råproduktet ble renset ved kromatografi (silika, 20% etylacetat/heksaner) og løsningsmiddelet ble fjernet/vakuum, og man fikk sluttproduktet som en harpiks (0,063 g, 46%). A stirred solution of 4-(4-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)cyclohexane (0.150 g, 0.12 mmol) in tetrahydrofuran (7 mL) was treated with 3N hydrochloric acid (0.70 ml) as described in example 14 above. The crude product was purified by chromatography (silica, 20% ethyl acetate/hexanes) and the solvent was removed/vacuum to give the final product as a resin (0.063 g, 46%).

Anal. (C28H30O5 I/IO H20) beregnet: C 75,01, H 6,79, funnet: C 74,97, H 6,87. Anal. (C 28 H 30 O 5 I/10 H 2 O) calcd: C 75.01, H 6.79, found: C 74.97, H 6.87.

<1>H-NMR (400 MHz, CDCI3) 6 8,01 (d, J=8,5 Hz, 2H), 7,53 (d, J=8,5 Hz, 2H), 7,20 (d, J=2,4 Hz, 1H), 7,11 (d-d, J=8,5 Hz, J=2,4Hz, 1H), 6,87 (d, J=8,5, 1H), 4,80 (p, 1H), 3,93 (s, 3 H), 3,86 (s, 3H), 3,04 (d-t, J=6,2 Hz, J=14,4, 2H), 2,50 (d,br, <1>H-NMR (400 MHz, CDCl3) 6 8.01 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.20 (d , J=2.4 Hz, 1H), 7.11 (d-d, J=8.5 Hz, J=2.4Hz, 1H), 6.87 (d, J=8.5, 1H), 4, 80 (p, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.04 (d-t, J=6.2 Hz, J=14.4, 2H), 2, 50 (d,br,

J=14,9, 2H), 2,42-2,32 (m, 2H), 2,26 (d-t, J=2,8 Hz, J=14,4Hz, 2H), 2,00-1,5 (m, 11H med H2O). J=14.9, 2H), 2.42-2.32 (m, 2H), 2.26 (d-t, J=2.8 Hz, J=14.4Hz, 2H), 2.00-1, 5 (m, 11H with H2O).

Eksempel 34Example 34

Fremstilling av 4-(4-karboksyfenyletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on Preparation of 4-(4-carboxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one

En omrørt løsning of 4-(4-karbometoksyfenyletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan (0,146 g, 0,326 mmol) i tørr metanol (5 ml) ble behandlet med 10% vandig natriumhydroksydløsning (0,46 ml, 1,15 mmol) under en argonatmosfære som beskrevet i eksempel 13. Den urene syren ble renset med kromatografi (silika, etylacetat/metylenklorid/maursyre; 10:90:1), produkt-fraksjoner ble vasket med vann tre ganger, ble strippet /' vakuum, ble krystallisert med eter og tørket /' vakuum, og man fikk sluttproduktet som et hvitt, fast stoff (0,077 g, 55%), Sm.p. 170-171°C. A stirred solution of 4-(4-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane (0.146 g, 0.326 mmol) in dry methanol (5 mL) was treated with 10% aqueous sodium hydroxide solution (0.46 mL , 1.15 mmol) under an argon atmosphere as described in Example 13. The impure acid was purified by chromatography (silica, ethyl acetate/methylene chloride/formic acid; 10:90:1), product fractions were washed with water three times, were stripped /' vacuum, was crystallized with ether and dried /' vacuum to give the final product as a white solid (0.077 g, 55%), m.p. 170-171°C.

Anal. (C27H28O5) beregnet: C 74,98, H 6,53 funnet: C 74,78, H 6,54. Anal. (C27H28O5) calcd: C 74.98, H 6.53 found: C 74.78, H 6.54.

Eksempel 35Example 35

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)4-(2-[4-(1 -piperidinkarbonyl-metoksy)fenyl]etynyl)cykloheksan-1-on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)4-(2-[4-(1-piperidinecarbonylmethoxy)phenyl]ethynyl)cyclohexan-1-one

35a) 4-jodfenoksyeddiksyre metylester35a) 4-iodophenoxyacetic acid methyl ester

En omrørt blanding av 4-jodfenol (0,50 g, 2,27 mmol), metyl-2-bromacetat (0,382 g, 2,50 mmol) og pulverisert kaliumkarbonat (0,314 g, 2,27 mmol) i tørr aceton under argon ble forseglet og oppvarmet ved 70°C i 4 timer. Den avkjølte blandingen ble filtrert og filtratet ble fordampet/vakuum. Resten ble renset ved kromatografi (silika, 40 til 50% metylenklorid i cykloheksan) og løsningsmiddelet ble fjernet /' vakuum, og man fikk mellomproduktet som et hvitt, fast stoff (0,41 g, 62%), Sm.p. 69-70°C. A stirred mixture of 4-iodophenol (0.50 g, 2.27 mmol), methyl 2-bromoacetate (0.382 g, 2.50 mmol) and powdered potassium carbonate (0.314 g, 2.27 mmol) in dry acetone under argon was sealed and heated at 70°C for 4 hours. The cooled mixture was filtered and the filtrate was evaporated/vacuum. The residue was purified by chromatography (silica, 40 to 50% methylene chloride in cyclohexane) and the solvent was removed in vacuo to give the intermediate as a white solid (0.41 g, 62%), m.p. 69-70°C.

35b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(2-[4-(1-piperidin-karbonylmetoksy)fenyl]etynyl)cykloheksan 35b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(2-[4-(1-piperidine-carbonylmethoxy)phenyl]ethynyl)cyclohexane

En omrørt blanding of 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-etynylcykloheksan (0,150 g, 0,42 mmol) og 4-jodfenoksyeddiksyremetylester (0,123 g, 0,42 mmol) i tørr piperidin (2 ml) ble behandlet ved 80°C i 1,5 timer etter fremgangsmåten i eksempel 11 med en blanding av tetrakis(trifenylfosfin)palladium (0,027 g, 0,023 mmol), kobber-(l)-jodid (0,0048 g, 0,025 mmol) og trifenylfosfin (krystall). Råproduktet ble kromatografert (silika 50 til 75% etylacetat i petroleter) og ble strippet /' vakuum, og man fikk mellom-produktet som en viskøs, gul olje (0,232 g, 96%). A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.150 g, 0.42 mmol) and 4-iodophenoxyacetic acid methyl ester (0.123 g, 0.42 mmol) in dry piperidine (2 mL) was treated at 80°C for 1.5 h following the procedure of Example 11 with a mixture of tetrakis(triphenylphosphine)palladium (0.027 g, 0.023 mmol), copper (l)-iodide (0.0048 g, 0.025 mmol) and triphenylphosphine (cryst.). The crude product was chromatographed (silica 50 to 75% ethyl acetate in petroleum ether) and stripped in vacuo to give the intermediate as a viscous yellow oil (0.232 g, 96%).

<1>H-NMR (400 MHz, CDCI3) 6 7,38 (d, J=8,7Hz, 2H), 7,24 (d, J=2,3 Hz, 1H), 7,13 (d-d, J=8,4 Hz, J=2,3Hz, 1H), 6,89 (d, J=8,9, 1H), 6,84 (d, J=8,4, 1H),4,81 (p, 1H), 4,69 (s, 2H), 4,00 (s, 4H), 3,84 (s, 3H), 3,56 (t, J=5,5 Hz, 2H), 3,49 (t, J=5,5 Hz, 2H), 2,3 til 1,5 (m, 32H med H2O). <1>H-NMR (400 MHz, CDCl3) 6 7.38 (d, J=8.7Hz, 2H), 7.24 (d, J=2.3 Hz, 1H), 7.13 (d-d, J=8.4 Hz, J=2.3Hz, 1H), 6.89 (d, J=8.9, 1H), 6.84 (d, J=8.4, 1H), 4.81 ( p, 1H), 4.69 (s, 2H), 4.00 (s, 4H), 3.84 (s, 3H), 3.56 (t, J=5.5 Hz, 2H), 3, 49 (t, J=5.5 Hz, 2H), 2.3 to 1.5 (m, 32H with H 2 O).

35c) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[4-(1-piperidinkarbonyl-metoksy)fenyl]etynyl)cykloheksan-1-on 35c) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-(1-piperidinecarbonyl-methoxy)phenyl]ethynyl)cyclohexan-1-one

En omrørt løsning av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-(2-[4-(1-piperidinkarbonylmetoksy)fenyl]etynyl)cykloheksan (0,232 g, 0,40 mmol) i tetrahydrofuran (9 ml) ble behandlet med 3N saltsyre (0,90 ml) som beskrevet i eksempel 12 ovenfor. Råproduktet ble renset ved kromatografi (silika, 50% etylacetat/heksaner) og løsningsmiddelet fjernet / vakuum, og man fikk sluttproduktet som en harpiks (0,127 g, 59%). A stirred solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(2-[4-(1-piperidinecarbonylmethoxy)phenyl]ethynyl)cyclohexane (0.232 g, 0.40 mmol ) in tetrahydrofuran (9 ml) was treated with 3N hydrochloric acid (0.90 ml) as described in Example 12 above. The crude product was purified by chromatography (silica, 50% ethyl acetate/hexanes) and the solvent removed / vacuum to give the final product as a resin (0.127 g, 59%).

Anal. (C28H30O5 I/IO H2O) beregnet: C 75,01, H 6,79, funnet: C 74,97, H 6,87. Anal. (C28H30O5 I/10 H2O) calcd: C 75.01, H 6.79, found: C 74.97, H 6.87.

<1>H-NMR(400MHz, CDCI3) 5 7,41 (d, J=9,1 Hz, 2H), 7,22 (d, J=2,3 Hz, 1H),7,11 (d-d, J=8,4 Hz, J=2,3 Hz, 1H), 6,92 (d, J=8,6, 1H), 6,86 (d, J=8,5, 1H),4,80 (p, 1H), 4,70 (s, 2H), 4,00 (s, 4H), 3,85 (s, 3H), 3,56 (t, J=5,5Hz, 2H), 3,48 (t, J=5,5 Hz, 2H), 3,03 (d-t, J=6,1Hz, J=14,3, 2H), 2,47 (d,br, J=14,9, 2H), 2,4-2,2 (m, 4H), 2,0 til 1,5 (m, 25H med H2O). <1>H-NMR(400MHz, CDCl3) δ 7.41 (d, J=9.1 Hz, 2H), 7.22 (d, J=2.3 Hz, 1H),7.11 (d-d, J=8.4 Hz, J=2.3 Hz, 1H), 6.92 (d, J=8.6, 1H), 6.86 (d, J=8.5, 1H), 4.80 (p, 1H), 4.70 (s, 2H), 4.00 (s, 4H), 3.85 (s, 3H), 3.56 (t, J=5.5Hz, 2H), 3, 48 (t, J=5.5 Hz, 2H), 3.03 (d-t, J=6.1Hz, J=14.3, 2H), 2.47 (d,br, J=14.9, 2H ), 2.4-2.2 (m, 4H), 2.0 to 1.5 (m, 25H with H2O).

