SI9300167A

SI9300167A - New compounds useful for treating or inhibiting phospodiesterase iv (pde iv) enzyme activity

Info

Publication number: SI9300167A
Application number: SI9300167A
Authority: SI
Inventors: Siegfried Benjamin Christensen; Cornelia Jutta Forster
Original assignee: Smithkline Beecham Corp
Priority date: 1992-04-02
Filing date: 1993-04-02
Publication date: 1993-12-31

Abstract

Tu notri so opisani novi cikloheksan-ilidenski derivati s formulo: X Sl 9300167 A Z Te spojine inhibirajo tvorbo faktorja tumorske nekroze in so uporabne pri zdravljenju bolezenskih stanj povzročenih ali poslabšanih s TNF tvorbo; te spojine so tudi uporabne pri zdravljenju ali inhibiciji encimatske ali katalitske aktivnosti fosfodieteraze IV in so potemtakem uporabne pri zdravljenju bolezenskih stanj, ki jih je potrebno zdraviti in inhibirati.New cyclohexane-ylidene is described herein derivatives of the formula: X Sl 9300167 A Z These compounds inhibit the formation of tumor necrosis factor and are useful in treating disease states caused or exacerbated by TNF formation; these compounds they are also useful in treating or inhibiting enzymatic or the catalytic activities of phosphodieterase IV and are therefore useful in the treatment of diseases conditions that need to be treated and inhibited.

Description

Te spojine inhibirajo tvorbo faktorja tumorske nekroze in so uporabne pri zdravljenju bolezenskih stanj povzročenih ali poslabšanih s TNF tvorbo; te spojine so tudi uporabne pri zdravljenju ali inhibiciji encimatske ali katalitske aktivnosti fosfodieteraze IV in so potemtakem uporabne pri zdravljenju bolezenskih stanj, ki jih je potrebno zdraviti in inhibirati.These compounds inhibit tumor necrosis factor formation and are useful in the treatment of disease states induced or exacerbated by TNF formation; these compounds are also useful in the treatment or inhibition of the enzymatic or catalytic activity of phosphodiesterase IV and are therefore useful in the treatment of conditions that need to be treated and inhibited.

SMITHKLINE BEECHAM CORPORATIONSMITHKLINE BEECHAM CORPORATION

Nove spojine, ki so uporabne pri posredovanju ali inhibiciji encimske aktivnosti fosfodiesteraze IV (PDE IV)Novel compounds useful for mediating or inhibiting the enzymatic activity of phosphodiesterase IV (PDE IV)

Področje izumaFIELD OF THE INVENTION

Pričujoči izum se nanaša na nove spojine, na farmacevtske pripravke, ki vsebujejo te spojine, in na njihovo uporabo pri zdravljenju alergijskih in vnetnih bolezni in za inhibiranje nastajanja faktorja tumorske nekroze (TNF).The present invention relates to novel compounds, to pharmaceutical compositions containing these compounds, and to their use in the treatment of allergic and inflammatory diseases and in the inhibition of tumor necrosis factor (TNF) production.

Ozadje izumaBACKGROUND OF THE INVENTION

Bronhialna astma je kompleksna, multifaktorialna bolezen, za katero je značilno reverzibilno zoženje dihalnih poti in hiperreaktivnost respiratornega trakta na zunanje dražljaje.Bronchial asthma is a complex, multifactorial disease characterized by reversible airway narrowing and hyperresponsiveness of the respiratory tract to external stimuli.

Identifikacijo novih terapevtskih sredstev za astmo otežkoča dejstvo, da so za razvoj bolezni odgovorni številni mediatorji. Zato se zdi malo verjetno, da bo imelo odstranjenje učinkov enega samega mediatorja bistven učinek na vse tri komponente kronične astme. Alternativa mediatorskemu pristopu je reguliranje aktivnosti celic, ki so odgovorne za patofiziologijo bolezni.The identification of new therapeutic agents for asthma is complicated by the fact that many mediators are responsible for the development of the disease. Therefore, it seems unlikely that eliminating the effects of a single mediator will have a significant effect on all three components of chronic asthma. An alternative to the mediator approach is to regulate the activity of the cells responsible for the pathophysiology of the disease.

En tak način je z zvišanjem nivojev cAMP (ciklični adenozin 3’,5’-monofosfat).One way is by raising cAMP levels (cyclic adenosine 3 ', 5'-monophosphate).

Pokazalo se je, da je ciklični AMP drugi prenašalec informacij, ki posreduje biološke odzive Širokemu krogu hormonov, nevrotransmiterjev in učinkovin [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29,Cyclic AMP has been shown to be the second transmitter of information that mediates biological responses to a wide range of hormones, neurotransmitters and agents [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29;

1973], Če se ustrezni agonist veže na specifične receptorje na celični površini, se aktivira adenilat ciklaza, ki pospešeno pretvori Mg⁺²-ATP v cAMP.1973], If an appropriate agonist binds to specific receptors on the cell surface, adenylate cyclase is activated, which rapidly converts Mg ⁺² -ATP to cAMP.

Ciklični AMP modulira aktivnost večine, če ne vseh celic, ki prispevajo k patofiziologiji astme, ki jo povzročajo zunanji vzroki (alergijske astme). Kot tako bi zvišanje cAMP povzročilo ugodne učinke, vševši: 1) relaksacijo gladkega mišičja dihal, 2) inhibiranje sproščanja mediatorja mastocitov, 3) supresijo degranulacije nevtrofilcev, 4) inhibicijo degranulacije bazofilcev, in 5) inhibicijo aktivacije monocitov in makrofagov. Zato naj bi bile spojine, ki aktivirajo adenilat ciklazo ali inhibirajo fosfodiesterazo, učinkovite pri supresiji neustrezne aktivacije gladkega mišičja dihal in širokega kroga vnetnih celic. Glavni celični mehanizem za inaktivacijo cAMP je hidroliza 3’-fosfodiestrske vezi z enim ali več člani iz družine izocimov, kijih označujemo kot ciklične nukleotid fosfodiesteraze (PDE).Cyclic AMP modulates the activity of most, if not all, cells that contribute to the pathophysiology of asthma caused by external causes (allergic asthma). As such, an increase in cAMP would have beneficial effects, including: 1) relaxation of respiratory smooth muscle, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of activation of monocytes and macrophages. Therefore, compounds that activate adenylate cyclase or inhibit phosphodiesterase are effective in suppressing inappropriate activation of respiratory smooth muscle and a wide range of inflammatory cells. The main cellular mechanism for cAMP inactivation is the hydrolysis of the 3′-phosphodiester bond with one or more members of the isozyme family, termed cyclic nucleotide phosphodiesterase (PDE).

Sedaj pa se je pokazalo, da je določeni izocim ciklične nukleotid fosfodiesteraze (PDE), PDE IV, odgovoren za razpad cAMP v gladkem mišičju dihal in vnetnih celicah. [Torphy, Phosphodiesterase Isozymes: Potential Targets for Novel Antiasthmatic Agents v New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Raziskave kažejo, da inhibicija tega encima ne le, da povzroči relaksacijo gladkega mišičja dihal, temveč tudi prepreči degranulacijo mastocitov, bazofilcev in nevtrofilcev in obenem inhibira aktivacijo monocitov in nevtrofilcev. Še več, ugodni učinki inhibitorjev PDE IV so izrazito potencirani, če zvečamo s primernimi hormoni ali avtokoidi, kot se to dogaja in vivo, aktivnost adenat ciklaze tarčnih celic. Zato bodo inhibitorji PDE IV učinkoviti v astmatskih pljučih, kjer so nivoji prostaglandina E₂ in prostaciklina (aktivatorja adenilat ciklaze) zvišani. Take spojine bi nudile edinstven pristop k farmakoterapiji bronhialne astme in bi imele pomembne terapevtske prednosti pred sredstvi, ki so trenutno na tržišču.However, it has now been shown that a particular isocyme of cyclic nucleotide phosphodiesterase (PDE), PDE IV, is responsible for the disintegration of cAMP in respiratory smooth muscle and inflammatory cells. [Torphy, Phosphodiesterase Isozymes: Potential Targets for Novel Antiasthmatic Agents in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research shows that inhibition of this enzyme not only causes relaxation of the respiratory smooth muscle but also prevents degranulation of mast cells, basophils and neutrophils, while inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when increased with the appropriate hormones or autocoids, as in vivo, the activity of the target cell cyclase adenate. Therefore, PDE IV inhibitors will be effective in asthmatic lungs where the levels of prostaglandin E ₂ and prostacyclin (adenylate cyclase activator) are elevated. Such compounds would offer a unique approach to the pharmacotherapy of bronchial asthma and would have significant therapeutic advantages over currently available commercially available agents.

Spojine v smislu izuma tudi inhibirajo nastajanje faktorja tumorske nekroze (TNF), kije serumski glikoprotein. Pretirano ali neurejeno nastajanje TNF je udeleženo pri posredovanju ali poslabšanju vrste bolezni, vključno revmatičnega artritisa, revmatičnega spondilitisa, osteoartritisa, protina in drugih artritičnih stanj; sepse, septičnega šoka, endotoksičnega šoka, gramnegativne sepse, sindroma toksičnega šoka, sindroma respiratorne stiske odraslih, cerebralne malarije, kronične pljučne vnetne bolezni, silikoze, pljučne sarkoidoze, bolezni resorpcije kosti, reperfuzijske poškodbe, reakcije prejemnika pri presaditvi, zavračanje alotransplantatov, vročine in mialgij zaradi okužbe, kot so influenca, kaheksija po okužbi ali malignosti, kaheksija po sindromu pridobljene humane imunske pomanjkljivosti (AIDS), AIDS, ARC (AIDS-u soroden kompleks), nastanek keloidov, nastanek brazgotinskega tkiva, Crohnova bolezen, ulcerativni kolitis ali pireza poleg vrste avtoimunskih bolezni, kot multiple skleroze, avtoimunskega diabetesa in sistemskega eritematoznega lupusa.The compounds of the invention also inhibit the production of tumor necrosis factor (TNF), which is a serum glycoprotein. Excessive or disorderly TNF formation is involved in the transmission or exacerbation of a variety of diseases, including rheumatic arthritis, rheumatic spondylitis, osteoarthritis, gout, 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 disease, reperfusion injury, transplant recipients, transplant recipients, transplant recipients, transplant recipients myalgia due to infection such as influenza, cachexia after infection or malignancy, cachexia after acquired human immunodeficiency syndrome (AIDS), AIDS, ARC (AIDS-related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis or pyresis in addition to a variety of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes, and systemic lupus erythematosus.

AIDS je posledica okužbe limfocitov T z virusom humane imunske pomanjkljivosti (HIV). Identificirali so vsaj tri vrste sevov HIV, to je HIV-1, HIV-2 in HIV-3. Posledica okužbe s HIV je, da je imunost, ki jo posredujejo celice T oslabljena in da kažejo okužene osebe resne oportunistične okužbe in/ali nenavadne neoplazme. Za vdor HIV v limfocit T je potrebna aktivacija limfocitov T. Virusi, kot je HIV-1 ali HIV-2, okužijo limfocite T po aktivaciji celic T in tako ekspresijo in/ali replikacijo virusnega proteina posreduje ali ohranja taka aktivacija celic T. Ko je aktivirani limfocit T enkrat okužen s HIV, mora ostati limfocit T v aktiviranem stanju, da je omogočena ekspresija gena HIV in/ali replikacija HIV.AIDS is caused by human immunodeficiency virus (HIV) infection of T lymphocytes. At least three types of HIV strains have been identified, namely HIV-1, HIV-2 and HIV-3. The consequence of HIV infection is that T cell-mediated immunity is impaired and that infected persons show serious opportunistic infections and / or unusual neoplasms. T lymphocyte invasion requires activation of T. lymphocytes. Viruses such as HIV-1 or HIV-2 infect T lymphocytes upon activation of T cells, and thus the expression and / or replication of the viral protein mediates or maintains such activation of T. cells. once activated HIV lymphocyte T, lymphocyte T must remain in the activated state to allow HIV gene expression and / or HIV replication.

Citokini, posebej TNF, so udeleženi pri ekspresiji proteina HIV in/ali replikaciji virusa, ki ju posredujejo aktivirane celice T, ker igrajo citokini določeno vlogo pri ohranjanju aktivacije limfocitov T. Zato bo motenje aktivnosti citokinov, kot npr. z inhibiranjem nastajanja citokinov, zlasti TNF, v osebi, okuženi s HIV, pomagalo s tem, da bo omejevalo ohranjanje aktivacije celic T in s tem zmanjševalo napredovanje infektivnosti HIV na celice, ki so bile prej neokužene, kar bo imelo za posledico upočasnitev ali eliminacijo napredovanja imunske disfunkcije, ki jo povzroča okužba s HIV. Tudi monociti, makrofagi in sorodne celice, kot Kuppferjeve celice in glijalne celice, so udeleženi pri ohranjanju okužbe s HIV. Te celice so, podobno kot celice T, tarče za virusno replikacijo in nivo virusne replikacije je odvisen od stanja aktivacije celic [glej Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, 1989]. Pokazalo se je, da monokini, kot je TNF, aktivirajo replikacijo HIV v monocitih in/ali makrofagih [glej Poli et al., Proč. Natl. Acad. Sci., 87:782-784, 1990], zato inhibicija nastajanja ali aktivnosti monokinov pomaga pri omejevanju napredovanja HIV, kot smo navedli zgoraj za celice T.Cytokines, especially TNFs, are involved in HIV protein expression and / or virus replication mediated by activated T cells, since cytokines play a role in maintaining T lymphocyte activation. Therefore, disruption of cytokine activity such as e.g. by inhibiting the production of cytokines, in particular TNF, in the HIV-infected person, will help to limit the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells, resulting in a slowdown or elimination progression of immune dysfunction caused by HIV infection. Monocytes, macrophages and related cells, such as Kuppfer cells and glial cells, are also involved in maintaining HIV infection. These cells are, like T cells, targets for viral replication and the level of viral replication depends on the state of cell activation [see Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, 1989]. Monokines such as TNF have been shown to activate HIV replication in monocytes and / or macrophages [see Poli et al., Et al. Natl. Acad. Sci., 87: 782-784, 1990], therefore, inhibition of monokine formation or activity helps limit HIV progression, as noted above for T cells.

TNF je bil tudi udeležen v različnih vlogah pri drugih virusnih okužbah, kot s citomegalovirusom (CMV), virusom gripe, adenovirusom in herpes virusom, iz podobnih razlogov, kot so zgoraj omenjeni.TNF has also been involved in various roles in other viral infections, such as cytomegalovirus (CMV), influenza virus, adenovirus, and herpes virus, for similar reasons as mentioned above.

TNF je povezan tudi z okužbami s kvasovkami in glivicami. Posebno za Candido albicans se je pokazalo, da inducira nastajanje TNF in vitro v humanih monocitih in naravnih celicah ubijalkah [glej Riipi et al., Infection and Immunity, 58(9):2750-54, 1990; in Jafari et al., Journal of Infectious Diseases, 164:389-95, 1991. Glej tudi Wasan et al., Antimicrobial Agents and Chemotherapy, 35, (10):2046:48, 1991; in Luke et al., Journal of Infectious Diseases, 162:211-214,1990].TNF is also associated with yeast and fungal infections. Candido albicans, in particular, have been shown to induce TNF formation in vitro in human monocytes and natural killer cells [see Riipi et al., Infection and Immunity, 58 (9): 2750-54, 1990; and Jafari et al., Journal of Infectious Diseases, 164: 389-95, 1991. See also Wasan et al., Antimicrobial Agents and Chemotherapy, 35, (10): 2046: 48, 1991; and Luke et al., Journal of Infectious Diseases, 162: 211-214,1990].

Sposobnost za kontroliranje neugodnih učinkov TNF podpira uporaba spojin, ki inhibirajo TNF pri sesalcih, ki jim je taka uporaba potrebna. Obstaja potreba po spojinah, ki so uporabne pri zdravljenju bolezenskih stanj, ki jih posreduje TNF, ki jih poslabšuje ali povzroča pretirano in/ali neurejeno nastajanje TNF.The ability to control the adverse effects of TNF is supported by the use of TNF-inhibiting compounds in mammals in need of such use. There is a need for compounds useful in the treatment of TNF-mediated disease states that exacerbate or cause excessive and / or disorderly TNF production.

Kratka vsebina izumaSUMMARY OF THE INVENTION

Ta izum se nanaša na nove spojine s formulo (I), kot je prikazana niže, ki so uporabne pri posredovanju ali inhibiciji encimske aktivnosti (ali katalitske aktivnosti) fosfodiesteraze IV (PDE IV). Nove spojine s formulo (I) imajo tudi inhibitorni učinek na faktor tumorske nekroze (TNF).The present invention relates to novel compounds of formula (I) as shown below, which are useful in mediating or inhibiting the enzymatic activity (or catalytic activity) of phosphodiesterase IV (PDE IV). Novel compounds of formula (I) also have an inhibitory effect on tumor necrosis factor (TNF).

Ta izum se nanaša tudi na farmacevtske pripravke, ki obsegajo spojino s formulama (I) in farmacevtsko sprejemljiv nosilec ali razredčilo.The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

Izum se nanaša tudi na metodo za posredovanje ali inhibicijo encimske aktivnosti (ali katalitske aktivnosti) encima PDE IV pri sesalcih, vključno ljudeh, ki obsega dajanje učinkovite količine spojine s formulo (I), kot je prikazana niže, sesalcu, ki mu je potrebna.The invention also relates to a method for mediating or inhibiting the enzymatic activity (or catalytic activity) of a PDE IV enzyme in mammals, including humans, comprising administering to the mammal in need thereof an effective amount of a compound of formula (I) as shown below.

Izum nadalje zagotavlja postopek za zdravljenje alergijske in vnetne bolezni, ki obsega dajanje učinkovite količine spojine s formulo (I) sesalcu, vključno ljudem, ki jim je potrebna. Izum tudi zagotavlja postopek za zdravljenje astme, ki obsega dajanje učinkovite količine spojine s formulo (I) sesalcu, vključno ljudem, ki jim je potrebna.The invention further provides a method of treating an allergic and inflammatory disease comprising administering to an mammal an effective amount of a compound of formula (I), including humans in need thereof. The invention also provides a method for treating asthma comprising administering to an mammal an effective amount of a compound of Formula (I), including humans in need thereof.

Ta izum se nanaša tudi na postopek za inhibiranje nastajanja TNF pri sesalcih, vključno ljudeh, ki obsega dajanje učinkovite količine spojine s formulo (I), ki inhibira TNF, sesalcu, ki mu je tako zdravljenje potrebno. Ta postopek lahko uporabimo za profilaktično zdravljenje ali preprečevanje določenih bolezenskih stanj, ki jih posredujejo TNF, na katerega reagirajo.The present invention also relates to a method for inhibiting the production of TNF in mammals, including humans, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (I) that inhibits TNF. This procedure can be used to prophylactically treat or prevent certain TNF-mediated disease states to which they respond.

Ta izum se nanaša tudi na postopek za zdravljenje človeka, okuženega z virusom humane imunske pomanjkljivosti (HIV), ki obsega dajanje učinkovite količine spojine s formulo (I), ki inhibira TNF, takemu človeku.The present invention also relates to a method for treating a human being infected with a human immunodeficiency virus (HIV), comprising administering to an individual an effective amount of a compound of formula (I) that inhibits TNF.

Spojine s formulo (I) so tudi uporabne pri zdravljenju virusnih okužb, kjer so taki virusi zelo občutljivi za pozitivni vpliv TNF ali bodo izzvali nastajanje TNF in vivo.The compounds of formula (I) are also useful in the treatment of viral infections where such viruses are highly sensitive to the positive effect of TNF or will induce TNF production in vivo.

Spojine s formulo (I) so tudi uporabne pri zdravljenju okužb s kvasovkami in glivicami, kjer so take kvasovke in glivice občutljive za pozitivni vpliv TNF ali bodo izzvale nastajanje TNF in vivo.The compounds of formula (I) are also useful in the treatment of yeast and fungal infections, where such yeasts and fungi are sensitive to the positive effect of TNF or will induce TNF production in vivo.

Nove spojine v smislu predloženega izuma predstavimo s strukturo:The novel compounds of the present invention are represented by the structure:

kjer je R_x -(CR₄R₅) C(O)O(CR₄R₅)_mR₆, -(CR₄R₅) C(O)NR₄(CR₄R₅)_mR₆,where R _x - (CR ₄ R ₅ ) C (O) O (CR ₄ R ₅ ) _m R ₆ , - (CR ₄ R ₅ ) C (O) NR ₄ (CR ₄ R ₅ ) _m R ₆ ,

-(CR₄R₅)_nO(CR₄R₅)_mR₆, ali -(CR₄R₅)_rR₆, kjer so lahko alkilni deli v danem primeru substituirani z enim ali več halogeni;- (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _m R ₆ , or - (CR ₄ R ₅ ) _r R ₆ , wherein the alkyl moieties may optionally be substituted by one or more halogens;

je m 0 do 2;m is 0 to 2;

je n 1 do 4;n is 1 to 4;

je r 1 do 6;r is 1 to 6;

sta R₄ in R₅ neodvisno izbrana iz vodika ali C₁₂alkila;R ₄ and R _{5 are} independently selected from hydrogen or C ₁₂ alkyl;

je R_fi vodik, metil, hidroksil, aril, halo substituiran aril, ariloksiC₁₃alkil, halo substituiran ariloksiC₁₃alkil, indanil, indenil, C_{? n}policikloalkil, tetrahidrofuranil, furanil, tetrahidropiranil, piranil, tetrahidrotienil, tienil, tetrahidrotiopiranil, tiopiranil, C^cikloalkil ali C^cikloalkil in vsebuje eno ali dve nenasičeni vezi, kjer so cikloalkilni in heterociklični deli lahko v danem primeru substituirani z 1 do 3 metilnimi skupinami ali eno etilno skupino;R _fi is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC ₁₃ alkyl, halo substituted aryloxyC ₁₃ alkyl, indanyl, indenyl, _{C? n} polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C 1-4 cycloalkyl or C 1-4 cycloalkyl and containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 substituted methyl, groups or one ethyl group;

pod pogojem, daprovided that

a) kadar je R₆ hidroksil, potem je m 2; alia) when R _{6 is} hydroxyl then m 2; or

b) kadar je R₆ hidroksil, potem je R 2 do 6; alib) when R _{6 is} hydroxyl, then R 2 is to 6; or

c) kadar je R₆ 2-tetrahidropiranil, 2-tetrahidrotiopiranil, 2-tetrahidrofuranil, ali 2-tetrahidrotienil, potem je m 1 ali 2; alic) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) kadar je R₆ 2-tetrahidropiranil, 2-tetrahidrotiopiranil, 2-tetrahidrofuranil ali 2-tetrahidrotienil, potem je R 1 do 6;d) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then R 1 is 6;

e) kadar je n 1 in je m 0, potem je R₆ drugačen od H v -(CR₄R₅)O(CR₄R₅)_mR₆;e) when n is 1 and m is 0, then R _{6 is} other than H in - (CR ₄ R ₅ ) O (CR ₄ R ₅ ) _m R ₆ ;

X je YR₂, halogen, nitro, NR₄R₅ ali formil amin;X is YR ₂ , halogen, nitro, NR ₄ R ₅ or formyl amine;

Y je O ali S(O)_m>;Y is O or S (O) _m> ;

m’je število, ki ima vrednost 0,1 ali 2;less than 0.1 or 2;

Χ^βΟ ali NR_g;Χ ^ βΟ or NR _g ;

Xg je vodik ali X;Xg is hydrogen or X;

R₂ je neodvisno izbran iz -CH₃ ali -CH₂CH₃, v danem primeru substituiran z 1 ali več halogeni;R ₂ is independently selected from -CH ₃ or -CH ₂ CH ₃ optionally substituted by 1 or more halogens;

s je 0 do 4;s is 0 to 4;

R₃ je vodik, halogen, C^alkil, halo-substituiran C^alkil, CH2NHC(O)C(O)NH₂, -CH=CR_g,R_g„ ciklopropil v danem primeru substituiran z R_g„ CN, ORg, CH₂OR₈, NRgR₁₀, CH₂NR_gR₁₀, C(Z’)H, C(O)OR_g, C(O)NR_gR₁₀ ali C=CR_g>;R ₃ is hydrogen, halogen, C 1-6 alkyl, halo-substituted C 1-6 alkyl, CH ₂ NHC (O) C (O) NH ₂ , -CH = CR _g , R _g 'cyclopropyl optionally substituted by R _g ' CN, ORg , CH ₂ OR ₈ , NR _g R ₁₀ , CH ₂ NR _g R ₁₀ , C (Z ') H, C (O) OR _g , C (O) NR _g R ₁₀ or C = CR _g> ;

Z’je O, NR₉, NOR_g, NCN, C(-CN)₂, CR_gCN, CR_gNO₂, CR_gC(O)OR_g,Z'is O, NR ₉ , NOR _g , NCN, C (-CN) ₂ , CR _g CN, CR _g NO ₂ , CR _g C (O) OR _g ,

CR_gC(O)NR_gR_g, C(-CN)NO₂, C(-CN)C(O)OR₉, ali C(-CN)C(O)NR_gR_g;CR _g C (O) NR _g R _g , C (-CN) NO ₂ , C (-CN) C (O) OR ₉ , or C (-CN) C (O) NR _g R _g ;

Z je OR₁₄, OR_1S, SR,,, S(O)_m.R₇. S(O)₂NR₁₀R₁₄, NR_1(IR₁₄, NR₁₄C(O)R,,Z is OR ₁₄ , OR _1S , SR ,,, S (O) _m .R ₇ . S (O) ₂ NR ₁₀ R ₁₄ , NR _{1 (I} R ₁₄ , NR ₁₄ C (O) R,,

NR₁₀C(Y’)R₁₄, NR,„C(O)OR₇, NR_i0C(Y’)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R_14> NR ₁₀ C (Y ') R ₁₄ , NR,' C (O) OR ₇ , NR _i0 C (Y ') NR ₁₀ R ₁₄ , NR ₁₀ S (O) ₂ NR ₁₀ R _14>

NR₁₀C(NCN)NR₁₀R₁₄, NR_ioS(0)₂R„ NR_wC(CR₄NO₂)NR₁₀R₁₄,NR ₁₀ C (NCN) NR ₁₀ R ₁₄ , NR _io S (0) ₂ R 'NR _w C (CR ₄ NO ₂ ) NR ₁₀ R ₁₄ ,

