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  • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
  • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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  • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C235/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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  • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
  • C07C255/44—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms at least one of the singly-bound nitrogen atoms being acylated
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  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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  • C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
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  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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  • C07C311/04—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/40—Esters thereof
  • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
  • C07F9/4062—Esters of acids containing the structure -C(=X)-P(=X)(XR)2 or NC-P(=X)(XR)2, (X = O, S, Se)
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  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/44—Amides thereof
  • C07F9/4403—Amides thereof the acid moiety containing a substituent or a structure which is considered as characteristic
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Definitions

• Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyper-reactivity of the respiratory tract to external stimuli. It is now understood that the symptoms of chronic asthma are the manifestations of three distinct processes: 1) an early response to antigen, 2) a delayed or late response to antigen, and 3) chronic inflammation and airway hyper-reactivity. Cockcroft, Ann. Allergy 55:857-862, 1985; Larsen, Hosp. Practice 22:113-127, 1987.
• the agents currently available ⁇ -adrenoceptor agonists, steroids, methylxanthines, disodium cromoglycate
• Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation.
• compounds that activate adenylate cyclase or inhibit PDE should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.
• the principal cellular mechanism for the inactivation of c AMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
• PDE IN cyclic nucleotide phosphodiesterase
• PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo.
• PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated.
• Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
• TNF Tumor Necrosis Factor
• rheumatoid arthritis rheumatoid spondylitis
• osteoarthritis gouty arthritis and other arthritic conditions
• sepsis septic shock, endotoxic shock, gram negative sepsis
• toxic shock syndrome adult respiratory distress syndrome
• cerebral malaria chronic pulmonary inflammatory disease
• silicosis pulmonary sacroidosis
• bone resoiption diseases reperfusion injury, graft vs.
• allograft rejections fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis.
• AIDS cachexia secondary to infection or malignancy
• AIDS cachexia secondary to acquired immune deficiency syndrome
• AIDS AIDS
• ARC AIDS related complex
• keloid formation scar tissue formation
• Crohn's disease Crohn's disease
• ulcerative colitis or pyresis.
• TNF has been implicated in various roles with the human acquired immune deficiency syndrome (AIDS). AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV).
• HIV Human Immunodeficiency Virus
• monokines, specifically TNF are implicated in the infection of T lymphocytes with HTV by playing a role in maintaining T lymphocyte activation.
• monokines, specifically T ⁇ F are implicated in activated T cell-mediated HIN protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation.
• interference with monokine activity such as by inhibition of monokine production, notably T ⁇ F, in an HTV-infected individual aids in Umiting the maintenance of T cell activation, thereby reducing the progression of HIN infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIN infection.
• Monocytes, macrophages, and related cells such as kupffer and glial cells, have also been implicated in maintenance of the HIN infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopatho-genesis of HTV Infection, Advances in Immunology, Vol. 57, (1989)].
• Monokines such as TNF have been shown to activate HTV replication in monocytes and/or macrophages [See Poli, et al., Proc. Natl. Acad. Sci., 87:782-784 (1990)], therefore, inhibition of monokine production or activity aids in limiting HTV progression as stated above for T cells.
• monokine activity such as by inhibition of TNF production
• an HlV-infected individual aids in enhancing the quality of life of HTV-infected patients by reducing the severity of monokine-mediated disease associated problems such as cachexia and muscle degeneration.
• TNF is also associated with yeast and fungal infections. Specifically Candida Albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al., Infection and Immunity, Vol. 58, No.9, p.2750-54 (1990); and Jafari et al., Journal of Infectious Diseases, Vol. 164, p. 389-95 (1991). See also Wasan et al., Antimicrobial Agents and Chemotherapy, Vol. 35, No. 10, p. 2046-48 (1991) and Luke et al., Journal of Infectious Diseases, Vol. 162, p.211-214 (1990)].
• the discovery of a class of compounds which inhibit the production of TNF will provide a therapeutic approach for the diseases in which excessive, or unregulated TNF production is implicated. That is provided herewith.