Eksempel 36Example 36

Fremstilling av 4-(2-[4-karboksymetyloksyfenyl]etynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1 -on 19a) 4-(2-[4-Karbometoksymetyloksyfenyl]etynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)cykloheksan Preparation of 4-(2-[4-carboxymethyloxyphenyl]ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one 19a) 4-(2-[4-Carbomethoxymethyloxyphenyl]ethynyl)-4-(3 -cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)cyclohexane

En omrørt blanding av 4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-etynylcykloheksan (0,075 g, 0,21 mmol) og 4-jodfenoksyeddiksyremetylester (0,060 g, 0,21 mmol, fremstilt som beskrevet i eksempel 35a) i tørr trietylamin (2 ml) ble behandlet ved 80°C i 1,5 timer etter fremgangsmåten i eksempel 11 med en blanding av tetrakis(trifenylfosfin)palladium (0,018 g, 0,016 mmol), kobber-(l)-jodid (0,004 g, 0,021 mmol) og trifenylfosfin (krystall). Råproduktet ble kromatografert (silika 40 til 50% etylacetat i heksaner) og strippet / vakuum, og man fikk mellomproduktet som en mørk, rød olje (0,080 g, 73%).<1>H-NMR (400 MHz, CDCI3) 8 7,98 (d, 9,4 Hz, 2H), 7,50 (d, J=9,4Hz, 2H), 7,20 (d, J=1,9 Hz, 1H), 7,12 (d-d, J=1,9 Hz, J=8,6 Hz, 1H), 6,84 (d, J=8,6, 1H), 4,80 (p, J=3,8 Hz, 1H), 4,00 (s, br, 4H), 3,92 (s, 3H), 3,85 (s, 3H), 2,3 til 1,5 (m, 17H med H20). A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.075 g, 0.21 mmol) and 4-iodophenoxyacetic acid methyl ester (0.060 g, 0.21 mmol, prepared as described in Example 35a) in dry triethylamine (2 ml) was treated at 80°C for 1.5 hours following the procedure in Example 11 with a mixture of tetrakis(triphenylphosphine)palladium (0.018 g, 0.016 mmol), copper-(l )-iodide (0.004 g, 0.021 mmol) and triphenylphosphine (cryst.). The crude product was chromatographed (silica 40 to 50% ethyl acetate in hexanes) and stripped / vacuum to give the intermediate as a dark red oil (0.080 g, 73%).<1>H-NMR (400 MHz, CDCl3) 8 7 .98 (d, 9.4 Hz, 2H), 7.50 (d, J=9.4Hz, 2H), 7.20 (d, J=1.9 Hz, 1H), 7.12 (d-d, J=1.9 Hz, J=8.6 Hz, 1H), 6.84 (d, J=8.6, 1H), 4.80 (p, J=3.8 Hz, 1H), 4, 00 (s, br, 4H), 3.92 (s, 3H), 3.85 (s, 3H), 2.3 to 1.5 (m, 17H with H 2 O).

36b) 4-(2-[4-karboksymetyloksyfenyl]etynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on 36b) 4-(2-[4-carboxymethyloxyphenyl]ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

En omrørt løsning of 4-(2-[4-karbometoksymetyloksyfenyl]etynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)cykloheksan (0,232 g, 0,40 mmol) i tetrahydrofuran (9 ml) ble behandlet med 3N saltsyre (0,90 ml) som beskrevet i eksempel 12 ovenfor. Råproduktet ble renset ved kromatografi (silika, 50% etylacetat/heksaner) og løsningsmiddelet ble fjernet /' vakuum, og man fikk sluttproduktet som en harpiks (0,127 g, 59%). A stirred solution of 4-(2-[4-carbomethoxymethyloxyphenyl]ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)cyclohexane (0.232 g, 0.40 mmol) in tetrahydrofuran (9 ml) was treated with 3N hydrochloric acid (0.90 ml) as described in Example 12 above. The crude product was purified by chromatography (silica, 50% ethyl acetate/hexanes) and the solvent was removed in vacuo to give the final product as a resin (0.127 g, 59%).

Anal. (C28H30O5-1/10 H2O) beregnet: C 75,01, H 6,79, funnet: C 74,97, H 6,87. Anal. (C28H30O5-1/10 H2O) calcd: C 75.01, H 6.79, found: C 74.97, H 6.87.

<1>H-NMR (400 MHz, CDCI3) S 8,01 (d, J=8,5Hz, 2H), 7,53 (d, J=8,5 Hz, 2H), 7,20 (d, J=2,4 Hz, 1H), 7,11 (d-d, J=8,5Hz, J=2,4Hz, 1H), 6,87 (d, J=8,5, 1H), 4,80 (p, 1H), 3,93 (s, 3 H), 3,86 (s, 3H), 3,04 (d-t, J=6,2 Hz, J=14,4, 2H), 2,50 (d.br, J=14,9, 2H), 2,42-2,32 (m, 2H), 2,26 (d-t, J=2,8 Hz, J=14,4 Hz, 2H), 2,00-1,5 (m, 11H med H2O). <1>H-NMR (400 MHz, CDCl3) S 8.01 (d, J=8.5Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.20 (d, J=2.4 Hz, 1H), 7.11 (d-d, J=8.5Hz, J=2.4Hz, 1H), 6.87 (d, J=8.5, 1H), 4.80 ( p, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.04 (d-t, J=6.2 Hz, J=14.4, 2H), 2.50 ( d.br, J=14.9, 2H), 2.42-2.32 (m, 2H), 2.26 (d-t, J=2.8 Hz, J=14.4 Hz, 2H), 2 .00-1.5 (m, 11H with H2O).

Eksempel 37Example 37

Fremstilling av 4-(2-[4-karbometoksymetyloksyfenyl]etynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on Preparation of 4-(2-[4-carbomethoxymethyloxyphenyl]ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

En omrørt blanding av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan-1-on (0,075 g, 0,24 mmol) og 4-jodfenoksyeddiksyremetylester (0,070 g, 0,24 mmol, fremstilt som beskrevet i eksempel 35a) i tørr trietylamin (1,2 ml) ble behandlet ved 75°C i 1 time med en blanding av tetrakis(trifenylfosfin)-palladium (0,012 g, 0,010 mmol), kobber-(l)-jodid (0,0024 g, 0,013 mmol) og trifenylfosfin (en liten krystall) under argon. Reaksjonsblandingen ble konsentrert /' vakuum og resten behandlet med kald, fortynnet saltsyre, ble ekstrahert to ganger med etylacetat og den organiske fasen ble vasket med vann, saltløsning og ble tørket over vannfri natriumsulfat. Råproduktet ble kromatografert (silika, 25 til 30% etylacetat i heksaner) og ble strippet /' vakuum, og man fikk mellomproduktet som en ravfarget harpiks (0,097 g, 85%). A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.075 g, 0.24 mmol) and 4-iodophenoxyacetic acid methyl ester (0.070 g, 0.24 mmol, prepared as described in Example 35a) in dry triethylamine (1.2 mL) was treated at 75°C for 1 h with a mixture of tetrakis(triphenylphosphine)-palladium (0.012 g, 0.010 mmol), copper (l)-iodide (0.0024 g , 0.013 mmol) and triphenylphosphine (a small crystal) under argon. The reaction mixture was concentrated in vacuo and the residue treated with cold dilute hydrochloric acid, extracted twice with ethyl acetate and the organic phase washed with water, brine and dried over anhydrous sodium sulfate. The crude product was chromatographed (silica, 25 to 30% ethyl acetate in hexanes) and stripped in vacuo to give the intermediate as an amber resin (0.097 g, 85%).

Anal. (C29H32O6) beregnet: C 73,09, H 6,77, funnet: C 72,91, H 6,78.Anal. (C29H32O6) calcd: C 73.09, H 6.77, found: C 72.91, H 6.78.

<1>H-NMR (400 MHz, CDCI3) 5 7,41 (d, J=8,9 Hz, 2H), 7,21 (d, J=2,2 Hz, 1H), 7,11 (d-d, J=1,9 Hz, J=8,4Hz, 1H), 6,87 (d, J=8,9, 2H), 6,85 (d, J=8,4, 1H), 4,80 (p, J=4,4 Hz, 1H), 4,65 (s, 2H), 3,84 (s, 3H), 3,81 (s, 3H), 3,02 (d-t, J=6,2 Hz, J=14,2, 2H), 2,46 (d.br, J=14,8, 2H), 2,4-1,5 (m, 16H med H2O). <1>H-NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.9 Hz, 2H), 7.21 (d, J=2.2 Hz, 1H), 7.11 (d-d , J=1.9 Hz, J=8.4Hz, 1H), 6.87 (d, J=8.9, 2H), 6.85 (d, J=8.4, 1H), 4.80 (p, J=4.4 Hz, 1H), 4.65 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.02 (d-t, J=6, 2 Hz, J=14.2, 2H), 2.46 (d.br, J=14.8, 2H), 2.4-1.5 (m, 16H with H2O).

Eksempel 38Example 38

Fremstilling av 4-(2-karbometoksyfenyletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on Preparation of 4-(2-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

En blanding av 4-(4-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan-1-on (0,150 g, 0,48 mmol) og metyl-2-jodbenzoat (0,126 g, 0,48 mmol) i trietylamin (2,4 ml, tørr) ble behandlet med en blanding av tetrakis(trifenylfosfin)-palladium(O) (0,024 g, 0,021 mmol), kobber-(l)-jodid (0,0048 g, 0,026 mmol) og trifenylfosfin (krystall) under en argonatmosfære og omrørt ved 80°C i 7 timer. Reaksjonsblandingen ble konsentrert /' vakuum og resten ble behandlet som beskrevet i eksempel 20, kromatografert to ganger (silika, 20% etylacetat i heksaner; og 2% etylacetat i metylenklorid) krystallisert fra eter.heksaner og tørket ved 60°C / vakuum, og man fikk et hvitt pulver (0,051 g, 24%), Sm.p. 88,5-90°C. Anal. (C28H30O5) beregnet: C 75,31, H 6,77, funnet: C 75,11, H 6,78. A mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.150 g, 0.48 mmol) and methyl 2-iodobenzoate (0.126 g, 0.48 mmol) in triethylamine (2 .4 mL, dry) was treated with a mixture of tetrakis(triphenylphosphine)-palladium(O) (0.024 g, 0.021 mmol), copper (l)-iodide (0.0048 g, 0.026 mmol) and triphenylphosphine (cryst. under an argon atmosphere and stirred at 80°C for 7 hours. The reaction mixture was concentrated /' vacuum and the residue was treated as described in Example 20, chromatographed twice (silica, 20% ethyl acetate in hexanes; and 2% ethyl acetate in methylene chloride) crystallized from ether.hexanes and dried at 60°C / vacuum, and a white powder was obtained (0.051 g, 24%), m.p. 88.5-90°C. Anal. (C28H30O5) calculated: C 75.31, H 6.77, found: C 75.11, H 6.78.

Eksempel 39Example 39

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3,5-dikarbometoksy-fenyl]etynyl)cykloheksan-1 -on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3,5-dicarbomethoxy-phenyl]ethynyl)cyclohexan-1-one

En blanding av 4-(4-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan-1-on (0,075 g, 0,24 mmol) og dimetyl-5-jodisoftalat (Trans World Chemicals, 0,107 g, 0,33 mmol) i trietylamin (1,9 ml, tørr) ble behandlet med en blanding av tetrakis(trifenylfosfin)palladium (0,012 g, 0,010 mmol), kobber-(l)-jodid (0,0025 g, 0,013 mmol) og trifenylfosfin (en liten krystall) under en argonatmosfære og ble omrørt ved 80°C i 1 time. Reaksjonsblandingen ble konsentrert / vakuum og resten ble kromatografert (silika, 1 til 2% etylacetat i metylenklorid) og ble tørket ved 50°C /' vakuum, og man fikk en lysebrunt pulver (0,100 g, 83%), Sm.p. 133,5-135OC. A mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.075 g, 0.24 mmol) and dimethyl 5-iododiphthalate (Trans World Chemicals, 0.107 g, 0.33 mmol) in triethylamine (1.9 mL, dry) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.012 g, 0.010 mmol), copper (l)-iodide (0.0025 g, 0.013 mmol) and triphenylphosphine (a small crystal) under an argon atmosphere and was stirred at 80°C for 1 hour. The reaction mixture was concentrated/vacuum and the residue was chromatographed (silica, 1 to 2% ethyl acetate in methylene chloride) and dried at 50°C/vacuum to give a light brown powder (0.100 g, 83%), m.p. 133.5-135OC.

Anal. (C30H33O7) beregnet: C 71,41, H 6,39, funnet: C 71,19, H 6,41. Anal. (C30H33O7) calcd: C 71.41, H 6.39, found: C 71.19, H 6.41.