NR₁₀C(NCN)SR₉, NR_wC(CR₄NO₂)SR₉, NR₁₀C(NR₁₀)NR_wR₁₄,NR ₁₀ C (NCN) SR ₉ , NR _w C (CR ₄ NO ₂ ) SR ₉ , NR ₁₀ C (NR ₁₀ ) NR _w R ₁₄ ,

NR₁₀C(O)C(O)NR₁₀R₁₄ ali NR₁₀C(O)C(O)OR₁₄;NR ₁₀ C (O) C (O) NR ₁₀ R ₁₄ or NR ₁₀ C (O) C (O) OR ₁₄ ;

Y’ je O ali S;Y 'is O or S;

R_? je -(CR₄R₅)_qR₁₂ ali C^alkil, kjer je R₁₂ ali C₁₆alkilna skupina v danem primeru substituirana enkrat ali večkrat s C₁₂alkilom, v danem primeru substituirana z enim do tremi fluori, -F, -Br, -Cl, -NO₂, -NR₁₀R_1P -C(O)R_g, -C(O)OR_g, -OR_g, -CN, -C(O)NR₁₀R_n, -OC(O)NR₁₀R_n, -OC(O)R_g, -NR₁₀C(O)NR₁₀R_n, -NR_WC(O)R_U, -NR₁₀C(O)OR₉, -NR₁₀C(O)R₁₃, -C(NR₁₀)NR₁₀R_n, -C(NCN)NR₁₀R_n, -C(NCN)SR₉, -NR₁₀C(NCN)SR₉, -NR₁₀C(NCN)NR₁₀R_n, -NR₁₀S(O)₂R₉, -S(O)_m,R₉, -NR₁₀C(O)C(O)NR₁₀R_n, -NR₁₀C(O)C(O)R₁₀, tiazolil, imidazolil, oksazolil, pirazolil, triazolil ali tetrazolil;R _? is - (CR ₄ R ₅ ) _q R ₁₂ or C 1-6 alkyl, wherein R ₁₂ or C ₁₆ alkyl is optionally substituted once or more than once with C ₁₂ alkyl, optionally substituted by one to three fluorines, -F, -Br, -Cl, -NO ₂ , -NR ₁₀ R _1P -C (O) R _g , -C (O) OR _g , -OR _g , -CN, -C (O) NR ₁₀ R _n , -OC (O) NR ₁₀ R _n , -OC (O) R _g , -NR ₁₀ C (O) NR ₁₀ R _n , -NR _W C (O) R _U , -NR ₁₀ C (O) OR ₉ , -NR ₁₀ C (O) R ₁₃ , -C (NR ₁₀ ) NR ₁₀ R _n , -C (NCN) NR ₁₀ R _n , -C (NCN) SR ₉ , -NR ₁₀ C (NCN) SR ₉ , -NR ₁₀ C (NCN) NR ₁₀ R _n , -NR ₁₀ S (O) ₂ R ₉ , -S (O) _m , R ₉ , -NR ₁₀ C (O) C (O) NR ₁₀ R _n , -NR ₁₀ C (O) C (O) R ₁₀ , thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl or tetrazolyl;

q je 0,1 ali 2;q is 0.1 or 2;

R₁₂ je C_{3 7}cikloalkil, (2,-, 3- ali 4-piridil), pirimidil, pirazolil, (1- ali 2imidazolil), tiazolil, triazolil, pirolil, piperazinil, piperidinil, morfolinil, furanil, (2ali 3-tienil), (4- ali 5-tiazolil), kinolinil, naftil ali fenil;R ₁₂ is C _3-7 cycloalkyl, (2-, 3-, or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2 or 3- thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl or phenyl;

R_g je neodvisno izbran iz vodika ali R₉;R _g is independently selected from hydrogen or R ₉ ;

R_g, je R_g ali fluor;R _g is R _g or fluorine;

R₉ je C^alkil, v danem primeru substituiran z enim do tremi fluori;R ₉ is C 1-6 alkyl optionally substituted by one to three fluorines;

^RioJ^{e 0R}s ^aliRii’ ^R ioJ ^{e 0R} s ^aliR ii '

R_u je vodik, ali C^alkil, v danem primeru substituiran z enim do tremi fluori; ali, kadar sta R₁₀ in R_n kot NR_1QR_n, lahko skupaj z dušikom tvorita 5 do 7 členski obroč, ki v danem primeru vsebuje vsaj en dodaten heteroatom izbran iz O, N ali S;R _u is hydrogen or C 1-6 alkyl optionally substituted by one to three fluorines; or, when R ₁₀ and R _{n are} NR _1Q R _n , together with nitrogen, they may form a 5 to 7 membered ring containing optionally at least one additional heteroatom selected from O, N or S;

R₁₃ je oksazolidinil, oksazolil, tiazolil, pirazolil, triazolil, tetrazolil, imidazolil, imidazolidinil, tiazolidinil, izoksazolil, oksadiazolil ali tiadiazolil in je vsak od teh heterocikličnih obročev povezan preko ogljikovega atoma in vsak je lahko nesubstituiran ali substituiran z eno ali dvema C₁₂alkilnima skupinama;R ₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted with one or two C ₁₂ alkyl groups;

R₁₄ je vodik ali R_?; ali, kadar sta R₁₀ in R₁₄ kot NR₁₍₎R₁₄, lahko ti skupaj z dušikom tvorita 5 do 7 členski obroč, ki v danem primeru vsebuje enega ali več dodatnih heteroatomov izbranih iz O, N ali S;R ₁₄ is hydrogen or R _? ; or, when R ₁₀ and R _{14 are} NR _{1 ()} R ₁₄ , they together with nitrogen may form a 5 to 7 membered ring containing optionally one or more additional heteroatoms selected from O, N or S;

R₁₅ je C(O)R₁₄, C(O)NR₄R₁₄, S(O)₂R₇, ali S(O)₂NR₄R₁₄; pod pogojem, da:R ₁₅ is C (O) R ₁₄ , C (O) NR ₄ R ₁₄ , S (O) ₂ R ₇ , or S (O) ₂ NR ₄ R ₁₄ ; provided that:

f) kadar je Z OH, X YR₂, Y kisik, X₂ kisik, X₃ vodik, s 0, R₂ CH₃ v YR₂, in je R₄ CH₃, potem je R₃ drugačen od CN ali COOH;f) when Z is OH, X YR ₂ , Y is oxygen, X _{2 is} oxygen, X _{3 is} hydrogen, with 0, R _{2 is} CH ₃ in YR ₂ , and R _{4 is} CH ₃ , then R _{3 is} different from CN or COOH;

g) kadar je Z OH ali OCH₃, X₂ kisik, X₃ vodik, s 0, in je X YR₂, potem je R₃drugačen od H;g) when Z is OH or OCH ₃ , X _{2 is} oxygen, X _{3 is} hydrogen, s 0, and X is YR ₂ , then R _{3 is} other than H;

h) kadar je Z OSCO^C^alkil ali OS(O)₂ariI, X₂ kisik, X₃ vodik, s 0, potem je R₃ drugačen od OR_g;h) when Z is OSCO ^ C 1-6 alkyl or OS (O) ₂ aryl, X _{2 is} oxygen, X _{3 is} hydrogen, s 0, then R _{3 is} different from OR _g ;

i) kadar je R₁₂ N-pirazolil, N-imidazolil, N-triazolil, N-pirolil, N-piperazinil, N-piperidinil ali N-morfolinil, potem q ni 1; alii) when R _{12 is} N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl or N-morpholinyl, then q is not 1; or

j) kadar je Z OH ali OSO₂R₇ in je R₃ CH₃, CHOH ali CH₂OC₁₃alkil, potem RjK, ni C_{7 3}alkoksi, in X ni halogen, metoksi, etoksi, metiltio ali etiltio;j) when Z is OH or OSO ₂ R _7, and R ₃ is CH _3, CHOH or CH ₂ OC ₁₃ alkyl, then Rjk, is C _{7 3} alkoxy and X is not halogen, methoxy, ethoxy, methylthio or ethylthio;

k) kadar je Z NH₂, NH^alkil), N(C₁.₃alkil)₂, NH(CH₂)₂.₅C(O)Ar, kjer je Ar naftil ali fenil, ali je Z nesubstituiran ali substituiran pirolidinil, piperidinil, morfolinil ali piperazinil, in je R₃ CH₃, CHOH ali CH₂OC₁₃alkil, potem RjX₂ nik) when Z is NH _2, NH alkyl), N (C _first ₃ alkyl) _2, NH (CH ₂₎ _second ₅ C (O) Ar, where Ar is naphthyl or phenyl, or Z is unsubstituted or substituted pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, and R _{3 is} CH ₃ , CHOH or CH ₂ OC ₁₃ alkyl, then R 1 X ₂ is not

Q ₃alkoksi in X ni halogen, metoksi, etoksi, metiltio ali etiltio; ali njene farmacevtsko sprejemljive soli.Q _{3 is} alkoxy and X is not halogen, methoxy, ethoxy, methylthio or ethylthio; or a pharmaceutically acceptable salt thereof.

Podroben opis izumaDETAILED DESCRIPTION OF THE INVENTION

Ta izum se nanaša na nove spojine s formulo (I) in na farmacevtske sestavke, ki vsebujejo spojino s formulo (I) in farmacevtsko sprejemljiv nosilec ali razredčilo. Ta izum se tudi nanaša na postopek za posredovanje ali inhibiranje encimske aktivnosti (ali katalitske aktivnosti) PDE IV pri sesalcu, ki mu je to potrebno, in na inhibiranje nastajanja TNF pri sesalcu, ki mu je to potrebno, ki obsega dajanje učinkovite količine spojine s formulo (I) sesalcu, ki mu je to potrebno.The present invention relates to novel compounds of formula (I) and to pharmaceutical compositions containing a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. The present invention also relates to a method for mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof, and inhibiting the production of TNF in a mammal in need thereof, comprising administering an effective amount of a compound with formula (I) to a mammal in need thereof.

Inhibitorji fosfodiesteraze IV so uporabni pri zdravljenju različnih alergijskih in vnetnih bolezni, vključno astme, kroničnega bronhitisa, atopičnega dermatitisa, urtikarije, alergijskega rinitisa, alergijskega konjunktivitisa, pomladnega konjunktivitisa, eozinofilnega granuloma, psoriaze, revmatičnega artritisa, septičnega šoka, ulcerativnega kolitisa, Crohnove bolezni, reperfuzijske poškodbe miokardija in možganov, kroničnega glomerulonefritisa, endotoksičnega šoka in sindroma respiratorne stiske odraslih. Poleg tega so inhibitorji PDE IV uporabni pri zdravljenju diabetesa insipidusa [Kidney Int; 37:362,1990; Kidney Int, 35:494,1989] in motenj centralnega živčevja, kot sta depresija in multiinfarktna demenca.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, spring conjunctivitis, eosinophilic granuloma, psoriasis colitis, rheumatitis, rheumatitis, ulcer reperfusion injury to 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 [Kidney Int; 37: 362,1990; Kidney Int, 35: 494,1989] and central nervous system disorders such as depression and multi-infarct dementia.

Spojine s formulo (I) so tudi uporabne pri zdravljenju virusnih infekcij, kjer so taki virusi občutljivi na pozitivni vpliv TNF na njihov razvoj ali bodo izzvale tvorbo TNF. in vivo. Virusi, katerih zdravljenje obravnavamo tukaj, so tisti, ki tvorijo TNF kot posledico okužbe, ali tisti, ki so občutljivi za inhibicijo, kot z neposrednim ali posrednim zmanjšanjem replikacije, z inhibitorji TNF s formulo (I). Taki virusi vključujejo, vendar neomejujoče, HIV-1, HIV-2 in HIV-3, citomegalovirus (CMV), virus gripe, adenovirus in skupino herpes virusov, kot so, vendar neomejujoče, Herpes zoster in Herpes simplex.The compounds of formula (I) are also useful in the treatment of viral infections, where such viruses are sensitive to the positive effect of TNF on their development or will induce TNF formation. in vivo. The viruses addressed herein are those that produce TNF as a result of infection, or those that are susceptible to inhibition, as by directly or indirectly reducing replication, with TNF inhibitors of formula (I). Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza virus, adenovirus, and a group of herpes viruses such as, but not limited to, Herpes zoster and Herpes simplex.

Spojine s formulo (I) so uporabne tudi pri zdravljenju okužb s kvasovkami in glivicami, kjer so take kvasovke in glivice občutljive za pozitivni vpliv TNF na njihov razvoj ali bodo izzvale nastajanje (tvorbo) TNF in vivo. Prednostno bolezensko stanje za zdravljenje je glivični menigitis. Poleg tega lahko dajemo spojine s formulo (I) v kombinaciji z drugimi izbranimi zdravili za sistemske okužbe s kvasovkami in glivicami. Izbrana zdravila za glivične okužbe vključujejo, vendar neomejujoče, razred spojin, imenovanih polimiksini, kot polimicin B, razred spojin, imenovanih imidazoli, kot klotrimazol, ekonazol, mikonazol in ketokonazol; razred spojin, imenovanih triazoli, kot flukonazol in itranazol, in razred spojin, imenovanih amfotericini, zlasti amfotericin B in liposomski amfotericin B.The compounds of formula (I) are also useful in the treatment of yeast and fungal infections, where such yeasts and fungi are sensitive to the positive effect of TNF on their development or will induce TNF formation (vivo) in vivo. The preferred disease state for treatment is fungal menigitis. In addition, compounds of formula (I) may be administered in combination with other selected systemic agents for yeast and fungal infections. Selected drugs for fungal infections include, but are not limited to, a class of compounds called polymyxins, such as polymycin B, a class of compounds called imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; a class of compounds called triazoles, such as fluconazole and itranazole, and a class of compounds called amphotericins, in particular amphotericin B and liposomal amphotericin B.

Skupno dajanje protiglivičnega sredstva in spojine s formulo (I) se lahko vrši v katerem koli prednostnem pripravku za tako spojino, kakršni so strokovnjaku s tega področja dobro znani, npr. v različnih pripravkih amfotericina B. Skupno dajanje protiglivičnega sredstva in spojine s formulo (I) lahko pomeni istočasno dajanje ali, v praksi, ločeno, vendar zaporedno dajanje sredstev sesalcu. Zlasti lahko spojine s formulo (I) dajemo skupaj s pripravkom amfotericina B, zlasti za sistemske glivične okužbe. Prednostni organizem za zdravljenje je organizem Candida. Spojine s formulo (I) lahko na podoben način dajemo skupno z antivirusnimi ali antibakterijskimi sredstvi.The co-administration of an antifungal agent and a compound of formula (I) may be carried out in any preferred preparation for such a compound as is well known to one skilled in the art, e.g. in different preparations of amphotericin B. The combined administration of an antifungal agent and a compound of formula (I) may mean the simultaneous administration or, in practice, separate but sequential administration of the agents to a mammal. In particular, the compounds of formula (I) may be administered together with the preparation of amphotericin B, especially for systemic fungal infections. The preferred organism for treatment is the Candida organism. The compounds of formula (I) can be similarly administered together with antiviral or antibacterial agents.

Spojine s formulo (I) lahko uporabimo tudi za inhibiranje in/ali zmanjšanje toksičnosti protiglivičnega, antibakterijskega ali antivirusnega sredstva tako, da damo učinkovito količino spojine s formulo (I) sesalcu, ki mu je tako zdravljenje potrebno. Prednostno dajemo spojino s formulo (I) za inhibiranje ali zmanjšanje toksičnosti spojin iz razreda amfotericinov, zlasti amfotericina B.The compounds of formula (I) can also be used to inhibit and / or reduce the toxicity of an antifungal, antibacterial or antiviral agent by administering an effective amount of a compound of formula (I) to a mammal in need of such treatment. Preferably, a compound of formula (I) is provided to inhibit or reduce the toxicity of amphotericin class compounds, especially amphotericin B.

Priprava farmacevtsko sprejemljive soli je pogojena z naravo spojine same in jo lahko pripravimo z običajnimi tehnikami, ki so zlahka razpoložljive strokovnjaku.The preparation of a pharmaceutically acceptable salt is conditional on the nature of the compound itself and can be prepared by conventional techniques readily available to one skilled in the art.

Kadar je R_x alkil substituiran z 1 ali več halogeni, so halogeni prednostno fluor in klor, bolj prednostno C^alkil substituiran z 1 ali več fluori. Prednostna dolžina halosubstituirane alkilne verige je en ali dva ogljika, in najbolj prednostni so deli -CF₃, -CH₂F, -CHF₂, -CF₂CHF₂, -CH₂CF₃ in -CH₂CHF₂. Prednostni R_x substituenti za spojine s formulo (I) so CH₂-ciklopropil, CH₂-C₅^cikloalkil, C₄^cikloalkil,When R _x alkyl is substituted with 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably C 1-4 alkyl substituted with 1 or more fluorines. The preferred length of the halosubstituted alkyl chain is one or two carbons, and the most preferred moieties are -CF ₃ , -CH ₂ F, -CHF ₂ , -CF ₂ CHF ₂ , -CH ₂ CF ₃ and -CH ₂ CHF ₂ . Preferred R _x substituents for compounds of formula (I) are CH ₂ -cyclopropyl, CH ₂ -C ₅ cycloalkyl, C ₄ cycloalkyl,

C₇₁₁policikloalkil, (3- ali 4-ciklopentenil), fenii, tetrahidrofuran-3-il, benzil ali C_x ₂alkil v danem primeru substituiran z enim ali več fluori, -(CH^^^OJOfCH^CH,, -(CH₂), ₃O(CH₂)_{0 2}CH₃ in -(CH₂)_2j,OH.C ₇₁₁ polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C _x ₂ alkyl optionally substituted by one or more fluorines, - (CH 2 O 2 CH 2 CH 2 CH 3 - ( CH ₂ ), ₃ O (CH ₂ ) _{0 2} CH ₃ and - (CH ₂ ) _2j , OH.

Kadar izraz vsebuje del (CR₄R₅), sta izraza R₄ in R₅ neodvisno vodik ali alkil. To omogoča razvejanje posameznih metilenskih enot, kot (CR₄R₅)_n ali (CR₄R₅)_m; vsaka ponavljajoča metilenska enota je neodvisna od druge, npr. (CR₄R₅)_n, kjer je n 2, je lahko npr. -CH₂CH(-CH₃)-. Posamezne vodikove atome ponavljajoče metilenske enote ali razvejanega ogljikovodika lahko v danem primeru substituiramo s fluorom neodvisno drug od drugega, da dobimo, npr. prednostne R₁ substitucije, kot je navedeno zgoraj.When the term contains a moiety (CR ₄ R ₅ ), the terms R ₄ and R _{5 are} independently hydrogen or alkyl. This allows the branching of individual methylene units, such as (CR ₄ R ₅ ) _n or (CR ₄ R ₅ ) _m ; each repeating methylene unit is independent of the other, e.g. (CR ₄ R ₅ ) _n , where n 2 may be e.g. -CH ₂ CH (-CH ₃ ) -. The individual hydrogen atoms of a repeating methylene unit or a branched hydrocarbon can optionally be substituted with fluorine independently of one another to give, e.g. preferred R ₁ substitutions as indicated above.

Kadar je Rj C_{7 n}policikloalkil, so primeri biciklo[2.2.1]-heptil, biciklo[2.2.2]oktil, biciklo[3.2.ljoktil, triciklo[5.2.1.0^2,6]decil, itd. dodatni primeri, ki so opisani v Saccamano et al., WO 87/06576 objavljeno 5 november 1987, katerih opis je tu notri v celoti vključen kot referenca.When R 1 is C _{7 n} polycycloalkyl, bicyclo [2.2.1] -heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.octyl, tricyclo [5.2.1.0 ^2,6 ] decyl, etc. are examples. additional examples described in Saccamano et al., WO 87/06576 published November 5, 1987, the description of which is incorporated herein by reference in its entirety.

Z je prednostno OR₁₄, OR₁₅, SR₁₄, S(O)_mR_?, S(O)₂NR_1QR₁₄, NR₁₀R₁₄, NR₁₄C(O)R₉, NR₁₀C(O)R₁₄, NR₁₀C(O)OR₇, NR₁₀C(O)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄, NR₁₀C(NCN)NR₁₀R₁₄, NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR_1oC(NCN)SR₉, NR₁₀C(CR₄NO₂)SR₉, NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄ ali NR₁₀C(O)C(O)OR₁₄; najbolj prednostne so tiste spojine, kjer je R₁₄ skupina Z-ja R₄.Z is preferably OR ₁₄ , OR ₁₅ , SR ₁₄ , S (O) _m R _? , S (O) ₂ NR _1Q R ₁₄ , NR ₁₀ R ₁₄ , NR ₁₄ C (O) R ₉ , NR ₁₀ C (O) R ₁₄ , NR ₁₀ C (O) OR ₇ , NR ₁₀ C (O) NR ₁₀ R ₁₄ , NR ₁₀ S (O) ₂ NR ₁₀ R ₁₄ , NR ₁₀ C (NCN) NR ₁₀ R ₁₄ , NR ₁₀ S (O) ₂ R ₇ , NR ₁₀ C (CR ₄ NO ₂ ) NR ₁₀ R ₁₄ , NR ₁₀ C (NCN) SR ₉ , NR ₁₀ C (CR ₄ NO ₂ ) SR ₉ , NR ₁₀ C (NR ₁₀ ) NR ₁₀ R ₁₄ , NR ₁₀ C (O) C (O) NR ₁₀ R ₁₄ or NR ₁₀ C (O) C (O) OR ₁₄ ; most preferred are those compounds wherein R _{14 is a} group of Z's R ₄ .

Prednostne X skupine za formulo (I) so tiste, kjer je X YR₂ in je Y kisik. Prednostna X^ skupina za formulo (I) je tista, kjer je X₂ kisik. Prednostna X₃ skupina za formulo (I) je tista, kjer je X₃ vodik. Prednostne R₂ skupine so, kjer je primerno, C_{2 2}alkil, v danem primeru substituiran z 1 ali več halogeni. Halogenski atomi so prednostno fluor in klor, bolj prednostno fluor. Bolj prednostne R₂ skupine so tiste, kjer je R₂metil ali fluoro-substituirani alkili, posebno C₁₂alkil, kot je -C₃, -CHF₂ ali -CI^CHFj del. Najbolj prednostni so -CHF₂ in -CH₃ deli.Preferred X groups for formula (I) are those wherein X is YR ₂ and Y is oxygen. The preferred X ^ group for formula (I) is one where X _{2 is} oxygen. The preferred X ₃ group for formula (I) is one where X _{3 is} hydrogen. Preferred R ₂ groups are, where appropriate, C ₂ alkyl, optionally substituted by 1 or more halogens. Halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R ₂ groups are those wherein R _{2 is} methyl or fluoro-substituted alkyl, especially C ₁₂ alkyl, such as -C ₃ , -CHF ₂ or -C ₁ CHF ₁ moiety. Most preferred are -CHF ₂ and -CH ₃ parts.

Prednostni R₃ deli so C(O)NH₂, CH₂NHC(O)C(O)NH₂, OCR_g, CN, C(Z’)H, CH₂OH, CH₂F, CF₂H in CF₃. Najbolj prednostni so ΟξΟΗ in CN. Z’je prednostno O ali NOR₈.The preferred R ₃ moieties are C (O) NH ₂ , CH ₂ NHC (O) C (O) NH ₂ , OCR _g , CN, C (Z ') H, CH ₂ OH, CH ₂ F, CF ₂ H and CF ₃ . The most preferred are ΟξΟΗ and CN. Z is preferably O or NOR ₈ .

Prednostni R_? deli vključujejo v danem primeru substituiran -(CH₂)₁₂(ciklopropil),Preferred R _? parts include optionally substituted - (CH ₂ ) ₁₂ (cyclopropyl),

-(CH₂)_{0 2}(ciklobutil), -(CH₂)_{0 2}(ciklopentil), -(CH₂)_{0 2}(cikloheksil), -(CH₂)_{0 2}(2-, 3- ali- (CH ₂ ) _{0 2} (cyclobutyl), - (CH ₂ ) _{0 2} (cyclopentyl), - (CH ₂ ) _{0 2} (cyclohexyl), - (CH ₂ ) _{0 2} (2-, 3- or

4-piridil), (CH₂)₁₂(2-imidazolil), (CH₂)₂(4-morfolinil), (CH₂)₂(4-piperazinil), (CH₂)₁₂(2-tienil), (CH₂)₁₂(4-tiazolil) in (CH₂)_{0 2}fenil.4-pyridyl), (CH ₂ ) ₁₂ (2-imidazolyl), (CH ₂ ) ₂ (4-morpholinyl), (CH ₂ ) ₂ (4-piperazinyl), (CH ₂ ) ₁₂ (2-thienyl), ( CH ₂ ) ₁₂ (4-thiazolyl) and (CH ₂ ) _{O 2} phenyl.

Prednostni obroči, kadar R₁₀ in R_n v delu -NR₁₀R_n, skupaj z dušikom, na katerega sta vezana, tvorita 5 do 7 členski obroč, ki v danem primeru vsebuje vsaj en dodaten heteroatom, izbran iz O, N ali S, vključujejo, toda ne omejeno, 1-imidazolilni,Preferred rings when R ₁₀ and R _n in the -NR ₁₀ R _n moiety, together with the nitrogen to which they are attached, form a 5 to 7 membered ring, optionally containing at least one additional heteroatom selected from O, N or S , include, but not limited to, 1-imidazolyl,

2-(R_g)-l-imidazolilni, 1-pirazolilni, 3-(R_g)-1-pirazolilni, 1-triazolilni, 2-triazolilni, 5-(R_g)-l-triazolilni, 5-(R₈)-2-triazolilni, 5-(R_g)-l-tetrazolilni, 5-(R_g)-2-tetrazolilni,2- (R _g ) -1-imidazolyl, 1-pyrazolyl, 3- (R _g ) -1-pyrazolyl, 1-triazolyl, 2-triazolyl, 5- (R _g ) -1-triazolyl, 5- (R ₈ ) -2-triazolyl, 5- (R _g ) -1-tetrazolyl, 5- (R _g ) -2-tetrazolyl,

1-tetrazolilni, 2-tetrazolilni, morfolinililni, piperazinilni, 4-(R₈)-l-piperazinilni ali pirolilni obroč.1-tetrazolyl, 2-tetrazolyl, morfolinililni, piperazinyl, 4- _(R8) -l-piperazinyl, or pyrrolyl ring.

