AU708349B2 - 4,4-(disubstituted)cyclohexan-1-one monomers and related compounds - Google Patents
4,4-(disubstituted)cyclohexan-1-one monomers and related compounds Download PDFInfo
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- AU708349B2 AU708349B2 AU46883/96A AU4688396A AU708349B2 AU 708349 B2 AU708349 B2 AU 708349B2 AU 46883/96 A AU46883/96 A AU 46883/96A AU 4688396 A AU4688396 A AU 4688396A AU 708349 B2 AU708349 B2 AU 708349B2
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Description
WO 96/19995 PCT/US95/16858 4 4 -(Disubstituted)cyclohexan-l-one Monomers and Related Compounds Field of Invention The present invention relates to novel 4 4 -(disubstituted)cyclohexan- -ones and related compounds, pharmaceutical compositions containing these compounds, and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
Background of the Invention Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.
Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma. An alternative to the "mediator approach" is to regulate the activity of the cells responsible for the pathophysiology of the disease.
One such way is by elevating levels of cAMP (adenosine cyclic monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs 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, which converts Mg+ 2 -ATP to cAMP at an accelerated rate.
Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 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. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle 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 indicates that inhibition of this enzyme not -1 WO 96/19995 PCT/US95/16858 only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market The compounds of this invention also inhibit the production of Tumor Necrosis Factor (TNF), a serum glycoprotein. Excessive or unregulated TNF production has been implicated in mediating or exacerbating 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, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (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-cellmediated immunity is impaired and infected individuals manifest 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 after T cell activation and such virus protein expression and/or replication 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 permit HIV gene expression and/or HIV replication.
Cytokines, specifically TNF, are implicated in activated T-cell-mediated
HIV
protein expression and/or virus replication by playing a role in maintaining
T
lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the -2- WO 96/19995 PCT/US95/1685 8 progression of immune dysfunction caused by HIV infection. Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon 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 Poll et al., Proc.
Natl. Acad. Sci., 87:782-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells.
TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce 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):204-48, 1991; and Luke et al., Journal of Infectious Diseases, 162:211-214,1990].
The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF.
Summary of the Invention The novel compounds of this invention are represented by Formula
R
1
X
2
S(R
2 )s X
R
wherein:
R
1 is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R 5 )mR6 (CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0 to 2; n is 0 to 4; r is 0 to 6; R4 and R5 are independently hydrogen or C1-2 alkyl; -3- 7- 6-99;19:19 B/ 34 R6Is hyrOgen- M9141, hYdroxyL aryl, halo M~bsttc tYL, UYIaCKY I-3 aikyl.
halo msubittd ariOXYC 1.3 aiky indanyL. WnenytL-C7-11 polyqykl Iczmhyfreftzzayl fuanyL, teruhydIopmnytWY PyrinyL haydrmdhieyI, dicnyl.
WctrhYdrothiopyhanYl ddaPyrany4 C3-6 cycloulkyl Or "46 cYcloalkyl eawining one or two unWru bo"Is, whavin bhe qyclalkyl or beteroyclie moeY may b, uns'IW4zujid Or subatinigd by I wo 3naedayl puups, one sibyl VrOW or an hydroxyl -mie thaL a) wen R s h L ten m i Zor b) whnR shd y ~nri o(-c 0) wben R6 is 2 -myduyrunyl. 2 -hAydzbiopymnL :*So* 2 -orcnaydrofuznyl. or 2 -=euhydzwbienyL, dun m is I or 2; cir d) when R6 is 2- hydr1pymy1. 2 y&diApyay a. 2-ICCabydrofiwanyl, or 2-WcAhYddzucny then r is I to 6; e) wh n i ndni i s, fcr haH i a a- CP4R5)nO(R4R)nR& 2~ Xis YR2. fluwin, NR4Rs, cr Aurmyl amuaeg Y is 0oar (ur m is O, 1, or 2 X2 is 0or NRg X3is hydMgen or X; Rt 2 is -013 Or -0142013 ambstiawd or substinmta by 1 or mmr flUrnCs; s isOwo4; *R3 isCOORM
C(O)NR
4 4Or R 7 cabta awm% Z is 0, NR7, NCR4R5C 2 6 alkenyL, N0R14. NORI.5. NoCR4RSC2.6 00a. NNR4R04Eb1 NNR4R15 NCN. NNS ONSR4 NNRSC(S)NRSR1 4 o =Z iS .3ddaan), 2-(1-3-diibiolane) ditneddo WWrL diedaylthjo I=W. 2-(1.3dioxdane). 2(l3-dioxane), 2 -(l.3-*xzhican), diwgxhyl keral or dieihyl keW; R7 is {(CR4Rs)qR12 or Ci.6 alkyl wburein the Rt12 Or C 1 4 aikyl sioop is unsubstituteci or substituted one or more times by: methyl or ethyl unsubstituted or wbndwd by 1-3 fluarine 0 -Br, -CL -NO 2 -NR 1(RI 1 -C(O)ftg. -C2g -Q(C2)2-4OIRg. -O(qH2qRS -0q, -C(O)NRIoRIl I O(012)qC(O)NR ORI 1. O(CH2)qC(o)R9, -NRIOC(O)NR _NRIOC(O)R 1. _NRIOC(0)0R9.
-NR IOC(O)R 1 3, -C(NRt oNR IOR 11 -CCNCN NR IOR 11, C(NCN)SR9, -NR1OC(NCNSR9. -NRIoCNCN)NRIOR 11 I NRlOS(O)2R9. -S(O)m'Rg, -NROw )CcONRIcRI 1 -NRIoC(O)C(O)ft 10 or R3 RA4/q isO0.1lor 2:.4 ~07/06 '99 MON 19:27 ITX/RX NO 8115] Q~006 WO 96/1995 PCT/US95/16958 R12 is R 13 03-07 cycloakl, 3- or 4-pyridyl), pyrixnidyl, pyrazolyl, or 2-imidazolYl), pyrrolyl, piPerzinyl, Piperidinyl, morpholinyl, furfanyl, or 3-thienyl), quinolinyl, naphthyl, or phenyl;~
R
8 is hydrogen or R9;
R
9 is 0 1-4 alkyl unsubstituted or substituted by one to three fluorines; Rl 0 is 0R8 orRll;
R
1 1 is hydrogen, or C 1 4 alkyl unsubstituted or substituted by one to thre fluorines; or when RIO and RI 1 are as NRIORI 1 they may together with the nitrogen form a 5 to 7 membered ring conmised 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, ilnidazlyl, iniidazolidinyl, thiazolidinyl, isoxazolyl, oxadia.Zolyl, and thiadiazolyl, and where R 13 is substituted on R 12 or R 13 the rings are connected through a carbon atom and each second R 13 ring may be unsubstituted or substituted by one or two Ci1.2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms;
.R
14 is hydrogen or R7; or when R8 and R14 are as NR8Ri4 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from 0, N, or S; provided that: R7 is not C1-4 alkyl unsubstituted or substituted by one to three fluormnes; or or the pharmaceutically acceptable salts thereof.
Another set of compounds of this invention are represented by Formula
(HI)
0
R
1 2 (RZ 2
)S
X H (11) wherein: RI is -(CR4R5)nC(0)O(CR4RS)mR 6 -(CI{4R5)nC(0)NR4(CR4p 5 )mR 6 (CR4R5)nO(CR4RS)mR6, or -(CR4R5)R 6 wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0to 2; n isO0 to 4; r isO0 to 6; R4 and R5 are independently selected hydrogen or 01-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCI-3 alkyl, halo substituted aryloxyC 1-3 ailkyl, indanyl, indenyl, C7-11i polycycloalkyl, WO 96119995 PCT/US95165 tetrahydrofiuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl C3-6 cycloalkyl, or a C4-.6 cycloalkyl containing One Or two unSatzraze bonds, wherein the cycloalkyl and heterocyclic moieties is unsubstituted Or substitutedj by 1 to 3 methyl groups, an ethyl group, or an hydroxyl group; Provided that: a) when R6 is hydroxyl, then m is 2; or b) whelR6 ishydroxyl, then ris 2to 6 ;or c) when R6 is 2 -tetrahydropymanyl, 2 -tetrahydrohiopyayL, 2 -tetrahydrofuranyl, or 2 -tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2 -tetrahydropyranyl, 2 -tetrahydrohiopyayI, 2 -tetrahydrofmranylor 2 -tetrahydrothienyl, then r is I to 6; e) when nis Iand mis0, then R 6 isother anH in -(CR4R5)nO(CR4R 5 )rnR 6 X is YR2, fluorine, NR4R 5 or forinyl amine; Y is 0 or S(O)m'; m'is 0, 1, or 2; X2 is 0orNR 8 X3 is hydrogen or X;
R
2 is independently selected from -CH 3 Or -CH 2
CH
3 unsubstituted or substituted by 1 or more fluorines; s isO0 to 4;
R
3 is COOR 14 C(O)NR4RI 4 Or R7; W is alkyl of 2 to 6 carbons, ailcenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z is C(Y')R 14 C(O)0R 14
C(Y')NRIOR
14 C(NRI0)NRlOR1 4
CN,
C(NOR8)Rl 4 C(O)NR8NR8C(O)R 8 C(O)NR8NRIORl 4 C(NOR14)R 8 C(NR8)NRIOR1 4 C(NR14)NR 8
R
8
C(NCN)NR
10
R
14
C(NCN)SR
9 4- or 4- or 5-pyrazolyl), or 5-triazolyl[ or 5-triazolyl[ (5-tetrazolyl), 4- or 5-oxazolyl), 4- or 5-isoxazolyl), or 5-oxadiazolyl[1 2 -oxadiazolyl[1 2 -thiadiazolyl[ or or 5-oxazolidinyl), or 5-thiazolidinyl), or or wherein all of the heterocylic ring systems may be optionally substituted one or more times by R14; Y'is 0or S;
R
7 is -(CR4R5)qRl2 Or 01-6 alkyl wherein the R12 or CI- 6 alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -Br, -Cl, -NO 2 -NRORI 1 -C(O)R8, -C02R8,
-O(CH
2 2 4 0R 8 -O(CH2)qR8, -CN, -C(O)NRIORI 1 -O(CH2)qC(O)NRlORj 1 WO 96/19995 PCT/US95/16858 O(CH2)qC(O)R9,
-NRIOC(O)NRIOR
1 1 -NR10C(O)R11, -NR10C(O)OR 9 13 -C(NR10)NR1R 11, -C(NCN)NR 10
R
1 1 -C(NCN)SR9, 9 -NR10C(NCN)NRloR 1 1 -NR10S(0)2R 9 -S(O)mR9, -NRIOC(O)C(O)NRIOR11, -NRIOC(0)C(O)R 10 or R13 qis0,1,or2; R12 is R 1 3 C3-C 7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of 3- or 4-pyridyl), pyrimidyl, pyrazolyl, or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, or 3-thienyl), quinolinyl, naphthyl, and phenyl; Rg is independently selected from hydrogen or R9;
R
9 is C1-4 alkyl unsubstituted or substituted by one to three fluorines;
R
10 is OR8 or R11;
R
1 1 is hydrogen, or C1- 4 alkyl unsubstituted or substituted by one to three fluorines; or when R10 and R11 are as NRIOR11 they may together with the nitrogen form a 5 to 7 membered ring comprised 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 1 3 is substituted on R 1 2 or R 13 the rings are connected through a carbon atom and each second R 1 3 ring may be unsubstituted or substituted by one or two C1- 2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms;
R
14 is hydrogen or R7; or when R8 and R14 are as NR8R14 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatoms selected from O, N, or S; provided that: R7 is not C1- 4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.
This invention also relates to the pharmaceutical compositions comprising a compound of Formula and (II) and a pharmaceutically acceptable carrier or diluent The invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula and as shown below.
The invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula and (II).
-7- ~111 la~ Ilr WO 96/19995 PCTIUS95/16858 The invention also provides a method for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula and (II).
This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which method comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of Formula and This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.
This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a compound of Formula and Compounds of Formula and (II) are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.
In addition, compounds of Formula and are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
Detailed Description of the Invention This invention also relates to a method of mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof and to inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula and (II).
Phosphodiesterase IV inhibitors are useful in the treatment of a variety 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 adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus and central nervous system disorders such as depression and multi-infarct dementia.
The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula and Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering -8rkl II 1. ~I I r I WO 96/19995 PCT/US95/16858 to such mammal an effective TNF inhibiting amount of a compound of Formula and
(II).
The compounds of this invention may also be used in association with the veterinary treatment of animals, other than in humans, in need of inhibition of TNF production. TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular 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, visna virus, maedi virus and other lentiviruses.
The compounds of this invention are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. A preferred disease state for treatment is fungal meningitis. Additionally, the compounds of Formula and (II) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections.
Drugs of choice for fungal infections, include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; the class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin
B.
The compounds of Formula and (II) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of Formula and to a mammal in need of such treatment Preferably, a compound of Formula and is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin
B.
The term "C 1 3 alkyl", "C 1 4 alkyl", "C 1 6 alkyl" or "alkyl" groups as used herein is meant to include both straight or branched chain radicals of 1 to 10, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
"Alkenyl" means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1propenyl, 2 -propenyl, or 3 -methyl-2-propenyl.
The term "cycloalkyl" or "cycloalkyl alkyl" means groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.
"Aryl" or "aralkyl", unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl.
Preferably the aryl is monocyclic, i.e, phenyl. The alkyl chain is meant to include both -9- ~1111 WO 96/19995 PCTIUS95/16858 straight or branched chain radicals of 1 to 4 carbon atoms. "Heteroaryl" means an aromatic ring system containing one or more heteroatoms.
"Halo" means all halogens, chloro, fluoro, bromo, or iodo.
"Inhibiting the production of IL-1" or "inhibiting the production of TNF" means: a) a decrease of excessive in vivo IL- or TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of the in vivo release of IL-1 by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the translational or transcriptional level, of excessive in vivo IL- or TNF levels, respectively, in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of the direct synthesis of IL-1 or TNF levels as a postranslational event The phrase "TNF mediated disease or disease states" means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for instance is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TNF-B (also known as lymphotoxin) has close structural homology with TNF-a (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-a and TNF-B are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF' unless specifically delineated otherwise. Preferably TNF-a is inhibited.
"Cytokine" means any secreted polypeptide that affects the functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses. A cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce them. The cytokine inhibited by the present invention for use in the treatment of a HIV-infected human must be a cytokine which is implicated in the initiation and/or maintenance ofT cell activation and/or activated T cell-mediated HIV gene expression and/or replication, and/or any cytokine-mediated disease associated problem such as cachexia or muscle degeneration. Preferrably, his cytokine is TNF-a.
All of the compounds of Formula and are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the compounds of Formula and (II) are useful in the method of inhibiting or mediating the enzymatic or catalytic activity of PDE IV and in treatment of disease states mediated thereby.
10 I I WO 96/19995 PCTIUS951658 Preferred compounds are as follows: When R I for the compounds of Formula and (11) is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a C1-4 alkyl substituted by 1 or more fluorines. The preferred halo-substituted alkyl chain length is One Or two carbons, and most preferred are the moieties -CF3, -CH2F,- CHF2, -CF2CHF 2 -CH2CF 3 and -CH2CHF2. Preferred R I substitutents for the compounds of Formula and (11) are C 11 2-cYcloprOPYI, CH2-CS..
6 cycloalkyl, C4-.6 cycloalkyl unsubstituted or substituted with OH, I I polycycloalkyL, or 4cyclopentenyl), Phenyl, tetrahydrofiuran.3-.yi benzyl Or C 1.2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH2)1..3C(O)O(CH 2 0 2
CH
3 -(CH2)..3C(CH2)O..
2 C1 3 and -(CH2)240FL When the R I term is (CR4R 5 the R4 and R5 terms are independently hydrogen or alkyL. This allows for branching of the individual methylene units as Or (CR4R5)n each repeating methylene unit is independent of the other, (CR4R5)n wherein n is 2 can be -CH2CH(-CH 3 for instance. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can be unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred R I substitutions, as noted above.
When R 1 is a C7- I1 polycycloalkyl, examples are bicyclo[2.2. I -heptyl, bicyclo[2.2.2loctyl, bicyclo[3.2. 1]octyl, tricyclo[5.2. 1.0 2 6 ]decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published November 1987, whose disclosure is incorporated herein by reference in its entirety.
Preferred Z terms are 0, NCN, NR7, NORM4,
NORM
5 NNR4R14, NNR4R 15 2 3 -ciithiane), diniethylthio ketal, 2 3 -dioxolane), or dimethyl ketal. More preferred are 0, NR7, NORM4 NORM~ and 2 -(l,3-dioxolane).