• this invention covers a compound of formula I
• Rl is lower alkyl substituted by 1 or more halogens, aryl, halo substituted aryl, aryloxyCl-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuryl, furyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, -CR4R5-C3-6 cycloalkyl, C3-6 cycloalkyl, or a C4-6 cycloalkenyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclyl moieties unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group;
• R2 is -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more halogens
• R3 is lower alkyl unsubstituted or substituted by one or more halogens, -CR4R5OR4, -CR4R5NR4R9, -CR4(OR4)CR4R5OR4, 2,2-dimethyl- 1 ,3-dioxolan-4-yl, -NR9C(O)NR4R9, -NR4R9, -S(CR4 5) n CH3 where n is 0-5, or -P(O)(ORi2)2;
• R4 and R5 are independently hydrogen, methyl or ethyl
• R8 is H, F, CN, Cl-2 alkyl optionally substituted by 1 or more fluoro groups,
• R9 is H, -ORi 1, unsubstituted or substituted -(CH2) m Ar where m is 0-2, or unsubstituted or substituted Ci-6 alkyl, wherein optional substituents comprise from one to three groups independently selected from the group consisting of -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more halogens, -NO2, -Si(R4)3, -NRJORU, - C(O)R4, -C(O)OR4, -OR4, -CN, -C(O)NRioRll, -OC(O)NRioRll, -OC(O)Ri2, -NRi ⁇ C(O)NRi ⁇ Rll, -NR ⁇ oC(O)Rn, -NRioC(O)ORi2, -NRioC(O)Ri3, -C(NR ⁇ o)NRioRll, -C(NCN)NR ⁇ oRll, -
• RiO is -ORil or -Rn
• Rl 1 is hydrogen, or -C1.4 alkyl unsubstituted or substituted by one to three fluoro groups; or when Rio and Rl 1 are comprise part of the group -NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring which may contain at least one additional heteroatom which is O, N, or S;
• Rj2 s -C ⁇ _4 alkyl unsubstituted or substituted by one to three fluoro groups
• Rl3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, wherein each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C ⁇ _2 alkyl groups
• R14 is OH or OR12;
• Rl5 is unsubstituted or substituted -(CH2) m Ar where m is 0-2, or unsubstituted or substituted Ci-6 alkyl, wherein optional substituents comprise from one to three groups independently selected from the group consisting of -CH3 or -CH2CH3 unsubstituted or substituted by 1 or more halogens, -NO2, -Si(R4)3, -NRIQRH, -C(O)R4, -C(O)OR4, -OR4, -CN, -C(O)NR ⁇ oRl 1, -OC(O)NRioRl 1, -OC(O)Ri2, -NR ⁇ oC(O)NR ⁇ oRll, -NR ⁇ oC(O)Rn, -NRioC(O)ORi2, -NRi()C(O)Ri3, -C(NR ⁇ o)NRioRll, -C(NCN)NRl ⁇ Rll, -C(NCN)
• AT is 2-, 3- or 4-pyridyl, pyrimidyl, pyridazyl, 2-imidazolyl, mo holino, or phenyl;
• Xl is YR2, halogen, nitro, -NR4R5, or formyl amine;
• X2 is O or NR4
• X3 is hydrogen or X ⁇ ;
• Y is O, S, SO or SO2;
• Z is O or NCN; provided that a) Z is NCN only when R3 is -NR4R5 or -S(CR4R5) n CH3; or b) when Xi is -NR4R5 or formyl amine, then Rl is not CH3 or C2H5 when X2 is O and X3 is H or halogen; or c) when R3 is CR4R5NR4R9, and X2 is O, and Rl is phenyl, then one of R6.