Prednostni obroči, kadar R₁₀ in R₁₄ v delu -NR₁₀R₁₄, skupaj z dušikom, na katerega sta vezana lahko tvorita 5 do 7-členski obroč, ki v danem primeru vsebuje vsaj en dodaten heteroatom izbran iz O, N ali S, vključujejo, toda neomejeno, 1-imidazolil,Preferred rings when R ₁₀ and R ₁₄ in the -NR ₁₀ R ₁₄ moiety, together with the nitrogen to which they are attached, may form a 5 to 7 membered ring, optionally containing at least one additional heteroatom selected from O, N or S , include, but are not limited to, 1-imidazolyl,

1- pirazolil, 1-triazolil, 2-triazolil, 1-tetrazolil, 2-tetrazolil, morfolinil, piperazinil in pirolil. Posamezni obroči so lahko dodatno substituirani, kjer je primerno, na razpoložljivem dušiku ali ogljiku z delom R_?, kot je opisano tu notri za formulo (I). Ponazoritve takšnih substitucij ogljika vključujejo, toda neomejeno,1- pyrazolyl, 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl and pyrrolyl. The individual rings may be further substituted, where appropriate, on the available nitrogen or carbon by part R _? , as described herein for Formula (I). Illustrations of such carbon substitutions include, but are not limited to,

2- (R₇)-l-imidazolil, 4-(R₇)-l-imidazolil, 5-(R₇)-l-imidazolil, 3-(R₇)-l-pirazolil, 4-(R_?)-l-pirazolil, 5-(R₇)-l-pirazolil, 4-(R₇)-2-triazolil, 5-(R₇)-2-triazolil,2- _(R7) -l-imidazolyl, 4- _(R7) -l-imidazolyl, 5- _(R7) -l-imidazolyl, 3- _(R7) -l-pyrazolyl, 4- _(R?) -l-pyrazolyl, 5- _(R7) -l-pyrazolyl, 4- _(R7) -2-triazolyl, 5- _(R7) -2-triazolyl,

4- (R₇)-l-triazolil, 5-(R₇)-l-triazolil, 5-(R₇)-l-tetrazolil in 5-(R_?)-2-tetrazolil.4- _(R7) -l-triazolyl, 5- _(R7) -l-triazolyl, 5- _(R7) -l-tetrazolyl, and 5- _(R?) -2-tetrazolyl.

Primerna substitucija dušika z R_? vključuje, toda neomejeno l-(R_?)-2-tetrazolil,Suitable nitrogen substitution by R _? includes but is not limited to 1- (R _? ) -2-tetrazolyl,

2-(R_?)-l-tetrazolil, 4-(R₇)-l-piperazinil. Kjer je primerno, je lahko obroč enkrat ali večkrat substituiran z R_?.2- _(R?) -L-tetrazolyl, 4- _(R7) -l-piperazinyl. Where appropriate, the ring may be substituted one or more times with R _? .

Prednostne skupine za NR_1QR₁₄, ki vključujejo heterocikličen obroč, so 5-(R₁₄)-ltetrazolil, 2-(R₁₄)-l-imidazolil, 5-(R₁₄)-2-tetrazolil, 4-(R₁₄)-l-piperazinil ali 4-(R₁₅)1-piperazinil.Preferred groups for NR _1Q R _14, which include a heterocyclic ring are 5- (R ₁₄₎ -ltetrazolil, 2- (R ₁₄₎ -l-imidazolyl, 5- _(R14) -2-tetrazolyl, 4- (R ₁₄ -l-piperazinyl or 4- (R ₁₅ ) 1-piperazinyl.

Prednostni obroči za R₁₃ vključujejo (2-, 4- ali 5-imidazolil), (3-, 4- ali 5-pirazolil), (4ali 5-triazolil[l,2,3]), (3- ali 5-triazolil[l,2,4]), (5-tetrazolil), (2-, 4- ali 5-oksazolil), (3-, 4- ali 5-izoksazolil), (3- ali 5-oksadiazolil[l,2,4]), (2-oksadiazolil[l,3,4j), (2-tiadiazolil[l,3,4j), (2-, 4- ali 5-tiazolil), (2-, 4- ali 5-oksazolidinil), (2-, 4- aliPreferred rings for R ₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4 or 5-triazolyl [1,2,3]), (3- or 5- triazolyl [1,2,4], (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl [1, 2,4]), (2-oxadiazolyl [1,3,4j], (2-thiadiazolyl [1,3,4j), (2-, 4- or 5-thiazolyl), (2-, 4- or 5 -oxazolidinyl), (2-, 4- or

5- tiazolidinil) ali (2-, 4- ali 5-imidazolidinil).5- Thiazolidinyl) or (2-, 4- or 5-imidazolidinyl).

Kadar je R_? skupina v danem primeru substituirana s heterocikličnim obročem, kot je imidazolil, pirazolil, triazolil, tetrazolil ali tiazolil, je lahko sam heterocikličen obroč v danem primeru substituiran z R_g ali na razpoložljivem dušikovem ali ogljikovem atomu, kot je l-(R_g)-2-imidazolil, l-(R_g)-4-imidazolil, l-(R_g)-5imidazolil, l-(R_g)-3-pirazolil, l-(R_g)-4-pirazolil, l-(R_g)-5-pirazolil, l-(R_g)-4-triazolil ali l-(R_g)-5-triazolil. Kjer je primerno, je lahko obroč enkrat ali večkrat substituiran zWhere is R _? the group optionally substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl or thiazolyl, the heterocyclic ring itself may be optionally substituted with R _g or on an available nitrogen or carbon atom, such as 1- (R _g ) - 2-imidazolyl, l- _(Rg) -4-imidazolyl, l- _(Rg) -5imidazolil, l- _(Rg) -3-pyrazolyl, l- _(Rg) -4-pyrazolyl, l- (R _g ) -5-pyrazolyl, 1- (R _g ) -4-triazolyl or 1- (R _g ) -5-triazolyl. Where appropriate, the ring may be substituted one or more times with

R₈Prednostne so tiste spojine s formulo (I), kjer je Rj -CH₂-ciklopropil, -CH₂-C₅^-cikloalkil, -C^cikloalkil, tetrahidrofuran-3-il, (3- ali 4-ciklopentenil), benzil ali -Cj ₂alkil v danem primeru substituiran z 1 ali več fluori in -(CH₂)₂^OH; R₂ je metil ali fluoro-substituiran alkil, R₃ je CN ali ChCR₈; in je X YR₂.R ₈ Preferred are those compounds of formula (I) wherein R 1 is -CH ₂ -cyclopropyl, -CH ₂ -C ₅ -cycloalkyl, -C 4 cycloalkyl, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl) , benzyl or -C ₂ alkyl optionally substituted by 1 or more fluorine and - (CH ₂ ) ₂ ^ OH; R ₂ is methyl or fluoro-substituted alkyl, R ₃ is CN or ChCR ₈ ; and X is YR ₂ .

Najbolj prednostne so tiste spojine, kjer je Rj -CH₂-ciklopropil, ciklopentil, metil ali CF₂H, je R₃ CN ali C=CH; je X YR₂; je Y kisik; je X-, kisik;; je X, vodik; in je R₂CF₂H ali metil.Most preferred are those compounds wherein R 1 is -CH ₂ -cyclopropyl, cyclopentyl, methyl or CF ₂ H, R _{3 is} CN or C = CH; X is YR ₂ ; Y is oxygen; is X-, oxygen ;; X is hydrogen; and R _{2 is} CF ₂ H or methyl.

Prednostna podvrsta formule (I) sta spojini s formulo (la) in (Ib)Preferred subtypes of formula (I) are compounds of formula (Ia) and (Ib)

kjer je:where:

R_x -CH₂-ciklopropil, -CH₂-C₅^-cikloalkil, -C^cikloalkil, C_{7 u}policikloalkil, (3- ali 4-ciklopentenil), fenil, tetrahidrofuran-3-il, benzil ali C_{t 2}alkil v danem primeru substituiran z 1 ali več fluori, -(CH₂)₁₃C(O)O(CH₂)₀_₂CH₃,R _x -CH ₂ -cyclopropyl, -CH ₂ -C ₅ -cycloalkyl, -C 4 cycloalkyl, C _{7 to} polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C _{t 2} alkyl optionally substituted by 1 or more fluorine, - (CH ₂ ) ₁₃ C (O) O (CH ₂ ) ₀ _ ₂ CH ₃ ,

-(0^),.,0(0¾)^¾ in -(CH₂)₂.₄OH;- (0 ^),., 0 (0¾) ^ ¾ in - (CH ₂ ) ₂ . ₄ OH;

m O do 2;m O to 2;

n 1 do 4;n 1 to 4;

r 1 do 6;r 1 to 6;

sta R₄ in R₅ neodvisno izbrana iz vodika ali C_{3 2}alkila;R ₄ and R _{5 are} independently selected from hydrogen or C _{3 2} alkyl;

R₆ vodik, metil, hidroksil, aril, halo substituiran aril, ariloksiCj ,alkil, halo substituiran ariloksiC, ,alkil, indanil, indenil, C₇ policikloalkil, tetrahidro13 furanil, furanil, tetrahidropiranil, piranil, tetrahidrotienil, tienil, tetrahidrotiopiranil, tiopiranil, C₃^cikloalkil ali C_{4 6}cikloalkil, ki vsebuje eno ali dve nenasičeni vezi, kjer so cikloalkilni in heterociklilni deli lahko v danem primeru substituirani z 1 do 3 metilnimi skupinami ali eno etilno skupino;R ₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxy, alkyl, halo substituted aryloxyC,, alkyl, indanyl, indenyl, C ₇ polycycloalkyl, tetrahidro13 furanyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, _C3 ^ cycloalkyl, or C _{4 6} cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group;

pod pogojem, da:provided that:

b) kadar je R₆ hidroksil, potem je r 2 do 6; alib) when R _{6 is} hydroxyl, then r is 2 to 6; or

c) kadar je R₆ 2-tetrahidropiranil, 2-tetrahidrotiopiranil, 2-tetrahidrofuranil alic) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or

2-tetrahidrotienil, potem je m 1 ali 2; ali2-tetrahydrothienyl, then m is 1 or 2; or

d) kadar je R₆ 2-tetrahidropiranit, 2-tetrahidrotiopiranil, 2-tetrahidrofuranil alid) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or

2-tetrahidrotienil, potem je r 1 do 6;2-tetrahydrothienyl, then r is 1 to 6;

e) kadar je n 1 in je m 0; potem je R₆ drugačen od H v -(CR₄R₅)_nO(CR₄R₅)_fflR₆;e) when n is 1 and m is 0; then R _{6 is} other than H in - (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _ffl R ₆ ;

YjeOali S(O)_m,;Y is O or S (O) _m ,;

m’je 0,1 ali 2;m is 0.1 or 2;

R₂ je -CH₃ ali -CH₂CH₃, v danem primeru substituiran z 1 ali več halogeni;R ₂ is -CH ₃ or -CH ₂ CH ₃ optionally substituted by 1 or more halogens;

R₃ je vodik, C^alkil, CH₂NHC(O)C(O)NH₂, halo-substituiran C^alkil, CN, CH₂OR₈, C(Z’)H, C(O)OR_g, C(O)NR₈R_w ali C=CR_g;R ₃ is hydrogen, C 1-6 alkyl, CH ₂ NHC (O) C (O) NH ₂ , halo-substituted C 1-6 alkyl, CN, CH ₂ OR ₈ , C (Z ') H, C (O) OR _g , C (O) NR ₈ R _w or C = CR _g ;

Z’je O ali NOR_g;Z 'is O or NOR _g ;

Z je OR₁₄, OR₁₅, SR₁₄, S(O)_m.R₇, S(O)₂NR_1QR₁₄, NR_WR₁₄, NR₁₄C(O)R₉, NR₁₀C(O)R₁₄, NR₁₀C(O)OR₇, NR₁₀C(O)NR₁₀R₁₄, nr₁₀s(O)₂nr₁₀r₁₄, NR₁₀C(NCN)NR₁₀R₁₄, NR_wS(O)₂R₇, NR₁₀C(CR₄NO₂)NR_wR₁₄, NR_1oC(NCN)SR₉, NR₁₀C(CR₄NO₂)SR₉, NR₁₀C(NR_w)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄ ali NR₁₀C(O)C(O)OR₁₄;Z is OR ₁₄ , OR ₁₅ , SR ₁₄ , S (O) _m. R ₇ , S (O) ₂ NR _1Q R ₁₄ , NR _W R ₁₄ , NR ₁₄ C (O) R ₉ , NR ₁₀ C (O) R ₁₄ , NR ₁₀ C (O) OR ₇ , NR ₁₀ C (O) NR ₁₀ R ₁₄ , nr ₁₀ s (O) ₂ nr ₁₀ r ₁₄ , NR ₁₀ C (NCN) NR ₁₀ R ₁₄ , NR _w S ( O) ₂ R ₇ , NR ₁₀ C (CR ₄ NO ₂ ) NR _w R ₁₄ , NR ₁₀ C (NCN) SR ₉ , NR ₁₀ C (CR ₄ NO ₂ ) SR ₉ , NR ₁₀ C (NR _w ) NR ₁₀ R ₁₄ , NR ₁₀ C (O) C (O) NR ₁₀ R ₁₄ or NR ₁₀ C (O) C (O) OR ₁₄ ;

Rj je -(CR₄R₅)_qR₁₂ ali C^alkil, kjer je R₁₂ ali C₁₆alkilna skupina v danem primeru enkrat ali večkrat substituirana z C₁₂alkilom, v danem primeru substituiranim z 1 do 3, kot so fluor, -F, -Br, -Cl, -NO₂, -NR₁₀R_n, -C(O)R_g, -C(O)OR_g, -OR_g, -CN, -C(O)NR₁₀R_n, -OC(O)NR₁₀R_n, -OC(O)R_g, -NR₁₀C(O)NR₁₀R_n, -NR₁₀C(O)R_n, -NR₁₀C(O)OR₉, -NR₁₀C(O)R₁₃, -C(NR₁₀)NR₁₀R_n, -C(NCN)NR₁₀R_n, -C(NCN)SR₉, -NR₁₀C(NCN)SR₉, -NR₁₀C(NCN)NR₁₀R_n, -NR₁₀S(O)₂R₉, -S(O)_m,R₉, -NR₁₀C(O)C(O)NR₁₀R_n, -NR₁₀C(O)C(O)R₁₀, tiazolil, imidazolil, oksazolil, pirazolil, triazolil ali tetrazolil;R 1 is - (CR ₄ R ₅ ) _q R ₁₂ or C 1-6 alkyl, wherein R ₁₂ or C ₁₆ alkyl is optionally substituted one or more times with C ₁₂ alkyl, optionally substituted by 1 to 3, such as fluorine , -F, -Br, -Cl, -NO ₂ , -NR ₁₀ R _n , -C (O) R _g , -C (O) OR _g , -OR _g , -CN, -C (O) NR ₁₀ R _n , -OC (O) NR ₁₀ R _n , -OC (O) R _g , -NR ₁₀ C (O) NR ₁₀ R _n , -NR ₁₀ C (O) R _n , -NR ₁₀ C (O) OR ₉ , -NR ₁₀ C (O) R ₁₃ , -C (NR ₁₀ ) NR ₁₀ R _n , -C (NCN) NR ₁₀ R _n , -C (NCN) SR ₉ , -NR ₁₀ C (NCN) SR ₉ , -NR ₁₀ C (NCN) NR ₁₀ R _n , -NR ₁₀ S (O) ₂ R ₉ , -S (O) _m , R ₉ , -NR ₁₀ C (O) C (O) NR ₁₀ R _n , -NR ₁₀ C (O) C (O) R ₁₀ , thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl or tetrazolyl;

qje 0,1, ali 2;q is 0.1 or 2;

R₁₂ je C_{3 7}cikloalkil, (2-, 3 ali 4-piridil), (1- ali 2-imidazolil), piperazinil, morfolinil, (2ali 3-tienil), (4- ali 5-tiazolil) ali fenil;R ₁₂ is C _3-7 cycloalkyl, (2-, 3 or 4-pyridyl), (1- or 2-imidazolyl), piperazinyl, morpholinyl, (2 or 3-thienyl), (4- or 5-thiazolyl) or phenyl;

R₉ je C_{7 4}alkil, v danem primeru substituiran z enim do tremi fluori;R ₉ is C _{7 4} alkyl optionally substituted by one to three fluorines;

^Rioje OR₈ ali R_n; ^R 10 is OR ₈ or R _n ;

R_u je vodik ali C^alkil, v danem primeru substituiran z enim do dvemi fluori; ali, kadar sta R₁₀ in R_n kot NR_1OR_U, lahko skupaj z dušikom tvorita 5 do 7-členski obroč, ki v danem primeru vsebuje vsaj en dodaten heteroatom izbran iz O, N ali S; R₁₃ je oksazolidinil, oksazolil, tiazolil, pirazolil, triazolil, tetrazolil, imidazolil, imidazolidinil, tiazolidinil, izoksazolil, oksadiazolil ali tiadiazolil in vsak od teh heterocikličnih obročev je povezan preko ogljikovega atoma in vsak je lahko nesubstituiran ali substituiran z eno ali dvema C₁₂alkilna skupinama;R _u is hydrogen or C 1-6 alkyl optionally substituted by one to two fluorines; or, when R ₁₀ and R _{n are} as NR _1O R _U may, together with the nitrogen form a 5 to 7-membered ring which optionally contains at least one additional heteroatom selected from O, N or S; R ₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted with one or two C ₁₂ alkyl groups;

R₁₄ je vodik ali R_?; ali kadar sta R₁₀ in R₁₄ kot NR_J0R₁₄, lahko skupaj z dušikom tvorita 5 do 7 členski obroč, ki v danem primeru vsebuje en ali več dodatnih heteroatomov izbranih iz O, N ali S;R ₁₄ is hydrogen or R _? ; or when R ₁₀ and R _{14 are} NR _{10 O} R ₁₄ , together with nitrogen, they may form a 5 to 7 membered ring containing optionally one or more additional heteroatoms selected from O, N or S;

R₁₅ je C(O)R₁₄, C(O)NR₄R₁₄, S(O)₂R₇ ali S(O)₂NR₄R₁₄;R ₁₅ is C (O) R ₁₄ , C (O) NR ₄ R ₁₄ , S (O) ₂ R ₇ or S (O) ₂ NR ₄ R ₁₄ ;

pod pogojem, da:provided that:

f) kadar je Z OH, X YR₂, Y kisik, kisik, X₃ vodik, s 0, R₂ CH₃ v YR₂ in je R₁ CH₃, potem je R₃ drugačen od CN ali COOH;f) when Z is OH, X is YR ₂ , Y is oxygen, oxygen, X _{3 is} hydrogen, with 0, R _{2 is} CH ₃ in YR ₂ and R _{1 is} CH ₃ , then R _{3 is} different from CN or COOH;

g) kadar je Z OH ali OCH₃, kisik, X₃ vodik, s 0, in je X YR₂, potem je R₃drugačen od H;g) when Z is OH or OCH ₃ , oxygen, X _{3 is} hydrogen, s 0, and X is YR ₂ , then R _{3 is} other than H;

h) kadar je Z S(O)₂C₁₆alkil ali S(O)₂ aril, kisik, X₃ vodik, s 0, potem je R₃drugačen od OR_g;h) when ZS (O) ₂ C _{16 is} alkyl or S (O) ₂ aryl, oxygen, X ₃ hydrogen, s 0, then R _{3 is} other than OR _g ;

i) kadar je R₁₂ N-pirazolil, N-imidazolil, N-triazolil, N-pirolil, N-piperazinil, N-piperidinil ali N-morfolinil, potem q ni 1;i) when R _{12 is} N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl or N-morpholinyl, then q is not 1;

ali njene farmacevtsko sprejemljive soli.or a pharmaceutically acceptable salt thereof.

Primeri spojin s formulo (I) so:Examples of compounds of formula (I) are:

cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-olj;cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-oil;

trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-ol];trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-ol];

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)cikloheksan-l-ol];cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-ol];

cis-[4-(3,4-bisdifluorometoksifenil)-4-ciano-cikloheksan-l-ol];cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-cyclohexan-1-ol];

trans-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)cikloheksan-l-ol];trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-ol];

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-difluorometoksifenil)cikloheksan-l-ol];cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol];

trans-[4-ciano-4-(3-ciklopropilmetoksi-4-difluorometoksifenil)cikloheksan-l-ol];trans- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol];

cis-[4-(3-ciklopentiloksi-4-metoksifenil)-4-etinilcikloheksan-l-ol];cis- [4- (3-cyclopentyloxy-4-methoxyphenyl) -4-ethynylcyclohexan-1-ol];

trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-formiloksicikloheksan];trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-formyloxycyclohexane];

trans-4-(3,4-bisdifluorometoksifenil)-4-ciano-cikloheksan-l-ol;trans-4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-cyclohexan-1-ol;

trans-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-formiloksicikloheksan];trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-formyloxycyclohexane];

cis-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-metilcikloheksan-l-ol];cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-methylcyclohexan-1-ol];

trans-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-metilcikloheksan-l-ol];trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-methylcyclohexan-1-ol];

cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil-l-amin];cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl-1-amine];

trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil-l-amin];trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl-1-amine];

cis-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil-l-amin];cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1-amine];

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)cikloheksil-l-aminj;cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexyl-1-amine;

trans-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)cikloheksil-l-amin];trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexyl-1-amine];

cis-[4-(3,4-bisdifluorometoksifeml)-4-cianocikloheksil-l-(N,N-dimetil)amin];cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1- (N, N-dimethyl) amine];

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)cikloheksil-l-(N,Ndimetil)amin];cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexyl-1- (N, N-dimethyl) amine];

cis-[4-(3,4-bisdifluorometoksifenil)-4-cianocikIoheksil-l-(N-metil)amin];cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1- (N-methyl) amine];

trans-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil-l-(N-metil)amin];trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1- (N-methyl) amine];

trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-ftalimidocikloheksan];trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-phthalimidocyclohexane];

trans-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-ftalimidocikloheksan];trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-phthalimidocyclohexane];

trans-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil-l-amin];trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1-amine];

trans-[l-N-(2-hidrazmokarbonilbenzamido)-4-(3,4-bisdifluorometoksifenil)cianocikloheksan];trans- [1-N- (2-hydrazmocarbonylbenzamido) -4- (3,4-bisdifluoromethoxyphenyl) cyanocyclohexane];

cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-ureidocikloheksan];cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-ureidocyclohexane];

cis-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-ureidocikloheksan];cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-ureidocyclohexane];

trans-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-ureidocikloheksanj;trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-ureidocyclohexane;

cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan];cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane];

trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan];trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane];

cis-[4-ciano-4-(3-{4-fluorobenzil}-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan];cis- [4-cyano-4- (3- {4-fluorobenzyl} -4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane];

trans-[4-ciano-4-(3-{4-fluorobenzil}-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan];trans- [4-cyano-4- (3- {4-fluorobenzyl} -4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane];

cis-[4'Ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan];cis- [4'Cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane];

trans-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)-l-(N-hidroksiureido) cikloheksan];trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane];

cis-[l-acetamido-4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan]; trans-[l-acetamido-4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksan]; metil N-{cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-cikloheksil}-loksamat];cis- [1-acetamido-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane]; trans- [1-acetamido-4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexane]; methyl N- {cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -cyclohexyl} -loxamate];

metil N-{trans-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil}-loksamat];methyl N- {trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl} -loxamate];

N-{cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil}-l-oksamid];N- {cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl} -1-oxamide];

N-{trans-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil}-l-oksamid];N- {trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl} -1-oxamide];

N-{cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil}-l-oksamska kislina];N- {cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl} -1-oxamic acid];

cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-metoksicikloheksan];cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-methoxycyclohexane];

trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-metoksicikloheksan];trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-methoxycyclohexane];

cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-(N-hidroksiamino)cikloheksan];cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (N-hydroxyamino) cyclohexane];

trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-(N-hidroksiamino)cikloheksan];trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (N-hydroxyamino) cyclohexane];

cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan]; in trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan];cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane]; and trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane];

cis-[4-ciano-4-(3-{4-fluorobenzil}-4-metoksifenil)-l-(N-hidroksiamino)cikloheksan];cis- [4-cyano-4- (3- {4-fluorobenzyl} -4-methoxyphenyl) -1- (N-hydroxyamino) cyclohexane];

trans-[4-ciano-4-(3-{4-fluorobenzil}-4-metoksifenil)-l-(N-hidroksiamino)cikloheksan].trans- [4-cyano-4- (3- {4-fluorobenzyl} -4-methoxyphenyl) -1- (N-hydroxyamino) cyclohexane].

Upoštevati je treba, da lahko nekatere spojine s formulo (I) obstajajo v obeh, racemnih in optično aktivnih oblikah, nekatere lahko obstajajo tudi v različnih diastereomernih oblikah, ki imajo različne fizikalne in biološke lastnosti. Smatramo, da so vse te spojine znotraj obsega predloženega izuma. Potemtakem je še en vidik predloženega izuma dajanje ali racemata, ene enantiomerne oblike, ene diastereomerne oblike ali njihove zmesi.It will be appreciated that some of the compounds of formula (I) may exist in both racemic and optically active forms, and some may also exist in different diastereomeric forms having different physical and biological properties. All of these compounds are believed to be within the scope of the present invention. Therefore, another aspect of the present invention is the administration or racemate, one enantiomeric form, one diastereomeric form, or mixtures thereof.

Izraza cis in trans pomenita stereokemijo na C-l položaju cikloheksanskega obroča glede na R₃ skupino na C-4 položaju.The terms cis and trans mean stereochemistry at the Cl position of the cyclohexane ring relative to the R ₃ group at the C-4 position.

Izraz Cj ₃alkil, C_Malkil, C^alkil ali alkil vključuje oboje, ravne in razvejane verižne radikale s 1 do 10, če ni dolžina verige na to omejena, vključno, toda neomejeno na metil, etil, n-propil, izopropil, n-butil, sek-butil, izobutil, terc.-butil.The term C ₃ alkyl, C _M alkyl, C ^ alkyl or alkyl include both straight and branched chain radicals of 1 to 10, unless the chain length to be limited, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl.

Alkenil pomeni oboje, ravne in razvejane verižne radikale z dolžinami 1 do 6 ogljikov, če ni dolžina verige na to omejena, vključno, todo neomejeno na vinil,Alkenyl means both straight and branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl,

1-proprenil, 2-propenil, 2-propinil ali 3-metil-2-propenil.1-proprenyl, 2-propenyl, 2-propynyl or 3-methyl-2-propenyl.

Izraz cikloalkil ali cikloalkil alkil pomeni skupine s 3-7 ogljikovimi atomi, kot je ciklopropil, ciklopropilmetil, ciklopentil ali cikloheksil.The term cycloalkyl or cycloalkyl alkyl means groups of 3-7 carbon atoms such as cyclopropyl, cyclopropylmethyl, cyclopentyl or cyclohexyl.