Preferred X groups for Formula and (HI) are those wherein X is YR2 and Y is oxygen. The preferred X2 group for Formula and (ED) is that wherein X2 is oxygen. The preferred X3 group for Formula and (II) is that wherein X3 is hydrogen. Preferred R2 groups, where applicable, is a C 1 -2 alkyl unsubstituted or substituted by 1 or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R2 groups are those wherein R2 is methyl, or the fluoro-substituted alkyls, specifically a C 1 2 alkyl, such as a -CF3, CHF2, Or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.
Preferred R7 moieties include R 13 unsubstituted or substituted -(CH2)0..
2 3- or 4-pyridyl), (CH2)l..2(2-imidazolyl), (CH2)2(4-morpholinyl), (CH2)2(4- Piperazinyl), (CR2) 1-2(2-thienyl), (CR2) 1-2(4-thiazolyl), unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH2)o..2phenyl.
Preferred rings when Ri1o and Ri II in the moiety -NR1IORi11 together with the nitrogen to which they are attached form a 5 to 7 membered ring comprised only of 11 WO 96/19995 PCTJ(US95/16958 carbon atoms Or carbon atoms and at least one heteroatom selected from 0, N, or S include, but are not limited to 1-inlidazolyl, 2-(R8-l-imidazolyl, 1-pyrazolyl, 3-(R8)-l-pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tiazolyL, 5-(R8)-2-triazolyl, -tetrazolyl, 5-(R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, Il-piperazinyl, or pyrrolyl ring.
Preferred rings when R8 and R14 in the moiety -NR8Rl 4 together with the nitrogen to which they are attached may form a 5 to 7 membered ring comprised only of carbon atoms Or carbon atoms and at least one heteroatomn selected from 0, N, or S include, but are not limited to Il-imidazolyl, Il-pyrazolyLI -triazolyl, 2 -triazolyl I1_ tetrazolyl, 2-tetrazolyl, morpholinyl, piperzinyL, and pyrrolyL Thbe respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula and Illustrations of such carbon substitutions includes, but is not limited to, 2 -(R7)-lI-imidazolyl, l-iniidazolyl, l-imidazolyL, 3-(R7)-I1-pyrazolyl, l-pyrazolyl, l-triazolyl, 5-(R7)-l1-tetraolyl, and 5-(R7)-2-tetrazolyl. Applicable nitrogen substitution by R7 includes, but is not limited to, I -(R7)-2-tetrazolyl, 2 -(R7)-l-tetrazolyl, 4 -(R7)-l-piperazinyl- Where applicable, the ring may be substituted one or more tims by R7.
Preferred groups for NR8RI 4 which contain a heterocyclic ring are 5-(R 14)-i1tetrazolyl, 2-(R14)- l-imidazolyl, 5-(R 14)- 2 -tetrazolyl, 4-(R14)-l -piperazinyl, or 4 .Preferred rings for R 13 include 4- or 5-iniidazolyl), 4- or or 5-triazolyl[ or 5-triazolyl[ 1,2,41), (5-tetrazolyl), 4- or 5-oxazolyl), 4- or 5-isoxazolyl), or 5-oxadiazolyl[ 2 -oxadiazolyl[ (2-thiadiazolyl[ 1,3,4) or 5-thiazolyl), 4-, or 5-thiazolidinyl), or or When the R7 group is unsubstituted or substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, pyrixnidinyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be unsubstituted or substituted by R8 either on an available nitrogen or carbon atomn, such as 1-(R8)-2-imidazolyl, l-(R8)-4-imidazolyl, N-R8)-3-pyrazolyl, 1-(R8)-4-PYrazolyl, 1-(R8)-5-pyrazolyl, 1-(R8)-4-triazolyl, or 1-(R8)-5-triazolyl. Where applicable, the ring may be substituted one or more times by R8.
W is Preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and where it is alkenyl or alkcynyl, that one or two double or triple bonds be present. It is most preferred that W is ethynyl or 1,3-butadiynyl.
Preferred are those Compounds of Formula and (II) wherein R I is -CH2cyclopropyl, -CH2-C5-.
6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted with 12 WO 96/19995 PCTUS95/16858 OH, tetrahydrofuran-3-yl, or 4-cyclopentenyl), benzyl or -C1-2 alkyl unsubstituted or substituted by 1 or more fluorines, and -(CH2)2- 4 OH; R 2 is methyl or fluorosubstituted alkyl, R 3 is R 7 where R 7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2, and Z is O, NR7.
Z' is preferably COOR14.
Most preferred are those compounds wherein R is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R 2 is CF2H or methyl, W is ethynyl or 1,3-butadiynyl,
R
3 is a substituted or unsubstituted pyrimidinyl ring, and Z is O, NR7.
Pharmaceutically acceptable salts of the instant compounds, where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use.
By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases.
Pharmaceutically acceptable salts are prepared in a standard manner.
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 where the molecule contains a COOH for example.
Pharmaceutical compositions of the present invention comprise a pharmaceutical carrier or diluent and some amount of a compound of the Formula (I) and The compound may be present in an amount to effect a physiological response, or it may be present in a lesser amount such that the user will need to take two or more units of the composition to effect the treatment intended. These compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at the time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol.
The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.
For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, aerosols, and drops suitable for administration to the skin, eye, ear, or nose.
For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension.
13 .X WO 96/19995 PCT/US95/16858 For oral administration the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water, for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.
In these compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.
Usually a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor. Topical formulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required as a preventative or curative agent to the affected area. When employed as an oral, or other ingested or injected regimen, the dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg.
It will be recognized that some of the compounds of Formula and (II) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. All of these compounds are considered to be within the scope of the present invention.
Compounds of Formula where Z is 0 or (II) may exist in a tautomeric form, such as the enol form. This may be represented by the =0 being exocyclic to the 14 1 WO 96/19995 WO 96/195 PCT/US95/16858 H
R
W
I
cyclohexane ring (or as contrasted to the endocyclic or moiety wherein the cyclohexane'ring is now unsaturated in the 1-2 position, i.e.
R H
N
0
W
cyclohex-1-ene, or R3 and R is Z in Formula It is also recognized that the 2-position of the ring in the exocyclic form can be substituted such as in the compounds of Formula or (II).
The following examples are given to further illustrate the described invention.
These examples are intented solely for illustrating the invention and should not be read to limit the invention in any manner. Reference is made to the claims for what is reserved to the inventors hereunder.
No unacceptable toxicological effects are expected when these compounds are administered in accordance with the present invention.
15 111[ 1 C I II WO 96/19995 PCT/US95/16858 Methods Of Preparation Synthetic Scheme(s) With Textual Description Compounds of Formula may be prepared by the processes disclosed herein which comprise reacting a terminal acetylene as, compound with an aryl halide, such as phenyl iodide, in the presence of a suitable catalyst, such as n copper() halide and a bivalent or zerovalent palladium compound in the presence of, triphenylphosphine, in a suitable solvent, such as an amine, as in the procedure of Brandsma et al. (Syn. Comm., 1990, 20, 1889), followed by hydrolysis of the ketal protecting group under standard conditions, provides a compound of the Formula 2- Scheme. Compounds of the Formula 1-Scheme may be prepared by procedures analogous to those described in prior filed co-pending U.S. applications 07/862,083, 07/968,753 and PCT/US93/01990 designating the United States and filed 05 March 1993 (WIPO publication No. WO 93/19748) or PCT application PCT/US93/02325 published as WO 93/19750.
Schemel a.b 0
H
3 CO
H
3
CO
H
a) Pd(PPh PPh 3, Cul, C 6 Hsl, piperidine; b) pyridinium p-toluenesulfonate, (H 3 C) 2 CO/H Alternatively, compounds of Formula may be prepared by reacting a terminal acetylene as, compound cheme2, with an appropriate halide, R3X, wherein R3 represents R3 as defined in relation to Formula or a group convertible to R3, in the presence of a suitable catalyst, such as a copper halide and a bivalent or zerovalent palladium compound in the presence of, triphenylphosphine, in a suitable solvent, such as an amine, as in the procedure of Brandsma et al. (Syn.
Comm., 1990, 20, 1889), to provide a compound of the Formula 2-Scheme 2; such compounds of the Formula may then be converted to other compounds of the Formula by standard manipulation of the functional groups on the R3 moiety.
Compounds of the Formula -Scheme 2 may be prepared by procedures analogous to those described in prior filed co-pending U.S. applications 07/862,083, 07/968,753 and PCT/US93/01990 designating the United States and filed 05 March 1993 (WIPO 16 ~111 WO 96/19995 PCT/US95/16858 publication No. WO 93/19748) or PCI application PCT/US93/02325 published as WO 93/19750..
Scheme 2 a
H
3
CO'
a) Pd(PPh 3)4, PPh 3, Cul, R 3 X, piperidine Alternatively, oxidative carbonylation of a terminal acetylene as, e.g., compound -Scheme3, using an appropriate 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 standard conditions, then provides the compound of the Formula (2-Scheme such compounds of the Formula may then be converted to other compounds of the Formula by standard manipulation of the carboxylic ester moiety.
a im- Qr
H
3
CO
COOCH a) PdCI 2, CuCI 2 NaO 2 CCH3, CO, CH 3 0H Compounds of Formula (HI) may be prepared by processes analogous to those in Schemes 1, 2 and3 above, as illustrated in Scheme 4 wherein. Depending upon the exact nature of the Z' groups of the compounds of the Formula the =0 group may 17 II r ~1~1 WO 96/19995 PCT/US95/16858 require protection during the coupling steps described herein as, a compound of the Formula (II) wherein =O is a dimethyl ketal or 2 -(l,3-dioxolane), followed by deprotection and then reaction by the synthetic procedures described in prior filed copending U.S. applications 07/862,083,07/968,753 and PCT/US93/01990 designating the United States and filed 05 March 1993 (WIPO publication No. WO 93/19748) or PCT application PC/US93/02325 published as WO 93/19750, to provide the Formula (II) compound; likewise, the Z group may require protection during the coupling steps, followed by deprotection to provide the Formula (II) compound and such protective groups are well known to those skilled in the art (See: Greene, T. and Wuts, Protecting Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons, New York, 1991.) Scheme 4 000 0'
H
3 COa
H
3
CO
H
2.
a) Pd(PPh 3)4, PPh s, Cul, R 3 X, piperidine Preparation of the remaining compounds of the Formulas and (II) may be accomplished by procedures analogous to those described above and in the Examples, infra.
It will be recognized that compounds of the Formulas and (II) may exist in distinct diastereomeric forms possessing distinct physical and biological properties; such isomers may be separated by standard chromatographic methods.
The following examples are given to further illustrate the described invention.
These examples are intented solely for illustrating the invention and should not be read to limit the invention in any manner. Reference is made to the claims for what is reserved to the inventors hereunder.
Synthetic examples Example 1 Prearation of 4 3 -cyclopentloxy-4-methoxvyhenvl)- 1. -(ethylenedioxy)-442pyridylethynyl)cyclohexane la) 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1, -(ethylenedioxy)cyclohexane 18 WO 96/19995 PCT/US95/16858 A solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxypheny l)cyclohexan-1-one g, 3.19 mmol, prepared by the procedures described in PCT applications PCT/JS3/01990 (WIPO publication No. WO 93/19748) and PC application PC/US93/02325 published as WIPO number 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 heated to reflux under 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, was dried (potassium carbonate) and was evaporated to provide a clear colorless oil. 1H NMR(250 MHz, CDC13) 57.0 2H), 6.85 J=7 Hz, 1H), 4.8 1H), 4.0 411H), 3.85 3H), 1.58-2.20 16H).
lb) 4 3 -cyclopentyloxy4-methoxyphenyl)-1,1-(ethylenedioxy)-4-formylcyclohexane 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 h at room temperature, saturated aqueous sodium bisulfite (100 mL) was added and the mixture was extracted three times with dichloromethane.
The combined organic extract was washed with brine, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 4:1 hexanes/ethyl acetate, provided a clear colorless oil. 1 H NMR(400 MHz, CDCl3) 8 9.35 1H), 6.88 (br s, 2H), 6.80 1H), 4.73 1H), 3.95 4H), 3.85 3H), 2.33 2H), 2.10 2H), 1.57-1.99 12H).
lc) 4 3 -cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane A solution of dimethyl (diazomethyl)phosphonate (0.516 g, 3.44 mmole, prepared as in Seyferth, Marmor, R. Hilbert, P. J. Org. Chem. 1971, 36(10), 1379-1386) dissolved in dry tetrahydrofuran (10 mL) was added via cannulation to a solution of potassium t-butoxide (0.386 g, 3.4 mmol) dissolved in dry tetrahydrofuran mL) at -78oC under an argon atmosphere. To this was added rapidly 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 h, the reaction was warmed to room temperature, water was added and the mixture was extracted three times with ethyl acetate. The combined organic extract was washed with brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 hexanes/ethyl acetate provided a white solid. mp 53.5-55oC.
ld) 4 3 -cyclopentyloxy-4-methoxyphenyl)-1,1 -(ethylenedioxy)-4-(2-pyridylethynyl)cyclohexane To a solution of 4 3 -cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4ethynylcyclohexane (0.15 g, 0.42 mmol) and 2-bromopyridine (0.040 mL, 0.42 mmol) in piperidine (2 mL) under an argon atmosphere were added 19 7- 6-99;19!19 34 tckS(lzphxnylphoSphne).palladiz(0) (0.02 g. copper iodide (0.005 g, and a small crystal of triphenyiphosphine, and the mixtwe was beWAe at 800C for hi. Water was =d and the mixture was exfactod dheames with dehironduane, the exmict was dried (mapeuium sulfate) and was evapime Nyjfiicajioc by flash chnxnaagrahy, cluting with 35-65 edhyl acettbezanes, pmidl 4 -(Y3oY xy4-oxbmya yl),(*Yknediy).
2 P~r*e~hnyI);Yclobexane as a white fan nip 41-42 0 C. IH..NM4 (400 Mbz, CDC13) 8 8.58 Jas4.6 Hz, IH). 7.65 J-7.7 Hz, 111), 7.43 J=8.OHz. 111), 7.2 1 (mii 21). 7.17
J
2 8.j Hz, 11). 6.84 J=11-5 Wz IH). 4.51 1N). 3.99 4H1), 3.54 311), 2.25 (mm, 211), 2.15 (in, 4H1), 1.8-2.0 (Mn M1~, 1.59 (Mn 2M1.
Prdaon-of 4 3 I]gouoxvl~~mexypen,, 7.11 4ethlendox 0 (phenylethynyIcycohexn *A sample of 1,-ehkeix)-Xylpgtby4mtmpcy).
erhynycyclobexa= 15 g. 0.42 umm) was neeted wih -ic- anounts of triphaiy~phosphine s(ph1"pnhnp Mj and onppe icxbe.
0 0 lvdohonzent (0.47 niL, 4.2 frW) and pipetidine (2 niL) were duni added and the J '*00inzxmu was beawd under an agon stmophm. After 3 h, the zeixtur was diluted with ethyl acetate (50 was washed once with dilate aquwus HC, was dried (magnesum, sulfate) and was evapaedL Purfic~nom by flaah chm-nuxography (4:1 kzan.VeIy actae) Provided a clem cokalca oil. IH NM(400 MRz, CDCI3) 8 .00 ~7.44 (mn 2H). 7.3 (in, 3M1. 7.23 J-2 Hz. 1M), 7.12 (dd, J=2 and 8 Hz. 111), 6.51 J=4Hz, 11). 4.5 11M 4 .0 4H), 3.55 3H), 2.25 (nt. 2H). 7-10 (mn 2H), 1.78-2-03 (MD 1011), 1.6 (Mn 2H).
EaUwke Preparation of 4-3ccgmyov4mtoyhni)4(~eveh~y~ylhxn 00To a solution o C~Poyx--ebmo y).,-Uyadoy4 (phenylethyy)cyclohexame 18 g, 0.42 rnrnol) dissolved in 4:1 acetone/water (5 niL) was added pyrdimum p-toluentsulfanate, (5 mo). The uz was beased to =flumx Mne aM argon =0sphcre. After 6 h, wae (15 niL) was added anid the =nxrWu ernered due times with ethyl acenz. The comid nanic emet was dried (magmesium sulfat) and was gvaxaw. Piicazion by uituaion ftwz emlzr/eA=ne provDed a white solid. nip 99- 1000C A muxte of 4 3 -cycloentyloxy4 mrhoxyphwcnyl)-.. (ethylcnedioxy>.4(2- PYidylethyny)cyclohemae 17 S, 0.39 inzool) and pyridiniuzn p-roluenesulfonate 07/06 '99 MON 19:27 fTX/Rx NO 81151 900O7 WO 96/19995 PCrflJS95I16ss 8 10 g, 0.39 minol) in acetone (4 rnL) and water (I111oL) was refluxed for three days, then was evaporated. Water was added, the mixture was extracted three times with dichiorornethane, the extract was dried (magnesium sulfate) and was evaporated.
