Field of Invention The present invention relates to novel oxamides, pharmaceutical compositions containing these compounds and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).

Background of the Invention Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperactivity 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 hyperactivity. Cockcroft, Ann. Allergy 55:857-862, 1985; Larsen, Hosp. Practice 22:113-127, 1987.

The agents currently available (β-adrenoceptor agonists, steroids, methylxanthines, disodium cromoglycate) are inadequate to control the disease; none of them modify all three phases of asthma and nearly all are saddled with limiting side effects. Most importantly, none of the agents, with the possible exception of steroids, alter the course of progression of chronic asthma.

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 sooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit 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 cAMP is hydrolysis of the 3'- phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cyclic AMP breakdown in airway smooth muscle and inflammatory cells. Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma. Barnes, ed. IBC Technical Services Ltd. (1989). Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated. Such

compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.

The compounds of this invention also inhibit production of Tumor Necrosis Factor (TNF), a serum glycoprotein. Excessive or unregulated TNF production is implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sacroidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, 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). It has now been discovered that monokines, specifically TNF, are implicated in the infection of T lymphocytes with HIV by playing a role in maintaining T lymphocyte activation. Furthermore, once an activated T lymphocytes is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication. It has also been discovered that monokines, specifically TNF, are implicated in activated T cell-mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with monokine activity such as by ihibition of monokine production, notably TNF, in an HTV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection. Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV

Infection, Advances in Immunology. Vol. 57, (1989)]. Monokines, such as TNF, have been shown to activate HTV replication in monocytes and/or macrophages [See Poli, et al., Proc. Natl. Acad. Sri.. 87:782-784 (1990)], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells. It has now been discovered that monokines are implicated in certain disease- associated problems such as cachexia and muscle degeneration. Therefore, interference with monokine activity, such as by inhibition of TNF production, in an HTV-infected individual aids in enhancing the quality of life of HIV-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 el sL, 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.

Summary of the Invention This invention comprises oxamides represented by Formula (I)

Rl s Cj.12 aikyl unsubstituted or substituted by 1 or more halogens, C3.6 cyclic alkyl unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group, C4.6 cycloalkyl containing one or two unsaturated bonds, C7.11 polycycloalkyl, - (CRi4Ri4) _n C(O)-O-(CRi4Ri4) _m -Rιo, .(CR ₁₄ Ri4) _n C(O)-O-(CRi4Ri4) _r -Rι ι, -(CR ₁₄ R ₁₄ ) _x OH, -(CRι ₄ Ri4) _s O(CRi4R ₁₄ ) _m -Rιo. -(CRι ₄ Ri4) _s O(CRι ₄ Ri4) _r -Rι _{l f} -(CR ₁ 4R ₁ 4) _n -(C(O)NRi4)-(CRi4Ri4) _m -Rιo, -(CR ₁ 4R ₁ 4) _n -(C(O)NRi4)-(CR ₁₄ Ri4) _r - Rl l. -(CRι ₄ Ri4) _y -Rn, or -(CR ₁₄ Rι ₄ ) _z -Rι ₀ ;

X is YR2. halogen, nitro, NR14R 4, or formamide; X2 is O or NRi4; X3 is hydrogen or X;

Y is O or S(O) _m ;

R2 is -CH3 or -CH2CH3, each may be unsubstituted or substituted by 1 to 5 fluorines;

R3 is hydrogen, halogen, CN, Cι_4alkyl, halo- substituted Cι_4alkyl, cyclopropyl unsubstituted or substituted by R9, -OR5, -CH2OR5, -NR5R16, -CH2NR5R16, -C(O)OR ₅ , -C(O)NR ₅ Ri6, -CH=CR9R9, -C≡CR ₉ or -C(Z)H;

R4 is independently hydrogen, Br, F, Cl, -NR5R16, NR6 ^R 16 _> - ^N0 2 _> -C(Z)R ₇ , -S(O) _m R ₁₂ , -CN, OR5, -OC(O)NR ₅ Rι ₆ , (1 or l-(R ₅ )-2-imidazolyl), -C(NR ₁₆ )NR ₅ Rι ₆ , -C(NR ₅ )SR ₁₂ , -OC(O)R ₅ , -C(NCN)NR ₅ R ₁₆ , -C(S)NR ₅ R ₁₆ , N(R ₁₆ )C(O)R ₁₅ , oxazolyl, thiazolyl, pyrazolyl, triazolyl or tetrazolyl, or when R5 and R 15 are NR5R1 they may

together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N or S;