Aril aliaralkil, če ni določeno drugače, pomeni aromatski obroč ali obročni sistem s 6-10 ogljikovimi atomi, kot je fenil, benzil, fenetil ali naftil. Prednostno je aril monocikličen, t.j. fenil. Alkilna veriga vključuje oboje, ravne in razvejane verižne radikale s 1 do 4 ogljikovimi atomi.Aryl or aralkyl, unless otherwise specified, means an aromatic ring or ring system of 6-10 carbon atoms such as phenyl, benzyl, phenethyl or naphthyl. Preferably, aryl is monocyclic, i.e. phenyl. The alkyl chain includes both straight and branched chain radicals having 1 to 4 carbon atoms.

Heteroaril pomeni aromatski obročni sistem, ki vsebuje enega ali več heteroatomov, kot je imidazolil, triazolil, oksazolil, piridil, pirimidil, pirazolil, pirolil, furanil ali tienil.Heteroaryl means an aromatic ring system containing one or more heteroatoms such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl or thienyl.

Halo pomeni kloro, fluoro, bromo ali jodo.Halo means chloro, fluoro, bromo or iodo.

Izraz ki inhibira nastajanje IL-1 ali ki inhibira nastajanje TNF pomeni:The term inhibiting IL-1 formation or inhibiting TNF formation means:

a) znižanje pretiranih nivojev IL-1 oz. TNF in vivo pri človeku na normalne ali ' pod normalne nivoje z inhibiranjem sproščanja IL-1 in vivo v vseh celicah, vključno, vendar neomejujoče, z monociti ali makrofagi;a) reduction of excessive levels of IL-1 or. TNF in vivo in humans to normal or 'below normal levels by inhibiting IL-1 release in vivo in all cells, including, but not limited to, monocytes or macrophages;

b) regulacijo navzdol - pri translacijskem ali transkripcijskem nivoju - pretiranih nivojev IL-1 oz. TNF in vivo pri človeku na normalne ali pod normalne nivoje; alib) down-regulation at translational or transcriptional levels of excessive levels of IL-1 or. TNF in vivo in humans to normal or below normal levels; or

c) regulacijo navzdol, z inhibiranjem direktne sinteze nivojev IL-1 ali TNF kot posttranslacijskega dogodka.c) down-regulation by inhibiting the direct synthesis of IL-1 or TNF levels as a posttranslational event.

S TNF posredovana bolezen ali bolezenska stanja pomeni katerokoli in vsa bolezenska stanja, pri katerih igra TNF določeno vlogo, bodisi z nastajanjem samega TNF bodisi s tem, da TNF povzroči sproščanje še drugega citokina, kakršen je, vendar neomejujoče, IL-1 ali IL-6. Bolezensko stanje, v katerem je IL-1 npr. glavna komponenta in katerega nastajanje ali delovanje se poslabšuje ali ki se izloča kot odgovor na TNF bomo zato smatrali kot bolezensko stanje, posredovano s TNF. Ker ima TNF-/3 (znan tudi kot limfotoksin) stukturno tesno homolognost s TNF-α (ki je znan tudi kot kahektin), in ker vsak inducira podobne biološke odzive in se veže na isti celični receptor, inhibirajo spojine v smislu izuma tako TNF-α kot TNF-/3 in zato govorimo tukaj o njih kolektivno kot o TNF, v kolikor ni posebej označeno drugače. Prednostno inhibirajo TNF-a.TNF mediated disease or disease states means any and all disease states in which TNF plays a role, either by the production of TNF itself or by TNF causing the release of another cytokine such as, but not limited to, IL-1 or IL- 6. A disease state in which IL-1 is e.g. a major component and the formation or function of which is impaired or secreted in response to TNF will therefore be considered as a TNF-mediated disease condition. Because TNF- / 3 (also known as lymphotoxin) has a structurally close homology to TNF-α (also known as cachectin), and because each induces similar biological responses and binds to the same cellular receptor, they inhibit the compounds of the invention by TNF-α. -α as TNF- / 3 and therefore we refer to them collectively as TNF- unless otherwise specifically indicated. Preferably, they inhibit TNF-α.

Citokin, ki ga inhibira pričujoči izum, za uporabo pri zdravljenju človeka, okuženega s HIV, mora biti citokin, ki je udeležen pri (a) iniciaciji in/ali vzdrževanju aktivacije celic T in/ali ekspresiji in/ali replikaciji gena HIV, ki ga posreduje aktivirana celica T, in/ali (b) pri katerem koli problemu, ki je povezan z boleznijo, ki jo posreduje citokin, kot je kaheksija ali mišična degeneracija. Prednostno je ta citokin TNF-a.The cytokine inhibited by the present invention for use in treating a human being infected with HIV must be a cytokine involved in (a) initiating and / or maintaining activation of T cells and / or expression and / or replication of the HIV gene by is mediated by an activated T cell, and / or (b) in any cytokine-mediated disease-related problem, such as cachexia or muscle degeneration. Preferably, this cytokine is TNF-α.

Vse spojine s formulo (I) so uporabne pri postopku za inhibiranje tvorbe TNF, prednostno v makrofagih, monocitih ali makrofagih in monocitih, v sesalcih, vključno ljudeh, ki jim je to potrebno. Vse spojine s formulo (I) so uporabne pri postopku za inhibiranje ali posredovanje encimske ali katalitske aktivnosti PDE IV in pri zdravljenju bolezenskih stanj, ki jih ta posreduje.All of the compounds of formula (I) are useful in a method of inhibiting TNF formation, preferably in macrophages, monocytes or macrophages, and monocytes, in mammals, including humans, in need thereof. All of the compounds of formula (I) are useful in a method of inhibiting or mediating the enzymatic or catalytic activity of PDE IV and in treating the conditions mediated therein.

POSTOPKI PRIPRAVEPREPARATION PROCEDURES

Pripravo spojin s formulo (I) lahko izvede strokovnjak po postopkih navedenih v primerih spodaj. Pripravo katerihkoli spojin s formulo (I), ki tu notri niso opisane, lahko izvedemo z analognimi tu notri opisanimi postopki, ki vključujejo:The preparation of the compounds of formula (I) may be performed by one skilled in the art as described below. The preparation of any of the compounds of formula (I) not described herein can be accomplished by analogous to the methods described herein, which include:

a) za spojine, Iger je R₃ drugačen od C(=Z’)H in Iger je Z OH, presnovimo spojino s formulo (2)a) for compounds, Iger is R ₃ different from C (= Z ') H and Iger is Z OH, and the compound of formula (2) is reacted

kjer Rj predstavlja R_p kot je definiran v zvezi s formulo (I), ali skupino, ki jo lahko pretvorimo v R_p in X in Xg predstavljata X in Xg, kot je definirano v zvezi s formulo (I) ali skupino, ki jo lahko pretvorimo v X ali X₃, in R₃ predstavlja Rg, kot je definiran v zvezi s formulo (I) ali skupino, ki jo lahko pretvorimo v R₃, s primernim reducimim sredstvom, kot je litijev borohidrid, diziamilboran, litijev aluminijev tris-(t-butoksid) ali natrijev borohidrid, v primernem ne-reaktivnem topilu, kot je 1,2-dimetoksietan, tetrahidrofuran ali alkohol, da zagotovimo spojine s formulo (I), kjer je Rg drugačen od C(=Z’)H in Iger je Z OH; priprava takšnih spojin s formulo (I), Iger je R₃C(=Z’)H poteka na analogen način iz spojine s formulo (Π), Iger je =Z’ aldehid zaščitna skupina, kot je dimetilacetal ali dioksolan, čemur sledi odstranitev zaščite za aldehid in kasnejša obdelava s standardnimi postopki znanim strokovnjakom, do preostalih spojin s formulo (I), Iger je Z’ drugačen od O.where Rj represents R _p as defined with respect to formula (I), or a group which can be converted to R _p and X and Xg represent X and Xg as defined with respect to formula (I) or a group which can be converted to X or X ₃ , and R ₃ represents R 8 as defined with respect to formula (I) or a group which can be converted to R ₃ with a suitable reducing agent such as lithium borohydride, disiamylborane, lithium aluminum tris - (t-butoxide) or sodium borohydride, in a suitable non-reactive solvent such as 1,2-dimethoxyethane, tetrahydrofuran or alcohol to provide compounds of formula (I) wherein Rg is other than C (= Z ') H and Iger is Z OH; the preparation of such compounds of formula (I), Iger is R ₃ C (= Z ') H is carried out in an analogous manner from a compound of formula (Π), Iger is = Z' an aldehyde protecting group such as dimethylacetal or dioxolane, followed by removal protection for the aldehyde and subsequent treatment by standard procedures known to one skilled in the art, to the remaining compounds of formula (I), Iger is Z 'different from O.

Za spojine, kjer je Rg drugačen od C(=Z’)H in Iger je Z NH₂, NHCHg ali N(CHg)₂, presnovitev spojine s formulo (II), Iger Rj predstavlja R_p kot je definiran v zvezi s formulo (I) ali skupino, ki jo lahko pretvorimo v R_p in X in Xg predstavljata X in Xg, kot sta definirana v zvezi s formulo (I) ali skupino, ki jo lahko pretvorimo v X ali Xg, in Rg predstavlja Rg, kot je definiran v zvezi s formulo (I) ali skupino, ki jo lahko pretvorimo v Rg, z amonijevo soljo, kot je npr. amonijev format, metilamin hidroklorid oz. dimetilamin hidroklorid, v prisotnosti ustreznega reducimega sredstva, kot je natrijev cianoborohidrid, v primernem topilu, kot je alkohol, da zagotovimo spojine s formulo (I), Iger je Z NH₂, NHCHg oz. N(CHg)₂; priprava takšnih spojin s formulo (I), kjer je R₃ C(=Z’)H, poteka na analogen način iz spojine s formulo (2), kjer je =Z’ aldehid zaščitna skupina, kot je dimetilacetal ali dioksolan, čemur sledi odstranitev zaščite za aldehid in kasnejša obdelava s standardnimi postopki znanimi strokovnjakom do preostalih spojin s formulo (I), kjer je Z’ drugačen od O.For compounds where Rg is other than C (= Z ') H and Iger is Z NH ₂ , NHCHg or N (CHg) ₂ , the metabolism of the compound of formula (II), Iger Rj represents R _p as defined in connection with formula (I) or a group that can be converted to R _p and X and Xg represent X and Xg, as defined in connection with formula (I), or a group that can be converted to X or Xg, and Rg represents Rg, as is defined with reference to formula (I) or a group which can be converted to R8 with an ammonium salt such as e.g. ammonium formate, methylamine hydrochloride or. dimethylamine hydrochloride, in the presence of a suitable reducing agent such as sodium cyanoborohydride, in a suitable solvent such as alcohol to provide the compounds of formula (I), Iger is Z NH ₂ , NHCHg or. N (CHg) ₂ ; the preparation of such compounds of formula (I) wherein R _{3 is} C (= Z ') H is carried out in an analogous manner from a compound of formula (2) wherein = Z' is an aldehyde protecting group such as dimethylacetal or dioxolane, followed by deprotection of the aldehyde and subsequent treatment by standard procedures known to one skilled in the art to the remaining compounds of formula (I) wherein Z 'is other than O.

Alternativno lahko spojine s formulo (I), kjer je Z NH₂, pripravimo s presnovitvijo primernega alkohola s formulo (2), kjer je Z OH, R_] predstavlja R_p kot je definiran v zvezi s formulo (I) ali skupino, ki jo lahko pretvorimo v R_p in X in X₃ predstavljata X in Xy kot sta definirana v zvezi s formulo (I) ali skupino, ki jo lahko pretvorimo v X ali in R₃ predstavlja R₃, kot je definiran v zvezi s formulo (I) ali skupino, ki jo lahko pretvorimo v R₃, s kompleksom fosfina, kot je trifenil fosfin in azodikarboksilatni ester v prisotnosti imida, kot je ftalimid, ki mu sledi npr. hidrazinoliza v alkoholnem topilu.Alternatively, compounds of formula (I) wherein Z is NH _2, is prepared by reacting an appropriate alcohol of the formula (2) wherein Z is OH, _R] represents R _p is as defined in relation to formula (I) or a group it can be converted to R _p and X and X ₃ represent X and Xy as defined with respect to formula (I) or a group which can be converted to X or and R ₃ represents R ₃ as defined with respect to formula ( I) or a group which can be converted to R ₃ with a phosphine complex such as triphenyl phosphine and azodicarboxylate ester in the presence of an imide such as phthalimide followed by e.g. hydrazinolysis in an alcoholic solvent.

Spojine s formulo (I), kjer je Z SR₁₄, lahko pripravimo s presnovitvijo primerne spojine s formulo (2), kjer je Z odhodna skupina, npr. mezilat, tozilat, klorid ali bromid, Rj predstavlja Rj kot je definiran v zvezi s formulo (I) ali skupino, ki jo lahko pretvorimo v R_p in X in Xg predstavljata X in Xy kot sta definirana v zvezi s formulo (I) ali skupino, ki jo lahko pretvorimo v X ali X₃, in R₃ predstavlja R₃, kot je definiran v zvezi s formulo (I) ali skupino, ki jo lahko pretvorimo v R₃, s kovinsko soljo merkaptana, kot je NaSR₁₄ v primernem aprotičnem topilu. Spojine s formulo (I), kjer je Z SH, lahko pripravimo s presnovitvijo primernega alkohola s formulo (2), kjer je Z OH, s kompleksom fosfina, kot je trifenil fosfin in azodikarboksilatni ester v prisotnosti tioocetne kisline, kiji sledi hidroliza nastalega tiolacetata.Compounds of formula (I) wherein Z is SR ₁₄ can be prepared by reacting a suitable compound of formula (2) wherein Z is a leaving group, e.g. mesylate, tosylate, chloride or bromide, Rj represents Rj as defined with respect to formula (I) or a group which can be converted to R _p and X and Xg represent X and Xy as defined with respect to formula (I) or a group which can be converted to X or X ₃ and R ₃ represents R ₃ as defined in connection with formula (I) or a group which can be converted to R ₃ with a mercaptan metal salt such as NaSR ₁₄ in to a suitable aprotic solvent. Compounds of formula (I) wherein Z is SH can be prepared by metabolizing a suitable alcohol of formula (2) wherein Z is OH with a phosphine complex such as triphenyl phosphine and azodicarboxylate ester in the presence of thioacetic acid followed by hydrolysis of the resulting thiolacetate .

Spojine s formulo (I), kjer je Z OH, lahko notranje pretvorimo z uporabo standardnih, v stroki znanih postopkov alkoholne inverzije. Upoštevati moramo, da lahko spojine s formulo (I) obstajajo v dveh različnih diastereomemih oblikah, ki imata različne fizikalne in biološke lastnosti; takšne izomere lahko ločimo s standardnimi kromatografskimi postopki. Takšne izomere lahko neodvisno pretvorimo v preostale spojine s formulo (I), kjer je Z drugačen od OH, SH in NH₂ s katerimkoli izmed širokega izbora postopkov O, S in N alkilacije, sulfamidacije, imidacije, oksidacije ali acilacije, ki so znani strokovnjakom.Compounds of formula (I) wherein Z is OH can be internally converted using standard alcoholic inversion techniques known in the art. It should be appreciated that the compounds of formula (I) may exist in two different diastereomic forms having different physical and biological properties; such isomers can be separated by standard chromatographic procedures. Such isomers can be independently converted to the remaining compounds of formula (I) wherein Z is other than OH, SH and NH ₂ by any of a wide variety of O, S and N alkylation, sulfamidation, imidation, oxidation or acylation processes known to those skilled in the art .

Npr. s primerno obdelavo katerihkoli kemijsko funkcionalnih skupin lahko pridobimo spojine s formulo (I), kjer NR₁₃R₁₄ predstavlja obroč, kot je 1- aliE.g. by suitable treatment of any chemically functional group, compounds of formula (I) can be obtained, wherein NR ₁₃ R ₁₄ represents a ring such as 1- or

2-tetrazol, iz presnovitve ustrezne spojine s formulo (I), kjer je Z odhodna skupina, npr. mezilat, tozilat, klorid ali bromid, s primerno kovinsko soljo HNR₁₃R₁₄, npr. 5-(R₁₄)-tetrazolom; primerno spojino s formulo (I), kjer je Z mezilat, tozilat, Br ali Cl pridobimo v pretvorbi iz primerne spojine s formulo (I), kjer je Z OH.2-tetrazole, from the metabolism of the corresponding compound of formula (I) wherein Z is a leaving group, e.g. mesylate, tosylate, chloride or bromide, with a suitable metal salt of HNR ₁₃ R ₁₄ , e.g. 5- (R ₁₄ ) -tetrazole; a suitable compound of formula (I) wherein Z is mesylate, tosylate, Br or Cl is obtained in conversion from a suitable compound of formula (I) wherein Z is OH.

Spojine s formulo (2) lahko pripravimo v pretvorbi opisanega postopka v prijavi, ki je v postopku P 50071.The compounds of formula (2) can be prepared in the conversion of the process described in the application, which is in process P 50071.

Naslednji nizi primerov so zagotovljeni za ponazoritev kako narediti in uporabiti predloženi izum. Primerni niso namenjeni, da omejijo obseg izuma, ampak so podani samo za ponazoritvene namene.The following sets of examples are provided to illustrate how to make and use the present invention. They are not intended to limit the scope of the invention, but are intended for illustrative purposes only.

SINTEZNI PRIMERISYNTHESIS EXAMPLES

PRIMER 1EXAMPLE 1

4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-on (Intermediat s formulo 2) la. (3-ciklopentiloksi-4-metoksifenil)acetonitril4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one (Intermediate of Formula 2) 1a. (3-Cyclopentyloxy-4-methoxyphenyl) acetonitrile

K raztopini 3-ciklopentiloksi-4-metoksibenzaldehida (20 g, 90,8 mmol) v acetonitrilu (100 ml) dodamo litijev bromid (15 g, 173 mmol), čemur sledi dodajanje po kapljicah trimetilsililklorida (17,4 ml, 137 mmol). Po 15 min reakcijsko zmes ohladimo na 0 °C, po kapljicah dodamo 1,1,3,3-tetrametildisiloksan (26,7 ml, 151 mmol) in nastalo zmes pustimo, da se segreje na sobno temperaturo. Po mešanju 3 h zmes ločimo v dve plasti. Spodnjo plast odstranimo, razredčimo z metilenkloridom in filtriramo preko Celite-a. Filtrat koncentriramo pod znižanim tlakom, raztopimo v metilen kloridu in ponovno filtriramo. Topilo odstranimo v vakuumu, da zagotovimo rahlo rumeno rjavo olje. K raztopini tega surovega a-bromo-3-ciklopentiloksi-4-metoksitoluena v dimetilformamidu (160 ml) pod atmosfero argona dodamo natrijev cianid (10,1 g, 206 mmol) in nastalo zmes mešamo pri sobni temperaturi 18 h, jo nato zlijemo v hladno vodo (600 ml) in ekstrahiramo 3-krat z etrom. Organski ekstrakt 3-krat speremo z vodo, enkrat s slanico in posušimo (kalijev karbonat). Topilo odstranimo v vakuumu in ostanek prečistimo s flash kromatografijo, eluiramo z 10 % etil acetatom/heksani, da zagotovimo sivobelo trdno snov (17,7 g, 84 %): tal. 32-34 °C; izoliramo tudi dodatno količino (1,3 g) rahlo nečistega materiala.To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8 mmol) in acetonitrile (100 ml) was added lithium bromide (15 g, 173 mmol) followed by trimethylsilyl chloride (17.4 ml, 137 mmol) dropwise. . After 15 min, the reaction mixture was cooled to 0 ° C, 1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise and the resulting mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was separated into two layers. The bottom layer was removed, diluted with methylene chloride and filtered through Celite. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and filtered again. The solvent is removed in vacuo to provide a slightly yellowish brown oil. To a solution of this crude α-bromo-3-cyclopentyloxy-4-methoxytoluene in dimethylformamide (160 ml) was added sodium cyanide (10.1 g, 206 mmol) under argon atmosphere and the resulting mixture was stirred at room temperature for 18 h, then poured into cold water (600 ml) and extracted 3 times with ether. The organic extract was washed 3 times with water, once with brine and dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 10% ethyl acetate / hexanes to give a off-white solid (17.7 g, 84%): mp. 32-34 C; an additional amount (1.3 g) of slightly impure material is also isolated.

b. Dimetil 4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)pimelatb. Dimethyl 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) pimelate

K raztopini (3-ciklopentiloksi-4-metoksifenil)acetonitrila (7 g, 30,3 mmol) v acetonitrilu (200 ml) pod atmosfero argona dodamo 40 % raztopine Tritona-B v metanolu (1,4 ml, 3,03 mmol) in zmes segrevamo do refluksa. Previdno dodamo metil akrilat (27 ml, 303 mmol), reakcijsko zmes vzdržujemo pri refluksu 5 h in jo nato ohladimo. Zmes razredčimo z etrom, enkrat speremo z IN klorovodikovo kislino in enkrat s slanico, posušimo (magnezijev sulfat) in topilo odstranimo v vakuumu. Trden ostanek trituriramo s 5 % etanolom/heksanom, da zagotovimo belo trdno snov (9 g, 74 %): tal. 81-82 °C; iz filtrata pridobimo tudi dodatnih 1,1 g (9 %). Analiza izrač. za C₂₂H₂₉NO₆: C 65,49, H 7,25, N 3,47;To a solution of (3-cyclopentyloxy-4-methoxyphenyl) acetonitrile (7 g, 30.3 mmol) in acetonitrile (200 ml), under an argon atmosphere, 40% of Triton-B solution in methanol (1.4 ml, 3.03 mmol) was added. and the mixture was heated to reflux. Methyl acrylate (27 ml, 303 mmol) was carefully added, the reaction mixture was maintained at reflux for 5 h and then cooled. The mixture was diluted with ether, washed once with 1N hydrochloric acid and once with brine, dried (magnesium sulfate) and the solvent removed in vacuo. The solid was triturated with 5% ethanol / hexane to provide a white solid (9 g, 74%): m.p. 81-82 ° C; an additional 1.1 g (9%) was also obtained from the filtrate. Analysis of calc. for C ₂₂ H ₂₉ NO ₆ : C 65.49, H 7.25, N 3.47;

ugotovljeno: C 65,47, H 7,11, N 3,49 lc. 2-karbometoksi-4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-onfound: C 65.47, H 7.11, N 3.49 lc. 2-Carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one

K raztopini dimetil 4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)pimelata (5,9 g, 14,6 mmol) v suhem 1,2-dimetoksietanu (120 ml) pod atmosfero argona dodamo natrijev hidrid (80 % suspenzije v mineralnem olju, 1,05 g, 43,8 mmol). Zmes segrevamo do refluksa 4,5 h, jo nato ohladimo do sobne temperature in mešamo 16 h. Dodamo vodo in reakcijsko zmes porazdelimo med eter in nakisano vodo. Oranski ekstrakt posušimo, magnezijev sulfat in topilo odstranimo v vakuumu. Ostanek prečistimo s flash kromatografijo, eluiramo s 3:1 heksani/etil acetatom, da zagotovimo belo peno (4,9 g, 93%).Sodium hydride (80%) was added to a solution of dimethyl 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) pimelate (5.9 g, 14.6 mmol) in dry 1,2-dimethoxyethane (120 ml). suspensions in mineral oil, 1.05 g, 43.8 mmol). The mixture was heated to reflux for 4.5 h, then cooled to room temperature and stirred for 16 h. Water was added and the reaction mixture was partitioned between ether and acidified water. The orange extract was dried, magnesium sulfate and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with 3: 1 hexanes / ethyl acetate to provide a white foam (4.9 g, 93%).

Analiza za izrač. za C₁₉H₂₃NO₃.l/4 H₂O: C 67,09, H 6,84, N 3,72;Analysis for calculation. for C ₁₉ H ₂₃ NO ₃ .l / 4 H ₂ O: C 67.09, H 6.84, N 3.72;

ugotovljeno: C 66,92, H 6,61, N 3,74 ld. 4-ciano-4-(3-ciklopentiloksi-4-metoksifeniDcikloheksan-l-onfound: C 66.92, H 6.61, N 3.74 ld. 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenylcyclohexan-1-one

Zmes 2-karbometoksi-4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan1-ona (0,80 g, 2,15 mmol), dimetil sulfoksida (16 ml), vode (1 ml) in natrijevega klorida (0,8 g) pod atmosfero argona segrevamo 5 ur pri 140-145 °C. Reakcijsko zmes ohladimo in koncentriramo. Ostanek prečistimo s flash kromatografijo, eluiramo s 3:1 heksani/etil acetatom, da zagotovimo rumeno trdno snov. Trituracija s heksani/etil acetatom da belo trdno snov (0,52 g, 77 %): tal, 111-112 °C.A mixture of 2-carbomethoxy-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one (0.80 g, 2.15 mmol), dimethyl sulfoxide (16 ml), water (1 ml) and sodium chloride (0.8 g) was heated to 140-145 ° C for 5 hours under argon. The reaction mixture was cooled and concentrated. The residue was purified by flash chromatography eluting with 3: 1 hexanes / ethyl acetate to provide a yellow solid. Trituration with hexanes / ethyl acetate gave a white solid (0.52 g, 77%): mp, 111-112 ° C.

Analiza za izrač.: za C₁₉H₂₃NO₃: C 72,82, H 7,40, N 4,47;Calcd for C ₁₉ H ₂₃ NO ₃ : C 72.82, H 7.40, N 4.47;

ugotovljeno: C 72,72, H 7,39, N 4,48.found: C 72.72, H 7.39, N 4.48.

PRIMER 2EXAMPLE 2

4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksan-l-on (Intermediat s formulo 2)4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-one (Intermediate of Formula 2)

2a. 3,4-bisdifluorometoksibenzaldehid2a. 3,4-bisdifluoromethoxybenzaldehyde

Močno mešano zmes 3,4-dihidroksibenzaldehida (40 g, 290 mmol) in kalijevega karbonata (120 g, 870 mol) v dimetilformamidu (500 ml) segrevamo 7 ur pod atmosfero klorodifluorometana pri 80 °C in jo nato mešamo pri sobni temperaturi preko noči.A strongly stirred mixture of 3,4-dihydroxybenzaldehyde (40 g, 290 mmol) and potassium carbonate (120 g, 870 mol) in dimethylformamide (500 ml) was heated for 7 hours under chlorodifluoromethane at 80 ° C and then stirred at room temperature overnight. .