Eksempel 40Example 40

Fremstilling av 4-(2-[4-klorfenyl]etynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on Preparation of 4-(2-[4-chlorophenyl]ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one

En blanding av 4-(4-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan-1-on (0,075 g, 0,24 mmol) og 4-klor-1-jodbenzen (0,057 g, 0,24 mmol) i trietylamin (1,7 ml, tørr) ble behandlet med en blanding av tetrakis(trifenylfosfin)palladium (0,012 g, 0,010 mmol), kobber-(l)-jodid (0,0025 g, 0,013 mmol) og trifenylfosfin (en liten krystall) under en argonatmosfære og ble omrørt ved 80°C i 2 timer. Reaksjonsblandingen ble konsentrert /' vakuum og resten behandlet med fortynnet saltsyre, ble ekstrahert tre ganger med etylacetat og den organiske fasen ble tørket over natriumsulfat og ble konsentrert/vakuum. Resten ble kromatografert (silika, 0,05 til 1% etylacetat i metylenklorid/heksaner 3:1) og sluttproduktet ble tørket ved 25°C /' vakuum, og man fikk et hvitt pulver (0,051 g, 50%), Sm.p. 104-105<0>c. A mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.075 g, 0.24 mmol) and 4-chloro-1-iodobenzene (0.057 g, 0.24 mmol) in triethylamine (1.7 mL, dry) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.012 g, 0.010 mmol), copper (l)-iodide (0.0025 g, 0.013 mmol) and triphenylphosphine (a small crystal) under an argon atmosphere and was stirred at 80°C for 2 hours. The reaction mixture was concentrated in vacuo and the residue treated with dilute hydrochloric acid, extracted three times with ethyl acetate and the organic phase dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed (silica, 0.05 to 1% ethyl acetate in methylene chloride/hexanes 3:1) and the final product was dried at 25°C /' vacuum to give a white powder (0.051 g, 50%), mp . 104-105<0>c.

Anal. (C26H27CIO3) beregnet: C 73,83, H 6,43, funnet: C 73,69, H 6,41. Anal. (C 26 H 27 CIO 3 ) calcd: C 73.83, H 6.43, found: C 73.69, H 6.41.

Eksempel 41Example 41

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-metyl-[1,2,4]oksadiazol-3-yl)fenyl]etynyl)cykloheksan-1 -on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-one

41a) 3-(3-jodfenyl)-5-metyl-[1,2,4]oksadiazol 41a) 3-(3-iodophenyl)-5-methyl-[1,2,4]oxadiazole

3-(3-Jodfenyl)-5-metyl-[1,2,4]oksadiazol ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var et hvitt, fast stoff, Sm.p. 90-91,5<0>C. 3-(3-Iodophenyl)-5-methyl-[1,2,4]oxadiazole was prepared by conventional methods well known to those skilled in the art and was a white solid, m.p. 90-91.5<0>C.

41b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-metyl-[1,2,4]oksadiazol-3-yl)fenyl]etynyl)cykloheksan-1 -on 41b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-one

En omrørt blanding av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan-1-on (0,200 g, 0,64 mmol) og 3-(3-jodfenyl)-5-metyl-[1,2,4]oksadiazol (0,201 g, 0,70 mmol) i tørr trietylamin (4,6 ml) ble behandlet med en blanding av tetrakis(trifenylfosfin)palladium (0,032 g, 0,028 mmol), kobber-(l)-jodid (0,0067 g, 0,035 mmol) og trifenylfosfin (en liten krystall) ved 75°C i 1 time 20 minutter under argon. Reaksjonsblandingen ble konsentrert / vakuum og resten ble behandlet med kald, fortynnet saltsyre, ble ekstrahert to ganger med metylenklorid og den organiske fasen ble vasket med vann, saltløsning og ble tørket over vannfri natriumsulfat. Råproduktet ble kromatografert (silika, 3 til 6% etylacetat i metylenklorid/heksaner 4:1) og de rene fraksjonene ble samlet, konsentrert /' vakuum , ble krystalliert fra etyleter og ble tørket ved 60°C /' vakuum, og man fikk sluttproduktet som et hvitt, fast stoff (0,235 g, 78%), Sm.p. 122,5-123,5<0>C. A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.200 g, 0.64 mmol) and 3-(3-iodophenyl)-5-methyl-[1,2, 4]oxadiazole (0.201 g, 0.70 mmol) in dry triethylamine (4.6 mL) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.032 g, 0.028 mmol), copper (l)-iodide (0, 0067 g, 0.035 mmol) and triphenylphosphine (a small crystal) at 75°C for 1 h 20 min under argon. The reaction mixture was concentrated / vacuum and the residue was treated with cold dilute hydrochloric acid, was extracted twice with methylene chloride and the organic phase was washed with water, brine and was dried over anhydrous sodium sulfate. The crude product was chromatographed (silica, 3 to 6% ethyl acetate in methylene chloride/hexanes 4:1) and the pure fractions were collected, concentrated under vacuum, crystallized from ethyl ether and dried at 60°C under vacuum to give the final product as a white solid (0.235 g, 78%), m.p. 122.5-123.5<0>C.

Anal. (C29H30N2O4) beregnet: C 74,02, H 6,43, N 5,95, funnet: C 73,94, H 6,37, N 5,96. Anal. (C29H30N2O4) calcd: C 74.02, H 6.43, N 5.95, found: C 73.94, H 6.37, N 5.96.

Eksempel 42Example 42

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(3-metyl-[1,2,4]oksadiazol-5-yl)fenyl]etynyl)cykloheksan-1 -on 42a) 5-(3-jodfenyl)-3-metyl-[1,2,4]oksadiazol Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-one 42a ) 5-(3-iodophenyl)-3-methyl-[1,2,4]oxadiazole

5-(3-Jodfenyl)-3-metyl-[1,2,4]oksadiazol ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var et hvitt, fast stoff, Sm.p. 102-103<0>c. 5-(3-Iodophenyl)-3-methyl-[1,2,4]oxadiazole was prepared by conventional methods well known to those skilled in the art and was a white solid, m.p. 102-103<0>c.

42b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(3-metyl-[1,2,4]oksadiazol-5-yl)fenyl]etynyl)cykloheksan-1-on 42b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-one

En omrørt blanding av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan-1-on (0,200 g, 0,64 mmol) og 5-(3-jodfenyl)-3-metyl-[1,2,4]oksadiazol (0,201 g, 0,70 mmol) i tørr trietylamin (4,6 ml) ble behandlet under argon med en blanding av tetrakis(trifenylfosfin)palladium (0,032 g, 0,028 mmol), kobber-(l)-jodid (0,0067 g, 0,035 mmol) og trifenylfosfin (en liten krystall) ved 70°C i 1 time og ved 25°C i 15 timer. Reaksjonsblandingen ble konsentrert i vakuum og en løsning av resten ble oppløst i metylenklorid, ble behandlet med kald, fortynnet saltsyre og ble tørket over vannfri natriumsulfat. Råproduktet ble kromatografert (silika, 5 til 10% etylacetat i metylenklorid/heksaner 1:1) og de rene fraksjonene ble samlet, konsentrert / vakuum , krystallisert fra etyleter og tørket ved 60°C/vakuum, og man fikk sluttproduktet som et gråhvitt pulver (0,235 g, 78%), Sm.p. 88-91 °C. A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.200 g, 0.64 mmol) and 5-(3-iodophenyl)-3-methyl-[1,2, 4]oxadiazole (0.201 g, 0.70 mmol) in dry triethylamine (4.6 mL) was treated under argon with a mixture of tetrakis(triphenylphosphine)palladium (0.032 g, 0.028 mmol), copper (l)-iodide ( 0.0067 g, 0.035 mmol) and triphenylphosphine (a small crystal) at 70°C for 1 hour and at 25°C for 15 hours. The reaction mixture was concentrated in vacuo and a solution of the residue was dissolved in methylene chloride, treated with cold dilute hydrochloric acid and dried over anhydrous sodium sulfate. The crude product was chromatographed (silica, 5 to 10% ethyl acetate in methylene chloride/hexanes 1:1) and the pure fractions were collected, concentrated/vacuum, crystallized from ethyl ether and dried at 60°C/vacuum, and the final product was obtained as an off-white powder (0.235 g, 78%), m.p. 88-91 °C.

Anal. (C29H30N2O4) beregnet: C 74,02, H 6,43, N 5,95, funnet: C 73,77, H 6,53, N 5,78. Anal. (C29H30N2O4) calcd: C 74.02, H 6.43, N 5.95, found: C 73.77, H 6.53, N 5.78.

Eksempel 43Example 43

Fremstilling av 4-(2-[3-cyanofenyl]etynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1 -on Preparation of 4-(2-[3-cyanophenyl]ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

En blanding av 4-(4-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan-1-on (0,100 g, 0,32 mmol) og 3-jodbenzonitril (0,088 g, 0,38 mmol) i trietylamin (2,5 ml, tørr) ble behandlet med en blanding av tetrakis(trifenylfosfin)palladium (0,016 g, 0,013 mmol), kobber-(l)-jodid (0,0033 g, 0,017 mmol) og trifenylfosfin (en liten krystall) under en argonatmosfære og ble omrørt ved 75°C i 1 time 15 minutter, etterfulgt av romtemperatur i 15 timer.. Reaksjonsblandingen ble konsentrert /' vakuum og en løsning av resten ble oppløst i metylenklorid, ble vasket med fortynnet saltsyre, vann, saltløsning og tørket over natriumsulfat. Råproduktet ble kromatografert (silika, 3% etylacetat i metylenklorid/heksaner4:1) og sluttproduktet tørket ved 60°C/vakuum, og man fikk et hvitt, fast stoff (0,075 g, 47%), Sm.p. 123,5-125,5°C. A mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.100 g, 0.32 mmol) and 3-iodobenzonitrile (0.088 g, 0.38 mmol) in triethylamine (2.5 ml, dry) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol), copper (l)-iodide (0.0033 g, 0.017 mmol) and triphenylphosphine (a small crystal) under an argon atmosphere and was stirred at 75°C for 1 hour 15 minutes, followed by room temperature for 15 hours. The reaction mixture was concentrated in vacuo and a solution of the residue was dissolved in methylene chloride, washed with dilute hydrochloric acid, water, brine and dried over sodium sulfate. The crude product was chromatographed (silica, 3% ethyl acetate in methylene chloride/hexanes 4:1) and the final product dried at 60°C/vacuum to give a white solid (0.075 g, 47%), m.p. 123.5-125.5°C.

Anal. (C27H27NO3) beregnet: C 78,42, H 6,58, N 3,39, funnet: C 78,13, H 6,67, N 3,40. Anal. (C27H27NO3) calculated: C 78.42, H 6.58, N 3.39, found: C 78.13, H 6.67, N 3.40.

Eksempel 44Example 44

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3,5-dicyanofenyl]etynyl)cykloheksan-1-on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3,5-dicyanophenyl]ethynyl)cyclohexan-1-one

44a) 3,5-dicyanofenyljodid44a) 3,5-dicyanophenyl iodide

3,5-Dicyanofenyljodid ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var et hvitt, fast stoff, Sm.p. 145,5-146,5°C. 3,5-Dicyanophenyl iodide was prepared by conventional methods well known to those skilled in the art and was a white solid, m.p. 145.5-146.5°C.

44b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3,5-dicyanfenyl]etynyl)-cykloheksan-1-on 44b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3,5-dicyanophenyl]ethynyl)-cyclohexan-1-one

En blanding av 4-(4-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan-1-on (0,150 g, 0,48 mmol) og 3,5-dicyanofenyljodid (0,171 g, 0,67 mmol) i trietylamin (7,5 ml, tørr) ble behandlet med en blanding av tetrakis(trifenylfosfin)-palladium (0,024 g, 0,021 mmol), kobber-(l)-jodid (0,005 g, 0,026 mmol) og trifenylfosfin (en liten krystall) under en argonatmosfære og ble omrørt ved 80°C i 0,5 timer og ved 25°C i 15 timer. Reaksjonsblandingen ble konsentrert /' vakuum og en løsning av resten oppløst i metylenklorid ble vasket med fortynnet saltsyre, vann, saltløsning og ble tørket over natriumsulfat. Resten ble kromatografert (silika, 2 til 3% etylacetat i metylenklorid/heksaner 9:1) og ble tørket /' vakuum, og man fikk et hvitt pulver (0,177 g, 84%), Sm.p. 147,5-148,5°C. A mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.150 g, 0.48 mmol) and 3,5-dicyanophenyl iodide (0.171 g, 0.67 mmol) in triethylamine (7 .5 mL, dry) was treated with a mixture of tetrakis(triphenylphosphine)-palladium (0.024 g, 0.021 mmol), copper (l)-iodide (0.005 g, 0.026 mmol) and triphenylphosphine (a small crystal) under an argon atmosphere and was stirred at 80°C for 0.5 hours and at 25°C for 15 hours. The reaction mixture was concentrated in vacuo and a solution of the residue dissolved in methylene chloride was washed with dilute hydrochloric acid, water, brine and was dried over sodium sulfate. The residue was chromatographed (silica, 2 to 3% ethyl acetate in methylene chloride/hexanes 9:1) and dried in vacuo to give a white powder (0.177 g, 84%), m.p. 147.5-148.5°C.