R5 is independently hydrogen or Cι_4alkyl, unsubstituted or substituted by one to three fluorines; R ₆ is R ₅ , -C(0)R ₅ , -C(0)C(0)R ₇ , -C(0)NR ₅ R ₁₆ , -S(0) _m R ₁₂ , -C(NCN)SR ₁₂ ,

-C(NCN)Ri2- -C(NR ₁₆ )R ₁₂ , -C(NR ₁₆ )SRι ₂ , or -C(NCN)NR ₅ R ₁₆ ;

R ₇ is OR5, -NR5R 6, or R ₁₂ ;

Rg is hydrogen or A;

R9 is hydrogen, F or Rχ ₂ ; Rio is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi_3alkyl, halo substituted arIyoxyCι_3alkyl, indanyl, indenyl, Cη_\\ polycyclo-alkyl, furanyl, pyranyl, thienyl, thiopyranyl, (3- or 4-tetrahydropyranyl), (3- or 4-tetrahydrothiopyranyl), 3-tetrahydrofuranyl, 3-tetrahydrothienyl, C3.6 cylcoalkyl, or a C4.gcycloalkyl containing one or two unsaturated bonds, wherein the cylcoalkyl and heterocyclic moieties may be unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group;

R is 2-tetrahydropyranyl or 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydroώienyl unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group;

R 2 is Cι_4al yl unsubstituted or substituted by one to three fluorines;

Rl4 is independently hydrogen or a C _ alkyl unsubstituted or substituted by fluorine;

R 5 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, or pyrrolyl, and each of the heterocyclics may be unsubstituted or substituted by one or two Cj_ ₂ alkyl groups; R g is OR5 or R5 or when R5 and R g are NR5R6 they may, together with the nitrogen, form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S;

Rl7 and R ₂ 6 are independentiy hydrogen, halogen, C1.4a-.kyl, halo-substituted Cι_ 4--lkyl, cyclopropyl unsubstituted or substituted by R9, -CH ₂ OR5, -CH2NR5R16, -C(0)OR ₅ , -C(0)NR ₅ Rι ₆ or -C(Z)H;

^R 18> ^R 24 ^anc * ^R 25 ∞ ^& independentiy hydrogen, F, CN, and C1.4 alkyl optionally substituted by one or more fluorines; or

R3 and Ri together can form a (=0) keto or cyclopropyl moiety; provided that when R3 is OH then Rig is hydrogen or CH3; R19 is hydrogen, -(CH ) _m A, or -CH ₂ 0(CH) _m A;

R ₂₀ is -0(CH2) _q R ₈ , -NR ₅ OR ₅ , -NR ₅ NR ₅ R ₈ , -NR ₅ (CH _2)q R ₈ , -OCH ₂ NR ₅ C(0)R ₂ ι, -OCH ₂ C(0)NR ₂₂ R ₂ 3, -OCH(R ₅ )OC(0), Cι. ₄ alkyl, -OCH(R ₅ )C(0)OCι.3-ιlkyl;

R ₂ 1 is CH3 orphenyl; R ₂₂ is hydrogen, CH3, CH ₂ CH3, or CH CH ₂ OH;

R ₂₃ is hydrogen, CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ OH, or CH ₂ CONH ₂ ;

- 4 -

A is Cι_6alkyl (2-, 3-, or 4-pyridyl), 4-morpholinyl, 4-piperidinyl, (1-, 2-, 4- or 5- imidazolyl), (2- or 3-thienyl), (2- or 5-pyrimidyl), (4 or 5-thiazolyl), triazolyl or quinolinyl, all of which may be unsubstituted or substituted by one or more R4 groups; or A is -(CH2) _r SRi2. or A is a formula of (a) or (b)

(a) (b) where the R4 and R 4 groups on the naphtyl ring may be substituted at any open position; Z is O, NR12, NOR5, NCN, C(-CN) ₂ , CR ₅ NO ₂ , CR ₅ C(O)OR ₅ , CR ₅ C(O)NR ₅ R ₅ , -C(-CN)NO2, C(-CN)C(O)ORi2 or C(-CN)C(O)NR ₅ R ₅ ; m is 0 to 2; n is 1 to 4; q is O to 1; r is 1 to 2; s is 2 to 4; x is 2 to 6; y is 1 to 6; z is 0 to 6; or a pharmaceutically acceptable salt thereof; provided that: m is 2 when RIQ is OH in (CRi4Ri4) _n -C(O)O-(CRi4Ri4) _m -Rιo, (CR14R14 (C(O)NRi4)-(CRi4Ri4) _m -Rιo, or C(Ri4Ri4) _s O(CRi4Ri4) _m Rιo; and further provided that when A is N-morpholinyl, N-piperidinyl, N-imidazolyl or N- triazolyl, then q is not 1; and

Z is 2-6 in -C(R 4Ri4) _z Rιo when RJQ is OH.