Purification by flash chromatography, eluting with 25:75 ethyl acetare-hexanes, provided 4-3cccpnyoy4mhxpeyl--2prdld y~ylhxnl one as a wax. 1 H-NMR (400 Mfz, CDC13) 8 8.61 3=4.8 Hz, IM1, 7.68 (dt, 3=7.8, 1.8 Hz, IM1, 7.47 J=7.8 Hz, 111), 7.27 (ra, 1H), 7.20 (di, J=2.3 Hz, IHM, 7.15 (dd, 2.4 Hz, lH), 6.87 J=8.5 Hz, IH), 4.81 (mn, IH), 3.85 3H), 3.07 (dt, J=14.4, 5.8 Hz, 2ff), 2.49 J=14.8 Hz, 2H), 2.41 211), 2.27 (dt, J=13.4, 3.9 Hz, 2H1), 1.8-2.0 (mn, 6H1), 1.61 (in, 211). Anal. (C251127N0 3 .0.65 1120) calcd:
C,
74.84; H1, 7.11; N, 3.49; found: C, 75.00; H,6.83; N, 3.52.
Prpaato on MI vcoenox y_-4-m eth ox yhen y 1) 1. 1 Ih y-leneQdioxyhA..(..
mtropheny-lezhi)YnylgyclohexAne To a solution of 4 3 -cyclopentyloxy..4.methoxyphenyl).1, l-(ethylenedioxy)-4.
ethynylcycloheane 15 g, 0.42 inmol) and 4 -iodonitrophenol 11 g, 0.42 minol) in piperidine (2 rnL) under an argon atmosphere were added tetrkids(triphenylphosphine).
palladium(0) (0.02 g, copper iodide (0.005 g, and a small crystal of triphenylphosphine. After heating at 80 0 C for 0.5 h, water and IN hydrochloric acid were added. The mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 4 3 -cyclopentyloxy.
4 -methoxyphenyl)- 1, 1 -(tyeeix)4(-irohnlt~y~ylhxn as a redorange wax. mp 58-59 0 C. 1 11-NMR (400 MHz, CDCI3) 8 8.18 J=8.7 Hz, 211), 7.58 (di, J=8.7 Hz, 211), 7.16 J=2.5 Hz, 1H), 7.12 (dd, J=8.4,2.5 Hz, 1H), 6.86 (di, J=8.4 Hz, 111), 4.80 (in, 1H), 4.01 411), 3.85 311), 1.8-2.3 (in, 1411), 1.6 (mn, 211).
Preparation of ccle gyclohexan--one To 4 3 -cyclopentyloxy.4methoxyphenyl) 1, l-(ethylenedioxy)-4-(4.
nitrohenylethynyl)cyclohexane 19 g, 0.40 inrol) in methanol (1 mL), acetic acid (1.2 mL), and water (1.2 mQL under an argon atmosphere was added titanium trichloride (0.3 g, 2 iniol). After stirring for 1.5 h at room temperature, water (1.2 inL) and ammonium hydroxide (2.5 mL) were added. After stirring an additional 1 h, methanol (17.5 5% sodium carbonate (17.5 mL) and dichloroinethane (35 mL) were added, and stirring was continued for 3 days. The suspension was filtered through CeitM was washed well with dichloromethane, and was evaporated. Water was added, the mixture was extracted three times with dichloromethane, the extract -21 m WO 9611999S PCTIUS95/169 5 8 was dried (magnesium sulfate) and was evaporatedi. Purification by flash chromatography, eluting with 3:7 ethyl aCetate:hexanes, provided 4 3 -cyclopentyloxy_ 4 -methoxyphenyl)4(4inophelthllohexn -one as a colorless oil. 1H_ NMR (400 MHz, CDC1 3 857.28 J=8.4 Hz, 211), 7.24 J=2.1 Hz, IH), 7.12 (d, J=8.5 Hz, 1H), 6.85 (di, J=8.5 Hz, 111), 6.64 (di, J=8.1 Hz, 28), 4.80 (in, 111), 3.85 (s, 3H). 3.05 (cit, J=14.3, 4.1 Hz, 2H), 2.45 Obr di, J=14.6 Hz, 28), 2.29 (mn, 411), 1.8-2.0 (in, 611), 1.61 (in, 28).
cvlhx- i-n amiuophenylethynylcyclohean I one (0.12 g, 0.29 inmol) in dichloromethane (3 mL) under an argon atmosphere were added pyridine (five drops) and acetic anhydride (0.081 niL, 0.86 inmol) and the reaction was stirred at room temperatur for 2 h.
HiydroDchloric acid (1IN) was added, the mixture was extracted three times with dichioromethane,. the extract was dried (magnesium sulfate) and was evaporated.
Purification by flash chromatography, eluting with 1: 1 ethyl acetate:hexanes, provided 4 cyc open~lo Y -4 eth xyp enyl -4-4-ac tam dop enyl thy yl~c clo ex one as a white solid. nip 79-80OC; Anal. (C28H31IN0)4.5 820) caicci: C, 73.98;
H,
7.10; N, 3.08; found: C, 74.11; H, 7.24; N, 3.03.
Examnple 8 Prearto of 4 (~vlpnyox -methoxyhfy) l-ehlnd y4-(3nirohenvlethynyflcyclo-hexane To a solution of 4 3 -cyclopentyloxy4metoxyhenyl)- 1, 1-(ethylenedioxy).4 ethynylcycloheane (0.14 g, 0.38 mmiol) and 3 -iodonitrophenol (0.10 g, 0.38 nimol) in piPeridine (2 niL) under an argon atmosphere were added tetaks(triphenylphosphine).
Palladium(0) (0.02 g, copper iodide (.0.005 g, and a small crystal of triphenylphosphine. After heating at 7000 for 0.33 h, the mixture was diluted with dichloroinethane, was washed with IN hydrochloric, acid, was dried (magnesium sulfate) and was evaporated. purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided l,1-(ethylenedioxy)4(3-cyclopentloxy.4nitoyhnl--3ntohnltyy~ylhxn as an orange wax. 1 H4-'JR 4 00MIHz, CDCI3) 5 8.29 111), 8.16 (di, J=9.0 Hz, 111), 7.75 (ci, J=7.9 Hz, 111), 7.50 J=8.0 Hz, 1H1), 7.26 (ci, J=2 Hz, 111), 7.14 (dci, J=8.3, 2 Hz, 1H), 6.86 (di, J=8.3 Hz, 1H), 4.82 (mn, 1H), 4.01 411), 3.85 311), 2.18 (mn, 4H), 2.07 (in, 211), 1.93 (in, 411), 1.85 (in, 411), 1.6 (in, 211).
Example 9 Preparation of x e 4 hnlt cyTCMoexn-1-ne 22 WO 96119995 Pc~rfUS9s16ss To 4 3 -cyclopentyloxy-4-methoxyphenyl)-1, l-(ethylenedioxy)-4-(3.
mitrophenYletlynyI)cyclohexane (0.17 g, 0.35 mmol) in methanol (1 mL), acetic acid (1.2 niL) and water (1.2 niL) under an argon atmosphere was added titanium trichioride (0.3 g, 2 mmol). After stirring for 1.5 h at room temperature, titanium trichioride (0.3g, 2 nimol) 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 0 C, then was cooled to room temperature. Water (1.2 mL) and amnmonium hydroxide (2.5 niL) were added. After stirring an additional 1h, methanol (17.5 niL), 5 sodium carbonate (17.5 niL) and dichloromethane (35 niL) were added, and Stirring was continued for 2 h. 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, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate-.hexanes, provided a mixture of 4 3 -cyclopentyloxy-4.
mehxpey)4(-mnpenltyy)ccoea--n and 4 3 -cyclopentyloxy- 4 -miethoxyphenyl)- 1, -ehlndoy-4(-mnpeyetyy~ylhx (0.07 g).
This mixture and a spatula-tip of pyiiim-oleeufnt in acetone (4 niL) and water (1 mL) was refluxed for 3 days, then was evaporated. Water was added, the mixture was extracted three times with dichioromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes provided 4 3 -cyclopentyloxy.4 mehxpey)4(-niohnyehnlccoea-1-n as a colorless oil. 1
H-
NMR (400 MHz, CDC13) 5 7.22 J=2.2 Hz, 1H), 7.14 (in, 2H), 6.87 (in, 2H), 6.82 J=2.8 Hz, 1H), 6.66 (dd, 2.4 Hz, 1H), 4.81 m, 1H), 3.85 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 (in, 4H), 1.8- (in, 611), 1.61 (in, 2H).
Ptraration f:Lcyl~tLov-mtoy~ey)4(-c d~-ey yy) cQyclohexan- 1-one To 4 3 -cyclopentyloxy-4..methoxyphenyl)4(3aminophenylethynyl)cyclohexn-l-oe (0.0Y7 g, 0.18 nimol) in dichloromethane (2 niL) under an argon atmosphere- were added pyridine (three drops) and acetic anhydride (0.05 niL, 0.53 nimol) and the reaction was stirred at room temperature for 2 h.
Hydrochloric acid (iN) was added, the mixture was extracted three times with dichlowomethane, the extract was dried (magnesium sulfate) and was evaporated.
Purification by flash chromatography, eluting with 45:55 ethyl acetate:hexanes, provided 4 3 -cyclopentyloxy-4-methoxyphenyl)-4(3.
acetamidophenylethyny)cyclohexanone as a white solid. mp 63 -64 0 Q; Anal.
23 WO 96/19995 PCTIUS95I16858 (028H3 IN0 4 .1.75 H20) calcd: C, 70.49; H, 7.29; N, 2.94; found: C, 70.09; H, 6.94; N, 2.83.
caoehxpeyltyy ylhxa A mixture of 4 -(3-cyclOpcnloy4_ methoxypheny) I (ethylened iox)4-ty..~Illhex 0 1 50 g, 0.421 minol) and methyl 3-iodobenzoate 110 g, 0.42 1 inmol) in piperidine (2.1 juL. dry) under an argon atmosphere Was treated with a mixture of teraids(trphenylPhosPhie)Pal~li(O) (0.020 g, 0.0 17 mmol), cuprous iodide (0.0 10 g, 0.053 mmol) and triPhenylphosphine (crystal) and the mixture was heated at 8000 for 40 min. The reaction mixture was chilled to 000, was poured into ice-water, was acidified with 3N hydrochloric acid and was extracted five times with mnethylene chloride. The organic phase was washed with dilute hydrochloric acid, water, saturated brine, was dried over magnesium sulfate, was filtered and concentratedJ in vacuo. The residue was preadsorbed and chromatographed on silica gel, eluting the with 15 to 20% ethyl acetate in hexanes, to afford a light yellow oil. IH-NMR (250 MHZ, CDC13) 3 8.11 J=1.4 Hz, 1H), 7.97 J=1.3 Hz;J=7.9 Hz, 1H), 7.63 (d-d, J=7.8 HzJ=1.3 Hz, 1H), 7.39 J=7.8 Hz, 1H), 7.23 J=2.2, 1H), 7.15 J=8.4 Hz,J=2.3 Hz, 111), 6.89 J=8.4 Hz,IH), 4.80 (mi, 1H), 4.00 br, 4 3.92 (s, 3H), 3.84 3H), 2.4 to 1.75 (mn, 18H).
Exale 12 lrpaoxo of ox~ a-bmt~ hn ethyny-lccoeaM.i-on A solution of 4-3ccoetlxy4mtoyhnll,-(ethylenedioxy)-4-(3.
cabmtoyhnltyy~ylhxn (0.060 g, 0. 12 iniol) in tetrahydrofinran mL) containing 3N hydrochloric acid (0.60 mL) under an argon atmosphere was heated at 55-60 00 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, saturated brine, was dried over sodium sulfate,and was concentrated in vacuo. The residue was chroinatographed (silica gel), eluting with ethyl acetate/hexanes, to afford a resin. Anal. (C28H300 5 -1/4 H120) calcd:
C
74.56, H 6.82, found: C 74.43, H 6.80. 1 H-NMR (400 MHz, CDC13) 868.15 111), 8.00 (d4d J=1.5 Hz;J=6.6 Hz, 111), 7.65 J=1.3 Hz, J=7.7 Hz, 1H1), 7.43 J=7.7 Hz, 1H1), 7.21 J=2. 1, 1 7.12 J=2.0 Hz, J=8.5 Hz, 1H1), 6.87 Hz,1IH), 4.81 (mn, 111), 3.94 3 3.86 3H), 3.04 J=6.0 Hz, J=14.2, 2H1), 2.50 (d,br, J= 14.8, 2H1), 2.4-2.2 (mn, 4 2.0-1.5 (mn).
ExMplIe 13 Prearaionof ~cvlopntyox4mehoxD ClyI 1 I I-(ehlndoy4 carbox Mhenylet3Myr~yclohexane 24
M
WO 96/19995 PCTIUS95/16858 A solution of 4 3 -cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3carbomethoxyphenylethynyl)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 oC for 2.5 h. The cooled reaction mixture was concentrated in an argon stream and the residue was partitioned between cold water acidified with dilute hydrochloric acid and methylene chloride. The aqueous phase was extracted another two times with methylene chloride and the combined organic phase was dried over magnesium sulfate to afford the titled compound as an oil. H-NMR (400 MHIz, CDC3) 8 8.18 1H), 8.02 J=7.9 Hz, 1H), 7.68 (d, J=7.8 Hz,1H), 7.42 J=7.8 Hz, 1H), 7.23 J=2.2, 1H), 7.14 J=8.4 Hz;J=2.3 Hz, 1H), 6.85 J=8.4 Hz,1H), 4.82 1H), 4.01 4.2 3.85 3.2H), 2.4 to 17H).
Example 14 reparation of 4-(3-ccloen -4methoxhen-4-- x nethynyl)cyclohexane-one A solution of 4 3 -cyclopentyloxy-4-methoxyphenyl)- 1,1-(ethylenedioxy)-4-(3carboxyphenylethynyl)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 OC for 2 h. The cooled reaction mixture was concentrated in vacuo and the residue was partitioned between cold water and methylene chloride. The organic phase was washed with saturated brine solution, was dried over magnesium sulfate and was evaporated. The residue was chromatographed (silica), eluting with methylene chloride/methanol/water (90/5/0.25 to 90/10/0.5) and was concentrated in vacuo. The residue was dissolved in methanol and was foamed in vacuo to afford a white fractured glass. Anal. (C27H280 5 .1/4 H20*1/4 CH30H) calcd: C 73.55, H 6.68, found: C 73.51, H 6.66. 1H-NMR (400 MHz, CDCl3) 8 8.22 J=1.5 Hz, 1H), 8.09 (d-d, J=1.3 HzJ=7.9 Hz, 1H), 7.72 J=1.3 Hz, J=7.8 Hz, 1H), 7.47 J=7.8 Hz, 1H), 7.22 J=2.2, 1H), 7.13 J=2.3 Hz, J=8.4 Hz, 1H), 6.88 J=8.5 Hz,1H), 4.82 1H), 3.86 3H), 3.25 J=20 Hz, CH30H, 0.55H), 3.04 J=5.8 Hz, J=14.5, 1.7H), 2.50 (d,br, J=14.8, 1.8H), 2.4-2.2 4 2.0-1.5 Example 4-(3-yclnentvlox4methoxhenv4ordlethvnvl)yclohexan-1-one 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)-1,1- (ethylenedioxy)cyclohexane 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 were added tetrais(triphenyl-phosphine)palladium() (0.013 g, copper(I) iodide (0.004 g, and a small crystal of triphenylphosphine, and the mixture was heated at 80-85 0
C
25 W0 96/1"995 WO 9619995 PCTIUS9516858 for 0.5 h. Water was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate),and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3cyclopentyloxy4-4-methoxyphenyl)-4(4-pyridylethynyl)-1,1- (ethylenedioxy)cyclohexane as a pale yellow oil (0.11 g, 93%).
1H-NMR (400 MHz, CDCI3) 8.56 J=5.3 Hz, 2H), 7.33 J=5.3 Hz, 2H), 7.16 J=2.2 Hz, 1H), 7.09 (dd, J=8.5, 2.2 Hz, 1H), 6.85 J=8.5 Hz, 1H), 4.80 1H), 4.00 4H), 3.85 3H), 2.0 2.2 6 1.8 2.0 8H), 1.59 2H).