Anal. (C28H26N2O3) beregnet: C 76,69, H 5,98, N 6,39, funnet: C 76,41, H 5,92, N 6,39. Anal. (C28H26N2O3) calcd: C 76.69, H 5.98, N 6.39, found: C 76.41, H 5.92, N 6.39.

Eksempel 45Example 45

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[4-hydroksyfenyl]etynyl)cykloheksan-1-on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-hydroxyphenyl]ethynyl)cyclohexan-1-one

En blanding av 4-(4-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan-1-on (0,090 g, 0,29 mmol) og 4-jodfenol (0,076 g, 0,35 mmol) i trietylamin (3 ml, tørr) ble behandlet med en blanding av tetrakis(trifenylfosfin)palladium (0,013 g, 0,012 mmol), kobber-(l)-jodid (0,003 g, 0,016 mmol) og trifenylfosfin (en liten krystall) under en argonatmosfære og omrørt ved 75°C i 40 minutter. Reaksjonsblandingen ble konsentrert /' vakuum og en løsning av resten oppløst i metylenklorid ble vasket med fortynnet saltsyre, vann, saltløsning, ble tørket over natriumsulfat og ble konsentrert/vakuum. Resten ble kromatografert (silika, 4 til 7% etylacetat i metylenklorid/heksaner4:1) og sluttproduktet ble omkrystallisert fra metanol, og man fikk et hvitt pulver (0,035 g, 30%), Sm.p. 144-146°C. A mixture of 4-(4-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.090 g, 0.29 mmol) and 4-iodophenol (0.076 g, 0.35 mmol) in triethylamine (3 mL, dry) was treated with a mixture of tetrakis(triphenylphosphine)palladium (0.013 g, 0.012 mmol), copper (l)-iodide (0.003 g, 0.016 mmol) and triphenylphosphine (a small crystal) under an argon atmosphere and stirred at 75° C for 40 minutes. The reaction mixture was concentrated in vacuo and a solution of the residue dissolved in methylene chloride was washed with dilute hydrochloric acid, water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed (silica, 4 to 7% ethyl acetate in methylene chloride/hexanes 4:1) and the final product was recrystallized from methanol to give a white powder (0.035 g, 30%), m.p. 144-146°C.

Anal. (C26H2804-1/5 H2O) beregnet: C 76,52, H 7,01, funnet: C 76,57, H 6,97. Anal. (C26H2804-1/5 H2O) calcd: C 76.52, H 7.01, found: C 76.57, H 6.97.

<1>H-NMR (400 MHz, CDCI3) 5 7,36 (d, 8,5 Hz, 2H), 7,23 (d, J=2,2 Hz, 1H), 7,12 (d-d, J=2,2 Hz, J=8,5 Hz, 1H), 6,86 (d, J=8,5, 1H), 6,80 (d, J=8,5, 2H), 5,22 (s, 1H), 4,80 (p, J=3,8Hz, 1H), 3,85 (s, 3H), 3,04 (d-t, J=6,0Hz, J=14,2, 2H), 2,47 (d,br, J=14,8, 2H), 2,4-2,1 (m, 4 H), 2,0 til 1,5 (m, 12H med H2O). <1>H-NMR (400 MHz, CDCl3) δ 7.36 (d, 8.5 Hz, 2H), 7.23 (d, J=2.2 Hz, 1H), 7.12 (d-d, J =2.2 Hz, J=8.5 Hz, 1H), 6.86 (d, J=8.5, 1H), 6.80 (d, J=8.5, 2H), 5.22 ( s, 1H), 4.80 (p, J=3.8Hz, 1H), 3.85 (s, 3H), 3.04 (d-t, J=6.0Hz, J=14.2, 2H), 2.47 (d,br, J=14.8, 2H), 2.4-2.1 (m, 4H), 2.0 to 1.5 (m, 12H with H2O).

Eksempel 46Example 46

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-metyl-[1,3,4]tiadiazol-2-yl)fenyl]etynyl)cykloheksan-1-on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl-[1,3,4]thiadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-one

46a) 2-(3-jodfenyl)-5-metyl-[1,3,4]tiadiazol46a) 2-(3-iodophenyl)-5-methyl-[1,3,4]thiadiazole

2-(3-Jodfenyl)-5-metyl-[1,3,4]tiadiazol ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området. 2-(3-Iodophenyl)-5-methyl-[1,3,4]thiadiazole was prepared according to usual methods which are well known to those skilled in the art.

46b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-metyl-[1,3,4]tiadiazol-2-yl)fenyl]etynyl)cykloheksan-1 -on 46b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl-[1,3,4]thiadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-one

En omrørt blanding av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan-1-on (0,100 g, 0,32 mmol) og 2-(3-jodfenyl)-5-metyl-[1,3,4]tiadiazol (0,097 g, 0,32 mmol) i tørr trietylamin (2,5 ml) ble behandlet under argon med en blanding av tetrakis(trifenylfosfin)palladium (0,016 g, 0,013 mmol), kobber-(l)-jodid (0,0033 g, 0,017 mmol) og trifenylfosfin (en liten krystall) ved 70°C i 1 time og ved 25 °C i 15 timer. Reaksjonsblandingen ble konsentrert /' vakuum og resten ble fordelt mellom metylenklorid og kald, fortynnet saltsyre. Den organiske fasen ble kromatografert (silika, 10 til 20% etylacetat i metylenklorid) og de rene fraksjonene ble samlet, konsentrert/vakuum og tørket ved 50 °C /' vakuum, og den sprøe harpiksen ble malt, og man fikk sluttproduktet som et gult pulver (0,128g, 79%). A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.100 g, 0.32 mmol) and 2-(3-iodophenyl)-5-methyl-[1,3, 4]thiadiazole (0.097 g, 0.32 mmol) in dry triethylamine (2.5 mL) was treated under argon with a mixture of tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol), copper (l)-iodide ( 0.0033 g, 0.017 mmol) and triphenylphosphine (a small crystal) at 70 °C for 1 h and at 25 °C for 15 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride and cold dilute hydrochloric acid. The organic phase was chromatographed (silica, 10 to 20% ethyl acetate in methylene chloride) and the pure fractions were pooled, concentrated/vacuum and dried at 50°C/'vacuum and the friable resin was ground to give the final product as a yellow powder (0.128g, 79%).

Anal. (C29H30N2O3S H2O) beregnet: C 69,02, H 6,39, N 5,55, funnet: C 68,91, H 6,21, N 5,35. Anal. (C29H30N2O3S H2O) calcd: C 69.02, H 6.39, N 5.55, found: C 68.91, H 6.21, N 5.35.

<1>H-NMR (400 MHz, CDCI3) 6 8,06 (t, J=1,6 Hz, 1H), 7,88 (d-t, J=1,4 Hz, J=8,1 Hz, 1H), 7,58 (d-d, J=1,2 Hz, J=9,0 Hz, 1H), 7,45 (t, J=7,8 Hz), 7,21 (d, J=2,2, 1H), 7,14 (d-d, J=8,4Hz, J=2,1Hz, 1H), 6,88 (d, J=8,5, 1H), 4,82 (p, J=4,1 Hz, 1H), 3,86 (s, 3H), 3,04 (d-t, J=6,1Hz, J=14,2, 2H), 2,84 (s, 3 H), 2,50 (d,br, J=14,9, 2H), 2,42-2,32 (m, 2H), 2,27 (d-t, J=2,8Hz, J=14,2Hz, 2H), 2,00-1,5 (m, 12H med H2O). <1>H-NMR (400 MHz, CDCl3) 6 8.06 (t, J=1.6 Hz, 1H), 7.88 (d-t, J=1.4 Hz, J=8.1 Hz, 1H ), 7.58 (d-d, J=1.2 Hz, J=9.0 Hz, 1H), 7.45 (t, J=7.8 Hz), 7.21 (d, J=2.2 , 1H), 7.14 (d-d, J=8.4Hz, J=2.1Hz, 1H), 6.88 (d, J=8.5, 1H), 4.82 (p, J=4, 1 Hz, 1H), 3.86 (s, 3H), 3.04 (d-t, J=6.1Hz, J=14.2, 2H), 2.84 (s, 3H), 2.50 ( d,br, J=14.9, 2H), 2.42-2.32 (m, 2H), 2.27 (d-t, J=2.8Hz, J=14.2Hz, 2H), 2.00 -1.5 (m, 12H with H2O).

Eksempel 47Example 47

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-metyl-[1,3,4]oksadiazol-2-yl)fenyl]etynyl)cykloheksan-1 -on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-one

47a) 2-(3-jodfenyl)-5-metyl-[1,3,4]oksadiazol 47a) 2-(3-iodophenyl)-5-methyl-[1,3,4]oxadiazole

2-(3-Jodfenyl)-5-metyl-[1,3,4]oksadiazo! ble fremstilt etter vanlige metoder som er velkjente for fagmannen på området og var et hvitt, fast stoff, Sm.p. 112,5-113,5<0>C. 2-(3-Iodophenyl)-5-methyl-[1,3,4]oxadiazo! was prepared by usual methods which are well known to those skilled in the art and was a white, solid substance, Sm.p. 112.5-113.5<0>C.

47b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-metyl-[1,3,4]oksadiazol-2-yl)fenyl]etynyl)cykloheksan-1 -on 47b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-one

En omrørt blanding av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-etynylcykloheksan-1-on (0,100 g, 0,32 mmol) og 5-(3-jodfenyl)-2-metyl-[1,3,4]oksadiazol (0,0915 g, 0,32 mmol) i tørr trietylamin (3,5 ml) ble behandlet under argon med en blanding av tetrakis(trifenylfosfin)palladium (0,016 g, 0,013 mmol), kobber-(l)-jodid (0,0033 g, 0,017 mmol) og trifenylfosfin (en liten krystall) ved 75°C i 1 time. Reaksjonsblandingen ble konsentrert/vakuum, resten ble ekstrahert i metylenklorid og den organiske fasen ble vasket med kald, fortynnet saltsyre, vann, saltløsning og ble tørket (natriumsulfat). Rensning med kromatografi (silika, 10 til 20% etylacetat i metylenklorid) etterfulgt av tørking ved 50 °C / vakuum, ga sluttproduktet som et hvitt pulver (0,068 g, 45%), Sm.p. 139-141°C. A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.100 g, 0.32 mmol) and 5-(3-iodophenyl)-2-methyl-[1,3, 4]oxadiazole (0.0915 g, 0.32 mmol) in dry triethylamine (3.5 mL) was treated under argon with a mixture of tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol), copper-(l)- iodide (0.0033 g, 0.017 mmol) and triphenylphosphine (a small crystal) at 75°C for 1 h. The reaction mixture was concentrated/vacuum, the residue was extracted into methylene chloride and the organic phase was washed with cold dilute hydrochloric acid, water, brine and dried (sodium sulfate). Purification by chromatography (silica, 10 to 20% ethyl acetate in methylene chloride) followed by drying at 50 °C / vacuum gave the final product as a white powder (0.068 g, 45%), m.p. 139-141°C.

Anal. (C29H30N2O4 I/3 H2O) beregnet: C 73,09, H 6,49, N 5,88, funnet: C 73,07, H6.35, N 5,79. Anal. (C29H30N2O4 I/3 H2O) calcd: C 73.09, H 6.49, N 5.88, found: C 73.07, H6.35, N 5.79.