Zmes razredčimo z etrom in filtriramo. Filtrat koncentriramo pod znižanim tlakom, ostanek porazdelimo med eter in vodni kalijev karbonat in 5-krat ekstrahiramo z etrom. Organski ekstrakt speremo z vodnim kalijevim karbonatom in posušimo (kalijev karbonat). Topilo odstranimo v vakuumu in ostanek prečistimo s flash kromatografijo, eluiramo s 4:1 heksani/etrom, da zagotovimo olje (26,2 g, 38 %).The mixture was diluted with ether and filtered. The filtrate was concentrated under reduced pressure, the residue partitioned between ether and aqueous potassium carbonate and extracted 5 times with ether. The organic extract was washed with aqueous potassium carbonate and dried (potassium carbonate). The solvent was removed in vacuo and the residue purified by flash chromatography, eluting with 4: 1 hexanes / ether to provide an oil (26.2 g, 38%).

2b. 3,4-bisdifluorometoksibenzil alkohol2b. 3,4-bisdifluoromethoxybenzyl alcohol

3,4-bisdifluorometoksibenzaldehid (26,2 g, 110 mmol) v absolutnem etanolu (150 ml) obdelujemo 0,5 h z natrijevim borohidridom (8,32 g, 220 mmol) pod atmosfero argona pri sobni temperaturi. Dodamo 10 %-ni vodni natrijev hidroksid (130 ml), v vakuumu odstranimo etanol, zmes porazdelimo med eter in vodo in dvakrat ekstrahiramo z etrom. Organski ekstrakt posušimo (magnezijev sulfat) in uparimo do bledo rumenega olja (26,4 g, 100 %).3,4-bisdifluoromethoxybenzaldehyde (26.2 g, 110 mmol) in absolute ethanol (150 ml) was treated for 0.5 h with sodium borohydride (8.32 g, 220 mmol) under argon at room temperature. 10% aqueous sodium hydroxide (130 ml) was added, the ethanol removed in vacuo, the mixture was partitioned between ether and water and extracted twice with ether. The organic extract was dried (magnesium sulfate) and evaporated to a pale yellow oil (26.4 g, 100%).

2c. 2-(3,4-bisdifluorometoksifenil)acetonitril2c. 2- (3,4-bisdifluoromethoxyphenyl) acetonitrile

Raztopino 3,4-bisdifluorometoksibenzil alkohola (26,4 g, 110 mmol) in piridina (9,79 ml, 120 mmol) v kloroformu (200 ml) pod atmosfero argona obdelamo s tionil kloridom (9,62 ml, 130 mmol) in zmes segrevamo pri refluksu 1 h. Topilo odstranimo, dodamo eter in oborino odstranimo s filtracijo. Filtrat koncentriramo do škrlatnega olja. K raztopini tega 3,4-bisdifluorometoksibenzil klorida v dimetil formamidu (200 ml) pod atmosfero argona dodamo natrijev cianid (11,86 g, 240 mmol). Nastalo zmes mešamo in rahlo segrevamo pri 45 °C 3 h, ohladimo in koncentriramo. Zmes porazdelimo med eter in 5 %-ni vodni natrijev karbonat in 5-krat ekstrahiramo z etrom. Organski ekstrakt enkrat speremo s slanico, posušimo (natrijev karbonat) in topilo odstranimo v vakuumu, da zagotovimo olje (27 g).A solution of 3,4-bisdifluoromethoxybenzyl alcohol (26.4 g, 110 mmol) and pyridine (9.79 ml, 120 mmol) in chloroform (200 ml) was treated with thionyl chloride (9.62 ml, 130 mmol) under an argon atmosphere and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a scarlet oil. To a solution of this 3,4-bisdifluoromethoxybenzyl chloride in dimethyl formamide (200 ml) was added sodium cyanide (11.86 g, 240 mmol) under an argon atmosphere. The resulting mixture was stirred and gently heated at 45 ° C for 3 h, cooled and concentrated. The mixture was partitioned between ether and 5% aqueous sodium carbonate and extracted 5 times with ether. The organic extract was washed once with brine, dried (sodium carbonate) and the solvent removed in vacuo to provide an oil (27 g).

2d. Dimetil 4-ciano-4-(3,4-bisdifluorometoksifenil)pimelat2d. Dimethyl 4-cyano-4- (3,4-bisdifluoromethoxyphenyl) pimelate

K raztopini 2-(3,4-bisdifluorometoksifenil)acetonitrila (27 g, 108 mmol) in 40 % raztopini Tritona-B v metanolu (5 ml, 11 mmol) v acetonitrilu (450 ml) pod atmosfero argona pri sobni temperaturi dodamo metil akrilat (48,6 ml, 540 mmol). Po 20 min dodamo vodno klorovodikovo kislino (3N, 20 ml) in zmes koncentriramo. Ostanek porazdelimo med vodo in eter, 2-krat ekstrahiramo z etrom, etrsko plast posušimo (magnezijev sulfat) in uparimo v vakuumu, da zagotovimo rumeno olje (45,32 g, 99 %).Methyl acrylate was added to a solution of 2- (3,4-bisdifluoromethoxyphenyl) acetonitrile (27 g, 108 mmol) and 40% solution of Triton-B in methanol (5 ml, 11 mmol) under acetonitrile (450 ml) at room temperature. (48.6 ml, 540 mmol). After 20 minutes, aqueous hydrochloric acid (3N, 20 ml) was added and the mixture was concentrated. The residue was partitioned between water and ether, extracted twice with ether, the ether layer dried (magnesium sulfate) and evaporated in vacuo to provide a yellow oil (45.32 g, 99%).

2e. 2-karbometoksi-4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksan-l-on2e. 2-carbomethoxy-4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-one

K raztopini dimetil 4-(3,4-bisdifluorometoksifenil)-4-cianopimelata (45,32 g, 107 mmol) v suhem 1,2-dimetoksietanu (450 ml) pod atmosfero argona dodamo natrijev hidrid (80 %-na disperzija v mineralnem olju, 13 g, 432 mmol). Nastalo zmes refluktiramo 1 h, ohladimo na sobno temperaturo, pogasimo z vodo in koncentriramo. Zmes porazdelimo med eter in nakisano slanico, 2-krat ekstrahiramo z etrom, organsko plast posušimo (magnezijev sulfat) in topilo odstranimo v vakuumu. Ostanek prečistimo s flash kromatografijo, eluiramo s 3:1 heksani/etil acetatom, da zagotovimo bledo oranžno olje (19,5 g, 46,6 %).To a solution of dimethyl 4- (3,4-bisdifluoromethoxyphenyl) -4-cyanopimelate (45.32 g, 107 mmol) in dry 1,2-dimethoxyethane (450 ml), sodium hydride (80% mineral dispersion) was added under argon. oil, 13 g, 432 mmol). The resulting mixture was refluxed for 1 h, cooled to room temperature, quenched with water and concentrated. The mixture was partitioned between ether and acidified brine, extracted twice with ether, the organic layer dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with 3: 1 hexanes / ethyl acetate to provide a pale orange oil (19.5 g, 46.6%).

Analiza izrač. za C_1?H₁₅F₄NO₅: C 52,45, H 3,88, N 3,60;Analysis of calc. for C _1? H ₁₅ F ₄ NO ₅ : C 52.45, H 3.88, N 3.60;

ugotovljeno: C 52,60, H 4,07, N 3,22.found: C 52.60, H 4.07, N 3.22.

2f. 4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksan-l-on2f. 4- (3,4-Bisifluoromethoxyphenyl) -4-cyanocyclohexan-1-one

Zmes 2-karbometoksi-4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksan-l-ona (0,55 g, 1,4 mmol), dimetil sulfoksida (8 ml), voda (0,5 ml) in natrijevega klorida (0,5 g) pod atmosfero argona segrevamo pri 140-145 °C 4 h. Reakcijsko zmes ohladimo na sobno temperaturo in koncentriramo. Ostanek porazdelimo med eter in vodo, organsko plast posušimo (magnezijev sulfat) in topilo odstranimo v vakuumu. Produkt prečistimo s flash kromatografijo, eluiramo z 1:1 heksani/etrom. Ostanek porazdelimo med vodo in etil acetat in organsko plast uparimo, da dobimo rumeno trdno snov. Trituracija iz minimalne količine etil acetata/heksanov zagotovi trdno snov (0,3 g, 63,6%): tal. 64-66 °C.A mixture of 2-carbomethoxy-4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-one (0.55 g, 1.4 mmol), dimethyl sulfoxide (8 ml), water (0.5 ml) and sodium of chloride (0.5 g) under an argon atmosphere was heated at 140-145 ° C for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ether and water, the organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography eluting with 1: 1 hexanes / ether. The residue was partitioned between water and ethyl acetate and the organic layer was evaporated to give a yellow solid. Trituration from a minimal amount of ethyl acetate / hexanes provided a solid (0.3 g, 63.6%): m.p. 64-66 ° C.

Analiza izrač. za C₁₅H₁₃NO₃F₄: C 54,39, H 3,96, N 4,23;Analysis of calc. for C ₁₅ H ₁₃ NO ₃ F ₄ : C 54.39, H 3.96, N 4.23;

ugotovljeno: C 54,25, H 3,96, N 4,20.found: C 54.25, H 3.96, N 4.20.

PRIMERA 3 IN 4 cis in trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-ol]cis-14-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-ollEXAMPLE 3 IN 4 cis and trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-ol] cis-14-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1 -oll

K raztopini 4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-ona (0,25 g, 0,8 mmol) v 1,2-dimetoksietanu (5 ml) pod atmosfero argona dodamo natrijev borohidrid (0,06 g, 1,6 mmol) in zmes mešamo pri sobni temperaturi 0,25 h. Dodamo vodo, zmes porazdelimo med etil acetat in slanico, organski ekstrakt posušimo (magnezijev sulfat) in uparimo. Prečiščenje s flash kromatografijo, eluiranje z 1:1 heksani/etil acetatom zagotovi cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-ol] kot vosek (0,2 g, 79 %).To a solution of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one (0.25 g, 0.8 mmol) in 1,2-dimethoxyethane (5 ml) was added sodium borohydride (argon). 0.06 g, 1.6 mmol) and the mixture was stirred at room temperature for 0.25 h. Water was added, the mixture was partitioned between ethyl acetate and brine, the organic extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography eluting with 1: 1 hexanes / ethyl acetate provided cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-ol] as wax (0.2 g, 79%) .

Analiza izrač. za C₁₉H₂₅NO₃: C 72,35, H 7,99, N 4,44; ugotovljeno: C 72,20, H 7,94, N 4,17.Analysis of calc. for C ₁₉ H ₂₅ NO ₃ : C 72.35, H 7.99, N 4.44; found: C 72.20, H 7.94, N 4.17.

Iz tega postopka tudi izoliramo (0,05 g, 20 %) trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-ol](0.05 g, 20%) trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-ol] was also isolated from this process

S postopkom na enak način, toda s substituiranjem ustreznih intermediatov za tiste, opisani zgoraj, naredimo naslednje spojine:By the same procedure, but by substituting the appropriate intermediates for those described above, the following compounds are made:

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)cikloheksan-l-ol]: tal. 76 °C. Analiza za izrač. za C^H^NC^: C 71,73, H 7,69, N 4,65; ugotovljeno: C 71,41, H 7,55, N 4,56;cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-ol]: m.p. 76 ° C. Analysis for calculation. Calcd for C 16 H 16 N 4 O 3: C 71.73, H 7.69, N 4.65; found: C 71.41, H 7.55, N 4.56;

cis-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksan-l-ol]; tal. 48-51 °C.cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-ol]; m.p. 48-51 ° C.

Analiza izrač. za C₁₅H₁₅F₄NO₃: C 54,06, H 4,54, N 4,20; ugotovljeno: C 54,26, H 4,47, N 4,11;Analysis of calc. for C ₁₅ H ₁₅ F ₄ NO ₃ : C 54.06, H 4.54, N 4.20; found: C 54.26, H 4.47, N 4.11;

trans-[4-ciano-4-(3-cikloproilmetoksi-4-metoksifenil)cikloheksan-l-ol]: olje.trans- [4-cyano-4- (3-cycloproylmethoxy-4-methoxyphenyl) cyclohexan-1-ol]: oil.

Analiza izrač. za C_lgH₂₃NO₃.l/4 H₂O: C 70,68, H 7,74, N 4,58; ugotovljeno: C 70,97, H 7,56, N 4,59;Analysis of calc. for C _lg H ₂₃ NO ₃ .l / 4 H ₂ O: C 70.68, H 7.74, N 4.58; found: C 70.97, H 7.56, N 4.59;

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-difluorometoksifenil)cikloheksan-l-ol]: tal. 58-60 °C.cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol]: m.p. 58-60 ° C.

Analiza izrač. za C_lgH₂₁F₂NO₃.l/5 H₂O: C 63,41, H 6,33, N 4,11;Analysis of calc. for C _lg H ₂₁ F ₂ NO ₃ .l / 5 H ₂ O: C 63.41, H 6.33, N 4.11;

ugotovljeno: C 63,42, H 6,10, N 4,19;found: C 63.42, H 6.10, N 4.19;

trans-[4-ciano-4-(3-ciklopropiImetoksi-4-difIuorometoksifenil)cikloheksan-l-olj: olje. Analiza izrač. za C_lgH₂₁F₂NO₃.l/5 H₂O: C 63,41, H 6,33, N 4,11; ugotovljeno: C 63,43, H 6,12, N 3,89; in cis-[4-(3-ciklopropilmetoksi-4-metoksifenil)-4-etinilcikloheksan-l-ol]; tal.trans- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1-oil: oil. Analysis of calc. for C _lg H ₂₁ F ₂ NO ₃ .l / 5 H ₂ O: C 63.41, H 6.33, N 4.11; found: C 63.43, H 6.12, N 3.89; and cis- [4- (3-cyclopropylmethoxy-4-methoxyphenyl) -4-ethynylcyclohexan-1-ol]; m.p.

89-90 °C.89-90 ° C.

Analiza izrač. za (Σ^Η^Ο^Ι/δ H₂O: C 75,86, H 8,35;Analysis of calc. for (Σ ^ Η ^ Ο ^ Ι / δ H ₂ O: C 75.86, H 8.35;

ugotovljeno: C 75,94, H 8,35.found: C 75.94, H 8.35.

PRIMER 5 trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-formiloksicikloheksan] cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-ol] (0,2 g, 0,63 mmol), trifenilfosfin (0,17 g, 0,63 mmol) in formično kislino (0,024 ml, 0,63 mmol) v sveže destiliranem tetrahidrofuranu (10 ml) pod atmosfero argona pri sobni temperaturi močno mešamo, medtem ko počasi dodajamo dietilazodikarboksilat (0,1 ml, 0,63 mmol). Po mešanju v temi 18 h, dodamo dodaten ekvivalent vsakega reagenta in mešanje nadaljujemo 24 h. Tekočine odstranimo pod znižanim tlakom in ostanek prečistimo s flash kromatografijo, eluiramo s 3:1 heksani/etil acetatom, da zagotovimo trans-format kot olje (0,15 g, 69 %).EXAMPLE 5 trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-formyloxycyclohexane] cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-ol] ( 0.2 g, 0.63 mmol), triphenylphosphine (0.17 g, 0.63 mmol) and formic acid (0.024 ml, 0.63 mmol) in freshly distilled tetrahydrofuran (10 ml) under a strong argon atmosphere at room temperature stirred while slowly adding diethylazodicarboxylate (0.1 ml, 0.63 mmol). After stirring in the dark for 18 h, an additional equivalent of each reagent was added and stirring continued for 24 h. The liquids were removed under reduced pressure and the residue was purified by flash chromatography, eluting with 3: 1 hexanes / ethyl acetate to provide the trans-format as an oil (0.15 g, 69%).

PRIMER 6 trans-i4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-ol] trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-formiloksi-cikloheksanj (0,12 g, 0,35 mmol) v etil acetatu (2 ml) obdelujemo 5 h z 10 %-nim vodnim natrijevim hidroksidom (25 ml) pri 60 °C. Zmes porazdelimo med etil acetat in vodo, organsko plast posušimo (kalijev karbonat) in topilo odstranimo v vakuumu. Prečiščevanje s flash kromatografijo, eluiranje z 8 %-nim etil acetatom/kloroformom zagotovi transalkohol kot olje (0,09 g, 82 %).EXAMPLE 6 trans-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-ol] trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-formyloxy-cyclohexane ( 0.12 g, 0.35 mmol) in ethyl acetate (2 ml) was treated for 5 h with 10% aqueous sodium hydroxide (25 ml) at 60 ° C. The mixture was partitioned between ethyl acetate and water, the organic layer was dried (potassium carbonate) and the solvent was removed in vacuo. Purification by flash chromatography eluting with 8% ethyl acetate / chloroform provided trans-alcohol as an oil (0.09 g, 82%).

Analiza izrač. za C₁₉H₂₅NO₃.l/4 H₂O: C 71,33, H 8,03, N 4,38;Analysis of calc. for C ₁₉ H ₂₅ NO ₃ .l / 4 H ₂ O: C 71.33, H 8.03, N 4.38;

ugotovljeno: C 71,23, H 7,87, N 4,19.found: C 71.23, H 7.87, N 4.19.

S postopkom na enak način, toda s substituiranjem ustreznega intermediata, naredimo naslednjo spojino:By the same procedure but by substitution of the corresponding intermediate, the following compound is made:

trans-4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksan-l-ol; olje.trans-4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-ol; oil.

Analiza izrač. za C₁₅H₁₅F₄NO₃: C 54,06, H 4,54, N 4,20;Analysis of calc. for C ₁₅ H ₁₅ F ₄ NO ₃ : C 54.06, H 4.54, N 4.20;

ugotovljeno: C 54,05, H 4,60, N 4,20.found: C 54.05, H 4.60, N 4.20.

PRIMER 7 trans-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-formiloksicikloheksan1 cis-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksan-l-ol] (0,46 g, 1,38 mmol), trifenilfosfin (0,72 g, 2,76 mmol) in formično kislino (0,104 ml, 2,76 mmol) v sveže destiliranem tetrahidrofuranu (11 ml) pod atmosfero argona pri sobni temepraturi močno mešamo, medtem ko počasi dodajamo dietil azodikarboksilat (0,1 ml, 0,63 mmol). Po mešanju v temi preko noči, tekočine odstranimo pod znižanim tlakom in ostanek prečistimo s flash kromatografijo, eluiramo s 3:1 heksani/etil acetatom, da zagotovimo trans-format kot olje (0,41 g, 82 %): tal. 130-131 °C.EXAMPLE 7 trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-formyloxycyclohexane] cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexan-1-ol] (0.46 g, 1 , 38 mmol), triphenylphosphine (0.72 g, 2.76 mmol) and formic acid (0.104 ml, 2.76 mmol) in freshly distilled tetrahydrofuran (11 ml) stirred vigorously under argon at room temperature while slowly adding diethyl azodicarboxylate (0.1 ml, 0.63 mmol). After stirring in the dark overnight, the liquids were removed under reduced pressure and the residue was purified by flash chromatography, eluting with 3: 1 hexanes / ethyl acetate to provide the trans-format as an oil (0.41 g, 82%): mp. 130-131 ° C.

Analiza izrač. za C₁₆H₁₅F₄NO₄: C 53,19, H 4,18, N 3,88;Analysis of calc. for C ₁₆ H ₁₅ F ₄ NO ₄ : C 53.19, H 4.18, N 3.88;

ugotovljeno: C 53,03, H 3,99, N 4,12.found: C 53.03, H 3.99, N 4.12.

PRIMERA 8 IN 9 cis- in trans-I4-(3,4-bisdifluorometoksifenil)-4-ciano-l-metilcikloheksan-l-oljEXAMPLE 8 IN 9 cis- and trans-4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-methylcyclohexane-1-oil

K raztopini trimetilaluminija (2M v toluenu, 1,36 ml, 2,70 mmol) pri sobni temperaturi pod atmosfero argona dodamo raztopino 4-(3,4-bisdifluorometoksifenil)-4cianocikloheksan-l-ona (0,3 g, 0,9 mmol). Po 3,5 h zmes ohladimo na 0 °C in dodamo nasičeno vodno raztopino amonijevega klorida. Zmes 2-krat ekstrahiramo z metilen kloridom, organski ekstrakt posušimo (magnezijev sulfat) in uparimo. Prečiščenje s flash kromatografijo, eluiranje z 2:1 heksani/etil acetatom zagotovi trans-[4-(3,4bisdifluorometoksi-fenil)-4-ciano-l-metilcikloheksan-l-ol] kot trdno snov (0,12 g, 38 %): tal. 45-47 °C.To a solution of trimethylaluminium (2M in toluene, 1.36 ml, 2.70 mmol) at room temperature under an argon atmosphere was added a solution of 4- (3,4-bisdifluoromethoxyphenyl) -4cyanocyclohexan-1-one (0.3 g, 0.9 mmol). After 3.5 h, the mixture was cooled to 0 ° C and saturated aqueous ammonium chloride was added. The mixture was extracted twice with methylene chloride, the organic extract was dried (magnesium sulfate) and evaporated. Purification by flash chromatography eluting with 2: 1 hexanes / ethyl acetate provided trans- [4- (3,4bisifluoromethoxy-phenyl) -4-cyano-1-methylcyclohexan-1-ol] as a solid (0.12 g, 38 %): m.p. 45-47 ° C.

Analiza izrač. za: C₁₆H_1?F₄NO₃: C 55,33, H 4,93, N 4,03;Analysis of calc. for: C ₁₆ H _1? F ₄ NO ₃ : C 55.33, H 4.93, N 4.03;

ugotovljeno: C 55,27, H 4,96, N 3,93.found: C 55.27, H 4.96, N 3.93.

Iz tega postopka izoliramo tudi cis-[4-(3,4-bisdifluorometoksifenil)-4-ciano-lmetilcikloheksan-l-ol] kot trdno snov (0,05 g, 16 %): tal. 46-48 °C.Cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-methylcyclohexan-1-ol] was also isolated from this process as a solid (0.05 g, 16%): mp. 46-48 ° C.

PRIMERA 10 IN 11 cis- in trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil- 1-aminj cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil-l-amin].EXAMPLE 10 IN 11 cis- and trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl-1-amino cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl- l-amine].

K raztopini 4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-ona (0,2 g, 0,64 mmol) in amonijevega acetata (0,49 g, 6,4 mmol) v absolutnem etanolu (5 ml) pod atmosfero argona dodamo natrijev cianoborohidrid (0,08 g, 1,28 mmol) in zmes mešamo pri sobni temperaturi 4 h. Dodamo 5 %-ni vodni natrijev karbonat in zmes koncentriramo do blizu suhega. Ostanek porazdelimo med etil acetat in bazično slanico, še 2-krat ekstrahiramo z etil acetatom, organski ekstrakt posušimo (kalijev karbonat) in uparimo. Prečiščenje s flash kromatografijo, eluiranje z 90:10:1 kloroformom/metanolom/vodo, zagotovi cis-[4-ciano-4-(3-ciklopentiloksi-4metoksifenil)cikloheksil-l-aminj kot vosek (0,1 g, 50 %).To a solution of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one (0.2 g, 0.64 mmol) and ammonium acetate (0.49 g, 6.4 mmol) in absolute ethanol (5 ml) sodium cyanoborohydride (0.08 g, 1.28 mmol) was added under argon atmosphere and the mixture was stirred at room temperature for 4 h. 5% aqueous sodium carbonate was added and the mixture was concentrated to near dryness. The residue was partitioned between ethyl acetate and basic brine, extracted twice more with ethyl acetate, the organic extract dried (potassium carbonate) and evaporated. Flash chromatography, eluting with 90: 10: 1 chloroform / methanol / water, provided cis- [4-cyano-4- (3-cyclopentyloxy-4methoxyphenyl) cyclohexyl-1-amine as wax (0.1 g, 50%) ).

Analiza izrač. za C^H^N^.l# H₂O: C 70,55, H 8,41, N 8,66;Analysis of calc. for C 22 H 28 N ₄ O ₂ H ₂ O: C 70.55, H 8.41, N 8.66;

ugotovljeno: C 70,41, H 8,10, N 8,41.found: C 70.41, H 8.10, N 8.41.

Iz tega postopka izoliramo tudi trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil-l-amin kot olje (0,015 g, 7,5 %). Kot stranski produkt izoliramo tudi trans-amin (5 %) s podobno reakcijo vodeno na količini 2 g ketona.Trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl-1-amine as an oil (0.015 g, 7.5%) was also isolated from this process. As a by-product, trans-amine (5%) was isolated by a similar reaction, guided by a quantity of 2 g of ketone.

Analiza izrač. za C₁₉H₂₆N₂O₂.1/2 H₂O: C 70,55, H 8,41, N 8,66;Analysis of calc. for C ₁₉ H ₂₆ N ₂ O ₂ .1 / 2 H ₂ O: C 70.55, H 8.41, N 8.66;

ugotovljeno: C 70,71, H 8,28, N 8,45.found: C 70.71, H 8.28, N 8.45.

S postopkom na podoben način naredimo:In a similar way, we do:

cis-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil-l-aminj: vosek. Analiza izrač. za C₁₅H₁₆F₄N₂O₂: C 54,22, H 4,85, N 8,43; ugotovljeno: C 53,98, H 4,79, N 8,30;cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1-amine: wax. Analysis of calc. for C ₁₅ H ₁₆ F ₄ N ₂ O ₂ : C 54.22, H 4.85, N 8.43; found: C 53.98, H 4.79, N 8.30;

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)cikloheksil-l-aminj: tal. 84-86 °C. Analiza izrač. za C_lgH₂₄N₂O₂: C 71,97, H 8,05, N 9,33; ugotovljeno: C 71,67, H 7,79, N 9,10;cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexyl-1-amine: m.p. 84-86 ° C. Analysis of calc. for C _lg H ₂₄ N ₂ O _2: C 71.97, H 8.05, N 9.33; found: C 71.67, H 7.79, N 9.10;

trans-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)cikloheksil-l-amin]: olje; cis-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil-l-(N,N-dimetil)amin] (uporabimo dimetilamin hidroklorid namesto amonijevega acetata) kot olje, ki ga pretvorimo v hidrokloridno sol: tal. 228-230 °C.trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexyl-1-amine]: oil; cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1- (N, N-dimethyl) amine] (use dimethylamine hydrochloride instead of ammonium acetate) as an oil converted to the hydrochloride salt: m.p. Mp 228-230 ° C.