4-(3-cyclopentyloxy-4-metoxyphenyl)-4-(4-pyridylethynyl)cyclohexan--one A mixture of 4-(3-cyclopentyloxy- 4 -methoxyphenyl)4-(4-pyridylethynyl)-1,1- (ethylenedioxy)cyclohexane (0.10 g, 0.24 mmol) and pyridinium p-toluenesulfonate (0.06g, 0.24 mmol) in acetone (4mL) and water (1 mL) was refluxed for 20 then was evaporated. Water was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan- -one (0.08 g, 91%) as a white solid, mp 148-149oC. Anal. (C25H27NO3-0.5 H20) calcd: C, 75.29; H, 7.08; N, 3.51; found: C, 75.51; H, 6.95; N, 3.42.
Example 16 -C1oenlox-4- xhenvl)-4-(3-one To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)4-ethynycyclohexan- 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 were added tetakis(triphenylphosphine)palladium(0) (0.034 g, copper(I) iodide (0.009 g, and a small crystal of triphenylphosphine, and the mixture was heated at 80-85 0 C for 0.5 h. Ammonium chloride was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4 3 -cyclopentyloxy4methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan--one as an off-white solid (0.22 g, The product was further triturated from ether-hexanes, mp 88-89oC. Anal.
(C25H27N0 3 0.375 H20) calcd: C, 75.78; H, 7.03; N, 3.53; found: C, 75.77; H, 6.89; N, 3.40.
Example 17 4-2-Carbomethoxvhie-5-ethnvl-4-(3-cycnl vx-4methoxvphenyl)cyclohexan-1-one 17a) 2 2 -Bromo-5-carboxymethylthiophene was prepared by standard chemistry well known to those versed in the art and was a white solid, mp 59-60oC.
26 WO 96/19995 WO 96/19995 PCT/US95/1658 17b) 4-(2-carbomethoxythien-5-ylethynyl)-4-(3-cyclopentyloxy-4methoxyphenyl)cyclohexan- 1-one To a solution of 4 3 -cyclopentyloxy-4-methoxyphenyl)-4ethynycyclohex- 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(0) (0.031 g, and copper(I) iodide (0.008 g, and the mixture was heated at 80-85oC for 4.5 h. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate),and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 4-(2-carbomethoxythien-5-ylethynyl)-4-( 3 cyclpentloxy-4-methoxyphenyl)cyclohexan-1-one as a yellow oil (0.25 g, 82%).
1 H-NMR (400 MHz, CDCI3) 57.67 J=4.0 Hz, 1 7.16 J=4.0 Hz, 1 7.15 J=2.2 Hz, 1 7.07 (dd, J=8.4, 2.2 Hz, 1H), 6.87 J=8.4 Hz, 1 4.80 1 3.89 3 3.85 3 2.95 (dt, J=14.5, 5.9 Hz, 2 2.49 (br d, J=14.5 Hz, 2 2.36 2 2.26 (dt, J=13.4, 4.0 Hz, 2 1.8 2.0 6 1.6 2H) ppm. Anal. (C26H2805S-0.25 H20) calcd: C, 68.32; H, 6.28; found: C, 68.25 H, 6.12.
Exampe 18 4-(2-Carbxvth vnvl)-4-(3ccloentloxv4-5-hlecleone, sodium salt A solution of 4-(2-carbomethoxythien-5-ylethynyl)-4-(3-cyclopentyloxy4methoxyphenyl)cyclohexan-1-one (0.13 g, 0.30 mmol) and coarsely ground 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 h. The reaction was acidified (10% HC), was extracted three times with 5:95 methanol:dichloromethane, was dried (magnesium sulfate) and was evaporated. The crude product was treated with 10% sodium hydroxide to form the salt. Reverse phase chromatography, eluting with 1:1 methanol:water, provided 4 2 -carboxythien- 5-ylethynyl)-4-(3-cyclopentyloxy4-methoxyphenyl)cyclohexan--one, sodium salt, as a white solid (0.070 g, mp 194-195oC. Anal. (C25H2505SNa.1.25 calcd: C, 62.16; H, 5.74; found: C, 61.90; H, 5.49.
Example 19 S4-2- Chin-thxthynl--phn liycohxa-1-one 19a) 2 2 -Bromo-5-cyanothiophene was prepared by standard chemistry well known to those versed in the art and was a colorless oil, 1 H-NMR (400 MHz, CDCI3): 8 7.40 J=4 Hz, 1 7.10 J=4 Hz, 11H1) ppm.
19b) 4-(2-cyanothien-5-ylethynyl)4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1-one 27 WO 96/19995 PCTrIUS9516858 To a solution of 4-(3-cyclopentylxy-4-methoxyphenyl-e Cy x I-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 teakis(triphenylphosphine)palladium() (0.034 g, and copper(I) iodide (0.007 g, and the mixture was heated at 85-900C for 2 h. Ammonium chloride was added and the mixture was extracted three times with diclloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 4-(2-cyanothien-5-ylethynyl)4-(3-cyc lo methoxyphenyl)cyclohexan-l -one (0.06 g, This was combined with product (0.017g) obtained in a second, similar reaction and was triturated from dichloromethane-hexanes to provide a white solid, mp 106-1070C. Anal.
(C25H25N03S-0.5 H20) calcd: C, 70.07; H, 6.11; N, 3.27; found: C, 70.15; ,5.84; N, 3.32.
&Emp-2 4 I A -ty Dv44hoxphe 2l5-mesthylrf 1.
2 4 ]oxAdao--ltin.
_j--l)tin2vlethInvllcyclohexan. 1-one 2 -bromo-5-f(5methyl12,4]oxadiazol-2-yl)thiophene 2 -Bromo-5-f5-methyl[1, 2 4 ]oxadiazol-2.yl)thiophene was prepared by standard chemistry well known to those versed in the art and was a white solid, np 48- 490C.
4-(3-cyclopentyloxy-4methoxyphenyl)-4-[5,2,4]oxadiazo-2yl)thien-2-ylethynylcyclohexan- 1-one To a solution of 4-cyclopentyoxymethoxyphenyl)-4tynyl 1-one (0.17 g, 0.88 mmol) and 2-bron>-5-f5-methyl-[1,4]oxadiazol-2-yt (0.18 g, 1.2 mmol) in triethylamine (5 nL) under an argon atmosphere were added tewais(triphenylphosphine)paljdium(0) (0.037 g, and copper(I) iodide (0.010 g, and the mixture was heated at 85-900C for 2 h. Anioniumn chloride was added and the mixture was extracted three times with dichioronethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, provided 4 3 -cyclopentyloxy-4methoxyphenyl)-4-[5-(5-methyl-[1,2,4]oxadizl2ythe-yehnlccoexone as a white wax (0.17 g, mp 94-950C. Anal. (C27H28N204S) calcd: C, 68.04; H, 5.92; N, 5.88; found: C, 67.83; H, 5.89; N, 5.92.
Example 21 2hexan- 1one 21a) 4 -bronio-2-carboxymethylthiophene 28 WO 96/19995 PCTIUS95I16858 4 -Bromo-2-carboxymethylthiophene was prepared by standard chemistry well known to those versed in the art and was a brown oil. lfj4NJR (400) Miz, CDCI3) 8 7.69 J=1.5 Hz, 1 7.45 J=1.5 Hz, 1 3.90 3 H) ppm.
21 b) 4 2 bcmethoxythien-4ylethynyl)-4-(3-yclopentyloxy 4 methoxyphenyl)cyclo-hexn-l-one.
To a solution of 4-3ccoetlx--ehxpey)4ehnlylhxn I-one (0.25 g, 0.8 mmol) and 4 -bromo-2-carboxymethylthiophene (0.27 g, 1.2 mmol) in triethylamine (3.5 rnL) under an argon atmosphere were added tedas(triphenylphospine)aladiu(O) (0.038 g, and copper(1) iodide (0.010 g, and the mixture was heated at 80-85 0 C for 0.5 h. Ammonium chloride was added and the mixture was extracted three times with dichioromethajie, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 4-( 2 -carbomethoxyutien.4ylethynyl).
4-3ccoetlx--ehxyhnlccoea-I-n as a yellow glass (0.15 g, 'H-NMR (400 MHz, CDCl3) 5 7.81 J=1.3 Hz, 1 7.60 J=1.3 Hz, 1 7.16 J=2.2 Hz, 1H), 7. 10 (dd, J=8.5, 2.2 Hz, 1 6.86 J=8.5 Hz, 1 H), 4.80 (in, 1 3.90 3 3.84 3 2.98 (dt, J= 14.8, 5.7 Hz, 2 2.48 (br d, J=14.8 Hz, 2 3.33 (in, 2 2.26 (dt, J=13.6, 4 Hz, 2 1.9 2.0 (in, 6 1.6 (in, 2 H) ppm. Anal. (C26H280 5 S) calcd: C, 69.00; H, 6.24; found: C, 68.82; H, 6.04.
Exmp-k22 4-2Croy=-leh~y)4(sw 4-1-ou'h-Ir one A solution of 4-( 2 -carbomethoxythien4ylethynyl)-4(3.cyclopentyloxy-4 methoxyphenyl)cyclohexanl ne 19 g, 0.43 mmol) and coarsely ground potassium hydroxide (0.03 6 g, 0.64 minol) in tetrahydrofuran (2mL), methanol (2niL), and water (0.4mL) was stirred at room temperature under an argon atmosphere for 24 h. The reaction was acidified (10% HQ), was extracted three times with 5:95 methanol:dicbloromethane, was dried (magnesium sulfate) and was evaporated.
Purification by flash chromatography, eluting with 0. 1: 3:97 acetic acid:methanol:dichloromethane, provided 4 2 -carboxythen4.ylethynyl)-4(3.
cyc~loperityloxy-4-methoxyphenyl)cyclohexa..-.I(-one as an off-white solid 18 g, mnp 80-820C. Anal. (C25H2605S.0.25 H20) calcd: C, 67.78; H, 6.03; found: C, 67.72; H, 6.02.
Example 23 4: he--lt~~l--3ac--n la-4-ehxpe 1~~lo a-one 23a) 4 -broino-2-cyanothiophene 4 -Bromo-2-cyanothiophene was prepared by standard chemistry Well known to those versed in the art and was a pinkish solid, rnp 43-440C.
29 WO 96/19995 PCT/US9/16858 23b) 4-(2yanothien-4-ylethynyl)4(3cyclopen 1-one.
To a solution of 4-(3-cyclopenyloxy-4-methoxyphenyl)-4-ethynyclohexan- 1-one (0.25 g, 0.8 mmol) and 4 -bromo-2-cyanothiophene (0.15 g, 0.8 mmol) in triethylamine (5 nL) under an argon atmosphere were added tetrakis(riphenyl_ phosphine)palladium(O) (0.038 g, and copper(l) iodide (0.008 g, and the mixture was heated at 85-900C for 24 h. Water was added and the mixture was extracted three times with dichioromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 4(2-cyanothien-4-yithynyl)-4-(3cyclope methoxypheny1)cychexan 1 -one, which was further triturated from dichioromethanehexanes as a white solid (0.08 g, mp 112-1130C. Anal. (C25H25N03S.0.375 calcd: C, 70.44; H, 6.09; N, 3.29; found: C, 70.38; H, 5.94; N, 3.20.
Example 24 1 4 xaiz-2-yfthien4 leth nll cclohexan-1-one 24a) 4 -bromo-2-(5-methyl-[1,2,4]oxadiazol-2-yl)thiophene 4 -Bromo-2-5-methyl [1, 2 4 ]oxadiazol-2-y1)thiophene was prepared by standard chemistry well known to those versed in the art and is a white solid, mp 66- 670C.
24b) cis-[ 4 3 cyclopentyloxy4methoxyphenyl)4[2-(5-methyl [l, 2 4 ]oxadiazol-2yl)thien-4-ylethynyl]cyclohexan-l-ol] To a solution of trans-[4-(3-cyclopentyloxymethoxyph t cyclohexan-l-ol] (0.25 g, 0.8 nmol, prepared as described in a co-pending application identified as P50287 and filed on even day herewith) and 4-bromo-2-f [l, 2 4 ]oxadiazl-2-yl)thiophene (0.20 g, 0.8 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(trphenylphosphine)pjadium() (0.038 g, copper(I) iodide (0.009 g, and a small crystal of triphenylphosphine, and the mixture was heated at 70-75 0 C for 0.5 h. Hydrochloric acid was added and the mixture was extracted three times with dichioromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 1:1 ethyl acetate:hexanes, provided cs-[4-(3-cyclopentyloxy-4-mpthoxyphenyl methyl-[1 oxadiazol-2-yItiey cyclohexan-l-ol] (0.20 g, which was further triturated from dichloromethane-hexanes to give a white solid, mp 142- 14300. Anal. (C27H30N204S) calcd: C, 67.76; H, 6.32; N, 5.85; found: C, 67.85; H, 6.42; N, 5.54.
24c) 4 3 cyclopentyloxy.4-methoxyphenyl)-4-[2(5-methy 1 1 ,2,4]oxadiazo-2yl)thien-4-ylethynyllcyclohexan- I-one 30 ~111 WO 96/19995 PCTUS9516858 To a suspension of pyridinjum chlorocomate (0.04 g, 0.20 mnmol) in dichioromethane (1 mL) at room temperature under an argon atmosphere was rapidly added a solution of cis-[ 4 3 cyclopentyloxy-4-methoxyphenyl)-4-[ 2 11,2, 4 ]oxadiazol-2-yl)thien4-ylethynyl]cyclohexan-1-oll (0.06 g, 0.13 mmol) in dichloromethane (2 mL) and the mixture was stirred for 1 h. Ether (20 mL) was added and stirring was continued for 0.25 h. The mixture was filtered through Celite® and was evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy4-methoxyphenyl)-4-2-(5-methyl- 11,2,4]oxadiazol-2-thn4ylethin ylt cyclohexan-1-one as a colorless oil Recrystallization from dichloromethane-hexanes provided a white solid (0.033 g, mp 94-95oC. Anal. (C27H28N 2 04S1.01 H20) calcd: C, 65.57; H, 6.11; N, 5.66; found: C, 65.46; H, 5.74; N, 5.60.
Examle h4-(4-Crbohxvthien-2vihvnvl)-4(3cycl- 15methoxyhenv1~cvhexan I-ne 2-bromo-4-carboxymethylthiophene 2-Bromo-4-carboxymethylthiophene was prepared by standard chemistry well known to those versed in the art and is a brown oil. 1 H-NMR (400 MHz, CDCI3) 6 7.99 1H), 7.47 1 3.86 311) ppm..
25b) 4-(4-carbomethoxythien-2-ylethynyl)-4-(3-cyclopentyloxy4methoxyphenyl)cyclohexan- I1-one To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynyl-cyclohexani-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 were added tetrakis(triphenyl-phosphine)paladium() (0.044 g, copper(I) iodide (0.011 g, and a small crystal of triphenylphosphine, and the mixture was heated at 80-85oC for 0.5 h. Water and hydrochloric acid were added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 4-(4-carbomethoxythien-2-ylethynyl)-4-(3-cyclopentyloxy- 4-methoxyphenyl)cyclohexan-1-one as a yellow gum (0.29 g, 1 H-NMR (400 MHz, CDC1 3 8 8.00 J=1.1 Hz, 1 7.61 J=1.1 Hz, 1 7.16 J=2.2 Hz, 1 7.07 (dd, J=8.4, 2.2 Hz, 1 6.87 J=8.4 Hz, 1 4.81 1 3.88 3 3.86 3 2.97 (dt, J=14.4,5.7 Hz, 2 2.49 (br d, J=13.5 Hz, 2 2.35 (m, 2 2.29 2 1.9 2.0 6 1.6 2 H) ppm. Anal. (C26H2805S) calcd: C, 69.00; H, 6.24; found: C, 68.76; H, 6.46.
Eamle 26 D -n 31 WO 96119995 PCTfUS9516858 A solution of 4 4 cabomethoxytien2etyylthyn( 3 ylopnyoy4 MethoxyphenYlOcyclohexan- I -on (0.12 g, 0.427 mmol) and coarsely ground Potassium hydroxide (0.045 g, 0.81 nimol) in tetrahydrofuran (2.5nmL), methanol and water (0.5mL) was stirred at room temperature under an argon atmosphere for thre days. The reaction was acidified (10% HCl) was extracted three times with 5:95 methanoldichlorometane, was dried (magnesium sulfate) and was evaporated- Purification by flash chromatography, eluting with 0.25:2.5:97.5 acetic acid-methanol:dichloromethane, provided 4 4 -carboxythien-2-ylethynyl)4( 3 c~l~n~oY-ehx~hnlccoea-I-n as an off- white foam 11 g, mp 75-76 0 C Anal (C25H2605S.0.25 1120) calcd: C, 67.78; H, 6.03; found: C, 67.73; H, 5.80.