This invention further comprises a method of inhibiting phosphodiesterase TV in an animal, including humans, which method comprises administering to an animal in need thereof an effective amount of a compound of Formula (I). This invention further comprises a method of inhibiting the production of TNF in an animal, including humans which method comprises administering to an animal in need thereof an effective amount of a compound of Formula (I).

This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HTV), AIDS Related Complex (ARC) or any other disease state associated with an HTV infection, which comprises administering to such a human an effective TNF inhibiting amount of a compound of Formula (I).

The present invention also provides a method of preventing a TNF mediated disease state in an animal in need thereof, including humans, by prophylactically administering an effective amount of a compound of Formula (I).

The compounds of the present invention 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. The viruses contemplated for treatment herein are those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (I). Such viruses include, but are not limited to; HIV-1, HTV-2 and HIN-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpes group of viruses, such as, Herpes Zoster and Herpes Simplex.

The compounds of Formula (I) are also useful in the treatment of yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TΝF or will elicit TΝF production in vivo. A preferred disease state for treatment is fungal meningitis.

Additionally, the compounds of the Formula (I) may be administered in conjunction with other drugs of choice, either simultaneously or in.a consecutive manner, for systemic yeast and fungal infections. Drugs of choice for fungal infections, include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidaozles, such as clotrimazole, econazole, miconazole, and ketoconazole; the class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B.

The preferred organism for treatment is the Candida organism. The compounds of the Formula (I) may be co-administered in a similar manner with anti-viral or anti-bacterial agents. The compounds of the Formula (I) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti-viral agent by administering an effective amount of a compound of the Formula (I) to a mammal in need of such treatment. Preferably, a compound of the Formula (I) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.

Detailed Description of the Invention All defined alkyl groups can be straight or branched.

The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are contemplated to be within the scope of the present invention. The term "halogen" is used to mean chloro, fluoro, bromo or iodo. Alkyl groups may be substituted by one or more halogens up to being perhalogenated.

By the term "cycloalkyl" as used herein is meant to include groups of 3-6 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl or cyclohexyl.

By the term "aryl" or "aralkyl", unless specified otherwise, as used herein is meant an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl or naphthyl. Preferably the aryl is monocyclic, i.e., phenyl.

Examples of C7.11 polycycloalkyl are bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo [5.2.1.0 ² _' ⁶ ]decyl, etc., additional examples of which are described in Saccamano et al.. WO 87/06576, published 5 November 1987 whose disclosure is incorporated herein by reference in its entirety.

Examples of rings when R5 and R^ in the moiety -NR5R1 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/ and S include, but are not limited to 1-imidazolyl, 1-pyrazolyl, 1-triazoly, 2-triazolyl, tetrazolyl, 2-tetrazoyl, morpholinyl, piperazinyl, or pyrrolyl ring.

The term "inhibiting the production of TNF" means: a) a decrease of excessive in vivo TNF levels in a human to normal levels or below normal levels by inhibition of the in yivo 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.

The term "TNF mediated disease states" means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to EL-1, or IL-6. A disease state in which IL-1, for instance is a major component, and whose production or action is exacerbated or which is secreted in response to TNF, would therefore be considered a disease state mediated by TNF. The term "cytokine" as used herein 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. For instance, a monokine is generally refeπ-ed 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, epidermal keratinocytes, and β-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines for the present invention include, but are not limited to Interleukin-1 (IL-1), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNFα) and Tumor Necrosis Factor beta (TNFβ). A preferred subgroup of Formula (I) is Formula (lb):

wherein:

Rl is phenyl, benzyl or C _2 alkyl unsubstituted or substituted by 1 or more fluorines, C4.6 cycloalkyl, CH2-cyclopentyl, CH2-cyclopropyl, C7.11 polycycloalkyl, 3-tetrahydrofuranyl, cyclopentenyl, -(CH2) _n C(O)-O-(CH ₂ ) _m CH3, -(CH ₂ )2-4OH, -(CH2) _s O(CH2) _m -CH ₃ , -(CH ₂ )n-(C(O)NRι ₄ )-(CH2) _m -CH3, all of which may be unsubstituted or substituted by 1 to 3 methyl groups or one ethyl group; s is 2 to 4; m is 0 to 2; n is 1 to 3;