Analiza izrač. za C₁₇H₂₀F₄N₂O₂.HCl: C 51,46, H 5,34, N 7,06;Analysis of calc. for C ₁₇ H ₂₀ F ₄ N ₂ O ₂ .HCl: C 51.46, H 5.34, N 7.06;

ugotovljeno: C 51,57, H 5,43, N 6,82;found: C 51.57, H 5.43, N 6.82;

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)cikloheksil-l-(N,Ndimetil)amin]: tal. 85-87 °C.cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexyl-1- (N, N-dimethyl) amine]: m.p. 85-87 ° C.

Analiza izrač. za CJFL^iJO^l/Z H₂O: C 71,18, H 8,66, N 8,30;Analysis of calc. for CJFL lie ^ ^ l / ZH ₂ O: C 71.18, H 8.66, N 8.30;

ugotovljeno: C 71,09, H 8,54, N 8,53;found: C 71.09, H 8.54, N 8.53;

cis-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil-l-(N-metil)amin]: olje.cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1- (N-methyl) amine]: oil.

Analiza izrač. za C₁₆H_lgF₄N₂O₂.l/10 H₂O: C 55,20, H 5,27, N 8,05;Analysis of calc. for C ₁₆ H _lg F ₄ N ₂ O ₂ .l / 10 H ₂ O: C 55.20, H 5.27, N 8.05;

ugotovljeno: C 55,08, H 5,14, N 7,90; in trans-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil-l-(N-metil)amin]: olje. Analiza izrač. za C₁₆H_lgF₄N₂O₂: C 55,49, H 5,24, N 8,09; ugotovljeno: C 55,20, H 5,30, N 7,91.found: C 55.08, H 5.14, N 7.90; and trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1- (N-methyl) amine]: oil. Analysis of calc. for C ₁₆ H _lg F ₄ N ₂ O _2: C 55.49, H 5.24, N 8.09; found: C 55.20, H 5.30, N 7.91.

PRIMER 12 trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-ftalimidocikloheksan1 cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-ol] (0,2 g, 0,63 mmol), trifenilfosfin (0,166 g, 0,63 mmol) in ftalimid (0,093 g, 0,63 mmol) v sveže destiliranem tetrahidrofuranu (10 ml) pod atmosfero argona pri sobni temperaturi močno mešamo z dietil azodikarboksilatom (0,1 ml, 0,63 mmol) v temi preko noči. Tekočine odstranimo pod znižanim tlakom, s prečiščenjem s flash kromatografijo, eluiranjem s 3:1 heksani/etil acetatom, zagotovimo trans-ftalimid kot trdno snov (0,12 g, 42%); tal. 130-131 °C.EXAMPLE 12 trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-phthalimidocyclohexane] cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-ol] (0 , 2 g, 0.63 mmol), triphenylphosphine (0.166 g, 0.63 mmol) and phthalimide (0.093 g, 0.63 mmol) in freshly distilled tetrahydrofuran (10 ml) were stirred vigorously at room temperature with diethyl azodicarboxylate under argon. (0.1 ml, 0.63 mmol) in the dark overnight. The liquids were removed under reduced pressure, purified by flash chromatography eluting with 3: 1 hexanes / ethyl acetate to provide trans-phthalimide as a solid (0.12 g, 42%); m.p. 130-131 ° C.

Analiza izrač. za C^H^N^.IM H₂O: C 72,22, H 6,40, N 6,24;Analysis of calc. for C25 H25 N4 O1 H ₂ O: C 72.22, H 6.40, N 6.24;

ugotovljeno: C 72,18, H 6,35, N 6,27.found: C 72.18, H 6.35, N 6.27.

S postopkom na podoben način naredimo naslednjo spojino:In a similar manner, the following compound is made:

trans-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-ftalimidocikloheksan].· tal. 38-42 °C. Analiza izrač. za C₂₃H_lgF₄N₂O₄: C 59,74, H 3,92, N 6,06; ugotovljeno: C 59,62, H 4,15, N 5,96.trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-phthalimidocyclohexane]. 38-42 ° C. Analysis of calc. for C ₂₃ H _lg F ₄ N ₂ O _4: C 59.74, H 3.92, N 6.06; found: C 59.62, H 4.15, N 5.96.

PRIMER 13 trans-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil-l-amm]EXAMPLE 13 trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1-amine]

Raztopino trans-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-ftalimidocikloheksana] (0,55 g, 1,19 mmol) v etanolu (30 ml) obdelujemo 1,5 h s hidrazin monohidratom (0,06 ml, 1,19 mmol) pri sobni temperaturi pod atmosfero argona in jo nato segrevamo pri refluksu 2,5 h. Zmes pustimo, da se ohladi, trdno snov odstranimo s filtracijo in filtrat koncentriramo. Prečiščenje s flash kromatografijo, eluiranje z 90:10:1 kloroformom/metanolom/vodo zagotovi trans-amin kot olje (0,21 g, 53%).A solution of trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-phthalimidocyclohexane] (0.55 g, 1.19 mmol) in ethanol (30 ml) was treated with 1.5 h with hydrazine monohydrate (0.06 ml, 1.19 mmol) at room temperature under an argon atmosphere and then refluxed for 2.5 h. The mixture was allowed to cool, the solid was removed by filtration and the filtrate was concentrated. Purification by flash chromatography eluting with 90: 10: 1 chloroform / methanol / water provided the trans-amine as an oil (0.21 g, 53%).

Analiza izrač. za C₁₅H₁₆F₄N₂O₂.l/8 H₂0: C 53,85, H 4,90, N 8,37;Analysis of calc. for C ₁₅ H ₁₆ F ₄ N ₂ O ₂ .l / 8 H ₂ 0: C 53.85, H 4.90, N 8.37;

ugotovljeno: C 53,69, H 4,82, N 8,11.found: C 53.69, H 4.82, N 8.11.

S postopkom na enak način, toda z vzdrževanjem sobne temperature bolje kot temperature refluksa, naredimo naslednjo spojino:By the same procedure, but maintaining the room temperature better than the reflux temperature, we make the following compound:

trans-[l-N-(2-hidrazinokarbonilbenzamido)-4-(3,4-bisdifluorometoksifenil)-4cianocikloheksan]; tal. 153-155 °C.trans- [1-N- (2-hydrazinocarbonylbenzamido) -4- (3,4-bisdifluoromethoxyphenyl) -4cyanocyclohexane]; m.p. Mp 153-155 ° C.

Analiza izrač. za C^H^F^O^ C 55,87, H 4,49, N 11,33; ugotovljeno: C 55,99, H 4,38, N 11,04.Analysis of calc. for C25 H28 F3 O4 C 55.87, H 4.49, N 11.33; found: C 55.99, H 4.38, N 11.04.

PRIMER 14 cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-ureidocikloheksanlEXAMPLE 14 cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-ureidocyclohexane

Raztopino cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil-l-amina](0,1 g, 0,32 mmol) in trimetilsilil izocianata (0,08 ml, 0,48 mmol) v tetrahidrofuranu (1,6 ml) pri refluksu pod atmosfero argona. Zmes pustimo, da se ohladi, porazdelimo med metilen klorid in nakisano vodo, organski ekstrakt posušimo (kalijev karbonat) in uparimo. Produkt trituriramo z metilen kloridom, da zagotovimo rumeno trdno snov (0,08 g, 72 %): tal. 273 °C.A solution of cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl-1-amine] (0.1 g, 0.32 mmol) and trimethylsilyl isocyanate (0.08 ml, 0.48 mmol) in tetrahydrofuran (1.6 ml) at reflux under an argon atmosphere. The mixture was allowed to cool, partitioned between methylene chloride and acidified water, the organic extract was dried (potassium carbonate) and evaporated. The product was triturated with methylene chloride to provide a yellow solid (0.08 g, 72%): m.p. 273 ° C.

Analiza izrač. za C^N^: C 67,20, H 7,61, N 11,75;Analysis of calc. Calcd for C25H26N3O: C 67.20, H 7.61, N 11.75;

ugotovljeno: C 67,08, H 7,23, N 11,52.found: C 67.08, H 7.23, N 11.52.

S postopkom na podoben način naredimo naslednje spojine:In a similar manner, the following compounds are made:

cis-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-ureidocikloheksanj: tal. 124-125 °C. Analiza izrač. za C₁₆H₁₇F₄N₃O₃.l/4 H₂O: C 50,59, H 4,64, N 11,06; ugotovljeno: C 50,59, H 4,42, N 10,83;cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-ureidocyclohexane: m.p. 124-125 ° C. Analysis of calc. for C ₁₆ H ₁₇ F ₄ N ₃ O ₃ .l / 4 H ₂ O: C 50.59, H 4.64, N 11.06; found: C 50.59, H 4.42, N 10.83;

trans-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-ureidocikloheksanj: tal. 161-162 °C; cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan]: tal. 108-109 °C.trans- [4- (3,4-Bisifluoromethoxyphenyl) -4-cyano-1-ureidocyclohexane: m.p. 161-162 ° C; cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane]: m.p. 108-109 ° C.

Analiza izrač. za C^H^N^.O^ H₂O: C 63,11, H 7,36, N 11,04;Analysis of calc. for C 22 H 27 N ₄ O ₄ H ₂ O: C 63.11, H 7.36, N 11.04;

ugotovljeno: C 63,15, H 7,36, N 10,81;found: C 63.15, H 7.36, N 10.81;

trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan]: tal. 102-103 °C.trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane]: m.p. 102-103 C.

Analiza izrač. za C₂₀H₂₇N₃O₄.l,4 H₂O: C 60,25, H 7,18, N 10,51;Analysis of calc. for C ₂₀ H ₂₇ N ₃ O _4.1 , 4 H ₂ O: C 60.25, H 7.18, N 10.51;

ugotovljeno: C 60,33, H 7,07, N 10,41;found: C 60.33, H 7.07, N 10.41;

cis-[4-ciano-4-(3-{4-fluorobenzil}-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan]: tal. 83-85 °C.cis- [4-cyano-4- (3- {4-fluorobenzyl} -4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane]: m.p. 83-85 ° C.

Analiza izrač. za C^FN^O^S H₂O: C 61,63, H 6,04, N 9,80;Analysis of calc. for C 16 FN ₄ O ₄ SH ₂ O: C 61.63, H 6.04, N 9.80;

ugotovljeno: C 61,81, H 5,82, N 9,75;found: C 61.81, H 5.82, N 9.75;

trans-[4-ciano-4-(3-{4-fluorobenzil}-4-metoksifeniI)-l-(N-hidroksiureido)cikloheksan]: tal. 87-89 °C.trans- [4-cyano-4- (3- {4-fluorobenzyl} -4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane]: m.p. 87-89 ° C.

Analiza izrač. za Ο^Η^ΡΝ^.Ο^ H₂O: C 61,63, H 6,04, N 9,80;Analysis of calc. for Ο ^ Η ^ ΡΝ ^ .Ο ^ H ₂ O: C 61.63, H 6.04, N 9.80;

ugotovljeno: C 61,64, H 5,76, N 9,69;found: C 61.64, H 5.76, N 9.69;

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan]: tal. 181-182 °C.cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane]: m.p. 181-182 ° C.

Analiza izrač. za H₂O: C 61,44, H 7,15, N 11,31;Analysis of calc. for H ₂ O: C 61.44, H 7.15, N 11.31;

ugotovljeno: C 61,57, H 6,81, N 11,14; in trans-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan]: tal. 137-138 °C.found: C 61.57, H 6.81, N 11.14; and trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane]: m.p. Mp 137-138 ° C.

Analiza izrač. za C^N^.IM H₂O: C 62,71, H 7,06, N 11,55;Analysis of calc. for C ^ N ^ micron H ₂ O: C 62.71, H 7.06, N 11.55;

ugotovljeno: C 62,80, H 6,82, N 11,31.found: C 62.80, H 6.82, N 11.31.

PRIMER 15 cis-[l-acetamido-4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan]EXAMPLE 15 cis- [1-acetamido-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane]

K raztopini cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil-lamina] (0,1 g, 0,32 mmol) v metilen kloridu (2 ml) pri 0 °C pod atmosfero argona dodamo trietil amin (0,044 ml, 0,32 mmol), 4-N,N-dimetilaminopiridin (0,04 g, 0,32 mmol) in ocetni anhidrid (0,06 ml, 0,64 mmol) in zmes pustimo, da se počasi segreje na sobno temperaturo. Po 4,5 h zmes porazdelimo med metilen klorid in nakisano vodo, jo 2-krat ekstrahiramo z metilen kloridom, organski ekstrakt posušimo (kalijev karbonat) in uparimo. Prečiščenje s flash kromatografijo, eluiranje s 5 % metanolom/kloroformom zagotovi belo trdno snov (0,11 g, 96 %): tal. 277-278 °C. Analiza izrač. za C^H^N^: C 70,75, H 7,91, N 7,85;To a solution of cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexylamine] (0.1 g, 0.32 mmol) in methylene chloride (2 ml) at 0 ° C under argon was added triethyl amine (0.044 ml, 0.32 mmol), 4-N, N-dimethylaminopyridine (0.04 g, 0.32 mmol) and acetic anhydride (0.06 ml, 0.64 mmol) and the mixture allowed to settle. slowly warms to room temperature. After 4.5 h, the mixture was partitioned between methylene chloride and acidified water, extracted twice with methylene chloride, the organic extract dried (potassium carbonate) and evaporated. Purification by flash chromatography eluting with 5% methanol / chloroform provided a white solid (0.11 g, 96%): m.p. 277-278 ° C. Analysis of calc. Calcd for C22 H27 N4 O: C 70.75, H 7.91, N 7.85;

ugotovljeno: C 70,61, H 7,82, N 7,51.found: C 70.61, H 7.82, N 7.51.

trans-[l-acetamido-4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksan] (vodimo v odsotnosti trietilamina in 4-N,N-dimetilaminopiridina): vosek.trans- [1-acetamido-4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexane] (conducted in the absence of triethylamine and 4-N, N-dimethylaminopyridine): wax.

Analiza izrač. za C_1?H₁₈F₄N₂O₃: C 54,55, H 4,85, N 7,48;Analysis of calc. for C _1? H ₁₈ F ₄ N ₂ O ₃ : C 54.55, H 4.85, N 7.48;

ugotovljeno: C 54,35, H 4,81, N 7,27.found: C 54.35, H 4.81, N 7.27.

PRIMER 16EXAMPLE 16

Metil N-{cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil}-loksamat]Methyl N- {cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl} -loxamate]

K raztopini cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil-lamina] (0,08 g, 0,25 mmol) in trietilamina (0,039 ml, 0,27 mmol) v metilen kloriduTo a solution of cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl-lamine] (0.08 g, 0.25 mmol) and triethylamine (0.039 ml, 0.27 mmol) in methylene chloride

1,6 mmol) pri 0 °C, pod atmosfero argona dodamo metil oksalilklorid (0,29 ml, 0,25 mmol). Po 0,25 h zmes porazdelimo med metilen klorid in nakisano vodo, jo 2-krat ekstrahiramo z metilen kloridom, organski ekstrakt posušimo (kalijev karbonat) in uparimo. Prečiščenje s flash kromatografijo, eluiranje s 5 % etil acetatom/metilen kloridom zagotovi belo trdno snov (0,09 g, 90 %).1.6 mmol) at 0 ° C, methyl oxalyl chloride (0.29 ml, 0.25 mmol) was added under an argon atmosphere. After 0.25 h, the mixture was partitioned between methylene chloride and acidified water, extracted twice with methylene chloride, the organic extract dried (potassium carbonate) and evaporated. Purification by flash chromatography eluting with 5% ethyl acetate / methylene chloride provided a white solid (0.09 g, 90%).

Na podoben način pripravimo:In a similar way, we prepare:

Metil N-{trans-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil}-loksamat]: olje.Methyl N- {trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl} -loxamate]: oil.

PRIMER 17EXAMPLE 17

N-{cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil}-l-oksamid]N- {cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl} -1-oxamide]

V raztopino metil N-{cis-[4-ciano-4-(3-ciklopentiIoksi-4-metoksifenil) cikloheksil }oksamata] (0,06 g, 0,15 mmol) v metanolu (3 ml), kije v tlačni posodi pri -78 °C, kondenziramo brezvodni amoniak (3 ml). Posodo zapremo, dovolimo da pride na sobno temperaturo in mešamo preko noči. Posodo ohladimo na -78 °C, odpremo in pustimo amoniak, da se upari pri sobni temperaturi. Zmes porazdelimo med kloroform in vodo, jo 2-krat ekstrahiramo s kloroformom, organski ekstrakt posušimo (kalijev karbonat) in uparimo. Trituracija produkta z metilen kloridom/etrom zagotovi belo trdno snov (0,05 g, 88 %): tal. >215 °C.To a solution of methyl N- {cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl} oxamate] (0.06 g, 0.15 mmol) in methanol (3 ml) contained in a pressure vessel at -78 ° C, anhydrous ammonia (3 ml) was condensed. Close the pan, allow to come to room temperature and stir overnight. Cool the vessel to -78 ° C, open and allow the ammonia to evaporate at room temperature. The mixture was partitioned between chloroform and water, extracted twice with chloroform, the organic extract dried (potassium carbonate) and evaporated. Trituration of the product with methylene chloride / ether provided a white solid (0.05 g, 88%): m.p. > 215 ° C.

Analiza izrač. za C₂₁H₂₇N₃O₄: C 65,44, H 7,06, N 10,90;Analysis of calc. for C ₂₁ H ₂₇ N ₃ O ₄ : C 65.44, H 7.06, N 10.90;

ugotovljeno: C 65,24, H 6,77, N 10,72.found: C 65.24, H 6.77, N 10.72.

Na podoben način pripravimo:In a similar way, we prepare:

N-{trans-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil}oksamid];N- {trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl} oxamide];

tal. 130-131 °C.m.p. 130-131 ° C.

Analiza izrač. za C₁₇H_1?F₄N₃O₄: C 50,63, H 4,25, N 10,42;Analysis of calc. for C ₁₇ H _1? F ₄ N ₃ O ₄ : C 50.63, H 4.25, N 10.42;

ugotovljeno: C 50,77, H 4,32, N 10,33.found: C 50.77, H 4.32, N 10.33.

PRIMER 18EXAMPLE 18

N-{cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil}-l-oksamska kislinaN- {cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl} -1-oxamic acid

Raztopino metil N-{cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksil}-loksamataj (0,05 g, 0,12 mmol) v metanolu (1 ml), tetrahidrofurana (1 ml) in vode pri sobni temperaturi mešamo 3 h z granulo natrijevega hidroksida. Topila odstranimo, ostanek raztopimo v metanolu in nakisamo s 3 N klorovodikovo kislino. Trdno snov zberemo in speremo z etrom, da zagotovimo belo trdno snov (0,03 g, 62 %): tal. 78-83 °C.A solution of methyl N- {cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexyl} -loxamate (0.05 g, 0.12 mmol) in methanol (1 ml), tetrahydrofuran (1 ml) and water was stirred at room temperature for 3 h with sodium hydroxide granules. The solvents were removed, the residue was dissolved in methanol and acidified with 3 N hydrochloric acid. The solid was collected and washed with ether to provide a white solid (0.03 g, 62%): m.p. 78-83 ° C.

Analiza izrač. za C₁₇H₁₆F₄N₂O₅.H₂O: C 48,34, H 4,30, N 6,63;Analysis of calc. for C ₁₇ H ₁₆ F ₄ N ₂ O ₅ .H ₂ O: C 48.34, H 4.30, N 6.63;

ugotovljeno: C 48,34, H 4,30, N 6,46.found: C 48.34, H 4.30, N 6.46.

PRIMER 19 cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-metoksicikloheksanj cis-[4-ciano-4-(3-ciklopentiIoksi-4-metoksifenil)cikloheksan-l-olj (0,17 g, 0,5 mmol), metil jodid (1 ml) in srebrov oksid (0,19 g, 0,8 mmol) v acetonitrilu (1 ml) pod atmosfero argona refluktiramo v temi preko noči. Zmes ohladimo, trdno snov odstranimo s filtracijo in filtrat uparimo. Ostanek prečistimo s flash kromatografijo., eluiramo z 2:1 heksani/etil acetatom, da zagotovimo olje (0,12 g, 66 %).EXAMPLE 19 cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-methoxycyclohexane cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-oil (0, 17 g, 0.5 mmol), methyl iodide (1 ml) and silver oxide (0.19 g, 0.8 mmol) in acetonitrile (1 ml) were refluxed overnight under argon. The mixture was cooled, the solid was removed by filtration and the filtrate was evaporated. The residue was purified by flash chromatography eluting with 2: 1 hexanes / ethyl acetate to provide an oil (0.12 g, 66%).

Analiza izrač. za C₁₆H_1?F₄NO₃: C 55,33, H 4,93, N 4,03; ugotovljeno: C 55,33, H 4,91, N 3,77.Analysis of calc. for C ₁₆ H _1? F ₄ NO ₃ : C 55.33, H 4.93, N 4.03; found: C 55.33, H 4.91, N 3.77.

Na podoben način pripravimo:In a similar way, we prepare:

trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-metoksicikloheksan]: olje. Analiza izrač. za C₁₆H_1?F₄NO₃: C 55,33, H 4,93, N 4,03; ugotovljeno: C 55,44, H 4,86, N 3,97.trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-methoxycyclohexane]: oil. Analysis of calc. for C ₁₆ H _1? F ₄ NO ₃ : C 55.33, H 4.93, N 4.03; found: C 55.44, H 4.86, N 3.97.

PRIMERA 20 IN 21 cis in trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-(N-hidroksiamino)cikloheksanjEXAMPLE 20 IN 21 cis and trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (N-hydroxyamino) cyclohexane

K raztopini 4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-on-oksima (0,42 g, 1,27 mmol) in sledi metil orangea v metanolu (5 ml) dodamo pri sobni temperaturi pod atmosfero argona en del natrijevega cianoborohidrida (0,054 g, 0,85 mmol), čemur sledi takojšnje dodajanje po kapljicah z vodikovim kloridom nasičenega metanola, da dobimo in vzdržujemo temno rdečo barvo. Po 1,5 h dodamo vodo in 15 %-ni vodni natrijev hidroksid (do pH >9), zmes 3-krat ekstrahiramo z metilen kloridom, organski ekstrakt posušimo (kalijev karbonat) in uparimo. Prečiščenje s flash kromatografijo, eluiranje s 50 % etil acetatom/heksani zagotovi cis izomer kot belo trdno snov (0,11 g, 27 %): tal. 103-104 °C.To a solution of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one-oxime (0.42 g, 1.27 mmol) followed by methyl orange in methanol (5 ml) was added at room temperature under argon atmosphere one part of sodium cyanoborohydride (0.054 g, 0.85 mmol) followed by immediate dropwise addition of saturated methanol with hydrogen chloride to give and maintain a dark red color. After 1.5 h, water and 15% aqueous sodium hydroxide (up to pH> 9) were added, the mixture was extracted 3 times with methylene chloride, the organic extract was dried (potassium carbonate) and evaporated. Purification by flash chromatography eluting with 50% ethyl acetate / hexanes provided the cis isomer as a white solid (0.11 g, 27%): m.p. 103-104 ° C.

Analiza izrač. za C^N^IM H₂O: C 68,14, H 7,98, N 8,36;Analysis of calc. for C ^ N ^ IM H ₂ O: C 68.14, H 7.98, N 8.36;

ugotovljeno: C 67,95, H 7,81, N 8,23.found: C 67.95, H 7.81, N 8.23.

Izoliramo tudi trans izomer kot belo trdno snov (0,08 g, 20 %): tal. 150-151 °C. Analiza izrač. za C₁₉H₂₆N₂O₃.l/4 H₂O: C 68,14, H 7,98, N 8,36; ugotovljeno: C 68,22, H 7,81, N 8,20.The trans isomer is also isolated as a white solid (0.08 g, 20%): m.p. 150-151 ° C. Analysis of calc. for C ₁₉ H ₂₆ N ₂ O ₃ .l / 4 H ₂ O: C 68.14, H 7.98, N 8.36; found: C 68.22, H 7.81, N 8.20.

Na podoben način pripravimo:In a similar way, we prepare:

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)-l-(N-hidroksiamino)cikloheksan]: pena. Analiza izrač. za CjgH^N^.lM H₂O: C 67,37, H 7,69, N 8,73; ugotovljeno: C 67,09, H 7,45, N 8,45;cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (N-hydroxyamino) cyclohexane]: foam. Analysis of calc. for C 18 H ₁₆ N 4 N 1 H ₂ O: C 67.37, H 7.69, N 8.73; found: C 67.09, H 7.45, N 8.45;

trans-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)-l-(N-hidroksiamino)cikloheksan]: tal. 142,5-144,5 °C. Analiza izrač. za C^H^N^.lM H₂O:trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (N-hydroxyamino) cyclohexane]: m.p. 142.5-144.5 ° C. Analysis of calc. for C ^ H ^ N ^ .lM H ₂ O:

C 67,37, H 7,69, N 8,73;C 67.37, H 7.69, N 8.73;

ugotovljeno: C 67,26, H 7,47, N 8,33.found: C 67.26, H 7.47, N 8.33.

cis-[4-ciano-4-(3-{4-fluorobenzil}-4-metoksifenil)-l-(N-hidroksiamino)cikloheksan]: tal. 118-120 °C. Analiza izrač. za C₂₁H₂₃FN₂O₃.0,45 H₂O: C 66,63, H 6,36, N 7,40; ugotovljeno: C 66,63, H 6,26, N 7,22; in trans-[4-ciano-4-(3-{4-fluorobenzil}-4-metoksifenil)-l-(N-hidroksiamino)cikloheksan]; tal. 135-136 °C.cis- [4-cyano-4- (3- {4-fluorobenzyl} -4-methoxyphenyl) -1- (N-hydroxyamino) cyclohexane]: m.p. 118-120 ° C. Analysis of calc. for C ₂₁ H ₂₃ FN ₂ O ₃ .0.45 H ₂ O: C 66.63, H 6.36, N 7.40; found: C 66.63, H 6.26, N 7.22; and trans- [4-cyano-4- (3- {4-fluorobenzyl} -4-methoxyphenyl) -1- (N-hydroxyamino) cyclohexane]; m.p. Mp 135-136 ° C.

Postopki za zdravljenjeTreatment procedures

Za uporabo spojine s formulo (I) ali njene farmacevtsko sprejemljive soli za zdravljenje ljudi in drugih sesalcev jo normalno formuliramo v skladu s standardno farmacevtsko prakso kot farmacevtski pripravek. Spojine s formulo (I) ali njihovo farmacevtsko sprejemljivo sol lahko uporabimo pri izdelavi zdravila za profilaktično ali terapevtsko zdravljenje katerega koli bolezenskega stanja pri človeku ali drugem sesalcu, ki se posreduje z inhibicijo PDEIV, kot so, vendar neomejujoče, astma, alergijske ali vnetne bolezni. Spojine s formulo (I) dajemo v količini, ki je zadostna za zdravljenje take bolezni pri človeku ali drugem sesalcu.For the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical preparation. The compounds of formula (I) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease condition in a human or other mammal mediated by PDEIV inhibition, such as, but not limited to, asthma, allergic or inflammatory diseases . The compounds of formula (I) are administered in an amount sufficient to treat such a disease in a human or other mammal.