31X--4(-gbl.
2 .Ioxa diazol-2-yl) hien.2 vleth mylclohexanign -one 27a) 2 -bromo-4-(s..methyl{1 2 4 ]oxadiazol-2..yl)thiophene 2-rm--5mty-124oaizl2y~hohn was prepared by standard chemistry well known to those versed in the art and was a white solid, nip 72- 730C 27b) cis-1(3- l~etlx-4mtoypey)-[-5 thyl-[ 2 ,4]oxadiazol-2yl)thien-2-ylethynyl] cyclohexan- 1-ol] To a solution of trn-4(-ylpnyoy-mhxpey)4ehnl cyclohexan-1I-ol (0.25 g, 0.8 nomol, Prepared as described in a co-pending application filed by the same inventors, identified as P50287 and filed on even day herewith) and 2-rm--5mty-124oaizl2y~hohn (0.20 g, 0.8 mmol) in triethylamine (5 niL) under an argon atmosphere were added teraks(trphenylphosphine)plldiu( 0 (0.038 g, copper(l) iodide (0.009 g, and a small crystal of triphenylphosphine, and the mixture was heated at 70-75 0
C
for 0.5 h. Hydrochloric acid was added and the mixture was extracted three times with dichioromethane, was dried (magnesium sulfate) and was evaporated.
Purification by flash chromatography, eluting with 1: 1 ethyl acetate:hexanes provided ci-4(-ylpnyoy4mtoyhny)4[-5mty-124oaiil2 Yl)thien-2-ylethynyl] cyclohexan- I which was further triturated from dichioromethane..hexanes to give a white solid (0.20 g, mp 142-143 0 C. Anal.
(C27H30N20j4S -0.75 H20) calcd: C, 65.90; H, 6.45; N, 5.69; found: C, 66.06; H, 6.42; N, 5.50.
27c) 4-3ccoetlx--ehxyhnl -4(-ehl[, 2 4 ]oxadiazo1-2- To a suspension of pyridinium chiorochromate (0.07 g, 0.31 nimol) in dichloromethane (1 niL) at room temperature under an argon atmosphere was rapidly 32 WO 96/19995 PCT/iUS9s16858 added a solution of cis-[4-(3-cyclopentyloxy-4methoxyphenyl)-4-[4-(5methyl- [12,]xadiazol-2 -)thien-2-ylethynylc enIo (0.10 g, 0.21 mnol) in dichloromethane (2 mL) and stirred 0.5 h. Ether (20 nL) was added and stirring continued for 0.5 h. The mixture was filtered through Celite® and was evaporated.
Purification by flash Chromatography, eluting with 25:75 ethyl acetate:hexanes, provided 4-(3cyclopentyloxy-4-mehoxyphenyl)-4-[4 yl)thien- 2 -ylethynycyclohexan-,.1n as a white solid, mp 90-91 0 C. Anal.
(C27H28N204S-O25 H20) calcd: C, 67.41; H, 5.97; N, 5.82; found: C, 67.43; H, 5.87; N, 5.80.
ExIM~l 28 '11VCIQ Lnyl -mth hsu WIRnaiddin-4cyclohexan-l1-one 28a) 4 -iodo- 2 -thiomethylpyrimidine 4 -Iodo- 2 -thiomethylpyrimidine was prepared following a literature procedure (AJ. Majeed, 0. Antonsen, T. Benneche, K. Undheim. Tetrahedron 1989, 45, 993- 1006).
28b) 4(3-cyclopentyoxy-4- methoxyphenyl)-4-(2 cyclohexan- i-one To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4 I-one (0.35 g, 1.12 mmol) and and 4-iodo-2-thiomethylpyrimidine(O.56 g, 2.4 mmol, as a mixture of 4 -iodo-2-thiomethylprimidine and 4 -chloro- 2 -thiomthylpyrimidine) in triethylamine (5 mL) under an argon atmosphere were added ttrads(triphenylphosphine)palladium() (0.051 g, and copper(l) iodide (0.014 g, and the mixture was heated at 85-90 0 C for 0.5 h. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, provided 4 3 -cyclopentyloxy-4-methoxyphenyl)-4-(2methylthiopyrixnidin-4.ylethynyl) cyclohexan-1-one as a yellow resin (0.35 g, 72%).
1 H-NMR (400 Mlz, CDC13) 8 8.50 J=5.3 Hz, 1 7.17 J=2.3 Hz, 1 7.08 (dd, J=8.5, 2.3 Hz, 1 7.03 J=5.3 Hz, 1 6.87 J=8.5 Hz, 1 4.81 1 3.86 3 2.99 (dt, J=14.7, 8.7 Hz, 2 2.58 3 2.46 (br d, J= 18.7 Hz, 2 2.40 2 2.29 2 1.8 2.0 6 1.6 2 H) ppm.
28c) -(3-cyclopentyoxy-4-methoxyphenyl)-4-( ylethynyl)cyclohexan- 1-one To a solution of 4 3 -cyclopentyloxy-4-methoxyphenyl)-4.(2methylthiopyriridin-4-ylethynyl)cyclohexa. 1-one (0.35 g, 0.81 numol) in chloroform at -10OC under an argon atmosphere was dropwise added over 20 min a solution of 3 -chloroperoxybenzoic_ acid (0.31 g, 1.78 mmol) in chloroform. The reaction was stirred for lh at -I0OC, then for 1 h at room temperature, then was 33 111111 WO 96/19995 PCT/US95/16858 treated with 5% sodium carbonate, was extracted three times with dichloromethane, was dried (potassium carbonate) and was evaporated. Purification by flash chromatography, eluting with 1:99 methanol:dichloromethane, provided 4-(3cyclopentyloxyA-4-mtxpnl -methyl(foetylpimidin-4ylethynyl)cyclohexan-1-one as a white foam (0.27 g, mnip 60-64oC. A second batch was provided by oxidation of the sulfoxide as a white foam, mnip 71-73oC. Anal.
(C25H28N20 5 S-0.25 H20) calcd: C, 63.47; H, 6.07; N, 5.92; found: C, 63.43; H, 6.07; N, 5.58.
Exampe 29 4-(2-Aminormidin-4-lethavl)-4-(3-c-- v cl I-one Into a solution of 4 3 -cyclopentyloxy-4-methoxyphenyl)-4-(2methylsulfonylpyriidin-4-ylethynyl)cyclohexan-1-one (0.26 g, 0.56 nmmol) in methanol (4mL) at -78 0 C was condensed liquid ammonia (4 mL), the pressure tube was sealed and the reaction was stirred at room temperature for 2.5 h. After cooling, the solvents were evaporated. Purification required two flash chromatographies, eluting first with 2:98 methanol:dichloromethane and secondly with 4:6 ethyl acetate:hexanes, to provide 4-( 2 -aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4methoxyphenyl)cyclohexan--one as a white solid (0.18 g, mnip 68-70oC. Anal.
(C24H27N303-0.2 H20) calcd: C, 70.46; H, 6.75; N, 10.27; found: C, 70.73; H, 6.79; N, 9.87.
Example 4-(3lox methoxhen-4-(-methi idazol-2-vethnl)clohexa 1one 30a) 1-methyl-2-iodoimidazole l-Methyl-2-iodoimniidazole was prepared by standard chemistry well known to those versed in the art and was a white solid, mnip 58-59oC.
4 3 -cyclopentyloxy-4-methoxyphenyl)-4-(1-methylimidazol-2-ylethynyl) cyclohexan- 1-one To a solution of 4 3 -cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan- 1-one (0.50 g, 1.6 mmol) and 1-methyl-2-iodoimidazole (0.35 g, 1.6 mmol) in triethylamine (50 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)paladium() (0.074 g, copper(I) iodide (0.018 g, and a small crystal of triphenylphosphine, and the mixture was heated at 80-85 0
C
for 1 h. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:1 ethyl acetate:hexanes, provided impure 4-(4carbomethoxythien-2-ylethynyl-4 -methoxyphenyl)cyclohexan-1one (0.16 g, which was combined with product from a second reaction (0.16 g, 34 3 Ilr WO 96/19995 PCTIUS95/16858 43%) and purified by flash chromatography, eluting with 1:99 methanol:dichloromethane, followed by recrystallization from dichioromethane.
hexanes, to provide pure -(3cyclopentyloxy- methoxyphenyl)-4-(l- 2 -ylethyny)cyclohexan-l-one (0.12 g) as an off-white solid, mp 137-1380C. Anal (C24H28N20 3 .O.2 H120) calcd: C, 72.77; H, 7.23; N, 7.07; found: C, 72.82; H, 7.99; N, 6.97.
flramli3 4 3 Yclopevloxy4metnoxph (imilen 1-ne bydnochioridesah 31a) l-ten-butylcarbonyl-2-iodoimidazole I -tert-Butylcarbonyl2-iodoimidazole was prepared by standard chemistry well known to those versed in the art and was a white'solid, np 77-780C.
31b) 4-(3-cyclopentyloxy-4-methoxyphenyl) rb k ylethynyl) cyclohexan- I-one To a solution of 4-3clopentyloxy-4-etho4h i-one (0.
2 8g, 0.9 mmol) and l-tert.-butylcabonyl-2-iodoinidazole (0.29 g, 0.97 mmol) in triethylamine (5 mL) under an argon atmosphere were added teks(tiphenyl-phosphine)pallaium(o) (0.042 g, copper(i)iodide (0.005g, and a small crystal of triphenyiphosphine, and the mixture was heated at 80-850C for 1 h. Water was added and the mixture was extracted three times with dichioromethane, was dried (magnesium sulfate) and was evaporated. Puification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes provided 4(3cyclopetyoxy-4 -methoxyphenyl)-4enyl (tel ylethyny)cyclohexan-l-one (0.18 g, as a colorless oil. 1 H-NMR (400 MHz, CDCl3) 8 7.36 1 7.20 J=2.1 Hz, 1 7.17 (dd, J=8.5, 2.1 Hz, 1 7.01 1 6.85 J=8.5 Hz, 1 4.85 1 3.84 3 3.18 2 2.44 (m, 4 2.22 2 1.8 2.0 6 1.6 II H) ppm.
31c) 4(3cyclopentyloxy-4-m etho xyphenyl (1 2 1 j) one, hydrochloride salt A solution of 4 3 -cycloentyloxy-4-mthoxyphenyl)4.( 1 -tertbut~carbonylimdazo-2-ylethynyl)cycloh (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 OOC and filtered to provide 4 3 -cyclopentyloxy-4-methoxyphenyl4 (imidazol-2-ylethynyl)-.cyclohexan- -one, hydrochloride salt (0.12 g, 76%) as a white solid, mp 183-184 0 C. Anal. (C23H26N20 3 -Ha-0.25 1120) calcd: C, 65.70; H, 6.83; N, 6.66; found: C, 65.46; H, 6.65; N, 6.44.
Example 32 35 I I a r- WO 96/19995 PCTIUJS5/16858 oxy~phnyl~lny~cpe~1- 32a) 4 2 -hydroxyethoxy)phenyl iodide A melt Of ethylene carbonate (6.5 g, 74 mimol) in a small flask under Argon Was treated with 4 -iodophenol (0.400 g, 1.82 mmol) and powdered potassium carbonate 1 2 6 g, 9.l1mmol) and was stirred at 9000 for 3 hr. The mixture was treated with cold dilute hydrochloric acid to decompose the excess potassium carbonate and excess aqueous sodium hydroxide solution was slowly added and the Mixture Was Stirred Over night. The Suspension was extracted with Methylene Chloride, was washed with water and brine, was dried over sodium sulfate and was stripped to afford a white solid, which was purified by flash chromatography on silica gel (20 mL) with methylene chloride to afford 128 9, 27%) of the titled intermediate as a white solid, mp 76-77.50C.
32b) 4-3ccoetlx--ehxphnl -2[-2hdoyd 15oxy)phenyllethYnyl)1 lI-(ethylenedioxy)cyclohexane A solution of 4 2 -hydroxyethoxy)phenyl iodide (0.059 g, 0.22 mmol), and 4- 3 -cyclopentyloxy.4.methoxphenyl)-j (tyeedoy--tynlylhxn (0.080 g, 0.22 rnmol) in dry piperidine (1 rnL) was treated with a mixture of tetrakis(triphenylphosphine)paJJadiu (0.0 13 g, 0.011 mmol), cuprous iodide (0.0025 g, 0.0 13 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 in vacuo afforded the titled intermediate as a viscous oil. 1 H-NMR (400 M&z, CDC13) 8 7.39 (di, J=9.0 Hz, 2H), 7.24 (di, J=2. 1 Hz, 1H), 7.13 J=8.3 Hz, J=2.1 Hz, 1H), 6.85 J=8.7, 2H), 6.84 J=8.3 Hz, 1H), 4.81 J=2.0 Hz, lH), 4.09 J=4.4 Hz, 2 4.00 4H), 3.97 J=4.4Hz, 2H1), 3.84 311), 2.3 to 1.5 (in, 2111 with 0XY)PhenYl~ethYnYl)cYclohexn- I -on A solution of 4-3CCOetlx--ehxpey)4(-4(-yrxehn I-x)hnlehnl-,-(tyeeix~ylhxn (0.090 g, 0.18 minol) in tetrahydrofuran (8 was treated with 3N hydrochloric acid (0.9 MnL) as in Example 12. Purification by chromatography (silica gel, 40 to 50% ethyl acetate in hexanes) folowed by drying in vacuc at 600 C afforded the titled compound as a glass. Anal.
(C28H320 5 -1/4 H20) calcd: C 74.23, H7.23, found: 074.31, H7.24. 1
H-NMR
(400 Wiz, CDC13) 8 7.41 Kci J=8.9 Hz, 211), 7.23 (di, J=2.3 Hz, 111), 7.13 (d-d, Hz, J=2.3 Hz, 111), 6.89 J=8.7, 2H), 6.86 (di, J=8.3 Hz, 4.80 1H), 4.11 J=4.5 Hz, 2 3.98 J=4.41z, 211), 3.85 311), 3.04 J=14.1 Hz, J=6.lHz, 2H), 2.47 (dbr, J=13.0, 2H), 2.4 to 1.5 (mn, 1911 with -36 WO 96/19995 PCTIUS95/16858 Prearation ofhspenltyy
A
rflth =yhenyflcvlohexan- 1 -one (ethylenedioxy)cyclohexane A stirred mixture of 4 4 -cyclopentyloxy.4.methoxypheflyI)-l.l (ethylenedioxy)4-ethYylcyclohexane (0.200 g, 0.56 mmol) and methyl 4iodobenzoate 147 g, 0.56 mmol) in triethylamine (2.5 mL, dry) was treated with a mixture of te -ads(triphenylphospie paLkdium(0.032 g, 0.028 mmol), cuprous iodide (0.0064 g, 0.034 mmol), and triphenylphosphine (crystal) by the procedure of Example id. The reaction mixture was extracted and chromatographed as described in Example id and stripped in vacuo to afford a light yellow oil (0.25 g,
IH-NMR
(400 MHz, CDC13) 8 7.98 9.4 Hz, 2H), 7.50 J--9.4 Hz, 2H1), 7.20 J=1.9 Hz, 1H), 7.12 J=1.9 Hz, J=8.6 Hz, 1H), 6.84 J=8.6, IH), 4.80 J=3.8 Hz, 1H), 4.00 br, 4H1), 3.92 3H1), 3.85 3H1), 2.3 to 1.5 (in, 17H1 with 33b) 4-4croehxpeyehny)4(-ylpnyoy4 methoxyphenyl)cyclohexane A stirred solution of 4-4c mtoyhnltyy)4(-ylpnyoy4 mehxpey) ,1-etyeeix~ylhxn 150 g, 0. 12 minol) in tetrahydrofuran (7 rnL) was treated with 3N hydrochloric acid (0.70 mL) as described in Example 14 above. The crude product was purified by chromatography (silica, ethyl acetate/hexanes) and the solvent removed in vacuc to afford the titled compound as a resin (0.063 g, Anal. (C28H300 5 1/10 H120) calcd: C 75.01, H 6.79, found: C 74.97, H 6.87. 1 H-NMR (400 M&z, CDC13) 8 8.01 J=8.5 Hz, 2H1), 7.53 J=8.5 Hz, 2H), 7.20 J=2.4 Hz, 1H1), 7.11 J=8.5 Hz, J=2.4 Hz, 1H), 6.87 J=8.5, 1H), 4.80 111), 3.93 3 3.86 3H1), 3.04 J=6.2 Hz, J=14.4,2H1), 2.50 (d,br, J=14.9, 2H), 2.42-2.32 (in, 2H), 2.26 J=2.8 Hz, J=14.4 Hz, 211), 2.00-1.5 (in, 1111 with H120).