<1>H-NMR (400 MHz, CDCI3) 8 8,15 (t, J=1,6Hz, 1H), 8,01 (d-t, J=1,4 Hz, J=7,9 Hz, 1H), 7,62 (d-d, J=1,5 Hz, J=7,8 Hz, 1H), 7,49 (t, J=7,9 Hz), 7,21 (d, J=2,3, 1H), 7,14 (d-d, J=8,5 Hz, J=2,4Hz, 1H), 6,88 (d, J=8,5, 1H), 4,82 (p, J=4,2 Hz, 1H), 3,86 (s, 3H), 3,04 (d-t, J=6,1 Hz, J=14,2, 2H), 2,64 (s, 3 H), 2,51 (d,br, J=15,0, 2H), 2,42-2,32 (m, 2H), 2,27 (d-t, J=2,8 Hz, J=14,2 Hz, 2H), 2,00-1,5 (m, 9H med H2O). <1>H-NMR (400 MHz, CDCl3) 8 8.15 (t, J=1.6Hz, 1H), 8.01 (d-t, J=1.4 Hz, J=7.9 Hz, 1H) , 7.62 (d-d, J=1.5 Hz, J=7.8 Hz, 1H), 7.49 (t, J=7.9 Hz), 7.21 (d, J=2.3, 1H), 7.14 (d-d, J=8.5 Hz, J=2.4Hz, 1H), 6.88 (d, J=8.5, 1H), 4.82 (p, J=4, 2 Hz, 1H), 3.86 (s, 3H), 3.04 (d-t, J=6.1 Hz, J=14.2, 2H), 2.64 (s, 3H), 2.51 (d,br, J=15.0, 2H), 2.42-2.32 (m, 2H), 2.27 (d-t, J=2.8 Hz, J=14.2 Hz, 2H), 2.00-1.5 (m, 9H with H2O).

Eksempel 48Example 48

Fremstilling av 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2[E]-(3-cyanofenyl)ethenyl)cykloheksan-1-on Preparation of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2[E]-(3-cyanophenyl)ethenyl)cyclohexan-1-one

48a) 3-cyanobenzylfosfonsyre-dietylester48a) 3-cyanobenzylphosphonic acid diethyl ester

En omrørt blanding av trietylfosfit (0,500 g, 2,95 mmol) og 3-cyanobenzyl-bromid (0,609 g, 2,95 mmol) ble tilbakeløpskokt ved 140°C under argon i 2 timer og de resulterende, flyktige stoffene ble fjernet ved romtemperatur / vakuum, og man fikk mellomproduktet som en fargeløs olje (0,62 g, 84%). A stirred mixture of triethyl phosphite (0.500 g, 2.95 mmol) and 3-cyanobenzyl bromide (0.609 g, 2.95 mmol) was refluxed at 140°C under argon for 2 h and the resulting volatiles were removed at room temperature / vacuum, and the intermediate was obtained as a colorless oil (0.62 g, 84%).

<1>H-NMR (400 MHz, CDCI3) 8 7,7-7,5 (m, 3H), 7,44 (t, J=7,8 Hz, 1H), 4,06 (p, J=7,6Hz, 4H), 3,17 (d J=21,8Hz, 2H), 1,27 (t, J=7,1Hz, 6H). <1>H-NMR (400 MHz, CDCl3) δ 7.7-7.5 (m, 3H), 7.44 (t, J=7.8 Hz, 1H), 4.06 (p, J= 7.6Hz, 4H), 3.17 (d J=21.8Hz, 2H), 1.27 (t, J=7.1Hz, 6H).

48b) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2[E]-(3-cyanofenyl)ethenyl)-1,1 - 48b) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2[E]-(3-cyanophenyl)ethenyl)-1,1 -

(etylendioksy)cykloheksan(ethylenedioxy)cyclohexane

En løsning av 3-cyanobenzylfosfonsyre-dietylester (0,54 g, 2,13 mmol) oppløst i tørr tetrahydrofuran (7 ml) ble tilsatt ved hjelp av en kanyle til en løsning av kalium-f-butoksyd (0,237 g, 2,11 mmol) oppløst i tørr tetrahydrofuran (15 ml), begge løsningene under argon og ble avkjølt til 0°C. Etter omrøring i 45 minutter, ble en løsning av 4-4-(3-cyklopentyloksy-4-metoksyfenyl)-1,1-(etylendioksy)-4-formylcykloheksan (0,38 g, 1,06 mmol) i tørr tetrahydrofuran (5 ml) tilsatt dråpevis. Man lot reaksjonsblandingen bli oppvarmet til romtemperatur. Etter 15 timer ble blandingen avkjølt med vandig ammoniumkloridløsning, ble konsentrert / vakuum , ble fordelt mellom metylenklorid/vandig ammoniumkloridløsning og det organiske ekstraktet ble vasket med vann, saltløsning, ble tørket (natriumsulfat) og konsentrert/' vakuum, og man fikk en blanding som inneholdt det ønskede sluttproduktet og overskudd av fosfonatester som en uren harpiks. A solution of 3-cyanobenzylphosphonic acid diethyl ester (0.54 g, 2.13 mmol) dissolved in dry tetrahydrofuran (7 mL) was added by cannula to a solution of potassium f-butoxide (0.237 g, 2.11 mmol) dissolved in dry tetrahydrofuran (15 mL), both solutions under argon and cooled to 0°C. After stirring for 45 min, a solution of 4-4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-formylcyclohexane (0.38 g, 1.06 mmol) in dry tetrahydrofuran ( 5 ml) added drop by drop. The reaction mixture was allowed to warm to room temperature. After 15 hours, the mixture was cooled with aqueous ammonium chloride solution, was concentrated/vacuum, was partitioned between methylene chloride/aqueous ammonium chloride solution and the organic extract was washed with water, brine, was dried (sodium sulfate) and concentrated/'vacuum, and a mixture was obtained which contained the desired end product and excess phosphonate ester as an impure resin.

<1>H-NMR (400 MHz, CDCI3) 5 7,62-7,4 (m, 4H), 7,36 (t, J=7,8 Hz, 1H), 6,90 (s og d, 2H), 6,83 (d, J=8,7Hz, 1H), 6,30 (d, J=16,4Hz, 1H), 6,16 (d, J=16,3 Hz, 1H), 4,75 (p, J=4,4 Hz, 1H), 4,06 (p, J=7,6Hz, 1H), 3,96 (q, J=3,3Hz, 4H), 3,84 (s, 3 H), 3,17 (d J=21,8 Hz, 0,3H), 2,35-1,5 (m, 20H med H2O), 1,27 (t, J=7,1 Hz, 1.3H). <1>H-NMR (400 MHz, CDCl3) δ 7.62-7.4 (m, 4H), 7.36 (t, J=7.8 Hz, 1H), 6.90 (s and d, 2H), 6.83 (d, J=8.7Hz, 1H), 6.30 (d, J=16.4Hz, 1H), 6.16 (d, J=16.3Hz, 1H), 4 .75 (p, J=4.4 Hz, 1H), 4.06 (p, J=7.6Hz, 1H), 3.96 (q, J=3.3Hz, 4H), 3.84 (s , 3 H), 3.17 (d J=21.8 Hz, 0.3H), 2.35-1.5 (m, 20H with H2O), 1.27 (t, J=7.1 Hz, 1.3H).

48c) 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2[E]-(3-cyanofenyl)ethenyl)-cykloheksan-1-on 48c) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2[E]-(3-cyanophenyl)ethenyl)-cyclohexan-1-one

En løsning av uren 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2[E]-(3-cyanofenyl)etenyl)-1,1-(etylendioksy)cykloheksan (0,58 g, 1,06 mmol) i tetrahydrofuran (20 ml) ble behandlet med 3N vandig saltsyre (2,3 ml) under argon og oppvarmet ved 75-80°C i 1 time. Ytterligere saltsyre (13 ml) ble deretter tilsatt og blandingen ble oppvarmet ved 75°C i ytterligere 15 minutter. Reaksjonsblandingen ble konsentrert / vakuum, ble ekstrahert i metylenklorid og det organiske ekstraktet ble vasket med vann, fortynnet natriumbikarbonatløsning, saltløsning og ble tørket (natriumsulfat). Rensning med kromatografi (silika, 1 til 2% etylacetat i metylenklorid) og krystallisering fra etyleter ga sluttproduktet som et hvitt, fast stoff (0,329 g, 74%). Sm.p. 116-117°C. A solution of impure 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2[E]-(3-cyanophenyl)ethenyl)-1,1-(ethylenedioxy)cyclohexane (0.58 g, 1.06 mmol) ) in tetrahydrofuran (20 mL) was treated with 3N aqueous hydrochloric acid (2.3 mL) under argon and heated at 75-80°C for 1 hour. Additional hydrochloric acid (13 mL) was then added and the mixture was heated at 75°C for a further 15 minutes. The reaction mixture was concentrated / vacuum, was extracted into methylene chloride and the organic extract was washed with water, dilute sodium bicarbonate solution, brine and was dried (sodium sulfate). Purification by chromatography (silica, 1 to 2% ethyl acetate in methylene chloride) and crystallization from ethyl ether gave the final product as a white solid (0.329 g, 74%). Sm.p. 116-117°C.

Anal. (C27H29NO3 I/6 H2O) beregnet: C 77,48, H 7,06, N 3,35, funnet: C 77,63, H 6,94, N 3,33. Anal. (C27H29NO3 I/6 H2O) calculated: C 77.48, H 7.06, N 3.35, found: C 77.63, H 6.94, N 3.33.

<1>H-NMR (400 MHz, CDCI3) 8 7,60 (s, 1H), 7,55-7,45 (m, 2H), 7,39 (t, J=7,7Hz, 1H), 6,97 (d-d, J=2,4Hz, J=8,5 Hz, 1H), 6,89 (d, J=8,4 Hz, 1H), 6,37 (d, J=16,1 Hz, 1H), 6,22 (d, J=16,2 Hz, 1H), 4,77 (p, J=4,5 Hz, 1H), 3,86 (s, 3H), 2,6-1,5 (m, 18H med H2O). <1>H-NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.55-7.45 (m, 2H), 7.39 (t, J=7.7Hz, 1H), 6.97 (d-d, J=2.4Hz, J=8.5 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.37 (d, J=16.1 Hz , 1H), 6.22 (d, J=16.2 Hz, 1H), 4.77 (p, J=4.5 Hz, 1H), 3.86 (s, 3H), 2.6-1 .5 (m, 18H with H2O).

Eksempel 49Example 49

Fremstilling av 4-(2-acetamidopyrimidin-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on Preparation of 4-(2-acetamidopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

Til en omrørt suspensjon av pyridinklorkromat (0,288 g, 1,34 mmol) i tørr metylenklorid (4 ml) under argon ble det tilsatt ved hjelp av en kanyle en løsning To a stirred suspension of pyridine chlorochromate (0.288 g, 1.34 mmol) in dry methylene chloride (4 mL) under argon was added by cannula a solution

av c/'s-[4-(2-acetamidopyrimidin-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-ol] (0,20 g, 0,445 mmol, fremstilt som beskrevet i "co-pending" U.S. patensøknad identifisert som P50287 (inngitt på samme dag) i metylenklorid (5 ml totalt). Etter 2 timer ved 25 °C ble etylacetat (ca. 10 ml) tilsatt, reaksjonsblandingen ble filtrert og bunnfallet ble vasket med ytterligere 10 ml etylacetat. Filtratet ble konsentrert og resten renset med flash-kromatografi på silikagel med 1:9 etylacetat:diklormetan, eluering av produktet med 20:80 til 30:70 etylacetatdiklormetan, og man fikk 4-(2-acetamidopyrimidin-5-yl-etynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on som et hvitt, fast stoff (0,033 g, 5,5%), Sm.p. 170-171°C. of c/'s-[4-(2-acetamidopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-ol] (0.20 g, 0.445 mmol, prepared as described in "co-pending" U.S. patent application identified as P50287 (filed on the same day) in methylene chloride (5 mL total). After 2 h at 25 °C, ethyl acetate (ca. 10 mL) was added, the reaction mixture was filtered, and the precipitate was washed with additional 10 mL ethyl acetate The filtrate was concentrated and the residue purified by flash chromatography on silica gel with 1:9 ethyl acetate:dichloromethane, eluting the product with 20:80 to 30:70 ethyl acetate dichloromethane to give 4-(2-acetamidopyrimidin-5-yl -ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one as a white solid (0.033 g, 5.5%), mp 170-171°C.