Postopek za zdravljenje in kontroliranje človeka, okuženega s HIV, ki kaže imunsko disfunkcijo, ali problemov, ki so povezani z boleznijo, ki jo posredujejo citokini, opisuje Hanna v WO 90/15534, 27. dec 1990. Na splošno lahko uporabimo enak režim začetnega zdravljenja, kot je tisti, za katerega je znano, da je učinkovit pri motenju aktivnosti TNF pri drugih bolezenskih stanjih, ki jih posreduje TNF, s spojinami s formulo (I). Zdravljene osebe bomo redno kontrolirali na število celic T in razmeije T4/T8 in/ali na merila viremije, kot so nivoji reverzne transkriptaze ali virusnih proteinov in/ali na napredovanje problemov, ki so povezani z boleznijo, ki jo posredujejo monokini, kot je kaheksija ali mišična degeneracija. Če po normalnem režimu zdravljenja ni opaziti učinka, zvečamo množino dajanega sredstva, ki moti aktivnost monokina, npr. za 50 % tedensko.A process for treating and controlling an HIV-infected person exhibiting immune dysfunction or problems associated with cytokine-mediated disease is described by Hanna in WO 90/15534, Dec 27, 1990. In general, the same initial regimen can be used treatments such as that known to be effective in disrupting TNF activity in other TNF-mediated disease states with compounds of formula (I). Treatment subjects will be monitored regularly for T cell counts and T4 / T8 deletions and / or for viremia criteria such as reverse transcriptase or viral protein levels and / or for progression of problems associated with a monokine-mediated disease such as cachexia or muscular degeneration. If no effect is observed after the normal treatment regimen, the amount of agent administered that disrupts monokine activity is increased, e.g. 50% weekly.

Farmacevtski sestavek v smislu predloženega izuma bo vključeval unčikovito netoksično količino spojine s formulo (I) in farmacevtsko sprejemljiv nosilec ali razredčilo. Spojine s formulo (I) dajemo v običajnih dozirnih oblikah pripravljenih s kombiniranjem spojine s formulo (I) v količini dovoljšni, da ima inhibitorsko delovanje na TNF tvorbo, s standardnimi farmacevtskimi nosilci po običajnih postop37 kih. Ti postopki lahko vključujejo mešanje, granuliranje in stiskanje ali raztapljanje sestavin kot je primerno za želen sestavek.The pharmaceutical composition of the present invention will include a non-toxic non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. The compounds of formula (I) are administered in conventional dosage forms prepared by combining a compound of formula (I) in an amount sufficient to have an inhibitory effect on TNF formation, using standard pharmaceutical carriers according to conventional procedures. These processes may include mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired composition.

Tako, če uporabimo trden nosilec, lahko pripravek tabletiramo, damo v trdo želatinasto kapsulo v obliki praška ali peleta, ali v obliki pastile. Količina trdnega nosilca široko variira, toda prednostno bo od okoli 25 mg do okoli 1 g. Kadar uporabimo tekoč nosilec, bo pripravek v obliki sirupa, emulzije, mehke želatinaste kapsule, sterilne injekcijske tekočine, kot je ampula ali navadna tekoča suspenzija. Kjer je sestavek v obliki kapsule, je primerna katerakoli rutinska zakapsulacija, npr. z uporabo prej omenjenih nosilcev v trdni želatinasti kapsulski lupini. Kjer je sestavek v obliki kapsule z mehko želatinasto lupino, lahko pride v poštev kakršenkoli farmacevtski nosilec, ki ga običajno uporabljamo za pripravo disperzij ali suspenzij, npr. vodni gumiji, celuloze, silikati ali olja, in jih (so) vključimo v mehko želatinasto kapsulsko lupino. Pripravek sirupa splošno sestoji iz suspenzije ali raztopine spojine ali soli v tekočem nosilcu, npr. etanolu, glicerinu ali vodi z aromatičnim ali barvalnim sredstvom.Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in lozenge form. The amount of solid carrier varies widely, but will preferably be from about 25 mg to about 1 g. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable fluid such as an ampoule or ordinary liquid suspension. Where the composition is in capsule form, any routine encapsulation, e.g. using the aforementioned carriers in a solid gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier that is typically used to prepare dispersions or suspensions, e.g. aqueous gums, celluloses, silicates or oils, and (are) incorporated into the soft gelatin capsule shell. The syrup preparation generally consists of a suspension or solution of a compound or salt in a liquid carrier, e.g. ethanol, glycerin or water with a flavoring or coloring agent.

Dnevni dozirni režim za oralno dajanje je primerno okoli 0,001 mg/kg do 100 mg/kg, prednostno 0,01 mg/kg do 40 mg/kg spojine s formulo (I) ali njene farmacevtsko sprejemljive soli preračunano na prosto bazo. Aktivno sestavino lahko dajemo od 1 do 6 krat dnevno da se pokaže delovanje.A daily dosage regimen for oral administration is suitably about 0.001 mg / kg to 100 mg / kg, preferably 0.01 mg / kg to 40 mg / kg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof calculated on a free base. The active ingredient can be administered from 1 to 6 times daily to show activity.

Medtem ko je možno, da aktivno sestavino dajemo čisto, je prednostno, da je prisotna kot farmacevtski pripravek. Aktivna sestavina lahko vključuje, za lokalno dajanje, od 0,001 % do 10 % m/m, npr. od 1 mas.% do 2 mas.% pripravka, čeprav lahko vključuje tudi celo 10 % m/m, toda prednostno ne nad 5 % m/m, in bolj prednostno od 0,1 % do 1 % m/m pripravka.While it is possible to administer the active ingredient purely, it is preferable that it be present as a pharmaceutical preparation. The active ingredient may include, for topical administration, from 0.001% to 10% w / w, e.g. from 1% to 2% by weight of the preparation, although it may also include as much as 10% w / w, but preferably not more than 5% w / w, and more preferably from 0.1% to 1% w / w of the preparation.

Pripravki v smislu predloženega izuma vključujejo aktivno sestavino skupaj z njenim enim ali več sprejemljivimi nosilci in v danem primeru katerokoli drugo terapevtsko sestavino(e), Nosilec(ci) mora biti sprejemljiv v smislu, da je kompatibilen z ostalimi sestavinami pripravka in ni škodljiv njegovemu recipientu.The compositions of the present invention include the active ingredient together with one or more acceptable carriers, and optionally any other therapeutic ingredient (s), The carrier (s) must be acceptable in that it is compatible with the other ingredients of the preparation and is not detrimental to its recipient .

Strokovnjak mora upoštevati, da je oblika in značaj farmacevtsko sprejemljivega nosilca ali razredčila pogojen s količino aktivne sestavine s katero ga kombiniramo, načino dajanja in drugimi, dobro znanimi spremenljivkami.One of skill in the art will appreciate that the form and character of the pharmaceutically acceptable carrier or diluent is contingent on the amount of active ingredient with which it is combined, the route of administration and other well known variables.

Primeri uporabnostiUsability examples

PRIMER AEXAMPLE A

Inhibitorni učinek spojin s formulo (I) na in vitro tvorbo TNF v humanih monocitih.Inhibitory effect of compounds of formula (I) on the in vitro formation of TNF in human monocytes.

Inhibitorni učinek spojin s formulo (I) na in vitro tvorbo TNF v humanih monocitih lahko določimo s predpisom, kot opisujejo Badger et al., objavljena EPO prijava 0 411754 A2,6. februar 1991, in Hanna, WO 90/15534,27. dec. 1990.The inhibitory effect of compounds of formula (I) on the in vitro formation of TNF in human monocytes can be determined by regulation, as described by Badger et al., EPO Publication No. 0 411754 A2,6 published. February 1991, and Hanna, WO 90 / 15534.27. Dec. 1990.

PRIMER BEXAMPLE B

Za določitev in vivo aktivnosti TNF za spojine s formulo (I) smo uporabili dva modela endotoksičnega šoka. Predpis, ki smo ga uporabili v teh modelih, opisujejo Badger et al., objavljena EPO prijava 0 411 754 A2, 6. februar 1991, in Hanna, WO 90/15534, 27. dec. 1990.Two endotoxic shock models were used to determine the in vivo activity of TNF for compounds of formula (I). The regulation used in these models is described by Badger et al., Published EPO application 0 411 754 A2, February 6, 1991, and Hanna, WO 90/15534, December 27. 1990.

Spojine, prikazane tukaj s primeri, so pokazale pozitiven odziv in vivo s tem, da so zmanjšale nivoje TNF v serumu, inducirane z injiciranjem endotoksina.The compounds shown here with the examples showed a positive response in vivo by reducing serum TNF levels induced by endotoxin injection.

Ne pričakujemo toksičnih učinkov, kadar te spojine dajemo v skladu s predloženim izumom.No toxic effects are expected when these compounds are administered in accordance with the present invention.

PRIMER CEXAMPLE C

Izolacija izocimov PDEIsolation of PDE isozymes

Inhibitorni učinek spojin s formulo (I) na fosfodiesterazo in njihovo selektivnost lahko določimo z uporabo skupine petih različnih izocimov PDE. Tkiva, ki smo jih uporabili kot vir različnih izocimov, so tale: 1) PDE Ib, prašičja aorta; 2) PDE lc, budrino srce; 3) PDE III, budrino srce; 4) PDE IV, humani monocit; in 5) PDE V (imenovan tudi la), pasja traheja. PDE la, Ib, lc in III delno očistimo z uporabo standardnih kromatografskih tehnik [Torphy in Cieslinski, Mol. Pharmacol., 37:206214, 1990]. PDE IV očistimo do kinetične homogenosti z zaporedno uporabo anionske izmenjave, kiji sledi kromatografija s heparin-Sepharoso [Torphy et al., J. Biol. Chem., 267:1798-1804,1992].The inhibitory effect of the compounds of formula (I) on phosphodiesterase and their selectivity can be determined using a group of five different PDE isozymes. The tissues used as the source of the various isozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE lc, bud heart; 3) PDE III, bud heart; 4) PDE IV, human monocyte; and 5) PDE V (also called la), a canine trachea. The PDEs of 1a, Ib, 1c and III are partially purified using standard chromatographic techniques [Torphy and Cieslinski, Mol. Pharmacol., 37: 206214, 1990]. PDE IV is purified to kinetic homogeneity by sequential use of anion exchange followed by heparin-Sepharosa chromatography [Torphy et al., J. Biol. Chem., 267: 1798-1804, 1992].

Aktivnost fosfodiesteraze testiramo tako, kot opisujeta v predpisu Torphy in Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Dokazali smo pozitivne vrednosti IC₅₀ v nanomolarnem do μΜ območju za spojine s formulo (I) iz tukaj opisanih izvedbenih primerov.Phosphodiesterase activity is assayed as described in Torphy and Cieslinski, Mol. Pharmacol., 37: 206-214, 1990. Positive IC ₅₀ values in the nanomolar to μΜ range for the compounds of formula (I) from the embodiments described herein have been demonstrated.

PRIMER DEXAMPLE D

Sposobnost izbranih inhibitorjev PDE IV, da povečajo nabiranje cAMP v nepoškodovanih tkivih, določimo ob uporabi celic U-937, linije humanih monocitov, za katero se je pokazalo, da vsebuje veliko količino PDE IV. Da bi določili aktivnost inhibicije PDE IV v nepoškodovanih celicah, smo nediferencirane celice U-937 (približno 10⁵ celic/epruveto) inkubirali z različnimi koncentracijami (0,01 do 1000 μΜ) inhibitorjev PDE eno minuto in 1 μΜ prostaglandina E2 še štiri minute. Pet minut po sproženju reakcije smo celice lizirali z dodatkom 17,5 %-ne perklorove kisline, z dodatkom 1 M kalijevega karbonata smo nevtralizirali pH in vsebnost cAMP določili z RIA. Splošen predpis za ta test je opisan v Brooker et ah, Radioimmunassay of cyclic AMP and cyclic GMP. Adv. Cyclic Nucleotide Res., 10:1-33, 1979. Spojine iz izvedbenih primerov, kot so tu opisane za formulo (I), so v gornjem testu pokazale pozitivne vrednosti EC_S0 νμΜ območju.The ability of selected PDE IV inhibitors to increase cAMP accumulation in intact tissues was determined using U-937 cells, a human monocyte lineage that has been shown to contain a large amount of PDE IV. To determine PDE IV inhibition activity in intact cells, undifferentiated U-937 cells (approximately 10 ⁵ cells / tube) were incubated with different concentrations (0.01 to 1000 μΜ) of PDE inhibitors for one minute and 1 μΜ of prostaglandin E2 for another four minutes. Five minutes after initiation of the reaction, cells were lysed by the addition of 17.5% perchloric acid, pH 1 was neutralized by the addition of 1 M potassium carbonate, and the cAMP content was determined by RIA. The general regulation for this test is described in Brooker et ah, Radioimmunassay of cyclic AMP and cyclic GMP. Adv. Cyclic Nucleotide Res., 10: 1-33, 1979. Compounds of embodiments as described herein for formula (I) showed positive EC _S0 νμΜ range in the above test.

Claims

PATENTNI ZAHTEVKIPATENT APPLICATIONS

1. Spojina s formulo (I):A compound of formula (I):

(R₂)s (I)(R ₂ ) with (I)

-(CR₄R_s)_nO(CR₄R₅)_mR₆, ali -(CR₄R₅)_rR₆, kjer so lahko alkilni deli v danem primeru substituiranimi z enim ali več halogeni; je m 0 do 2;- (CR ₄ R _s) _n O (CR ₄ R ₅₎ _m R _6, or - (CR ₄ R ₅₎ _r R ₆ wherein the alkyl moieties are optionally substituted with one or more halogens; m is 0 to 2;

je n 1 do 4;n is 1 to 4;

je r 1 do 6;r is 1 to 6;

je R₆ vodik, metil, hidroksil, aril, halo substituiran aril, ariloksiC₁₃alkil, halo substituiran ariloksiCj ₃alkil, indanil, indenil, C_{? n}policikloalkil, tetrahidrofuranil, furanil, tetrahidropiranil, piranil, tetrahidrotienil, tienil, tetrahidrotiopiranil, tiopiranil, C_{3 6}cikloalkil ali C_{4 6}cikloalkil, ki vsebuje eno ali dve nenasičeni vezi, kjer so cikloalkilni in heterociklični deli lahko v danem primeru substituirani z 1 do 3 metilnimi skupinami ali eno etilno skupino;R _{6 is} hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC ₁₃ alkyl, halo substituted aryloxyC _1-3 alkyl, indanyl, indenyl, C _{? n} polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C _{3 6} cycloalkyl or C _{4 6} cycloalkyl containing one or two unsaturated bonds, where cycloalkyl and heterocyclic moieties may optionally be substituted by 1 case up to 3 methyl groups or one ethyl group;

pod pogojem, daprovided that

e) kadar je n 1 in je m 0, potem je R₆ drugačen od H ve) when n is 1 and m is 0, then R _{6 is} different from H in

-(CR₄R₅)nO(CR₄R₅)_mR₆;- (CR ₄ R ₅ ) nO (CR ₄ R ₅ ) _m R ₆ ;

X je YR₂, halogen, nitro, NR₄R₅ ali formil amin; Yje O ali S(O)_m>;X is YR ₂ , halogen, nitro, NR ₄ R ₅ or formyl amine; Y is O or S (O) _m> ;

m’ je število, ki ima vrednost 0,1 ali 2;m 'is a number having a value of 0.1 or 2;

XJe O ali NR_g;X is O or NR _g ;

X₃ je vodik ali X;X ₃ is hydrogen or X;

R₂ je neodvisno izbran iz -CH₃ ali -CH₂CH₃, v danem primeru substituiran z 1 ali več halogeni; s je Odo 4;R ₂ is independently selected from -CH ₃ or -CH ₂ CH ₃ optionally substituted by 1 or more halogens; s is Odo 4;

R₃ je vodik, halogen, C_walkil, CH₂NHC(O)C(O)NH2, halo-substituiran CMalkil, -CH=CR₈,R_g„ ciklopropil v danem primeru substituiran z R_g), CN, OR_g, CH^ORg, NR_gR₁₀, CH^NRgR^, C(Z’)H, C(O)OR_g, C(O)NR_gR₁₀ ali C=CR_g);R ₃ is hydrogen, halogen, C _w alkyl, CH ₂ NHC (O) C (O) NH 2, halo-substituted CMalkyl, -CH = CR ₈ , R _g 'cyclopropyl optionally substituted by R _g) , CN, OR _g , CH ^ ORg, NR _g R ₁₀ , CH ^ NRgR ^, C (Z ') H, C (O) OR _g , C (O) NR _g R ₁₀ or C = CR _g) ;

Z’je O, NR₉, NOR_g, NCN, C(-CN)₂, CR_gCN, CR_gNO₂, CR_gqO)OR_g, CR_gC(O)NR_gR_g, C(-CN)NO₂, C(-CN)C(O)OR₉, ali C(-CN)C(O)NR_gR_g;Z'is O, NR ₉ , NOR _g , NCN, C (-CN) ₂ , CR _g CN, CR _g NO ₂ , CR _g qO) OR _g , CR _g C (O) NR _g R _g , C (- CN) NO ₂ , C (-CN) C (O) OR ₉ , or C (-CN) C (O) NR _g R _g ;

Zje OR₁₄, OR₁₅, SR₁₄, S(O)_m,R₇, S(O)₂NR_1QR₁₄, NR_1QR₁₄, NR₁₄C(O)R₉, NR₁₀C(Y’)R₁₄, NR₁₀C(O)OR₇, NR_1oC(Y’)NR_1oR₁₄, nr₁₀s(O)₂nr₁₀r₁₄, NR_1oC(NCN)NR_1oR₁₄, NR₁₀S(O)₂R₇, NR_wC(CR₄NO₂)NR₁₀R₁₄,Z is OR ₁₄ , OR ₁₅ , SR ₁₄ , S (O) _m , R ₇ , S (O) ₂ NR _1Q R ₁₄ , NR _1Q R ₁₄ , NR ₁₄ C (O) R ₉ , NR ₁₀ C (Y ') R _14, NR ₁₀ C (O) OR _7, NR _1o C (Y ') NR _1o R _14, NR ₁₀ S (O) ₂ NR ₁₀ R _14, NR _1o C (NCN) NR _1o R _14, NR ₁₀ S (O) ₂ R ₇ , NR _w C (CR ₄ NO ₂ ) NR ₁₀ R ₁₄ ,

NR_1oC(NCN)SR₉, NR₁₀C(CR₄NO₂)SR₉, NR_wC(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄ ali NR₁₀C(O)C(O)OR₁₄;NR ₁₀ C (NCN) SR ₉ , NR ₁₀ C (CR ₄ NO ₂ ) SR ₉ , NR _w C (NR ₁₀ ) NR ₁₀ R ₁₄ , NR ₁₀ C (O) C (O) NR ₁₀ R ₁₄ or NR ₁₀ C (O) C (O) OR ₁₄ ;

Y’jeOaliS;Y'jeOaliS;

R₇ je -(CR₄R₅)_qR₁₂ ali CMalkil, kjer je R₁₂ ali C^alkilna skupina v danem primeru substituirana enkrat ali večkrat s Cj ₂alkilom, v danem primeru substituirana z enim do tremi kot so fluori, -F, -Br, -Cl, -NO₂, -NR₁₀R_n, -C(O)R_g, -C(O)OR_g, -OR_g,-CN,R ₇ is - (CR ₄ R ₅ ) _q R ₁₂ or C 1-4 alkyl, wherein R ₁₂ or a C 1-6 alkyl group is optionally substituted one or more times with C _1-2 alkyl, optionally substituted by one to three such as fluorine, - F, -Br, -Cl, -NO ₂ , -NR ₁₀ R _n , -C (O) R _g , -C (O) OR _g , -OR _g , -CN,

-C(O)NR₁₀R_n, -OC(O)NR₁₀R_n, -OC(O)R_g, -NR₁₀C(O)NR₁₀R_n, -NR₁₀C(O)R_n, -NR₁₀C(O)OR₉, -NR₁₀C(O)R₁₃, -C(NR₁₀)NR₁₀R_n, -C(NCN)NR₁₀R_n, -C(NCN)SR₉, -NR₁₀C(NCN)SR₉, -NR₁₀C(NCN)NR₁₀R_n, -NR_1QS(O)₂R₉, -S(O)_m.R₉, -NR₁₀C(O)C(O)NR₁₀R_n, -NR₁₀C(O)C(O)R₁₀, tiazolil, imidazolil, oksazolil, pirazolil, triazolil ali tetrazolil;-C (O) NR ₁₀ R _n , -OC (O) NR ₁₀ R _n , -OC (O) R _g , -NR ₁₀ C (O) NR ₁₀ R _n , -NR ₁₀ C (O) R _n , -NR ₁₀ C (O) OR ₉ , -NR ₁₀ C (O) R ₁₃ , -C (NR ₁₀ ) NR ₁₀ R _n , -C (NCN) NR ₁₀ R _n , -C (NCN) SR ₉ , - NR ₁₀ C (NCN) SR ₉ , -NR ₁₀ C (NCN) NR ₁₀ R _n , -NR _1Q S (O) ₂ R ₉ , -S (O) _m .R ₉ , -NR ₁₀ C (O) C (O) NR ₁₀ R _n , -NR ₁₀ C (O) C (O) R ₁₀ , thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl or tetrazolyl;

q je 0,1 ali 2;q is 0.1 or 2;

Rg je neodvisno izbran iz vodika ali R₉;R 8 is independently selected from hydrogen or R ₉ ;

Rg, je Rg ali fluor;R 8 is R 8 or fluorine;

R₉ je C_Malkil, v danem primeru substituiran z enim do tremi fluori;R ₉ is C _M alkyl, optionally substituted with one to three fluorines;

^RioJ^{e OR}s ^{ali R}n» ^R ioJ ^{e OR} s ^{or R} n »

R_n je vodik, ali C_Malkil, v danem primeru substituiran z enim do tremi fluori;R _n is hydrogen or C _M alkyl, optionally substituted with one to three fluorines;

ali, kadar sta R₁₀ in R_n kot NR₁₀R_n, lahko skupaj z dušikom tvorita 5 do 7 členski obroč, ki v danem primeru vsebuje vsaj en dodaten heteroatom izbran iz O, N ali S;or, when R ₁₀ and R _{n are} NR ₁₀ R _n , together with nitrogen, they may form a 5 to 7 membered ring, optionally containing at least one additional heteroatom selected from O, N or S;

R₁₃ je oksazolidinil, oksazolil, tiazolil, pirazolil, triazolil, tetrazolil, imidazolil, imidazolidinil, tiazolidinil, izoksazolil, oksadiazolil ali tiadiazolil in je vsak od teh heterocikličnih obročev povezan preko ogljikovega atoma in vsak je lahko nesubstituiran ali substituiran z enim ali dvema C₁₂alkilnima skupinama;R ₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted with one or two C ₁₂ alkyl groups;

R₁₄ je vodik ali R_?; ali, kadar sta R_J0 in R₁₄ kot NR₁₀R₁₄, lahko skupaj z dušikom tvorita 5 do 7 členski obroč, ki v danem primeru vsebuje enega ali več dodatnih heteroatomov izbranih iz O, N ali S;R ₁₄ is hydrogen or R _? ; or, when R ₁₀ and R _{14 are} NR ₁₀ R ₁₄ , together with nitrogen, they may form a 5 to 7 membered ring, optionally containing one or more additional heteroatoms selected from O, N or S;

f) kadar je Z OH, X YR₂, Y kisik, X₂ kisik, X₃ vodik, s 0, R₂ CH₃ v YR₂, in je Rj CH₃, potem je R₃ drugačen od CN ali COOH;f) when Z is OH, X YR ₂ , Y is oxygen, X _{2 is} oxygen, X _{3 is} hydrogen, with 0, R _{2 is} CH ₃ in YR ₂ , and R 1 is CH ₃ , then R _{3 is} different from CN or COOH;

g) kadar je Z OH ali OCH₃, X₂ kisik, X_₃ vodik, s 0, in je X YR₂, potem je R₃drugačen od H;g) when Z is OH or OCH ₃ , X _{2 is} oxygen, X_ _{3 is} hydrogen, s 0, and X is YR ₂ , then R _{3 is} other than H;

h) kadar je Z OS(O)₂C_walkil ali OS(O)₂aril, X₂ kisik, X^ vodik, s 0, potem je R₃ drugačen od OR_g;h) when Z is OS (O) ₂ C _w alkyl or OS (O) ₂ aryl, X ₂ oxygen, X ₂ hydrogen, s 0, then R _{3 is} different from OR _g ;

j) kadar je Z OH ali OSO₂R₇ in je R₃ CH₃, CHOH ali CH₂OC₁₃alkil, potem R^ ni Cj ₃alkoksi in X ni halogen, metoksi, etoksi, metiltio ali etiltio; alij) when Z is OH or OSO ₂ R ₇ and R _{3 is} CH ₃ , CHOH or CH ₂ OC ₁₃ alkyl, then R 4 is not C _1-3 alkoxy and X is not halogen, methoxy, ethoxy, methylthio or ethylthio; or

k) kadar je Z NH₂, NH(C₁_₃alkil), N(C₁₃alkil)₂, NH(CH₂)_{2 5}C(O)Ar, kjer je Ar naftil ali fenil ali je Z nesubstituiran ali substituiran pirolidinil, piperidinil, morfolinil ali piperazinil in je R₃ CH₃, CHOH ali CIT₂OCj ₃alkil, potem RjX₂ nik) when Z is NH _2, NH (C ₁ _ ₃ alkyl), N _(C13 alkyl) _2, NH (CH ₂₎ _{2 5} C (O) Ar, wherein Ar is naphthyl or phenyl or Z is unsubstituted or substituted pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl and R _{3 is} CH ₃ , CHOH or CIT ₂ OC ₃ alkyl, then R 1 X ₂ is not

C j ₃alkoksi in X ni halogen, metoksi, etoksi, metiltio ali etiltio; ali njene farmacevtsko sprejemljive soli.C _1-3 alkoxy and X is not halogen, methoxy, ethoxy, methylthio or ethylthio; or a pharmaceutically acceptable salt thereof.