Pemparation f 4 44 cbxvphenvLethyvW4.(3..cylopentloxy 4
L
methoxvphenyl cclhexan-1-one A stirred solution of 4-4cbmtoyhnltyy)4(-ylpnyoy4 methoxyphenyl)cycloheane 146 g, 0.326 inmol) in dry methanol was treated with 10% aqueous sodium hydroxide solutiorn (0.46 mL, 1. 15 minol) under an argon atmnosphere as described in Example 13. The crude acid was purified by chromatography (silica, ethyl acetate/methylene chloride/formic acid; 10:90: the product fr-actions washed with water three times, was stripped in vacuo was crystalized with ether and was dried in vacuo to afford the titled compound as a white solid (0.077 g, mp 170-1710C. Anal. (C27H280 5 calcd: C 74.98, H 6.53 found: C 74.78, H 6.54.
37 WO 96/19995 PCTIUS95/16858 Exampe Preparation of 4 3 -cycloentvloxv-4-methoxvhenvl)4-(2piperidinocarbonvlmethoxvhenvllethvdl)clhean-1-one 4 -iodophenoxyacetic acid methyl ester 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 mmnol) in dry acetone under argon was sealed and heated at 70 0 C for 4 hr. The cooled mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by chromatography (silica, 40 to 50% methylene chloride in cyclohexane) and the solvent was removed in vacuo to afford the titled intermediate as a white solid (0.41 g, 62%), mp 69-70 0
C.
4 3 -cyclopentyloxy-4-methoxyphenyl)- 1,l-(ethylenedioxy)-4-(2[4(1pipeidinocarbonylmethoxy)phenyl]ethynyl)cyclohexane 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 0
C
for 1.5 hr by the procedure of Example 11 with a mixture of tetrakis(triphenylphosphine)palladium (0.027 g, 0.023 mmol), cuprous iodide (0.0048 g, 0.025 mmol), and triphenylphosphine (crystal). The crude product was chromatographed (silica 50 to 75% ethyl acetate in petroleum ether) and was stripped in vacuo to afford the titled intermediate as a viscous yellow oil (0.232 g, 1
H-
NMR (400 MHz, CDCI3) 8 7.38 J=8.7 Hz, 2H), 7.24 J=2.3 Hz, 1H), 7.13 (dd, J=8.4 Hz, J=2.3 Hz, 1H), 6.89 J=8.9, 1H), 6.84 J=8.4, 1H),4.81 1H), 4.69 2H), 4.00 4H), 3.84 3H), 3.56 J=5.5 Hz, 2H), 3.49 J=5.5 Hz, 2H), 2.3 to 1.5 32H with 4 3 -cyclopentyloxy-4-methoxyphenyl)-4-(2[4-( 1piperidinocarbonylmethoxy)phenyl]ethynyl)cyclohexan- 1 -one A stirred solution of 4 3 -cyclopentyloxy-4-methoxyphenyl)-1,1- (ethylenedioxy)-4-(2-[4-(1 -piperidinocarbonymethoxy)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 in vacuo to afford the titled compound as a resin (0.127 g, Anal. (C28H300 5 *1/10 calcd: C 75.01, H 6.79, found: C 74.97, H 6.87. 1 H-NMR (400 MHz, CDCl3) 8 7.41 J=9.1 Hz, 211), 7.22 J=2.3 Hz, 1H), 7.11 J=8.4 Hz, J=2.3 Hz, 1H), 6.92 J=8.6, 1H), 6.86 J=8.5, 1H),4.80 1H), 4.70 2H), 4.00 4H), 3.85 (s, 3H), 3.56 J=5.5 Hz, 2H), 3.48 J=5.5 Hz, 2H), 3.03 J=6.1 Hz, J=14.3, 2H), 2.47 (d,br, J=14.9, 211), 2.4-2.2 411), 2.0 to 1.5 2511 with 1120).
Example 36 38 rl a WO 96/19995 PCTIUS9s/16858 Prearation of 4-(2-4-car xvmthlo henvllethvnvl)-4 mnethoxyphenyl)cclohexn- -one 19a) 4 2 4 -CarbomethoxYmethyloxyphenyl]ethynyl)-4-( 3 -cyclopentyloxy-4methoxyphenyl)-,l-(ethylenedioxy)cyclohexane A stirred mixture of 4 3 -cyclopentyloxy-4-methoxyphenyl)- 1,1 (ethylenedioxythynylcyclohexane (0.075 g, 0.21 mmnol) 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 0 C for 1.5 hr by the procedure of Example 11 with a mixture of tetrads(triphenylphosphine)palladium (0.018 g, 0.016 mmol), cuprous iodide (0.004 g, 0.021 mmol), and triphenylphosphine (crystal). The crude product was chromatographed (silica 40 to 50% ethyl acetate in hexanes) and stripped in vacuo to afford the titled intermediate as a dark red oil (0.080 g, 1
H-NMR
(400 MHz, CDC13) 8 7.98 9.4 Hz, 2H), 7.50 J=9.4 Hz, 2H), 7.20 J=1.9 Hz, 1H), 7.12 J=1.9 Hz, J=8.6 Hz, 18), 6.84 J=8.6, 1H), 4.80 J=3.8 Hz, 1H), 4.00 br, 4H), 3.92 3H), 3.85 3H), 2.3 to 1.5 17H with 36b) 4-(2-[4-carboxymethyloxyphenylethynyl)-4-(3-cyclopentyloxy-4methoxyphenyl)dyclohexan- I1-one A stirred solution of 4-(2-[4-carbomethoxymethyloxyphenyl]ethynyl)-4-(3cyclopentyloxy-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 removed in vacuo to afford the titled compound as a resin (0.127 g, Anal. (C28H3 0 0 5 -1/10 H20) calcd: C 75.01, H 6.79, found: C 74.97, H 6.87. 1H-NMR (400 MHz, CDC13) 8 8.01 Hz, 2H), 7.53 J=8.5 Hz, 2H), 7.20 J=2.4 Hz, 1H), 7.11 J=8.5 Hz, J=2.4 Hz, 1H), 6.87 J=8.5, 1H), 4.80 1H), 3.93 3 3.86 3H), 3.04 J=6.2 Hz, J=14.4, 2H), 2.50 (d,br, J=14.9, 2H), 2.42-2.32 2H), 2.26 J=2.8 Hz, J=14.4 Hz, 2H), 2.00-1.5 11H with Example 37 Preparation of 4 2 4 -carbmethyoxethenvlye y4nv---cythlvntvloxv-4methoxYphenvlvclohexan- -one A stirred mixture of 4 3 -cyclopentyloxy-4methoxyphenyl)-4-ethynylcyclohexan-1-one (0.075 g, 0.24 mnmol) and 4iodophenoxyacetic 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 0 C for 1 hr with a mixture of tetrakids(triphenylphosphine)-palladium (0.012 g, 0.010 mmol), cuprous 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, was extracted twice with ethyl acetate and the organic phase was washed with water, brine and was dried over anhydrous sodium sulfate. The 39 WO 96/19995 PCT/US95/185 crude Product was chromatographed (silica, 25 to 30% ethyl acetate in hexanes) and was stripped in vacuo to afford the titled intermediate as an amber resin (0.097 g, Anal. (C29H320 6 calcd: C 73.09, H 6.77, found: C 72.91, H 6.78. 1
H-NMR
(400 MHz, CDC13) 8 7.41 J=8.9 Hz, 2H), 7.21 J=2.2 Hz, 111), 7.11 (d4d 3=1.9 Hz, J=8.4 Hz, 1H), 6.87 J=8.9, 2H), 6.85 J=8.4, 1H), 4.80 J=4.4 Hz, 111), 4.65 2H), 3.84 3H1), 3.81 3H), 3.02 J=6.2 Hz, 3=14.2, 2H), 2.46 (dbr, J=14.8, 2H), 2.4-1.5 (mn, 16H1 with H120).
mehxyheyclhx on A mixture of 4-4ccoetyoy4mtoypey)1ehyyccoeaone 150 g, 0.48 nimol) and methyl 2 -iodobenzoate 0 12 6 g, 0.48 minol) in tiethylainine (2.4 niL, dry) was treated with a mixture of tetraks(triphenylphosphine)paliu(O) (0.024 g, 0.02 1 mmnol), cuprous iodide (0.0048 g, 0.026 minol), and triphenylphospie (crystal) under an argon atmosphere and stirred at 80 0 C for 7 h. The reaction mixture was concentrated in vacuo, and the residue treated as described in example 20, chromnatographed twice (silica, 20% ethyl acetate in hexanes; and 2% ethyl acetate in methylene chloride) crystallized from etherhexanes and dried at 60 0 C in v acuo to afford a white powder (0.05 1 g, 24%), mp 88.5-90 0 C. Anal. (028113005) calcd: C 75.3 1, H 6.77, found: C 75.11, H 6.78.
ExMpl 392 Prpration of 4 -ylpn4x~ehx hen 3 A ixur o 4icamtoxpenylx--mhxey)4ethynylcyclclohn I on one (0.075 g, 0.24 minol) and dirnethyl 5..iodoisophthalate (Trans World Chemicals, 0. 107 g, 0.33 minol) in triethylamine (1.9 niL, dry) was treated with a mixture of ten-ads(triphenyphospne)padu (0.012 g, 0.0 10 mmol), cuprous iodide (0.0025 g, 0.0 13 minol), and triphenylphosphine (a small crystal) under an argon atmosphere and was stirred at 800C for 1 h. The reaction mixture was concentrated in vacuo, and the residue was chromatographed (silica, 1 to 2% ethyl acetate in methylene chloride) and was dried at 50 0 C in vacuo to afford a tan powder (0.100 g, mp 133.5- 1350C. Anal. (030H13307) calcd: C 71.41, H 6.39, found: C 71.19, H 6.41.
Preparation of 444-h h 1--3 yc 3lx4 methoyhnlcoea. 1-oe A mixture of 4 4 -cyclopentyloxy-4mthoxyphenyl).4.ethnlycoexn 1 one (0.075 g, 0.24 minol) and 4 -chloro-1I-iodobenzene (0.057 g, 0.24 inmol) in tniethylainine (1.7 inL, dry) was treated with a mixture of tehkids(triphenylphosphine)pajjdijm (0.012 g, 0.010 minol), cuprous iodide (0.0025 40 WO 96/19995 PCT/US9/16858 g, 0.013 mmol), and triphenylphosphine (a small crystal) under an argon atmosphere and swas tirred at 80 0 C for 2 h. The reaction mixture was concentrated in vacuo, and the residue treated with dilute hydrochloric acid, was extracted three times with ethyl acetate and the organic phase was dried over sodium sulfat& and was concentrated in vacuo. The residue was chromatographed (silica, 0.05 to 1% ethyl acetate in methylene chloride/exanes 3:1) and the titled compound was dried at 25 0 C in vacuo to afford a white powder (0.051 g, mp 104-105oC. Anal(C26H2 7
Q)
calcd: C 73.83, H 6.43, found: C 73.69, H 6.41.
Example 41 Prenaatin of 4 3 ncvloetyoxy4ethoxhnl 4 (FSt rI 2 4 loxadaok3..yDnplle mthy JQYd m ione 41a) 3 3 -iodophenyl)-5-methyl-f1, 2 4 joxadiazole 3 3 -Idophenyl)-5-methyl-[1,40xadiazole was prepared by standard chemistry well known to those versed in the art and is a white solid, mp 90-91.50C 41b) 4-( 3 cycl PentYloxy4-methoxyphenyl)-4-(2-[3-(5-methyl- 2 4 ]oxadiazol-3- Y')phenyl]ethynyl)cyclohexan-l-one A stirred mixture of 4(3-cyclopenyloxy_4methoxyphenyl4ethynylcyclohexan- I -one (0.200 g, 0.64 mmol) and 3 3 El, 2 4 ]xadiazle (0.201 g, 0.70 mmol) in dry trietbylamine (4.6 mL) was treated with a mixture of tewas(triphenyphosphine)paladium (0.032 g, 0.028 mmol), cuprous iodide (0.0067 g, 0.035 mmol), and triphenylphosphine (a small crystal) at 75 0 C for 1 h 20 min under argon. The reaction mixture was concentrated in vacuo 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 combined, concentrated in vacuc was crystallized from ethyl ether and was dried at 0 C in vacuo to afford the titled compound as a white solid (0.235 g, mp 1 2 2 .5-123.50C. Anal. (C29H30N 2 0 4 calcd: C 74.02, H 6.43, N 5.95, found:
C
73.94, H 6.37, N 5.96.
Example 42 Preparation f -c(cc lo xyroxh 4 2 3 (thyl rl.
2 4 1xadiazole-5 Y1Mpheny11eth-Yl-one 42a) 5-( 3 -iodophenyl)-3-methyl-[1,2,4]oxadiazol 5-(3-odophnyl)- 3-methyl-[1 2,oxadiazole was prepared by standard chemistry well known to those versed in the art and was a white solid, mp 102-103OC.
42b) 4 3 -cyclopentyloxy-4-methoxyphenyl)-4-(2-[ 3 -(3-methyl[1 2 yl)phenyl)ethynyl)cyclohexan- -one 41
I~
WO 96/19995 PCTUS95/168>58 A stirred mixture of 4 3 -cyclopentyloxy..4.methoxyphefl.
ethynylcyclohexan..lI.-one (0.200 g, 0.64 mmol) and 5-( 3 -iodophenyl)-3-methyl.
[l, 2 4 ]oxadiazole (0.2019g, 0.70 mmol) in dry -triethylamine (4.6 mL) was treated under argon with a mixture of teakis(tiphenylphosplhine)paL-iu (0.032 g, 0.028 mmol), cuprous iodide (0.0067 g, 0.035 nimol), and triphenyiphosphine (a small crystal) at 700C for 1 h and at 250C for 15 h The reaction mixture was concentrated in vacuo and a solution of the residue was dissolved in methylene chloride, was treated with cold dilute hydrochloric acid and was 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 combined, concentrated in vacuo crystallized from ethyl ether and dried at 6000 in vacuo to afford the titled compound as an off-white powder (0.235 g, mnp 88-91 0 C. Anal.
(C29H30N20 4 calcd: C 74.02, H1-6.43, N 5.95, found: C 73.77, H 6.53, N 5.78.
Example 43 BPrparation of 4-2 Inethxypsnyflcyclohexan-17ajnc A mixture Of 4-4ccoetlx--ehxpey)4ehnlylhxn 1one (0.100 g, 0.32 mmnol) and 3 -iodobenzonitrile (0.088 g, 0.38 nimol) in triethylamine mL, dry) was treated with a mixture of tetrks(tdphenylphoiea~di (0.016 g, 0.013 nimol), cuprous iodide (0.0033 g, 0.017 mmol), and triphenyiphosphine a small crystal) under an argon atmosphere and was stirred at 750C for 1 h 15 min, followed by ambient temperature for 15 The reaction mixture was concentrated in vacuo, and a solution of the residue was dissolved in methylene chloride, was washed with dilute hydrochloric acid, water, brine and was dried over sodium sulfate. The crude product was chromatographed (silica, 3% ethyl acetate in methylene chloride/hexanes 4: 1) and the titled compound was dried at 6000 in vacuo to afford a white solid (0.075 g, mp 123.5-125.50C. Anal. (C27H27N03) calcd: C 78.42, H 6.58, N 3.39, found: C 78.13, H 6.67, N 3.40.
Brearation of 4 1 clpntlxAmehxhny.4[ 3 dicvanophenyl1eth3MyLcycl hexan 1-one 44a) 3 ,5-dicyanophenyl iodide 3 ,5-Dicyanophenyl iodide was prepared by standard chemistry well known to those versed in the art and was a white solid, nip 145.5-146.50C.
44b) 4-3ccoetlx--ehxpey)4(-35dcapey~tyy) cyclohexan- 1-one A mixture .of 4 4 -cyclopentyloxy-4mthoxyphenyl) -thynylcyclohexan 1one (0.150 g, 0.48 nimol) and 3 ,5-dicyanophenyl iodide (0.171 g, 0.67 minol) in triethylarnine (7.5 niL, dry) was treated with a mixture of 42 WO 96119995 PCTIUJS95/16858 tetaads(triphenylphosphine)palladium (0.024 g, 0.021 inmol), cuprous iodide (0.005 g, 0.026 ramol), and triphenyiphosphine a small crystal) under an argon atmosphere and was stirred at 80 0 C for 0.5 h and at 25 0 C for 15 h. 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/exanes 9: 1) and was dried in vacuo to afford a white powder 177 g, mp 147.5-148.50C. Anal. (C28H26N20 3 calcd: C 76.69, H 5.98, N 6.39, found: C 76.41, H 5.92, N 6.39.