<1>H-NMR (400 MHz, CDCJ3) 8 8,65 (s, 2 H), 8,47 (s, 1 H), 7,14 (d, J=2,1 Hz, 1 H), 7,09 (dd, J=8,4, 2,3 Hz, 1 H), 6,87 (d, J=8,5Hz, 1 H), 4,80 (p, J=4,7, 1 H), 3,86 (s, 3 H), 2,94 (dt, J=23, 8,8 Hz, 2 H), 2,50 (s overlagret på 2,6-2,2 m, 9 H), 2,0-1,5 (m, overlagret på vann) ppm. <1>H-NMR (400 MHz, CDCJ3) 8 8.65 (s, 2 H), 8.47 (s, 1 H), 7.14 (d, J=2.1 Hz, 1 H), 7.09 (dd, J=8.4, 2.3 Hz, 1 H), 6.87 (d, J=8.5Hz, 1 H), 4.80 (p, J=4.7, 1 H), 3.86 (s, 3 H), 2.94 (dt, J=23, 8.8 Hz, 2 H), 2.50 (s superimposed on 2.6-2.2 m, 9 H ), 2.0-1.5 (m, superimposed on water) ppm.

Eksempel 50Example 50

Ved å gå frem som beskrevet i én eller flere av de foregående eksemplene, kan man fremstille de følgende forbindelsene: 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5- trifluormetyl[1,2,4]oksadiazol-3-yl)fenyl]etynyl)cykloheksan-1-on, By proceeding as described in one or more of the previous examples, the following compounds can be prepared: 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5- trifluoromethyl[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-one,

4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(3-trifluormetyl[1,2,4]oksadiazol-5-yl)fenyl]etynyl)cykloheksan-1-on, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-trifluoromethyl[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-one,

4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-trifluormetyl[1,3,4]oksadiazol-2-yl)fenyl]etynyl)cykloheksan-1-on, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-trifluoromethyl[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-one,

4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-trifluormetyl[1,3,4]tiadiazol-2-yl)fenyl]etynyl)cykloheksan-1 -on og 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-trifluoromethyl[1,3,4]thiadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-one and

4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[2-acetamidopyrimidin-5-yl]etynyl)cykloheksan-1 -on. 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[2-acetamidopyrimidin-5-yl]ethynyl)cyclohexan-1-one.

Anvendelse-eksemplerApplication examples

Eksempel AExample A

Hemmende virkning av forbindelser med formlene (I) og (II) på in vitro TNF-produksjonen av humane monocytter Inhibitory effect of compounds of formulas (I) and (II) on the in vitro TNF production of human monocytes

Den hemmende virkningen av forbindelsene med formlene (I) og (II) på in vitro TNF-produksjonen av humane monocytter kan bestemmes etter metoden som er beskrevet i Badger et al., EPO publisert søknad 0 411 754 A2, 6. februar 1991 og i Hanna, WO 90/15534, 27. desember 1990. The inhibitory effect of the compounds of formulas (I) and (II) on the in vitro TNF production of human monocytes can be determined by the method described in Badger et al., EPO published application 0 411 754 A2, February 6, 1991 and in Hanna, WO 90/15534, 27 December 1990.

Eksempel BExample B

To endotoksiske sjokkmodeller er blitt benyttet for å bestemme in vivo TNF-aktiviteten av forbindelsene med formlene (I) og (II). Metoden som ble anvendt i disse modellene er beskrevet i Badger et al., EPO publisert søknad 0 411 754 A2, 6. februar 1991 og i Hanna, WO 90/15534, 27. desember 1990. Two endotoxic shock models have been used to determine the in vivo TNF activity of the compounds of formulas (I) and (II). The method used in these models is described in Badger et al., EPO published application 0 411 754 A2, February 6, 1991 and in Hanna, WO 90/15534, December 27, 1990.

Forbindelsen i eksempel 1 utviser en positiv in v/Vo-respons ved å redusere serumnivåene av TNF fremkalt ved injeksjon av endotoksin. The compound of Example 1 exhibits a positive in v/Vo response by reducing the serum levels of TNF induced by endotoxin injection.

Eksempel CExample C

Isolering av PDE-isozymerIsolation of PDE isozymes

Den fosfodiesterase-inhiberende aktiviteten og selektiviteten av forbindelsene med formlene (I) og (II) kan bestemmes ved å anvende en serie av fem forskjellige PDE-isozymer. Vevene som anvendes som kilder for de forskjellige isozymer er som følger: 1) PDE Ib, svineaorta; 2) PDE le, marsvinhjerte; 3) PDE III, marsvinhjerte; 4) PDE IV, human monocytt; og 5) PDE V (også betegnet som "la"), canine trachealis. PDEs la, Ib, le og III renses delvis ved å anvende vanlige kromatografiske teknikker [Torphy og Cieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV renses til kinetisk homogenitet ved sekvensiell anvendelse av anion-byttere, etterfulgt av heparin-Sepharos kromatografi [Torphy et al., J. Biol. Chem., 267:1798-1804, 1992]. The phosphodiesterase inhibitory activity and selectivity of the compounds of formulas (I) and (II) can be determined by using a series of five different PDE isozymes. The tissues used as sources for the different isozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE le, guinea pig heart; 3) PDE III, guinea pig heart; 4) PDE IV, human monocyte; and 5) PDE V (also designated as "la"), canine trachealis. PDEs la, Ib, le and III are partially purified using standard chromatographic techniques [Torphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purified to kinetic homogeneity by sequential application of anion exchangers, followed by heparin-Sepharos chromatography [Torphy et al., J. Biol. Chem., 267:1798-1804, 1992].

Fosfodiesteraseaktivitet ble bestemt som beskrevet i metoden til Torphy og Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Det er vist at forbindelsene i eksemplene med formlene (I) og (II) har positive verdier for IC50i nanomolar til uM-området. Phosphodiesterase activity was determined as described in the method of Torphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. The compounds of the examples of formulas (I) and (II) have been shown to have positive values for IC 50 i nanomolar to the µM range.

Claims (10)