X is YR2, halogen, nitro, amine, Cι.2dialkylamine, Cι_2monoalkylamine or formamide;

Y is O or S(O) _m ; R2 is -CH3 or -CH2CH3, each may be unsubstituted or substituted by 1 to 4 fluorines;

R3 is independently hydrogen, OR5, F, CF2H, CH2F, -CH2OR5, C(O)OR5, C(O)NR ₅ R ₅ , C(O)H, C(NOR ₅ )H, CH ₃ , CN, -C=CR ₉ or CF3;

A is (2-, 3-, or 4-pyridyl), 4-morpholinyl, 4-piperidinyl, (1- or 2-imidazolyl), (2- or 3-thienyl) or (4- or 5-thiazolyl), all of which may be unsubstituted or substituted by one or more: Br, F, Cl, -NR5R6, NR ₅ R ₁₆ , NRόRifr NO2, -COR7, -S(O) _m Ri2, CN, OR ₅ , -OC(O)NR5Ri6, (1- or 2-imidazolyl), -C(NRi6)NR5Ri6, -C(NR ₅ )SR ₂ , -OC(O)R ₅ , -C(NCN)NR ₅ R 6, -C(S)NR5Ri6, -NRi6C(O)Ri5, oxazolyl, thiazolyl, pyrazolyl, triazolyl or tetrazolyl; or when R5 and Ri are as NR5R16 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N or S; or A is SR12;

R5 is independently hydrogen or Cι_4alkyl, unsubstituted or substituted by one to three fluorines;

R6 is R ₅ , -C(O)R ₅ , -C(O)C(O)R ₇ , -C(O)NR ₅ Rι ₆ , -S(O) _m Rι ₂ , -C(NCN)SRι ₂ or -C(NCN)NR ₅ R 6;

R7 is OR5, NR5R16 or R ₅ ; Rg is H or A; R9 is R5;

R 4 is independently hydrogen or a Cι_2 lkyl unsubstituted or substituted by fluorine;

R 5 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, moφholinyl, piperidinyl, piperazinyl or pyrrolyl, and each of these heterocyclic rings is connected at a carbon atom and may be unsubstituted or substituted by one or two Cι_ ₂ alkyl groups; Rj6 is OR5 ^or R5. ^{or a} pharmaceutically acceptable salt thereof;

Rl7 and R ₂ g are independently hydrogen, halogen, Cι- -dkyl, halo-substituted C\_ 4alkyl, cyclopropyl unsubstituted or substituted by R9, -CH ₂ OR5, -CH NR5R16, -C(0)OR ₅ , -C(0)NR ₅ R ₁₆ or -C(Z)H;

Rig, R ₂ 4 and R ₂ 5 are independently H, CN, and C1-.4 alkyl optionally substituted by one or more fluorines;

R ₁₉ is hydrogen, -(CH ₂ ) _m A, or -CH ₂ 0(CH ₂ ) _m A;

R ₂₀ is 0(CH ₂ ) _q Rg, -NR ₅ OR ₅ , NR ₅ (CH ₂ ) _q Rg, -OCH ₂ NR ₅ C(0)R ₂ ;

R ₂ 1 is CH3 or phenyl;

R ₂₂ is hydrogen, CH3, CH ₂ CH ₃ , or CH ₂ CH ₂ OH; R ₂ is hydrogen, CH3, CH ₂ CH ₃ , CH ₂ CH ₂ OH, or CH ₂ CONH ₂ ; when A is morpholin-4-yl, piperidin-4-yl, imidazol-4-yl, piperidin-4-yl or imidazol- 1-yl, then q is not 1.

Preferred compounds are those in which Rj is CH ₂ -cyclopropyl, CH ₂ -C5_g cycloalkyl, C4. cycloalkyl, phenyl, tetrahydrofuran-3-yl, 3- or 4-cyclopentenyl, -Cι_ ₂ alkyl optionally substituted by one or more fluorines, -(CH ₂ ) _n C(0)-0-(CH ₂ ) _m CH3,

-(CH ₂ ) _s O(CH ₂ ) _m -CH3 or -(CH ) ₂ -4θH; X ₂ is oxygen; X3 is hydrogen; X is YR ₂ and Y is 0; R ₂ is a C _ ₂ alkyl optionally substituted by one or more fluorines; R3 is hydrogen, C≡CR9, CN, C(0)H, CH ₂ OH, CH ₂ F, CF ₂ H, or CF3; Rig is hydrogen, CN or C^alkyl optionally substituted by one or more fluorines; R 9 is hydrogen or (CH ) _m A; R ₂ Q is 0(CH ₂ ) _q R ₈ , NR ₅ OR ₅ , or NR ₅ (CH ₂ ) _q Rg.