Preartin of 4 3 -cyclopntlxy4.to~ey)(r hydroxyPhen A thyy1 -cloe,-. -one A mixture of 4-4ccoetlxy4mtoyhnl41tyyccoeaone (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 tetmlds(tiphenylphosphine)padJj (0.0 13 g, 0.0 12 mmol), cuprous iodide (0.003 g, 0.0 16 mmol), and triphenylphosphine (a small crystal) under an argon atmosphere and stirred at 75 0 C for 40 min. 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, was dried over sodium sulfate and was concentrated in vacuo. The residue was chromatographed (silica, 4 to 7% ethyl acetate in methylene chloride/hexanes 4: 1) and the titled compound was recrystallized from methanol to afford a white powder (0.035 g, mp 144-1460C. Anal. (C26H2804-1/5 H20) calcd: C 76.52, H 7.01, found: C 76.57, H 6.97. 1 H-NMR (400 MHz, CDCl3) 8 7.36 8.5 H-z, 2H1), 7.23 J=2.2 Hz, 1H1), 7.12 d, J=2.2 Hz, J=8.5 Hz, 1H1), 6.86 J=8.5, 1H), 6.80 J=8.5, 21), 5.22 1H), 4.80 J=3.8 Hz, 1H), 3.85 3H1), 3.04 J=6.0 Hz, J=14.2, 2H1), 2.47 (dbr, J=14.8, 2H), 2.4-2.1 (in, 41H), 2.0 to 1.5 (in, 1211 with 1120).
ExamplIe46 PEparation of 4 3 y- Mlpetloxy~4methoxyphe yl)4(2r3(5-ethyl.
[1 3 4 lthiadiazol-2vl h n I ethynnylh, -n 46a) 2 3 -iodophenyl)-5-methyl-[ 1,3,4]thiadiazole 2 3 -Iodophenyl)-5-methyl-[1,3,4]tiadiazle was prepared by standard chemistry well known to those versed in the art.
46b) 4 3 -cyclopentyloxy4methoxyphenyl)4(2[3(5-ethyl-[1 ,3,4]thiadiazo1-2yl)phenyllethynyl)cyclohexan- 1-one A stirred mixture of 4 3 -cyclopentyloxy4medioxyphenyl)4..
ethynylcyclohexan- I -one 100 g, 0.32 inmol) and 2 [l, 3 4 ]thiadiazole (0.097 g, 0.32 minol) in dry triethylamine (2.5 mL) was treated under argon with a mixture of te akis(triphenylphosphine)palladium (0.0 16 g, 0.0 13 43 WO 96119995 PCTIUS95/16958 111o1l), cuprous iodide (0.0033 g, 0.0 17 mmol), and triphenyiphosphine (a small crystal) at 70 0 C for 1 h and at 25 OC for 15 h The reaction mixtur 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 combined, concentrated in vacuo and dried at 50 OC in vacuo and the brittle resin ground to afford the titled compound as a Yellow powder (0.128 g, Anal. (C29H30N203S.H 2 0) calcd: C 69.02, H 6.39, N 5.55, found: C 68.91, H 6.21, N 5.35. 1 H-NMR (400 MHfz, CDC13) 8 8.06 J=1.6 Hz, 1H), 7.88 J=1.4 Hz, J=8.1 Hz, 1H1), 7.58 J=1.2 Hz, J--9.0 Hz, 1H), 7.45 J=7.8 Hz), 7.21 J=2.2, 1H), 7.14 J=8.4 Hz, J=2.1 Hz, 111), 6.88 (d J=8.5, 1H1), 4.82 J-4.1 Hz, 1H), 3.86 3H), 3.04 J=6.1 Hz, J=14.2, 2H), 2.84 3 2.50 (d,br, J=14.9,211), 2.42-2.32 (in, 211), 2.27 (d-t, J=2.8 Hz, J=14.2 Hz, 2H), 2.00-1.5 (mn, 12H1 with Prprtion f 4fi 3 4 1oxad 1-ol2-.y1ph-nylth-0~y~oea 1one 47a) 2 3 -iodophenyl)-5-methyl.[ 1 3 4 loxadiazole 2 3 -Iodophenyl)-5-methy..[1 3 ,4]oxadiazole was prepared by standard chemistry well known to those versed in the art and was a white solid, mp 112.5- 113.50C.
47b) 4 3 -cyclopentyloxy.4mthoxyphenyl)4(2[3.(-methyl( 1 ,3,4]oxadiazol-2yl)phenyllethynyl)cyclohexan.. 1-one A stird mixture of 4- 3 -cyclopentyloxy-4methoxyphenyl)-4.
ethynylcyclohexan- 1 -one (0.100 g, 0.32 minol) and 5-( 3 -iodophenyl)-2-methyl- [l, 3 ,4]oxadiazole (0.0915 g, 0.32 minol) in dry n-iethylamine (3.5 mL) was treated under argon with a mixture of tetr ds(triphenylphosphine)pajja ium (0.016 g, 0.013 minol), cuprous iodide (0.0033 g, 0.0 17 mnmol), and triphenylphosphine (a small crystal) at 75 0 C for 1 h. The reaction mixture was concentrated in vacuo, the residue was extracted into methylene chloride and the organic phase was washed with cold dilute hydrochloric acid, water, brine and was dried (sodium sulfate). Purification by chromatography (silica, 10 to 20% ethyl acetate in methylene chloride) followed by drying at 50 OC in vacuo afforded the titled compound as a white powder (0.068 g, mp 139-1410C. Anal. (C29H30N20 4 .1/3H 2 0) calcd: C 73.09, H 6.49, N 5.88, found: C 73.07, H 6.35, N 5.79. IH-NMR (400 Mffz, CDC13) 8 8.15 J=1.6 Hz, 1H1), 8.01 J=1.4 Hz, J=7.9 Hz, 111), 7.62 J=1.5 Hz, J=7.8 Hz, 111), 7.49 J=7.9 Hz), 7.21 J=2.3, 1H), 7.14 J=8.5 Hz, J=2.4 Hz, 111), 6.88 (d, 111), 4.82 J=4.2 Hz, 1H), 3.86 3H), 3.04 J=6.1 Hz, J=14.2, 211), 2.64 3 2.51 (d,br, J=15.O, 2H), 2.42-2.32 (in, 211), 2.27 J=2.8 Hz, J=14.2 Hz, 211), 2.00-1.5 (mn, 911 with 1120).
44
M
WO 96/19995 PCT/US95/16858 Prenaration of 4 3 -cycloentoxv-4-ethoxvhenvl)I-4-.( 2 E1 3 48a) 3 -cyanobenzylphosphonic acid diethyl ester 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 140oC under argon for 2 h and the resulting volatiles were removed at room temperature in vacuo to afford the titled intermediate as a colorless oil (0.62 g, 1 H-NMR (400 MHz, CDC 3 6 7.7-7.5 3H), 7.44 J=7.8 Hz, 1H), 4.06 J=7.6 Hz, 4H), 3.17 (d J=21.8 Hz, 2H), 1.27 J=7.1 Hz, 61).
48b) 4 3 -cyclopentyloxy-4-methoxyphenyl)-4-(2[E]-(3-cyanophenyl)ethenyl)-1,1- (ethylenedioxy)cyclohexane A solution of 3 -cyanobenzylphosphonic acid diethyl ester (0.54 g, 2.13 mmol) dissolved in dry tetrahydrofuran (7 mL) was added via cannulation to a solution of potassium t-butoxide (0.237 g, 2.11 mmol) dissolved in dry tetrahydrofuran (15 mL), both solutions under argon and was chilled to OoC. After stirring for 45 min, a solution of 4-4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4formylcyclohexane (0.38 g, 1.06 mnmol) in dry tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature. After h, the mixture was quenched with aqueous ammonium chloride solution, was concentrated in vacuo was partitioned between methylene chloride/aqueous ammonium chloride solution, and the organic extract was washed with water, brine, was dried (sodium sulfate), and was concentrated in vacuo to afford a mixture containing the desired titled product and the excess phosphonate ester as a crude resin.
1 H-NMR (400 MHz, CDCI3) 6 7.62-7.4 (min, 4H), 7.36 J=7.8 Hz, 1H), 6.90 (s and d, 2H), 6.83 J=8.7 Hz, 1H), 6.30 J=16.4 Hz, 1H), 6.16 J=16.3 Hz, 1H), 4.75 J=4.4 Hz, 1H), 4.06 J=7.6 Hz, 1H), 3.96 J=3.3 Hz, 4H), 3.84 3 H), 3.17 (d J=21.8 Hz, 0.3H), 2.35-1.5 (min, 20H with H20), 1.27 J=7.1 Hz, 1.3H).
48c) 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2[E]-(3-cyanophenyl)ethenyl)cyclohexan-l-one A solution of crude 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 75-800C for 1 h. Additional hydrochloric acid (13 mL) was then added and the mixture heated at 75oC for another 15 min. The reaction mixture was concentrated in vacuo, 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 titled compound as a 45 B/ 24 wvhic solid (0.329 g, mp 11 6 -117 0 C. AnaL. (C27H29N0 3 1/6120) ca1cd:
C
77-48, H 7.06, N 3.35, found: C 77.63, H 6.94, N 3.33. IH-NNR (400o MW-2, CDCl3) 8 7.60 Ili), 7,55-7.45 (Mxi 2H), 7.39 W-77 Il), 6.97 1=2.4 lkz H z4. (p 6 8 95 l b 1 4 H 1 6 3 7 d 1 6& I N, 1 f 6 2 2 d J 1 6 2 IL 1 1 4.7 1..5 ix110.) 3.86 3H1). (Mn 18 H with To a szirzw mspcni of pyudifi 12 chwozbiehss 088. 1.34 toiol) in, dry znediyleae chlegICLe (4 rIL) Undcr azso. was added via cmnnula, a soluuam of Cu-_ cycloiazan. 1 -cl (0.20 S. 0.445 Uno1, Prepard as demr'ib cID3ndig U.S. 0* ~~applicano. identified4 s p,02M (MAWe cm even day htnwid) in inthyle. Clie( t o dSW in z a A te a 5 C t 00 ac ~W-Atr2h t2 C ty ee(ca. 10 ML) wu adde4d tie ata :000 S lUT4rI aNd the Pz~iPitf w"sWg with anoth.. 10 niL of ethyl =m.0 The umu wucuatmnhed and the IflSdu 3 e by Ohhcwmw h an isj1 5 With ethyl aceate4ichi c~ha cludug Ihe poduct with 20:30 to 30:70 ethyl dihm~ m oprovide -iCyy)-3 CYCIPMIIO" cft pbenlky anas a while solid (0.033 g, 20 nip 170-1710C 1 H.NM (400) biz
CDC
3 &88-65 2 HM, 8.47 I M, 7.14 (4, S. J=2-1 Hz, 1 7.09 (dd, J=8.4, 2.3 Hz, I 6.87 3=8.5 Hz, I 4.80 lmn4.7, c 0 3.36 (s,3 M. 2.9 (dt, 1.23, s Hz,2 2.50 (s ~ip duo to, 9 2.0-1.5 (iii supclimpoe upon wau) ppnx Nfctt in a fu a..fset h in myame cr -m afthe ececn aampilm the follwing MnRpm s my be pqew& 4 3 -cYciCp5rYoxy-4.mthoylI) 4 2 -3 4 .0copazlyloxy4aohml).-( 2 4 3 -CWc~Pencyxy4iretoxheyl) 4 2 43 ~RAL 46 07/06 '99 MON 19:27 TX/RX No 81151 I1008 7- 6-99,,19:19 S/ 34 4 -(-cyclqnyo--ehYoxyp oxy) 2 YI]CdynylNCyclhexn. .ame UFU~rff ExAmrLES The itliibitary effect ofe coxnpis Of FazMula a) O n iVV TN PlodiiCsOn by hum~an nmaot my bie demuined by the PrIMOW desaibed in Nugrer EPO PabLjSW AFPpHiea 04311754 A2. Fgfta 6, 1991. and in Hanna, WO 9015534,E 01 2r7,19.
0 Two WO"j Of aadoii Shock have u ~n dinid to devwn in. viwi TNF acvizy for the COMPOwads of Fuk~~ and TheC PMMI used in thw models is desicribe4 in Badger eu EP ubliskW Applicam 0 411 734 AZ Fdmiaiy 6, 1991. anid iU HMAMaWO 9y5534, Dmein 27. 1990.
Thr" omPound of E=amle I hCIin demonsued a positive im viva meponse in reducing 5aMM levels of TNF inducad by ClIe injecton of ezidoi EA~ip Tephophadiesr iNibitiiy Wtvity aMd inleevty of the COMPOUnds of @000 Fawwa (i)ad can bg deruuaied using a WVVuY Of fIve disit PDE qzy.
M The ssai used Is 500we of doe differun isozyUMs mm as Mallws; 1) EDE lb, POICine awwM 2) PDE kc, guineca-pig hewmt 3) PDE afl guineapig hear 4) pDE IV, h==a manc ad 5) PDE V cdW i PDEs u, Ac and M w prtaly pufiEwd using sVmdnUd cliM0~MS2ppi jc bnqns [Torphy and Cieslinski, Ma) FhWuuCCiL. 37206-214. 1990j. pDE IV is puziZfd 10 bae* bomogeneiry by the sequential use Of aicxhnefbiba-ed by hein-Sepha.m @00 ctuuwa ogrPhY TOOpy et al. L B oL. Cbea.. 267: 1798-1804. 1992.
ftxrpbodkmsw~ ctivty is amyaed as desibed in t PxManl of Toiphy and Qeulinshi, Mol. Phawcol., 37:206-2 14, 1990- P~ive IC50s in the nanomolar to PM rage f"r WOMpo& of the worings ezanaplS d=WAW Wein for Formula and (II) have bumt dnonjumMO& Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and 'variations such as "comprises#, and comPrising", will be understood to iMPly the inclsion of a stated integer orstep or group of integers or steps but not the exclusion of any other integer or step Or group Of integers or steps.