1. Forbindelse karakterisert ved formell 1. Connection characterized by formal hvor: Ri er-(CR4 R5 )n C(0)0(CR4 R5 )m R6 , -(CR4 R5 )n C(0)NR4 (CR4 R5)mR6, -(CR4 R5 )nO(CR4R5)mR6 eller -(CR4 Rs)r R6 hvor alkylgruppene kan være usubstituert eller substituert med ett eller flere fluoratomer; m er 0 til 2; n er 0 til 4; r er 0 til 6; R4 og R5 er uavhengig hydrogen eller Ci-2 -alkyl; R6 er hydrogen, metyl, hydroksyl, aryl, halogensubstituert aryl, aryloksy-Ci-3 -alkyl, halogensubstituert aryloksyCi-3 -alkyl, indanyl, indenyl, C7 -H-polycykloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrotienyl, tienyl, tetrahydrotiopyranyl, tiopyranyl, C3 -6 -cykloalkyl eller et C4 -6 -cykloalkyl inneholdende én eller to umettede bindinger, hvor cykloalkyl- eller den heterocykliske gruppen kan være usubstituert eller substituert med 1 til 3 metylgrupper, én etylgruppe eller én hydroksylgruppe; forutsatt at: a) når R6 er hydroksyl, er m 2; eller b) når R6 er hydroksyl, er r 2 til 6; eller c) når R6 er 2-tetrahydropyranyl, 2-tetrahydrotiopyranyl, 2-tetrahydrofuranyl eller 2-tetrahydrotienyl, er m 1 eller 2; eller d) når R6 er 2-tetrahydropyranyl, 2-tetrahydrotiopyranyl, 2-tetrahydrofuranyl eller 2-tetrahydrotienyl, er r 1 til 6; e) når n er 1 og m er 0, er R6 forskjellig fra H i -(CR4 R5 )n O(CR4 R5 )mR6; X er YR2 , fluor, NR4 R5 , eller formylamin; Y er O eller S(0)m' ; m' erO, 1 eller 2; X2 er O eller NR8 ; X3 er hydrogen eller X; R2 er -CH3 eller -CH2 CH3 usubstituert eller substituert med ett eller flere fluoratomer; s er 0 til 4; R3 er COOR14 , C(0)NR4 R14 eller R7 ; W er alkyl med 2 til 6 karbonatomer, alkenyl med 2 til 6 karbonatomer eller alkynyl med 2 til 6 karbonatomer; Z er O, NR7 , NCR4 R5 C2 -6 -alkenyl, NOR14 , NOR15 , NOCR4 R5 C2-6-alkenyl, NNR4 R14 , NNR4 R15 , NCN, NNR8 C(0)NR8 R14 , NNR8 C(S)NR8 R14 eller =Z er 2-(1,3-ditian), 2-(1,3-ditiolan), dimetyltioketal, dietyltioketal, 2-(1,3-dioksolan), 2-(1,3-dioksan), 2-(1,3-oksatiolan), dimetylketal eller dietylketal; R7 er -(CR4 R5 )qRi2 eller Ci_6 -alkyl hvor R12 eller Ci_6 -alkylgruppen er usubstituert eller substituert én eller flere ganger med metyl eller etyl som er usubstituert eller substituert med 1 til 3 fluoratomer, -F, -Br, -Cl, -NO2 , -NR-|qRi1 . -C(0)R8 , -CO2 R8. -0(CH2 )2 -4 0R8 , -0(CH2 )qR8 . -CN, -C(0)NRioRl 1, -O(CH2 )qC(O)NRl0 Rl1 , -0(CH2 )qC(0)R9 , -NRio C(0)NRi oRl1 , -NRioC(0)Rii, -NRioC(0)ORg, -NRioC(0)Ri3 , -C(NRi0)NRioRl 1, -C(NCN)NR10 R11 , -C(NCN)SRg, -NRioC(NCN)SRg , -NRi oC(NCN)NRioRl1. -NRioS(0)2R9 , -S(0)m' R9 , -NRioC(0)C(0)NRioRl1 , -NRioC(0)C(0)Rl o eller R13 <;> q erO, 1 eller2; R12 er Ri3> (CH2 )q, C3 -C7 -cykloalkyl, (2-, 3- eller 4-pyridyl), pyrimidyl, pyrazolyl, (1-eller 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morfolinyl, furanyl, (2- eller 3-tienyl), kinolinyl, naftyl eller fenyl; R8 er hydrogen eller Rg; Rg er C<|_4 -alkyl usubstituert eller substituert med ett til tre fluoratomer;where: Ri is-(CR4 R5 )n C(0)0(CR4 R5 )m R6 , -(CR4 R5 )n C(0)NR4 (CR4 R5 )m R6 , -(CR4 R5 )nO(CR4R5)mR6 or -(CR4 Rs)r R6 where the alkyl groups may be unsubstituted or substituted with one or more fluorine atoms; m is 0 to 2; n is 0 to 4; r is 0 to 6; R 4 and R 5 are independently hydrogen or C 1-2 alkyl; R 6 is hydrogen, methyl, hydroxyl, aryl, halogen substituted aryl, aryloxy-Ci-3 -alkyl, halogen-substituted aryloxyCi-3 -alkyl, indanyl, indenyl, C7 -H-polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3 -6 -cycloalkyl or a C4 - 6 -cycloalkyl containing one or two unsaturated bonds, where the cycloalkyl or heterocyclic group may be unsubstituted or substituted with 1 to 3 methyl groups, one ethyl group or one hydroxyl group; presumed that: a) when R6 is hydroxyl, m is 2; or b) when R 6 is hydroxyl, r is 2 to 6; or c) when R 6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, m is 1 or 2; or d) when R 6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, r is 1 to 6; e) when n is 1 and m is 0, R 6 is different from H i -(CR 4 R 5 )n O(CR 4 R 5 )m R 6 ; X is YR 2 , fluorine, NR 4 R 5 , or formylamine; Y is O or S(0)m'; m' is 0, 1 or 2; X 2 is O or NR 8 ; X 3 is hydrogen or X; R 2 is -CH 3 or -CH 2 CH 3 unsubstituted or substituted with one or more fluorine atoms; s is 0 to 4; R 3 is COOR 14 , C(O)NR 4 R 14 or R 7 ; W is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z is O, NR7 , NCR4 R5 C2 -6 -alkenyl, NOR14 , NOR15 , NOCR4 R5 C2-6-alkenyl, NNR4 R14 , NNR4 R15 , NCN, NNR8 C(0)NR8 R14 , NNR8 C(S)NR8 R14 or =Z is 2-(1,3-dithiane), 2-(1,3-dithiolane), dimethylthioketal, diethylthioketal, 2-(1,3-dioxolane), 2-(1,3-dioxane), 2-( 1,3-oxathiolane), dimethyl ketal or diethyl ketal; R7 is -(CR4 R5 )qRi2 or Ci_6 -alkyl where R12 or the Ci_6 -alkyl group is unsubstituted or substituted one or more times with methyl or ethyl which is unsubstituted or substituted with 1 to 3 fluorine atoms, -F, -Br, -Cl, -NO2 , -NR-|qRi1 . -C(O)R 8 , -CO 2 R 8 . -0(CH2 )2 -4 0R8 , -0(CH2 )qR8 . -CN, -C(0)NRioRl 1 , -O(CH2 )qC(O)NRl0 Rl1 , -0(CH2 )qC(0)R9 , -NRio C(0)NRi oRl1 , -NRioC(0)Rii, -NRioC(0)ORg, -NRioC(0)Ri3 , -C(NRiO)NRioRl 1, -C(NCN)NR10 R11 , -C(NCN)SRg, -NRioC(NCN)SRg , -NRi oC(NCN)NRioRl1. -NRioS(0)2R9 , -S(0)m' R9 , -NRioC(0)C(0)NRioRl , -NRioC(0)C(0)Rl o or R13 <;> q is 0, 1 or 2; R12 is Ri3> (CH2 )q, C3 -C7 -cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1-or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl or phenyl; R 8 is hydrogen or R 8 ; R 8 is C 1 -4 -alkyl unsubstituted or substituted with one to three fluorine atoms; R-|0 er 0R8 eller Rn; R-] i er hydrogen eller C<|_4 -alkyl usubstituert eller substituert med ett til tre fluoratomer; eller når Ri0 og Ri 1 er lik NRirjRl 1, kan de sammen med nitrogenatomet danne en 5- til 7-leddet ring som bare inneholder karbonatomer eller karbonatomer og minst et heteroatom valgt fra 0, N eller S; R13 er oksazolidinyl, oksazolyl, tiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, tiazolidinyl, isoksazolyl, oksadiazolyl eller tiadiazolyl, og hver av disse heterocykliske ringene er knyttet gjennom et karbonatom, og hver kan være usubstituert eller substituert med én eller to Ci_2 -alkylgrupper, som kan være usubstituert eller hvor metylgruppen er substituert med 1 til 3 fluoratomer; R-I4 er hydrogen eller R7 ; eller når Rs og R14 er lik NR8 R14 kan de sammen nitrogenatomet danne en 5- til 7-leddet ring som består av bare karbonatomer eller karbonatomer og minst ett heteroatom valgt fra O, N eller S; forutsatt at: f) R7 er ikke lik C-|_4-alkyl usubstituert eller substituert med ett til tre fluoratomer; eller farmasøytisk akseptable salter derav. R-|0 is 0R8 or Rn; R-] i is hydrogen or C<|-4 -alkyl unsubstituted or substituted with one to three fluorine atoms; or when Ri 0 and Ri 1 are equal to NRirjRl 1 , they may together with the nitrogen atom form a 5- to 7-membered ring containing only carbon atoms or carbon atoms and at least one heteroatom selected from 0, N or S; R 13 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl or thiadiazolyl, and each of these heterocyclic rings is linked through a carbon atom, and each may be unsubstituted or substituted with one or two Ci_2 -alkyl groups, which may be unsubstituted or where the methyl group is substituted with 1 to 3 fluorine atoms; R-I4 is hydrogen or R7; or when R 5 and R 14 are equal to NR 8 R 14 they may together with the nitrogen atom form a 5- to 7-membered ring consisting of only carbon atoms or carbon atoms and at least one heteroatom selected from O, N or S; presumed that: f) R 7 is not equal to C 1-4 alkyl unsubstituted or substituted with one to three fluorine atoms; or pharmaceutically acceptable salts thereof. 2. Forbindelse ifølge krav 1 karakterisert ved at Ri er-CH2 -cyklopropyl, -cyklopentyl, -3-hydroksycyklopentyl, metyl eller CF2 H; X er YR2 ; Y er oksygen; X2 er oksygen; X3 er hydrogen; R2 er CF2 H eller metyl, W er etynyl eller 1,3-butadiynyl, R3 er en substituert eller usubstituert pyrimidinylring, X er YR2 ogZerO, NR7 . 2. Compound according to claim 1, characterized in that Ri is -CH2 -cyclopropyl, -cyclopentyl, -3-hydroxycyclopentyl, methyl or CF2 H; X is YR 2 ; Y is oxygen; X 2 is oxygen; X 3 is hydrogen; R 2 is CF 2 H or methyl, W is ethynyl or 1,3-butadiynyl, R 3 is a substituted or unsubstituted pyrimidinyl ring, X is YR 2 and ZerO, NR 7 . 3. Forbindelse ifølge krav 2, karakterisert ved å være 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-metylsulfonylpyrimidin-4-yletynyl)cykloheksan-1-on, 4-(2-aminopyrimidin-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, eller 4-(2-acetamidopyrimidin-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on. 3. Compound according to claim 2, characterized by being 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl)cyclohexan-1-one, 4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, or 4-(2-acetamidopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one. 4. Forbindelse ifølge krav 1, karakterisert ved at R-| er -CH2 -cyklopropyl, -cyklopentyl, -3-hydroksycyklopentyl, metyl eller CF2 H; X er YR2 ; Y er oksygen; X2 er oksygen; X3 er hydrogen; R2 er CF2 H eller metyl, W er etynyl eller 1,3-butadiynyl, R3 er R7 hvor R7 er en usubstituert eller substituert aryl- eller heteroarylring, X er YR2 og Z er O. 4. Compound according to claim 1, characterized in that R-| is -CH 2 -cyclopropyl, -cyclopentyl, -3-hydroxycyclopentyl, methyl or CF 2 H; X is YR 2 ; Y is oxygen; X 2 is oxygen; X 3 is hydrogen; R2 is CF2 H or methyl, W is ethynyl or 1,3-butadiynyl, R3 is R7 where R7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2 and Z is O. 5. Forbindelse ifølge krav 1, karakterisert ved at den er 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-aminofenyletynyl)cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-acetamidofenyletynyl)-cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-acetamidofenyletynyl)-cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-karbometoksyfenyl-etynyl)cykloheksan-1 -on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-karboksyfenyl-etynyl)cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-aminofenyletynyl)cykloheksan-1-on 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(4-pyridyletynyl)cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-{[4-(2-hydroksyetan-1-oksy)fenyl]etynyl}cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(3-pyridyletynyl)cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[4-(2-hydroksyetan-1-oksy)fenyl]-etynyl)cykloheksan-1 -on, 4-(4-karbometoksyfenyletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, 4-(4-karboksyfenyletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)4-(2-[4-(1-piperidinokarbonylmetoksy)-fenyl]etynyl)cykloheksan-1 -on, 4-(2-[4-karboksymetyloksyfenyl]etynyl)-4-(3-cyklopentyloksy-4-metoksy-fenyl)cykloheksan-1 -on, 4-(2-[4-karbometoksymetyloksyfenyl]etynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1 -on, 4-(2-karbometoksyfenyletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3,5-dikarbometoksyfenyl]-etynyl)cykloheksan-1-on, 4-(2-[4-klorfenyl]etynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on, 4-(2-karbometoksytien-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, 4-(2-[3-cyanofenyl]etynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[4-hydroksyfenyl]etynyl)-cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2[E]-(3-cyanofenyl)ethenyl)-cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3,5-dicyanofenyl]etynyl)-cykloheksan-1-on, 4-(2-karboksytien-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, natriumsalt, 4-(2-cyanotien-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[5-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-2-yletynyl]cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-metyl-[1,2,4]oksadiazol-3-yl)fenyl]etynyl)cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(3-metyl-[1,2,4]oksadiazol-5-yl)fenyl]etynyl)cykloheksan-1-on, ^(S-cyklopentyloksy^-metoksyfenyO^-^^S-metyl-Il^.