2. Spojina po zahtevku 1, označena s tem, da ima strukturo s formulo (Ia) kjer:A compound according to claim 1, characterized in that it has a structure of formula (Ia) wherein:

je Rj -CH₂-ciklopropil, -CH₂-C₅^-cikloalkil, -C₄^cikloalkil, C_{7 n}policikloalkil, (3- ali 4-ciklopentenil), fenil, tetrahidrofuran-3-il, benzil ali C₁₂alkil v danem primeru substituiran z 1 ali več fluori, -(CH₂)₁₃C(O)O(CH₂)_{)2CH₃,R 1 is -CH ₂ -cyclopropyl, -CH ₂ -C ₅ -cycloalkyl, -C ₄ cycloalkyl, C _{7 n} polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C ₁₂ alkyl optionally substituted by 1 or more fluorine, - (CH ₂ ) ₁₃ C (O) O (CH ₂ ) _{{) 2} CH ₃ ,

-(CHJj^O^^CH, in -(CH^OH;- (CHJj ^ O ^^ CH, and - (CH ^ OH;

m je 0 do 2;m is 0 to 2;

n je 1 do 4;n is 1 to 4;

rje 1 do 6;r is 1 to 6;

je R₆ vodik, metil, hidroksil, aril, halo substituiran aril, ariloksiC₁₃alkil, halo substituiran ariloksiCj ₃alkil, indanil, indenil, C_{? n}policikloalkil, tetrahidrofuranil, furanil, tetrahidropiranil, piranil, tetrahidrotienil, tienil, tetrahidrotiopiranil, tiopiranil, C₃^cikloalkil ali C₄^cikloalkil, ki vsebuje eno ali dve nenasičeni vezi, kjer so cikloalkilni in heterociklilni deli lahko v danem primeru substituirani z 1 do 3 metilnimi skupinami ali eno etilno skupino;R _{6 is} hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC ₁₃ alkyl, halo substituted aryloxyC _1-3 alkyl, indanyl, indenyl, C _{? n} polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C ₃ ^ cycloalkyl, or C ₄ ^ cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted with 1 up to 3 methyl groups or one ethyl group;

pod pogojem, da:provided that:

d) kadar je R₆ 2-tetrahidropiranil, 2-tetrahidrotiopiranil, 2-tetrahidrofuranil alid) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or

2-tetrahidrotienil, potem je r 1 do 6;2-tetrahydrothienyl, then r is 1 to 6;

e) kadar je n 1 in je m 0; potem je R₆ drugačen od H v -(CR₄R₅)_nO(CR₄R₅)_mR₆;e) when n is 1 and m is 0; then R _{6 is} other than H in - (CR ₄ R ₅ ) _n O (CR ₄ R ₅ ) _m R ₆ ;

X je YR₂’ h^al°8^en> nitro, NR₄R₅ ali formil amin;X is YR ₂ 'h ^a l ° 8 ^en > nitro, NR ₄ R ₅ or formyl amine;

Y je O ali S(O)_m,;Y is O or S (O) _m ,;

m’je 0,1 ali 2;m is 0.1 or 2;

R₃ je vodik, C_Malkil, CH2NHC(O)C(O)NH₂, halo-substituiran C^alkil, CN, CHjORg, C(Z’)H, C(O)OR_g, C(O)NR_gR₁₀ ali C=CR_g;R ₃ is hydrogen, C _M alkyl, CH ₂ NHC (O) C (O) NH ₂ , halo-substituted C 1-6 alkyl, CN, CH 2 OR 2, C (Z ') H, C (O) OR _g , C (O) NR _g R ₁₀ or C = CR _g ;

Z’jeOaliNOR_g;Z'jeOaliNOR _g ;

Z je OR₁₄, OR₁₅, SR₁₄, S(O)_m,R₇, S(O)₂NR_1QR₁₄, NR₁₀R₁₄, NR₁₄C(O)R₉, NR₁₀C(O)R₁₄, NR₁₀C(O)OR₇, NR₁₀C(O)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄, NR₁₀C(NCN)NR₁₀R₁₄, NR^O)^, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR_1oC(NCN)SR₉, NR_wC(CR₄NO₂)SR₉, NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR₁₀R₁₄ ali NR₁₀qO)C(O)OR₁₄;Z is OR ₁₄ , OR ₁₅ , SR ₁₄ , S (O) _m , R ₇ , S (O) ₂ NR _1Q R ₁₄ , NR ₁₀ R ₁₄ , NR ₁₄ C (O) R ₉ , NR ₁₀ C (O) R ₁₄ , NR ₁₀ C (O) OR ₇ , NR ₁₀ C (O) NR ₁₀ R ₁₄ , NR ₁₀ S (O) ₂ NR ₁₀ R ₁₄ , NR ₁₀ C (NCN) NR ₁₀ R ₁₄ , NR ^ O) ^, NR ₁₀ C (CR ₄ NO ₂ ) NR ₁₀ R ₁₄ , NR ₁₀ C (NCN) SR ₉ , NR _w C (CR ₄ NO ₂ ) SR ₉ , NR ₁₀ C (NR ₁₀ ) NR ₁₀ R ₁₄ , NR ₁₀ C (O) C (O) NR ₁₀ R ₁₄ or NR ₁₀ qO) C (O) OR ₁₄ ;

R₇ je -(CR₄R₅)_qR₁₂ ali C₁₆alkil, kjer je R₁₂ ali C^alkilna skupina v danem primeru enkrat ali večkrat substituirana z C₁₂alkilom, v danem primeru substituiranim z 1 do 3, kot so fluor, -F, -Br, -Cl, -NO₂, -NR₁₀R_n, -C(O)R₈, -C(O)OR_g, -OR_g, -CN, -C(O)NR₁₀R_n, -OC(O)NR₁₀R₁₁, -OC(O)R_g, -NR_loqO)NR_wR_n, -NR_wC(O)R_n, -NR₁₀C(O)OR₉, -NR₁₀C(O)R₁₃, -C(NR₁₀)NR₁₀R_n, -C(NCN)NR₁₀R_n, -C(NCN)SR₉, -NR₁₀C(NCN)SR₉, -NR₁₀C(NCN)NR₁₀R_n, -NR₁₀S(O)₂R₉, -S(O)_m,R₉, -NR₁₀C(O)C(O)NR₁₀R_n, -NR₁₀C(O)C(O)R₁₀, tiazolil, imidazolil, oksazolil, pirazolil, triazolil ali tetrazolil;R ₇ is - (CR ₄ R ₅ ) _q R ₁₂ or C ₁₆ alkyl, wherein R ₁₂ or C 1-4 alkyl is optionally substituted one or more times with C ₁₂ alkyl, optionally substituted by 1 to 3, such as fluorine, -F, -Br, -Cl, -NO ₂ , -NR ₁₀ R _n , -C (O) R ₈ , -C (O) OR _g , -OR _g , -CN, -C (O) NR ₁₀ R _n , -OC (O) NR ₁₀ R ₁₁ , -OC (O) R _g , -NR _lo qO) NR _w R _n , -NR _w C (O) R _n , -NR ₁₀ C (O) OR ₉ , -NR ₁₀ C (O) R ₁₃ , -C (NR ₁₀ ) NR ₁₀ R _n , -C (NCN) NR ₁₀ R _n , -C (NCN) SR ₉ , -NR ₁₀ C (NCN) SR ₉ , -NR ₁₀ C (NCN) NR ₁₀ R _n , -NR ₁₀ S (O) ₂ R ₉ , -S (O) _m , R ₉ , -NR ₁₀ C (O) C (O) NR ₁₀ R _n , -NR ₁₀ C (O) C (O) R ₁₀ , thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl or tetrazolyl;

q je 0,1, ali 2;q is 0.1 but 2;

Rio J^{e 0R}8 ^{ali R}ll’Rio J ^{e 0R} 8 ^{or R} ll '

R_n je vodik ali C^alkil, v danem primeru substituiran z enim do tremi fluori; ali, kadar sta R₁₀ in R_n kot NR₁₀R_n, lahko skupaj z dušikom tvorita 5 do 7-členski obroč, ki v danem primeru vsebuje vsaj en dodaten heteroatom izbran iz O, N ali S; R₁₃ je oksazolidinil, oksazolil, tiazolil, pirazolil, triazolil, tetrazolil, imidazolil, imidazolidinil, tiazolidinil, izoksazolil, oksadiazolil ali tiadiazolil in vsak od teh heterocikličnih obročev je povezan preko ogljikovega atoma in vsak je lahko nesubstituiran ali substituiran z eno ali dvema C₁₂alkilna skupinama;R _n is hydrogen or C 1-6 alkyl optionally substituted by one to three fluorines; or, when R ₁₀ and R _{n are} NR ₁₀ R _n , together with nitrogen, they may form a 5 to 7 membered ring containing optionally at least one additional heteroatom selected from O, N or S; R ₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted with one or two C ₁₂ alkyl groups;

R₁₄ je vodik ali R_?; ali kadar sta R₁₀ in R₁₄ kot NR₁₀R₁₄, lahko skupaj z dušikom tvorita 5 do 7 členski obroč, ki v danem primeru vsebuje en ali več dodatnih heteroatomov izbranih iz O, N ali S;R ₁₄ is hydrogen or R _? ; or when R ₁₀ and R _{14 are} NR ₁₀ R ₁₄ , together with nitrogen, they may form a 5 to 7 membered ring, optionally containing one or more additional heteroatoms selected from O, N or S;

R₁₅ je C(O)R₁₄, C(O)NR₄R₁₄, S(O)₂R_? ali S(O)₂NR₄R₁₄;R ₁₅ is C (O) R ₁₄ , C (O) NR ₄ R ₁₄ , S (O) ₂ R _? or S (O) ₂ NR ₄ R ₁₄ ;

pod pogojem, da:provided that:

f) kadar je Z OH, X YR₂, Y kisik, X₂ kisik, X₃ vodik, s 0, R₂ CH₃ v YR₂ in je Rj CH₃, potem je R₃ drugačen od CN ali COOH; alif) when Z is OH, X YR ₂ , Y is oxygen, X _{2 is} oxygen, X _{3 is} hydrogen, with 0, R _{2 is} CH ₃ in YR ₂ and R 1 is CH ₃ , then R _{3 is} different from CN or COOH; or

g) kadar je Z OH ali OCH₃, X₂ kisik, X₃ vodik, s 0, in je X YR₂, potem je R₃drugačen od H; alig) when Z is OH or OCH ₃ , X _{2 is} oxygen, X _{3 is} hydrogen, s 0, and X is YR ₂ , then R _{3 is} other than H; or

h) kadar je Z SfO^C^alkil ali S(O)₂ aril, X₂ kisik, X₃ vodik, s 0, potem je R₃drugačen od OR_g; alih) when Z is C 1 -C 4 alkyl or S (O) ₂ aryl, X ₂ oxygen, X ₃ hydrogen, s 0, then R _{3 is} other than OR _g ; or

3. Spojina po zahtevku 2, kjer jeThe compound of claim 2, wherein

Rj -CH₂-ciklopropil, ciklopentil, metil ali CF₂H;R 1 is -CH ₂ -cyclopropyl, cyclopentyl, methyl or CF ₂ H;

R₃ CN ali C=CR_g;R ₃ CN or C = CR _g ;

XYR₂;XYR ₂ ;

Y kisik;Y oxygen;

Χ2 kisik; inΧ2 oxygen; and

X₃ vodik.X ₃ hydrogen.

4. Spojina po zahtevku 3, označena s tem, da je cis-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)cikloheksan-l-ol];A compound according to claim 3 wherein cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-ol];

cis- [4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)cikloheksan-1 -ol];cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-ol];

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)cikloheksil-l-amin];cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexyl-1-amine];

cis-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil-l-(N,N-dimetil)amin];cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1- (N, N-dimethyl) amine];

cis-[4-ciano-4-(3-cikIopropilmetoksi-4-metoksifenil)cikloheksil-l-(N,Ndimetil)amin];cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexyl-1- (N, N-dimethyl) amine];

cis-[4-(3,4-bisdifluorometoksifenil)-4-cianocikloheksil-l-(N-metil)amin];cis- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyanocyclohexyl-1- (N-methyl) amine];

trans-[4-(3,4-bisdifluorometoksifeniI)-4-ciano-l-ftalimidocikloheksan];trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-phthalimidocyclohexane];

trans-[l-N-(2-hidrazinokarbonilbenzamido)-4-(3,4-bisdifluorometoksifenil)-4cianocikloheksan];trans- [1-N- (2-hydrazinocarbonylbenzamido) -4- (3,4-bisdifluoromethoxyphenyl) -4cyanocyclohexane];

cis- [4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-1 -ureidocikloheksan];cis- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-ureidocyclohexane];

trans-[4-(3,4-bisdifluorometoksifenil)-4-ciano-l-ureidocikloheksan];trans- [4- (3,4-bisdifluoromethoxyphenyl) -4-cyano-1-ureidocyclohexane];

trans-[4-ciano-4-(3-ciklopentiloksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksanj;trans- [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane;

cis-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan];cis- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane];

trans-[4-ciano-4-(3-ciklopropilmetoksi-4-metoksifenil)-l-(N-hidroksiureido)cikloheksan];trans- [4-cyano-4- (3-cyclopropylmethoxy-4-methoxyphenyl) -1- (N-hydroxyureido) cyclohexane];

cis-[4-ciano-4-(3-{4-fluorobenzil}-4-metoksifenil)-l-(N-hidroksiamino)cikloheksan]; ali trans-[4-ciano-4-(3-{4-fluorobenzil}-4-metoksifenil)-l-(N-hidroksiamino)cikloheksan].cis- [4-cyano-4- (3- {4-fluorobenzyl} -4-methoxyphenyl) -1- (N-hydroxyamino) cyclohexane]; or trans- [4-cyano-4- (3- {4-fluorobenzyl} -4-methoxyphenyl) -1- (N-hydroxyamino) cyclohexane].

5. Spojina po zahtevku 1, označena s tem, da so spojine tiste s formulo (Ib) kjer:The compound of claim 1, wherein the compounds are those of formula (Ib) wherein:

je Rj -CH₂-ciklopropil, -CH₂-C₅^-cikloalkil, -C₄₄cikloalkil, C_{7 n}policikloalkil, (3- ali 4-ciklopentenil), fenil, tetrahidrofuran-3-il, benzil ali C₁₂alkil v danem primem substituiran z 1 ali več fluori, -(CH^ ₃C(O)(CH₂)_{0 2}CH₃,R 1 is -CH ₂ -cyclopropyl, -CH ₂ -C ₅ -cycloalkyl, -C ₄₄ cycloalkyl, C _{7 n} polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C ₁₂ alkyl optionally substituted by 1 or more fluorines, - (CH ^ ₃ C (O) (CH ₂ ) _{0 2} CH ₃ ,

-(CH₂)₁.₃O(CH₂)₀.₂CH₃ in -(CH^OH;- (CH ₂ ) ₁ . ₃ O (CH ₂ ) ₀ . ₂ CH ₃ in - (CH 2 OH;

m je 0 do 2;m is 0 to 2;

nje 1 do 4;n is 1 to 4;

rje 1 do 6;r is 1 to 6;

je R₆ vodik, metil, hidroksil, aril, halo substituiran aril, ariloksiC₁₃alkil, halo substituiran ariloksiCj ₃alkil, indanil, indenil, C_{? n}policikloalkil, tetrahidrofuranil, furanil, tetrahidropiranil, piranil, tetrahidrotienil, tienil, tetrahidrotiopiranil, tiopiranil, C_{3 6}cikloalkil ali C_{4 6}cikloalkil, ki vsebuje eno ali dve nenasičeni vezi, kjer so cikloalkilni in heterociklilni deli lahko v danem primem substituirani z 1 do 3 metilnimi skupinami ali eno etilno skupino;R _{6 is} hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC ₁₃ alkyl, halo substituted aryloxyC _1-3 alkyl, indanyl, indenyl, C _{? n} polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C _{3 6} cycloalkyl or C _{4 6} cycloalkyl containing one or two unsaturated bonds where the cycloalkyl and heterocyclyl moieties may be optionally substituted up to 3 methyl groups or one ethyl group;

pod pogojem, da:provided that:

c) kadar je R₆ 2-tetrahidropiranil, 2-tetrahidrotiopiranil, 2-tetrahidrofuranil ali 2-tetrahidrotienil, potem je m 1 ali 2; alic) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then m is 1 or 2; or

d) kadar je R₆ 2-tetrahidropiranil, 2-tetrahidrotiopiranil, 2-tetrahidrofuranil ali 2-tetrahidrotienil, potem je r 1 do 6;d) when R _{6 is} 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then r is 1 to 6;

X je YR2, halogen, nitro, NR₄R₅ ali formil amin;X is YR 2, halogen, nitro, NR ₄ R ₅ or formyl amine;

Y je O ali S(O)_m>;Y is O or S (O) _m> ;

m’je 0,1 ali 2;m is 0.1 or 2;

R₃ je vodik, C₁₄alkil, CH₂NHC(O)C(O)NH₂, halo-substituiran C^alkil, CN, CH₂OR_g, C(Z’)H, C(O)OR_g, C(O)NR_gR₁₀ ali C=CR_g;R ₃ is hydrogen, C ₁₄ alkyl, CH ₂ NHC (O) C (O) NH ₂ , halo-substituted C 1-6 alkyl, CN, CH ₂ OR _g , C (Z ') H, C (O) OR _g , C (O) NR _g R ₁₀ or C = CR _g ;

Z’je O ali NOR_g;Z 'is O or NOR _g ;

Z je OR₁₄, OR₁₅, SR₁₄, S(O)_m,R₇, S(O)₂NR₁₀R₁₄, NR₁₀R₁₄, NR₁₄C(O)R₉,Z is OR ₁₄ , OR ₁₅ , SR ₁₄ , S (O) _m , R ₇ , S (O) ₂ NR ₁₀ R ₁₄ , NR ₁₀ R ₁₄ , NR ₁₄ C (O) R ₉ ,

NR₁₀C(O)R₁₄, NR₁₀C(O)OR₇, NR₁₀C(O)NR₁₀R₁₄, NR₁₀S(O)₂NR₁₀R₁₄,NR ₁₀ C (O) R ₁₄ , NR ₁₀ C (O) OR ₇ , NR ₁₀ C (O) NR ₁₀ R ₁₄ , NR ₁₀ S (O) ₂ NR ₁₀ R ₁₄ ,

NR₁₀C(NCN)NR₁₀R₁₄, NR₁₀S(O)₂R₇, NR₁₀C(CR₄NO₂)NR₁₀R₁₄, NR^NCNjSR,,NR ₁₀ C (NCN) NR ₁₀ R ₁₄ , NR ₁₀ S (O) ₂ R ₇ , NR ₁₀ C (CR ₄ NO ₂ ) NR ₁₀ R ₁₄ , NR ^ NCNjSR ,,

NR₁₀C(CR₄NO₂)SR₉, NR₁₀C(NR₁₀)NR₁₀R₁₄, NR₁₀C(O)C(O)NR_l0R₁₄ aliNR ₁₀ C (CR ₄ NO ₂ ) SR ₉ , NR ₁₀ C (NR ₁₀ ) NR ₁₀ R ₁₄ , NR ₁₀ C (O) C (O) NR ₁₀ R ₁₄ or

NR₁₀C(O)C(O)OR₁₄;NR ₁₀ C (O) C (O) OR ₁₄ ;

R₇ je -(CR₄R₅) R₁₂ ali C^alkil, kjer je R₁₂ ali C^alkilna skupina v danem primeru enkrat ali večkrat substituirana z C₁₂alkilom, v danem primeru substituiranim z 1 do 3, kot so fluor, -F, -Br, -Cl, -NO₂, -NR₁₀R_n, -C(O)R₈, -C(O)OR₈, -OR₈, -CN, -C(O)NR₁₀R_n, -OC(O)NR₁₀R_n, -OC(O)R_g, -NR₁₀C(O)NR₁₀R_n, -NR₁₀C(O)R_n, -NR₁₀C(O)OR₉, -NR_wC(O)R₁₃, -C(NR₁₀)NR₁₀R_n, -C(NCN)NR₁₀R_n, -C(NCN)SR₉, -NR₁₀C(NCN)SR₉, -NR₁₀C(NCN)NR₁₀R_n, -NR₁₀S(O)₂R₉, -S(O)_m.R₉, -NR₁₀C(O)C(O)NR₁₀R_n, -NR₁₀C(O)C(O)R₁₀, tiazolil, imidazolil, oksazolil, pirazolil, triazolil ali tetrazolil;R ₇ is - (CR ₄ R ₅ ) R ₁₂ or C 1-6 alkyl, wherein R ₁₂ or C 1-4 alkyl is optionally substituted one or more times with C ₁₂ alkyl, optionally substituted by 1 to 3, such as fluorine , -F, -Br, -Cl, -NO ₂ , -NR ₁₀ R _n , -C (O) R ₈ , -C (O) OR ₈ , -OR ₈ , -CN, -C (O) NR ₁₀ R _n , -OC (O) NR ₁₀ R _n , -OC (O) R _g , -NR ₁₀ C (O) NR ₁₀ R _n , -NR ₁₀ C (O) R _n , -NR ₁₀ C (O) OR ₉ , -NR _w C (O) R ₁₃ , -C (NR ₁₀ ) NR ₁₀ R _n , -C (NCN) NR ₁₀ R _n , -C (NCN) SR ₉ , -NR ₁₀ C (NCN) SR ₉ , -NR ₁₀ C (NCN) NR ₁₀ R _n , -NR ₁₀ S (O) ₂ R ₉ , -S (O) _m .R ₉ , -NR ₁₀ C (O) C (O) NR ₁₀ R _n , -NR ₁₀ C (O) C (O) R ₁₀ , thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl or tetrazolyl;

q je 0,1, ali 2;q is 0.1 but 2;

R₁₂ je C_{3 7}cikloalkil, (2-, 3 ali 4-piridil), (1- ali 2-imidazoIil), piperazinil, morfolinil, (2ali 3-tienil), (4- ali 5-tiazolil) ali fenil;R ₁₂ is C _3-7 cycloalkyl, (2-, 3 or 4-pyridyl), (1- or 2-imidazolyl), piperazinyl, morpholinyl, (2 or 3-thienyl), (4- or 5-thiazolyl) or phenyl;

R_w je OR_g ali R_n;R _w is OR _g or R _n ;

R_n je vodik ali C₁_₄alkil, v danem primeru substituiran z enim do tremi fluori; ali, kadar sta R₁₀ in R_n kot NR₁₀R_n, lahko skupaj z dušikom tvorita 5 do 7-členski obroč, ki v danem primeru vsebuje vsaj en dodaten heteroatom izbran iz O, N ali S; R₁₃ je oksazolidinil, oksazolil, tiazolil, pirazolil, triazolil, tetrazolil, imidazolil, imidazolidinil, tiazolidinil, izoksazolil, oksadiazolil ali tiadiazolil in vsak od teh heterocikličnih obročev je povezan preko ogljikovega atoma in vsak je lahko nesubstituiran ali substituiran z eno ali dvema C₁₂alkilna skupinama;R _n is hydrogen or C ₁ _ ₄ alkyl optionally substituted with one to three fluorines; or, when R ₁₀ and R _{n are} NR ₁₀ R _n , together with nitrogen, they may form a 5 to 7 membered ring containing optionally at least one additional heteroatom selected from O, N or S; R ₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted with one or two C ₁₂ alkyl groups;

R₁₄ je vodik ali R₇; ali kadar sta R₁₀ in R₁₄ kot NR₁₀R₁₄, lahko skupaj z dušikom tvorita 5 do 7 členski obroč, ki v danem primeru vsebuje en ali več dodatnih heteroatomov izbranih iz O, N ali S;R ₁₄ is hydrogen or R ₇ ; or when R ₁₀ and R _{14 are} NR ₁₀ R ₁₄ , together with nitrogen, they may form a 5 to 7 membered ring, optionally containing one or more additional heteroatoms selected from O, N or S;

pod pogojem, da:provided that:

f) kadar je Z OH, X YR₂, Y kisik, \ kisik, X₃ vodik, s 0, R₂ CH₃ v YR₂ in je Rj CH₃, potem je R₃ drugačen od CN ali COOH;f) when Z is OH, X is YR ₂ , Y is oxygen, O oxygen, X _{3 is} hydrogen, with 0, R _{2 is} CH ₃ in YR ₂ and R 1 is CH ₃ , then R _{3 is} different from CN or COOH;

h) kadar je Z S(O)₂C₁₆alkil ali S(O)₂ aril, X₂ kisik, X₃ vodik, s 0, potem je R₃drugačen od OR_g; alih) when ZS (O) ₂ C _{16 is} alkyl or S (O) ₂ aryl, X ₂ oxygen, X ₃ hydrogen, s 0, then R _{3 is} other than OR _g ; or

6. Spojina po zahtevku 5, označena s tem, da je -CH₂-ciklopropil, ciklopentil, metil ali CF₂H; R₃ je CN ali C^CR_g; X je YR₂; Y je kisik; Χ^ je kisik; X₃ je vodik; in R₂ je CF₂H ali metil.A compound according to claim 5, wherein -CH _{2 is} cyclopropyl, cyclopentyl, methyl or CF ₂ H; R ₃ is CN or C 1-4 CR _g ; X is YR ₂ ; Y is oxygen; Χ ^ is oxygen; X ₃ is hydrogen; and R ₂ is CF ₂ H or methyl.

7. Farmacevtski sestavek, označen s tem, da vključuje spojino po kateremkoli od zahtevkov 1-7 in farmacevtsko sprejemljiv ekscipient.A pharmaceutical composition comprising the compound of any one of claims 1-7 and a pharmaceutically acceptable excipient.

8. Spojina po kateremkoli od zahtevkov 1-6, označena s tem, da jo uporabimo pri zdravljenju alergijskega ali vnetnega stanja pri pacientu, ki jo potrebuje.A compound according to any one of claims 1-6 for use in the treatment of an allergic or inflammatory condition in a patient in need thereof.

9. Spojina po kateremkoli od zahtevkov 1-6, označena s tem, da jo uporabimo pri inhibiranju tvorbe faktorja tumorske nekroze pri pacientu, ki to zdravljenje potrebuje.A compound according to any one of claims 1-6 for use in inhibiting the formation of tumor necrosis factor in a patient in need of this treatment.

10. Uporaba spojine po kateremkoli od zahtevkov 1-6 za uporabo pri pripravljanju zdravila za uporabo pri zdravljenju alergijskih ali vnetnih stanj.Use of a compound according to any one of claims 1-6 for use in the preparation of a medicament for use in the treatment of allergic or inflammatory conditions.