• R7, or R8 is other than H; or d) when Z is NCN, and X 1 is YR2, and Y is O, and R2 is CH3 and R3 is NH2, and R9 is H, OH, OCH3 or CH3, and R8 is H, and R6 and R7 are both hydrogen, or are hydrogen and methyl, hydrogen and CF3 or hydrogen and ethyl, and X2 is O, then Rl is not CF3, CF2H, or CF2CF2H; or e) when Z is NCN, and X is YR2» and Y is O, and R2 is CH3 and R3 is NH2, and R9 is H, OH, OCH3 or CH3, and R8 is H, and R6 and R7 are both hydrogen, or are hydrogen and methyl, hydrogen and CF3 or hydrogen and ethyl, and X2 is NR4 and R4 is CH3, then Ri is not CH3; or f) when Q is A, and X2 is
• novel compounds of the Formula (I) also have Tumor Necrosis Factor (TNF) inhibitory activity.
• TNF Tumor Necrosis Factor
• This invention also relates to a composition, including a pharmaceutical composition, comprising a compound of the Formula I and a carrier or diluent
• the invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of phosphodiesterase IV, including mammals which comprises administering to a mammal in need thereof an effective amount of a compound of Formula I.
• the invention further provides a method for treating allergic and inflammatory diseases which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of the Formula I.
• the invention also provides a method for treating asthma which comprises administering to a mammal, including humans, in need thereof an effective amount of a compound of the Formula I.
• This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which method comprises administering to a mammal in need of such treatment an effective TNF inhibiting amount of a compound of the Formula (I).
• This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.
• This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a compound of the Formula (I).
• HAV human immunodeficiency virus
• the compounds of the Formula (I) are also useful in the treatment of additional viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.
• this invention covers a process for making a compound of formula I, which process comprises one or more of the following steps: a) forming a salt; b) treating an amine with a lower alkyl acylating agent to form the corresponding amide; c) treating an amine with biuret to form the corresponding imidodicarbamide; d) hydrolyzing the product of an amine treated with trimethylsilyl isocyanate to form the corresponding urea; e) treating an amine with cyanodithioiminiocarbonate to form the corresponding N ⁇ -cyano-S -methyl-N * -isothiouriedo; f) treating an N ⁇ -cyano-S-methyl-N*- isothiouriedo with an amine to form the corresponding N'-cyanocarboximidamide; g) treating a amine with a mixture comprising (4S )-2,2-dimethyl- 1 ,3- dioxolane-4-carboxy
• “Lower alkyl” means a group having 1 to 6 carbon atoms. This included normal, secondary and tertiary form where such forms can exist e.g., isopropyl, t-butyl and the like. Normal, or linear, radicals are preferred, especially methyl, ethyl, propyl, butyl, pentyl and hexyl.
• Halo means fluoro, chloro, bromo and iodo.
• cycloalkyl or "cycloalkyl alkyl” as used herein is meant to include those rings of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl or cyclohexyl.
• Aryl unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms such as phenyl. Preferably the aryl is monocyclic, i.e., phenyl.
• the alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms.
• Inhibiting the production of TNF means, a) a decrease of excessive ia vivo TNF levels in a human to normal levels or below normal levels by inhibition of the in vivo release of TNF by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the translational or transcription level, of excessive in vivo TNF levels in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of the direct synthesis of TNF as a postranslational event 'TNF mediated disease states” means all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1, or IL-6.
• Cytokine means any secreted polypeptide that affects the functions of other cells, and is a molecule which modulates interactions between cells in the immune or inflammatory response.
• a cytokine includes, but is not limited to monokines and lymphokines regardless of which cells produce them.
• a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte but many other cells produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes, and ⁇ -lymphocytes.
• monokines such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes, and ⁇ -lymphocytes.
• Lymphokines are generally referred to as being produced by lymphocyte cells.
• cytokines examples include, but are not limited to Interleukin-1 (IL-1), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor beta (TNF ⁇ ).
• IL-1 Interleukin-1
• IL-6 Interleukin-6
• TNF- ⁇ Tumor Necrosis Factor-alpha
• TNF ⁇ Tumor Necrosis Factor beta
• Some compounds of formula I may exist in two distinct enantiomeric forms. Some compounds of Formula I may exist in at least two distinct diasteriomeric forms possessing distinct physical and biological properties. Furthermore some compounds of Formula I may exist in a tautomeric form, such as the enol or enamine. All these forms are within the scope of this invention.