^oksadiazol^-yl)tien-2-yletynyl]cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-metyl-[1,3,4]oksadiazol-2-yl)fenyl]etynyl)cykloheksan-1-on, 4-(2-karbometoksytien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, 4-(2-karboksytien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, 4-(2-cyanotien-4-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, -(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(3-metyl[1,2,4]oksadiazol-5-yl)fenyl]etynyl)cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-[2-(5-metyl-[1,2,4]oksadiazol-2-yl)tien-4-yletynyl]cykloheksan-1-on, 4-(4-karbometoksytien-2-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, 4-(4-karboksytien-2-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-metyl-[1> 3,4]tiadiazol-2-yl)fenyl]etynyl)cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(1-metylimidazol-2-yletynyl)-cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(imidazol-2-yletynyl)cykloheksan-1-on, saltsyresalt, 4-(2-acetamidopyrimidin-5-yletynyl)-4-(3-cyklopentyloksy-4-metoksyfenyl)-cykloheksan-1-on, 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-metyl[1,3,4]oksadiazol-2-yl)fenyl]etynyl)cykloheksan-1-on, eller 4-(3-cyklopentyloksy-4-metoksyfenyl)-4-(2-[3-(5-metyl[1,3,4]tiadiazol-2-yl)fenyl]etynyl)cykloheksan-1-on.5. Compound according to claim 1, characterized in that it is 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-aminophenylethynyl)cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-acetamidophenylethynyl)-cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-acetamidophenylethynyl)-cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-carbomethoxyphenyl-ethynyl)cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-carboxyphenyl-ethynyl)cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-aminophenylethynyl)cyclohexan-1-one 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-{[4-(2-hydroxyethane-1- oxy)phenyl]ethynyl}cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-pyridylethynyl)cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-(2-hydroxyethane- 1-oxy)phenyl]-ethynyl)cyclohexan-1-one, 4-(4-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, 4-(4-carboxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)4-(2-[4-(1-piperidinocarbonylmethoxy)-phenyl]ethynyl)cyclohexan-1-one, 4-(2-[4-carboxymethyloxyphenyl]ethynyl)-4-(3-cyclopentyloxy-4-methoxy-phenyl)cyclohexan-1-one, 4-(2-[4-carbomethoxymethyloxyphenyl]ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one, 4-(2-carbomethoxyphenylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3,5-dicarbomethoxyphenyl]-ethynyl)cyclohexan-1-one, 4-(2-[4-chlorophenyl]ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one, 4-(2-carbomethoxythien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, 4-(2-[3-cyanophenyl]ethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[4-hydroxyphenyl]ethynyl)-cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2[E]-(3-cyanophenyl)ethenyl)-cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3,5-dicyanophenyl]ethynyl)-cyclohexan-1-one, 4-(2-carboxythien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, sodium salt, 4-(2-cyanothien-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-one, ^(S-cyclopentyloxy^-methoxyphenyO^-^^S-methyl-II^.^oxadiazol^-yl)thien-2-ylethynyl]cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-one, 4-(2-carbomethoxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, 4-(2-carboxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, 4-(2-cyanothien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, -(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[2-(5-methyl-[1,2,4]oxadiazol-2-yl)thien-4-ylethynyl]cyclohexan-1-one, 4-(4-carbomethoxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, 4-(4-carboxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl-[1>3,4]thiadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(1-methylimidazol-2-ylethynyl)-cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(imidazol-2-ylethynyl)cyclohexan-1-one, hydrochloric acid salt, 4-(2-acetamidopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one, 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,3,4]oxadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-one, or 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5-methyl[1,3,4]thiadiazol-2-yl)phenyl]ethynyl)cyclohexan-1-one. 6. Forbindelse karakterisert ved formel II 6. Compound characterized by formula II hvor: R-l er-(CR4 R5 )n C(0)0(CR4 R5 )m R6 , -(CR4 R5 )n C(0)NR4 (CR4 R5 )mR6 , -(CR4R5)nO(CR4R5)mR6 eller (CR4 R5 )rR6 hvor alkylgruppene kan være usubstituerte eller substituerte med ett eller flere fluoratomer; m er 0 til 2; n er 0 til 4; r er 0 til 6; R4 og R5 er uavhengig valgt fra hydrogen eller Ci-2 -alkyl; R6 er hydrogen, metyl, hydroksyl, aryl, halogensubstituert aryl, aryloksyCi-3 -alkyl, halogensubstiuert aryloksyCi-3 -alkyl, indanyl, indenyl, C7 -ii-polycykloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrotienyl, tienyl, tetrahydrotiopyranyl, tiopyranyl, C3 -6 -cykloalkyl eller en C4 -6 -cykloalkylgruppe inneholdende én eller to umettede bindinger, hvor cykloalkyl- og de heterocykliske gruppene er usubstituert eller substituert med 1 til 3 metylgrupper, en etylgruppe eller en hydroksylgruppe; forutsatt at: a) når R6 er hydroksyl, er m 2; eller b) når R6 er hydroksyl, er r 2 til 6; eller c) når R6 er 2-tetrahydropyranyl, 2-tetrahydrotiopyranyl, 2-tetrahydrofuranyl eller 2-tetrahydrotienyl, er m 1 eller 2; eller d) når R6 er 2-tetrahydropyranyl, 2-tetrahydrotiopyranyl, 2-tetrahydrofuranyl eller 2-tetrahydrotienyl, er r 1 til 6; e) når n er 1 og m er 0, er R6 forskjellig fra H i -(CR4 R5 )n O(CR4 R5 )mR6 ; X er YR2 , fluor, NR4 R5 eller formylamin; Y er 0 eller S(0)m' ; m' erO, 1 eller 2; X2 er 0 eller NRs; X3 er hydrogen eller X; R2 er uavhengig valgt fra -CH3 eller -CH2 CH3 usubstituert eller substituert med ett eller flere fluoratomer; s er 0 til 4; R3 er COOR14, C(0)NR4 R14 eller R7 ; W er alkyl med 2 til 6 karbonatomer, alkenyl med 2 til 6 karbonatomer eller alkynyl med 2 til 6 karbonatomer; T erC(Y')Rl4 . C(0)ORi4 , C(Y')NRiqR14 , C(NRio)NRioR14- CN, C(N0R8 )R14 , C(0)NR8 NR8 C(0)R8 , C(0)NR8 NRioR14 , C(NORi4 )R8 . C(NR8 )NRioR14 , C(NR14 )NR8 R8 , C(NCN)NRioR14 , C(NCN)SRg, (2-, 4- eller 5-imidazolyl), (3-, 4- eller 5-pyrazolyl), (4- eller 5-triazolyl[1,2,3]), (3- eller 5-triazolyl[1,2,4]), (5-tetrazolyl), (2-, 4- eller 5-oksazolyl), (3-, 4- eller 5-isoksazolyl), (3- eller 5-oksadiazolyl[1,2,4]), (2-oksadiazolyl[1,3,4]), (2-tiadiazolyl[1,3,4]), (2-, 4-eller 5-tiazolyl), (2-, 4- eller 5-oksazolidinyl), (2-, 4- eller 5-tiazolidinyl) eller (2-, 4-eller 5-imidazolidinyl); hvor alle de heterocykliske ringsystemene eventuelt kan være substituert én eller flere ganger med R14 ; Y' er O eller S; R7 er -(CR4 R5 )qR<|2 eller Cf _g-alkyl hvor R12 eller Ci.ø-alkylgruppen er usubstituert eller substituert én eller flere ganger med metyl eller etyl som er usubstituert eller substituert med 1 til 3 fluoratomer, -F, -Br, -Cl, -NO2 , -NR<| <q>Rh . -C(0)R8 , -CO2R8 , -0(CH2 )2-4 0R8 . -0(CH2 )qR8 , -CN, -C(O)NRi0Rl1, -0(CH2 )qC(0)NRio Rl1 , -0(CH2 )qC(0)R9 , -NRi0 C(0)NRioRl1 , -NRioC(0)Rii, -NRioC(0)ORg, -NRioC(0)Ri3 , -C(NRio)NRioRl1. -C(NCN)NRio Rl1 , -C(NCN )SRg, -NRioC(NCN)SRg , -NRio C(NCN)NRioRl1 , -NRioS(0)2 Rg, -S(0)m' R9 , -NRioC(0)C(0)NRioRl1 , -NRioC(0)C(0)Rio eller R13 <!> q er 0, 1, eller 2; R12 er R13 , (CH2 )q,C3 -C7 -cykloalkyl, (2-, 3- eller 4-pyridyl), pyrimidyl, pyrazolyl, (1-eller 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morfolinyl, furanyl, (2- eller 3-tienyl), kinolinyl, naftyl eller fenyl; Rq er uavhengig valgt fra hydrogen eller Rg; Rg er C-|_4 -alkyl usubstituert eller substituert med ett til tre fluoratomer; R-IO er OR8 eller Rn; R-j 1 er hydrogen eller C-|_4 -alkyl usubstituert eller substituert med ett til tre fluoratomer; eller når Ri0 og Ri 1 er lik NR1 rjRl 1 kan de sammen med nitrogenatomet danne en 5- til 7-leddet ring som bare består av karbonatomer eller karbonatomer og minst ett heteroatom valgt fra 0, N, eller S; R13 er en substituert eller usubstituert heteroarylgruppe valgt fra gruppen bestående av oksazolidinyl, oksazolyl, tiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, tiazolidinyl, isoksazolyl, oksadiazolyl og tiadiazolyl og hvor R-|3 er substituert på R12 eller R13 er ringene bundet ved et karbonatom og hver annen Ri3 -ring kan være usubstituert eller substituert med én eller to C-i_2 -alkylgrupper, som kan være usubstituert eller substituert på metylgruppen med 1 til 3 fluoratomer; R14 er hydrogen eller R7 ; eller når Rs og R14 er lik NRsR14 kan de sammen med nitrogenatomet danne en 5- til 7-leddet ring som bare består av karbonatomer eller karbonatomer og minst et heteroatom valgt fra O, N eller S; forutsatt at: f) R7 er ikke C-|_4~ alkyl usubstituert eller substituert med ett til tre fluoratomer; eller farmasøytisk akseptable salter derav. where: R-1 is-(CR4 R5 )n C(0)0(CR4 R5 )m R6 , -(CR4 R5 )n C(0)NR4 (CR4 R5 )mR6 , -(CR4R5)nO(CR4R5)mR6 or (CR4 R5 )rR6 where the alkyl groups may be unsubstituted or substituted with one or more fluorine atoms; m is 0 to 2; n is 0 to 4; r is 0 to 6; R 4 and R 5 are independently selected from hydrogen or C 1-2 alkyl; R 6 is hydrogen, methyl, hydroxyl, aryl, halogen substituted aryl, aryloxyCi-3 -alkyl, halogen-substituted aryloxyCi-3 -alkyl, indanyl, indenyl, C7 -ii-polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3 -6 -cycloalkyl or a C4 -6 - cycloalkyl group containing one or two unsaturated bonds, where the cycloalkyl and the heterocyclic groups are unsubstituted or substituted with 1 to 3 methyl groups, an ethyl group or a hydroxyl group; presumed that: a) when R6 is hydroxyl, m is 2; or b) when R 6 is hydroxyl, r is 2 to 6; or c) when R 6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, m is 1 or 2; or d) when R 6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, r is 1 to 6; e) when n is 1 and m is 0, R6 is different from H i -(CR4 R5 )n O(CR4 R5 )mR6 ; X is YR 2 , fluorine, NR 4 R 5 or formylamine; Y is 0 or S(0)m' ; m' is 0, 1 or 2; X2 is 0 or NRs; X 3 is hydrogen or X; R 2 is independently selected from -CH 3 or -CH 2 CH 3 unsubstituted or substituted with one or more fluorine atoms; s is 0 to 4; R 3 is COOR 14 , C(O)NR 4 R 14 or R 7 ; W is alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; T is C(Y')Rl4 . C(0)ORi4 , C(Y')NRiqR14 , C(NRio)NRioR14- CN, C(N0R8 )R14 , C(0)NR8 NR8 C(0)R8 , C(0)NR8 NRioR14 , C(NORi4 ) R8. C(NR8 )NRioR14 , C(NR14 )NR8 R8 , C(NCN)NRioR14 , C(NCN)SRg, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), ( 4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), ( 3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]), (2-, 4-or 5 -thiazolyl), (2-, 4- or 5-oxazolidinyl), (2-, 4- or 5-thiazolidinyl) or (2-, 4- or 5-imidazolidinyl); where all the heterocyclic ring systems may optionally be substituted one or more times with R14; Y' is O or S; R7 is -(CR4 R5 )qR<|2 or Cf _g-alkyl where R12 or the C1-ø-alkyl group is unsubstituted or substituted one or more times with methyl or ethyl which is unsubstituted or substituted with 1 to 3 fluorine atoms, -F, -Br, -Cl, -NO2, -NR<| <q>Rh . -C(0)R8 , -CO2R8 , -O(CH2 )2-4 0R8 . -O(CH2 )qR8 , -CN, -C(O)NRi0Rl1, -0(CH2 )qC(0)NRio Rl1 , -0(CH2 )qC(0)R9 , -NRi0 C(0)NRioRl1 , -NRioC(0)Rii, -NRioC(0)ORg, -NRioC(O)Ri3 , -C(NRio)NRioR1. -C(NCN)NRio Rl1 , -C(NCN )SRg, -NRioC(NCN)SRg , -NRio C(NCN)NRioRl1 , -NRioS(0)2 Rg, -S(0)m' R9 , -NRioC(0)C(0)NRioRl 1 , -NRioC(0)C(0)Rio or R13 <!> q is 0, 1, or 2; R12 is R13 , (CH2 )q,C3 -C7 -cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1-or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl or phenyl; Rq is independently selected from hydrogen or Rg; R 8 is C 1-4 alkyl unsubstituted or substituted with one to three fluorine atoms; R-10 is OR8 or Rn; R-j 1 is hydrogen or C-1-4 alkyl unsubstituted or substituted with one to three fluorine atoms; or when Ri0 and Ri1 are equal to NR1 rjR1 1 they may together with the nitrogen atom form a 5- to 7-membered ring consisting only of carbon atoms or carbon atoms and at least one heteroatom selected from 0, N, or S; R13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl and thiadiazolyl and where R-|3 is substituted on R12 or R13 the rings are bonded at a carbon atom and every other R 13 ring may be unsubstituted or substituted with one or two C 1-2 alkyl groups, which may be unsubstituted or substituted on the methyl group with 1 to 3 fluorine atoms; R 14 is hydrogen or R 7 ; or when R 5 and R 14 are equal to NR 5 R 14 they may together with the nitrogen atom form a 5- to 7-membered ring consisting only of carbon atoms or carbon atoms and at least one heteroatom selected from O, N or S; presumed that: f) R7 is not C-1-4 alkyl unsubstituted or substituted with one to three fluorine atoms; or pharmaceutically acceptable salts thereof. 7. Forbindelse ifølge krav 6, karakterisert ved at Ri er -CH2 -cyklopropyl, -cyklopentyl, -3-hydroksycyklopentyl, metyl eller CF2 H; X er YR2 ; Y er oksygen; X2 er oksygen; X3 er hydrogen; R2 er CF2 H eller metyl, W er etynyl eller 1,3-butadiynyl, R3 er R7 hvor R7 er en usubstituert eller substituert aryl- eller heteroarylring, X er YR2 , Z er O og Z' er COOR14 . 7. Compound according to claim 6, characterized in that Ri is -CH 2 -cyclopropyl, -cyclopentyl, -3-hydroxycyclopentyl, methyl or CF 2 H; X is YR 2 ; Y is oxygen; X 2 is oxygen; X 3 is hydrogen; R 2 is CF 2 H or methyl, W is ethynyl or 1,3-butadiynyl, R 3 is R 7 where R 7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR 2 , Z is O and Z' is COOR 14 . 8. Forbindelse ifølge krav 7, karakterisert ved at W er 1,3-butadiynyl og R3 er usubstituert eller substituert pyrimidin-5-yl. 8. Compound according to claim 7, characterized in that W is 1,3-butadiynyl and R3 is unsubstituted or substituted pyrimidin-5-yl. 9. Farmasøytisk preparat, karakterisert ved at det består av en forbindelse ifølge ethvert av kravene 1 til 5 og en farmasøytisk akseptabel eksipient. 9. Pharmaceutical preparation, characterized in that it consists of a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient. 10. Fremgangsmåte for å behandle astma som omfatter administering til et pattedyr, omfattende mennesker, som har behov for dette, en effektiv mengde av en forbindelse ifølge ethvert av kravene 1 til 5.10. A method of treating asthma comprising administering to a mammal, including humans, in need thereof, an effective amount of a compound according to any one of claims 1 to 5.
NO972898A 1994-12-23 1997-06-20 4,4- (Disubstituted) Cyclohexan-1-One Monomers and Related Compounds NO972898L (en)

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