47 07/06 '99 MON 19:27 [TX/RX NO 81151 Q~009
Claims (8)
1.A compound of Formula I R 1 X 2 50 X W (R 2 )S X K 3 C wherein: RI is -<CR4R5)nC(OMOCR 4 R5)nMR 6 -(CR4R)nC(O)NR(CRpR 5 )R6 (CR4R5)n(CR4 5 )R6 Or -(CR4R5)rR6 wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0to 2; n isO0 to 4; r isO0 to 6; R4 and R5 are independently hydrogen Or C 1-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, ayloxyCl1 -3 alkyl, substituted arYloxyCI .3 ailkyl, indanyl, indenyl, C7-11 polycycloalcyl, tetrahydroffuranyl, fuiranyl, tetrahydropyranyi, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-.6 cycloalkyl, or a C4-. 6 cycloalcyl containing One Or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety may be unsubstituted or substituted by 1 to 3 methyl. groups, one ethyl group or an hydroxyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2 -tetrahydropyranyl, 2 -tetrahydrothiopyranyl, 2 -tetrahydrofuranyl, Or 2 -tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2 -tetrahydropyranyl, 2 -tetrahydrothiopyranyl, 2 -tetrahydrofuranyl, or 2 -tetrahydrothienyl, then r is 1 to 6; e) when nislIand mis, then R 6 is other than Hin -(CR4R5)nO(CR..R)mR6; X is YR2, fluorine, NR4R 5 or formyl amine; Y is 0 or S(Q)m'; m' isO0, 1, or 2; X2 is 0orNR8; X3 is hydrogen or X; R 2 is -CH 3 or -CH 2 CLJ 3 unsubstituted or substituted by 1 or more fluorines; 48 WO 96119995 PCTIUS95/16858 s isO0 to 4; R 3 is COORM~ C(Q)NR4RI 4 Or R7; W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; Z is 0, NR7, NCR4R5C 2 6 alkenyl, NORM~ NOR 1 5 NOCR4RSC 2 6 alkenyl, NNR4RI 4 NNR4R 15 NCN, NNR8C(O)NR 8 RI 4 NNR8C(S)NR 8 Rl 4 or =Z is 2-(1,3-dithiane), 2 -(l,3-dithiolane), dimethylthio ketal, diethylthio ketal,
2-(1,3- dioxolane), 2 (l, 3 -dioxane), 2 1 3 -Oxathiolane), dimethyl ketal or diethyl ketal; R7 is -(CR4R5)qR12 Or C 1 6 alkyl wherein the R12 or C 1 6 alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -Br, -Cl, N -NRORI 1, -C(0)R8, -C02R8, -O(CH2)2A40R 8 0 (CH2)qR8, .CN, -C(O)NR1OR1 1, 0 O(CH2)qC(0)NRIORlI1, 9 -NR 1OC(0)NRIORI I, NRIOC()RI I, -NR1OC(0)0R 9 -NRIOC(O)RI 3 -C(NRIo)NRIOR 1 -C(NCN)NRIORI 1 -C(NCN)SR 9 -NR1oC(NCN)SR 9 -NRIOC(NCN)NRlORII, -NR1OS(O) 2 R 9 S(O)m'R9, -NR1OC(O)C(O)NR lORI 1, -NR 1oC(0)C(0)RI 0 or R 1 3~; q isO0, 1,or 2; R12 is RI 3 (CH2)q, C3-C7 cycloalkyl,
3- or 4 -pyridyl), pyrimidyl, pyrazolyl, or 2 -irnidazolyl), pyrrolyl, piperazinyl. piperidinyl, morpholinyl, furanyl, or 3-thienyl), quinolinyl, naphthyl, or phenyl; R 8 is hydrogen or R9; R 9 is C 1 4 alkyl unsubstituted or substituted by one to three fluorines; RIO is 0R8 or RI 1; RI I is hydrogen, or Ci1A- alkyl unsubstituted or substituted by one to three fluorines; or when RIO and RI I are as NRloRi 1 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatomn selected from 0, N, or S; RI13 is oxazolidinyl, Oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyi, inhidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C 1 2 alkyl groups unsubstituted or wherein the methyl group is substituted with 1 to 3 fluoro atoms; R 14 is hydrogen or R7; or when R8 and R 14 are as NR8RI 4 they may together with the nitrogen form a '5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatom selected from 0, N, or S; provided that: R7 is not C 1 4 alkyl unsubstituted or substituted by one to three fluorines; or or the pharmaceutically acceptable salts thereof. 49 WO 6/1995PCTIJS95/168 5 8 2. A compound according to claim 1 wherein R I is -CH2-cyclopropyl, -cyclopentyl, 3 -hydroxycyclopentyl, methyl or CF2H; X is yR2; Y is oxygen; X2 is Oxygen; X3 is hydrogen; R 2 is CF2H Or Methyl, W is ethynyl or l,3-butadiynyl, R 3 is a substituted or unsubstituted pyrimidinyl ring, X is yR2, and Z is 0, NR7. 3. A compound according to claim 2 which is
4-3ccoetlx--ehxpeyl--2mtysloypfmdn4 ylethynyl) cyclohexan-1I-one, methoxyphenyl)cyclohxa.. 4 ,on, or 4. A compound according to claims 1 wherein RlI is -CH2-cyclopropyl, -cyclopentyl, 3 -hydroxycyclopentyl, methyl or CF2HL X is yR2; Y is oxygen; X2 is Oxygen; X3 is hydrogen; R 2 is CF2EI or methyl, W is ethynyl or l, 3 -butadiynyl, R 3 R 3 is R 7 where R 7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2, and Z isO0. A compound according to claim 5 which is 1ylha--one, 4 3 cyclopentyloxy4methoxyphenyl)4(cemnldoPheyledhynyl)- cyclohexan-l1-one, ehIcyclohexan- -one, ethynyl)cyclohexan.. 1-one, 304(-ylpnyoy4iehxpey)4(-yiyethynyl)cyclhexane..I-one, ox)n lehnIc~~hxn oe 303ccoetlx--ehxpeyl--3prdltyy~ylhxn 1 1-one, 4 3 -cyclopentYlOxY-4-methoxyphenyl)-4-(2[ 4 -(2-hydroxyethan-1 oxy)phenyl~ethynyl Icyclohexan- -one, oxy -henyloeeyny1)yhe~ nyenl--3ccoetlx-- Methoxyphenyl)cyclohexan- 1-one, 1-one, 4 3 -cYclOPentYlOxY-4methoxphenyl4-(2-[4-( 1 50 WO 96119995 PCTUS9SI16858 P1Poxetynoxypbonyethypny4 dcclntyloxy4mehehn~~ycoexl I-One, 4-( 2 -E4carboetoxYmoxhymeoxyphenyIy)4-3ce n(yll 4 methoxyphenyl)cyclohexan-l-.one, 4 2 -cmtOmhoxyphenylethynyy1-4-( 3 c~lpnyoy4mtoypey~ylhxnl e 4-(3-cyclopentyloxy-4- 4- 2 -carbomedioxythien5ylethyny1)-4(3.yclopentyloxy4 methoxyphenyl)cyclohexan1..one, 4 2 3 -cyanophenyehynyI)--..cycopentyloxy. 4 medhoxypheny)cycohexn-1-one, 4- 3 -yclopentyoxy4metoxphenyl).4-(2[ 4 hydoxyphenylJeffiyny1cyclohean 1 -one, 4 3 -cyclopentyloxy4-methoxyphenyl). 4- 2 3 -cyanophenyl)ethenyl)cyclohexan 1 -one, 4 3 -cyclopentyloxy4 methoxypheny)4(23dyophenyeny~yclohen I1-one, 4-2 sodium salt, 4-2caoie--ltyy)4(-ylpnyoy4 methoxyphenyl)cycohxn-1-one, 4 3 -cyclopentyoxy4methoxypheny[5(5mehyl-[ ,2,4]oxadiazol-2. yl)thien-2-ylethynyl]cycohexn 1 -one, 4-3ccoetlxy4mtoyhnl)4 -3(-ehl,2,4]oxadiazo1-3- yl)pheny1]ethynyl)cohexn- 1-one, 4 3 -cyclojentyloxy4methoxyphenyl).4(2-[ 3 (3-niethyl-[ l, 2 4 ]oxadiazo-5..yl)phenylIethyny)cycohexan 1 -one, 4-(3- ylethynyllcyclohexan. 1-one, 4-3Ccoetlx4mtoyhnl4-2[-5mty-134oaizl2 yl)pheny]ethynyl)clohean- I-one, 4 2 -Carbomethoxythien-.4ylethyny)-4-(3- cyclopeftyloxy4methoxyphenyl)cycohxan 1 -one, SB 4 2 -arboxythien-4yethyny)-4-(3.cyclopenyloxy 4 methoxyphenyl)cyclohexan..I.-one, S 4 2 -cyanothien-4-yethynyl)-4(3-.cyclopentyloxy 4 methoxyphenyl)cyclohexan. 1-one -(-ylpnyoy4mtoxpey)4 -3(-ehl,2,4]oxadiazol-5- yl)phenylethynyl)cyclohean- I-one, SB yl)tlien4-ylethynyIcyclohexan- 1 -one, rnethoxyphenyl)cyclohexan- 1 -one, 51 WO 96/19995 PCTIUS9SI16S58 methoxyphenyl)cYclohexan- 1-one, Yl)pheny1Iethyny1)cyclohexan- I1-one, 4 3 -Cccopentyloxy4methoxyphenyI)_..(l methyhmidez1l2-ylethynyl)cyclohexan_ I One, oneC, hydrochloride salt, 4 2 -acetamidopyimidims.ylethyny)4(3-cyC~per J 0 y methoxyphenyl)cyclohexan- I -onepetxy4 4-3ccoetlx--ehxYhn 2[-5mtyf,3,4]oxadiazol-2- yl)phenyllethynyl)cyclohexan- 1-one, or 4-3cCOetlx4mtoypey)-2 -5mtyf,3,4lthiadiawl12. yI)phenylethynyl)cycloheanl-one.
6. A compound of Formula II W (R,)s X K3I wherein: RI is -(CR4R5)nC(0)0(CR4R5)mR 6 (CR4R5)nC(0)NRA(ClR5)MR6, (CR4R5)nO(CR4RS)rnR 6 Or -(CR4R5)R 6 wherein the alkyl moieties may be unsubstituted or substituted with one or more fluorines; m is 0to 2; n isO0 to 4; r isO0 to 6; R4 and R5 are independently selected hydrogen Or Cl1.-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aylOxYCl.3 alkyl, haO substituted aryloxyC 1-3 alkyl, indanyl, indenyl, C7_11 pOlycycloaffLcl tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloallcyl, or a C4-.6 cYcloalkyl containing One Or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties is unsubstituted or substituted by 1 to 3 methyl groups, an ethyl group, or an hydroxyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or C) when R6 is 2 -tetrahydropyranyl, 2 -tetrahydrothiopyranyl, 2 -tetrahydrofuranyl, or 2 -tetrahydrothienyl, then m is 1 or 2; or 52 *WO 96/19995 PCTIUS95/16858 d) when R6 is 2-tetrahydropyranyl, 2-tetahydrotioyayl, 2 -tetrahydrofuranyl,or 2-tetrahydrothienyl, then r is 1 to 6; e) when nis 1adis 0,thenis he tanHin 4 RS)mR6, X is YR2, fluorine, NR4R5, Or formyl aie Y is 0or S(O)m'; m isO0, 1, or 2; X2 is 0 or NR8; X3 is hydrogen or X; R 2 is independently selected from -013 or -CH 2 CH 3 unsubstituted or substituted by 1 or more fluorines; s isO0 to 4; R 3 is COOR 14 C(O)NR4RI 4 or R7; W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or'alkynyl of 2 to 6 carbon atoms; Zis C(Y')R14, C(O)0R14, C(Y')NR 10 R 14 C(NR10)NRlOR1 4 CN, C(NOR8)Rl 4 C(O)NR8NR8C(O)R 8 C(O)NR8NR lOR 14, C(NOR 14)R8, C(NR8)NRlORl 4 C(NR14)NR8R 8 C(NCN)NR 10 R 14 C(NCN)SR 9 4- or 4- or 5 -pyrazolyl), or 5-triazolyl[ or 5-triazolyl[ 1,2,41), (5-tetrazolyl), 4- or 5-oxazolyl), 4- or 5-isoxazolyl), or 5-oxadiazolyl[1 2 -oxadiazolyl[1 2 -thiadiazolyl[ or or 5-oxazolidinyl), or 5-thiazolidinyl), or or wherein all of the heterocylic ring systems may be optionally substituted one or more times by R 14; Y'is 0or S; R7 is (CR4R5)qR12 or C 1 6 alkyl wherein the R12 or C 1 6 alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -Br, -Cl, -NO 2 -NRORI 1 -C(O)R8, -C02R8, -O(CH 2 2 4 0R 8 -O(CH2)qR8, -CN, -C(O)NR1ORI 1, -O(CH2)qC(O)NR1IOR1, O(CH2)qC(O)R9, -NR1OC(O)NR1ORl 1, -NR1OC(O)RI 1, -NR1OC(O)0R9, -NR 1OC(O)R 13, -C(NRi0)NR lORi 1, -C(NCN)NR 1ORl 1, -C(NCN)SR9, -NR1OC(NCN)SR 9 -NR1OC(NCN)NRIOR 1 1 -NR1OS(0)2R 9 -S(O)mYR9, -NR1oC(O)C(O)NRioRi i -NRIOC(O)C(0)RI 0 or R3 q isO, 1, or 2; k12 is R 13 (CH2)q, C3-C7 cycloalkyl, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, or 2-imridazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, or 3-thienyl), quinolinyl, naphthyl, or phenyl; R 8 is independently selected from hydrogen or R9; R 9 is C 1 4 alkyl unsubstituted. or substituted by one to three fluorines; -53 -x .:Ili .li-cu~cu~-- WO 96/19995 PCT/US95/16 8 5 8 R 10 is OR8 or R11; R 1 1 is hydrogen, or C1- 4 alkyl unsubstituted or substituted by one to three fluorines; or when R10 and R 11 are as NRIOR 1 they may together with the nitrogen form a 5 to 7 membered ring comprised 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 1 3 is substituted on R 12 or R 1 3 the rings are connected through a carbon atom and each second R 13 ring may be unsubstituted or substituted by one or two C 1 2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms; R 14 is hydrogen or R7; or when Rg and R14 are as NR8R1 4 they may together with the nitrogen form a 5 to 7 membered ring comprised only of carbon atoms or carbon atoms and at least one heteroatoms selected from O, N, or S; provided that: R7 is not C1- 4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.
7. A compound according to claim 6 R1 is -CH2-cyclopropyl, -cyclopentyl, 3 -hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; R 2 is CF2H or methyl, W is ethynyl or 1,3-butadiynyl, R 3 R 3 is R 7 where R 7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2, Z is 0, and Z' is COOR 14
8. A compound according to claim 7 wherein W is 1,3-butadiynyl and R 3 is unsubstituted or substituted
9. A pharmaceutically composition comprising a compound according to claim any one of claims 1 to 5 and a pharmaceutically acceptable excipient. A method for treating asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound according to any one of claims 1 to 54
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45623494A | 1994-12-23 | 1994-12-23 | |
| US08/456234 | 1994-12-23 | ||
| US45579695A | 1995-05-31 | 1995-05-31 | |
| US08/455796 | 1995-05-31 | ||
| PCT/US1995/016858 WO1996019995A1 (en) | 1994-12-23 | 1995-12-21 | 4,4-(disubstituted)cyclohexan-1-one monomers and related compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU4688396A AU4688396A (en) | 1996-07-19 |
| AU708349B2 true AU708349B2 (en) | 1999-08-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU46883/96A Ceased AU708349B2 (en) | 1994-12-23 | 1995-12-21 | 4,4-(disubstituted)cyclohexan-1-one monomers and related compounds |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0800393A4 (en) |
| CN (1) | CN1175211A (en) |
| AU (1) | AU708349B2 (en) |
| BR (1) | BR9510521A (en) |
| CA (1) | CA2208456A1 (en) |
| CZ (1) | CZ196297A3 (en) |
| FI (1) | FI972673A7 (en) |
| HU (1) | HUT78042A (en) |
| NO (1) | NO972898L (en) |
| NZ (1) | NZ301453A (en) |
| PL (1) | PL321001A1 (en) |
| WO (1) | WO1996019995A1 (en) |
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| MXPA02001471A (en) * | 1999-08-10 | 2002-07-02 | Smithkline Beecham Corp | 1,4-substituted 4,4-diaryl cyclohexanes. |
| DK3209655T3 (en) * | 2014-10-24 | 2020-09-28 | Landos Biopharma Inc | Lanthionine Synthesis C-like 2-based Therapeutica |
| CN104649882A (en) * | 2015-02-11 | 2015-05-27 | 南通恒盛精细化工有限公司 | Intermediate preparation process of phosphodiesterase inhibitor |
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| JP3192424B2 (en) * | 1992-04-02 | 2001-07-30 | スミスクライン・ビーチャム・コーポレイション | Compounds for the treatment of allergic or inflammatory diseases |
-
1995
- 1995-12-21 CA CA002208456A patent/CA2208456A1/en not_active Abandoned
- 1995-12-21 CN CN95197681A patent/CN1175211A/en active Pending
- 1995-12-21 HU HU9802635A patent/HUT78042A/en unknown
- 1995-12-21 WO PCT/US1995/016858 patent/WO1996019995A1/en not_active Ceased
- 1995-12-21 BR BR9510521A patent/BR9510521A/en not_active Application Discontinuation
- 1995-12-21 EP EP95944527A patent/EP0800393A4/en not_active Withdrawn
- 1995-12-21 NZ NZ301453A patent/NZ301453A/en not_active IP Right Cessation
- 1995-12-21 CZ CZ971962A patent/CZ196297A3/en unknown
- 1995-12-21 AU AU46883/96A patent/AU708349B2/en not_active Ceased
- 1995-12-21 FI FI972673A patent/FI972673A7/en unknown
- 1995-12-21 PL PL95321001A patent/PL321001A1/en unknown
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1997
- 1997-06-20 NO NO972898A patent/NO972898L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
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| FI972673L (en) | 1997-08-19 |
| NO972898D0 (en) | 1997-06-20 |
| HUT78042A (en) | 1999-06-28 |
| PL321001A1 (en) | 1997-11-24 |
| FI972673A7 (en) | 1997-08-19 |
| CA2208456A1 (en) | 1996-07-04 |
| WO1996019995A1 (en) | 1996-07-04 |
| FI972673A0 (en) | 1997-06-19 |
| AU4688396A (en) | 1996-07-19 |
| CZ196297A3 (en) | 1998-01-14 |
| NZ301453A (en) | 1999-02-25 |
| EP0800393A1 (en) | 1997-10-15 |
| EP0800393A4 (en) | 1998-05-06 |
| BR9510521A (en) | 1998-07-14 |
| CN1175211A (en) | 1998-03-04 |
| NO972898L (en) | 1997-08-20 |
| MX9704733A (en) | 1997-10-31 |
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