• Rl groups are cyclopropylmethyl, cyclopentymethyl, cyclohexylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, tet ⁇ ahydrofur-2-yl, cyclopentenyl, benzyl, or lower alkyl optionally substituted by 1 or more fluoro groups.
• the halogens are preferably fluorine and chlorine, more preferably a Ci-4 alkyl substituted by 1 or more fluoro groups, more preferably 1 or more times by fluorine.
• halo substituted chain length is one or two carbons, and most preferred are the moieties -CF3, -CH2F, -CHF2, -CF2CHF2, -CH2CF3, and - CH2CHF2.
• Preferred Ri substitutents are cyclopentyl, cyclopropylmethyl, -CF3, and - CHF2.
• R 1 is a C7.1 1 polycycloalkyl
• examples are bicyclo[2.2.1 ]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo 5.2.1.0 2 » 6 ]decyl, additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987 which is incorporated herein by reference in its entirety.
• Oxygen is the preferred X2 radical.
• the preferred radical is YR2 where Y is oxygen.
• the preferred R2 group is a methyl or ethyl unsubstituted or substituted by 1 or more halogens.
• the preferred halogens are fluoro and chloro, most preferably fluoro.
• the more preferred R2 groups are methyl, -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are difluoromethyl and methyl.
• Hydrogen is the referred X3 radical.
• the preferred radicals are those which form an amide, sulfonamide, imidodicarbamide, urea, N ⁇ -cyano-S-methyl-NMso ⁇ iouriedo, 2,3- dihydroxypropanamide, 2,2-ctimethyl-l,3-dioxolane-4-carboxamide, 2-acetoxyacetamide, or a 2-aminoacetamide.
• R6 moieties are H, C(O)NH2, C ⁇ CR4, CN, C(O)H, CH2OH, CH2F, CF2H, and CF3. More preferred are C ⁇ CH and CN.
• R7 is preferably H or CN.
• R ⁇ is preferably H, -C(O)NH2 or CN.
• Preferred R9 moieties include hydrogen, optionally substituted -(CH2)0-2(2-, 3- or4-pyridyl), (CH2)l-2(2-imidazolyl), (CH2)2(4-morpholinyl), (CH2)2(4-piperazinyl), (CH2)l-2(2-thienyl), (CH2)l-2(4-thiazolyl), and (CH2)0-2phenyl.
• Preferred rings when Rio and Ri 1 in the moiety -NRioRl 1 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 are not limited to 1- imidazolyl, 2-(R8)-l-imidazolyl, 1-pyrazolyl, 3-(R8)-l -pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)-l-triazolyl, 5-(R8)-2-triazolyl, 5-(R8)-l-tetrazolyl, 5-(R8)-2-tetrazolyl, 1- tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R8)-l-piperazinyl, or pyrrolyl ring.
• Preferred R15 moieties include, optionally substituted Ci-3alkyl, -(CH2)0-2(2-,
• Preferred rings for R13 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[l,2,3]), (3- or 5-triazolyl[ 1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[ 1,2,4]), (2-oxadiazolyl[ 1,3,4]),
• R2 is methyl or fluoro-substituted alkyl
• R6 is CN or C ⁇ CR4
• X is YR2-
• Ri is -CH2-cyclopropyl, cyclopentyl, or CF2H
• Rg is CN or C ⁇ CH
• X is YR2
• Y is oxygen
• X2 is oxygen
• X3 is hydrogen
• R2 is CF2H or methyl.
• Phosphodiesterase TV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, inflammatory bowel disease states including Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
• PDE TV inhibitors are useful in treating diabetes insipidus, (Kidnev Int. 37:362, 1990; Kidnev Int. 35:494, 1989) and central nervous system disorders such as depression and multi-infarct dementia.
• Compounds of Formula I are useful in treating, prophylactically or therapeutically, disease states in humans which are exacerbated or caused by excessive or unregulated
• the present invention also provides a method for inhibiting the production of tumor necrosis factor (TNF) in an animal in need thereof, including humans, which method comprises administering to said animal an effective amount of a compound of formula I alone or mixed with a carrier.
• TNF tumor necrosis factor
• Compounds of the Formula I may be administered systemically, topically, parenterally or by inhalation in conventional dosage forms prepared by combining such agent with standard carriers according to conventional procedures in an amount sufficient to produce the desired therapeutic activity for treatment of a TNF-mediated disease state or for use as a PDE TV inhibitor.
• the daily dosage regimen is suitably about .001 mg/kg to lOOmg/kg, preferably 0.01 mg Kg to 40 mg/Kg, of a compound of the Formula I or a pharmaceutically acceptable salt thereof calculated as the free base.
• the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity.
• compositions of the present invention will comprising an effective, non-toxic amount of a compound of the formula I and a pharmaceutically acceptable carrier or diluent
• a pharmaceutically acceptable carrier or diluent The carriers) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious in the intended use.
• the composition is in unit dosage form, for example a tablet capsule or metered aerosol dose, so that the patient may self-administer a single dose.
• systemic administration oral, intravenous, intraperitoneal, topical, inhalation and intramuscular administration.
• topical administration is meant non- systemic administration and includes the application of a compound externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
• parenteral' as used herein includes intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred.
• each dosage unit may contains from 1 mg to 100 mg, and preferably from 10 mg to 30 mg of a compound of the formula I or a pharmaceutically acceptable salt thereof calculated as the free base.
• Appropriate dosage forms for inhalation include an aerosol formulation or a metered dose inhaler.
• the daily dosage regimen for a compound of the Formula (I) for intranasal administration and oral inhalation is suitably about 10 to about 1200 mg.
• a suitable dose of a TNF production inhibiting compound of the formula I is from about 0.01 mg to about 100 mg of base for topical administration, the most preferred dosage being about 0.01 mg to about 30 mg, for example, 0.003 mg to 10 mg administered two or three times daily.
• Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. No unacceptable toxicological effects are expected when these compounds are administered in accordance with the present invention.
• an amine is first prepared, that is a compound where R is NH2, and then this intermediate is converted to the desired target compound by one or more steps, all of which are described below.
• These amines can be prepared by the methods set out in PCT/US91/04795; those processes and the amines disclosed there are incorporated herein by reference to the extent that information is necessary or useful for understanding how to make the amine precursors used in this work.
• a reducing agent such as lithium aluminum anhydride or hydrogen
• the aldehyde of formula a can be treated with a lithium halide and a silyl halide in an appropriate solvent followed by a reducing agent e.g., siloxane, providing a halide of formula (c)
• X4 is the halogen derived from the lithium halide.
• Cyanide is then used to displace the halide.
• This nitrile is then reduced, for example by hydrogen and suitable heavy metal catalyst such as nickel with ammonia or palladium on carbon with an acid such as perchloric acid to obtain the primary amine.
• R6 is nitrile
• such compounds can be prepared by dehydrating a compound of formula (d)
• the reaction mixture was cooled to 0°C and quenched by the successive dropwise addition of water (11 mL), 15% sodium hydroxide (11 mL) and water (33 mL).
• the mixture was filtered through a pad of Celite and the filtrate was washed successively with water, 10% hydrochloric acid and water.
• the aqueous washes were combined, made basic with saturated aqueous potassium carbonate and extracted three times with ether and twice with methylene chloride.
• the organic layers were combined and dried (potassium carbonate). Removal of the solvent in vacuo provided the amine.
• a portion of the crude amine was purified by flash chromatography, eluting with 1:10:90 water/methanol/chloroform. Analysis Calc.
• Example 4 Dimethyl N-r2-f3-cvclopentvloxv-4-methoxvphenvnethvnphosphonoformamide A mixture of trimethyl phosphonoformate (0.27 mL, 2.0 mmol) and 2-(3- cyclopentyloxy-4-methoxyphenyl)ethylamine (0.47 g, 2.0 mmol) was allowed to stand under an argon atmosphere for 3h. During this time, the mixture was sonicated twice for 3 min. The mixture was dissolved in methylene chloride and washed successively with 10% hydrochloric acid and water and dried (potassium carbonate).
• the mixture was concentrated under reduced pressure, dissolved in tetrahydrofuran (2 mL) and added to a -78°C solution containing 2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (0.48 g, 2.0 mmol) and diisopropylethylamine (0.39 mL, 2.2 mmol) in tetrahydrofuran (3 mL) under an argon atmosphere.
• the reaction mixture was stirred for 1.5h at -78°C and quenched by the addition of ammonium chloride.
• the solvent was removed under reduced pressure, and the residue was partitioned between dilute aqueous hydrochloric acid and methylene chloride.
• N-r2-r3-Cvclopentvloxv-4-methoxvphenvnethvnacetamide 10a N-(t-ButoxvcarbonvlV2-r3-cvclopentvloxv-4-methoxvphenvnethvlamine
• a solution of 2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine (2.5 g, 10.6 mmol) in methylene chloride (25 mL) was treated with t-butyloxycarbonylanhydride (2.5 mL, 11 mmol) and stirred under an argon atmosphere for 2h.
• N-r2-Cvano-2-f3-cvclopentvloxv-4-methoxvphenvnethvn-2-hvdroxvacetamide 13a ⁇ -Bromo-3-cyclopentyloxy-4-methoxytoluene
• lithium bromide 3.94 g, 45.4 mmol
• acetonitrile 25 mL
• Trimethylsilyl chloride 4.32 mL, 34.0 mmol
• N-r2-Cvano-2-f3-cvclopentvloxv-4-methoxvphenvnethvn-2-acetoxvacetamide A solution of 3-amino-2-(3-cyclopentyloxy-4-methoxyphenyl)propionitrile (0.095 g, 0.36 mmol) in methylene chloride (2 mL) was cooled to 0°C and was treated with methylamine (0.057 mL, 0.43 mmol) and acetoacetyl chloride (0.045 mL, 0.4 mmol).
• N-r2-Cyano-2-(3-cyclopentyloxy-4-methoxyphenvDethyll-2-hvdroxyacetamide A solution of N-[2-cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl]-2-acetoxyacetamide (0.102 g, 0.28 mmol) in methanol (5 mL) was treated with powdered potassium carbonate (0.096 g, 0.69 mmol) and stirred for 15 min. The mixture was diluted with water, was extracted three times with methylene chloride and the organic extract was dried (potassium carbonate) and evaporated.
• N-r2-(3-Cvclopentvloxv-4-methoxvphenvnethvl1-2-t-butvloxvcarbonvlamino- acetamide A solution of 3-cyclopentyloxy-4-methoxyphenethylamine (0.32 g, 1.37 mmol) in methylene chloride (5 mL) at room temperature under an argon atmosphere was treated with triethylamine (0.19 mL, 1.37 mmol), N,N-dimethylaminopyridine (0.17 g, 1.37 mmol) and N-t-butyloxycarbonylglycine-N-hydroxysuccinimide ester (0.37 g, 1.37 mmol).
• N-[2-(3-cyclopentyloxy-4-memoxyphenyl)ethyl]-2-t-butyloxycarrx)nylam__noacetamide (0.53 g, 1.35 mmol) in methylene chloride (16 mL) cooled to 0° C was treated with the dropwise addition of trifluoroacetic acid (1.7 mL), was allowed to come to room temperature and was stirred for 2.5h. The liquids were evaporated, the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate and was extracted three times. The organic extract was dried (potassium carbonate) and evaporated.
• a compound of formula I, (1 ⁇ g to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
• Step 1 Blend ingredients No. 1, No.2, No. 3 and No. 4 in a suitable mixer/blender.
• Step 2 Add sufficient water portion- wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
• Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
• Step 4 The wet granules are then dried in an oven at 140°F (60°C) until dry.
• Step 5 The dry granules are lubricated with ingredient No. 5.
• Step 6 The lubricated granules are compressed on a suitable tablet press.
• a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount f a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

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• 1994
  • 1994-08-19 EP EP94925286A patent/EP0714397A1/en not_active Withdrawn
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