More preferred are compounds in which Ri is Cι_ ₂ alkyl substituted by 1 or more fluorines, CH ₂ -cyclopropyl, CH -cyclopentyl, cyclopentyl or cyclopentenyl; R is methyl or fluoro substituted Cι_ ₂ alkyl; R3 is hydrogen, CΞCH or CN; and A is 2-, 3- or 4-pyridyl, 4-moφholinyl, 2-thienyl, 2-imidazole or 4-thiazolyl, each of which may be substituted or unsubstituted by NR5R16 or NR5C(0)R5; R ₂ Q is OR5, NR5OR5 or NHCH ₂ A.

Most preferred are compounds wherein R] is cyclopentyl, CF3, CH ₂ F, CHF , CF ₂ CHF ₂ , CH ₂ CF3, CH ₂ CHF ₂ , CH3, CH ₂ -cyclopentyl, CH ₂ -cyclopropyl or cyclopentenyl; R ₂ is CH3, CF3, CHF ₂ , or CH CHF ₂ ; one R3 is hydrogen and the other R3 is hydrogen, C^CH or CN and is in the 4-position. Especially preferred are the following compounds:

N-[3-(3-cyclopentyloxy-4-methoxyphenyl)propyl]oxamide; methyl N-[3-(3-cyclopropylmethoxy-4-difluoromethoxy- phenyl)propyl]oxamate;

N-[3-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)- propyljoxamide; and

- 9 -

SU3STITUTE SHEET

N-[3-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)- propyl]oxamic acid.

General Synthesis The preparation of the compounds of Formula 1(1) can be carried out by one of skill in the art according to the procedures outlined in the Examples, infra. The preparation of any remaining compounds of Formula 1(1)

Formula (1) not described therein may be prepared by the analogous processes disclosed herein, which comprises: a) for compounds wherein R3 is H, Ci-2 alkyl optionally substituted by 1 or more fluorines, R17, Rig, R 9, R24, R25 and R26 are H, and wherein Ri represents Ri as defined in relation to a compound of Formula (I) or a group convertible to Ri and X and X3 represents X and X3 as defined in relation to a compound of Formula (I) or a group convertible to X or X3, reacting a compound of the Formula (2)

Formula (2)

with a malonic acid derivative, such as malonic acid or a malonic acid half ester, in a suitable solvent such as pyridine with (or without) a catalyst at elevated temperatures to provide a compound of the Formula (3), wherein R27 is OH, O-alkyl, O-phenyl, or O-benzyl.

Formula (3)

Reduction with a suitable reductant such as hydrogen with a catalyst, except where X or X3 is SO, SO2 or NO2, Br, I and formyl amine; provides a compound of the Formula (4)

wherein R3, is as defined above for part a), Ri8, R17 and R24 are H, and R27 is OH, O- alkyl , O-phenyl, or O-benzyl.

Formula (4)

Convering a compound of Formula (4) wherein R27 is OH to a compound of Formula (4) wherein R27 is NHR19 may be accomplished by any of the standard peptide coupling methods well known in the art, e.g. mixed anhydride formation when R27 is OH followed by reaction with the amine, NH2R19- For those compounds in which R19 does not possess a reducible functionality, reduction of the amide moiety of a compound of the Formula (4) wherein R27 is NHR19 provides a compound of the Formula (5) wherein R3 is as defined above for part a), R17 is H and R19 is as defined in part in Formula (1)

Formula (5)

Compounds of Formula (5) wherein R3 is other than CH2NR7R8, unless protected by a group such as t-butoxycarbonyl or any other easily removed amino protecting groups well known to those skilled in the art, and Rig is defined for Formula (1), and R19 is H, ma be further modified, such as by imine formation with an appropriate aldehyde, followed by reduction, and further modification to produce compounds of Formula (5) wherein R19 is other than hydrogen.

Synthesis of compounds of Formula (1) wherein R3 is OR5 or F and Ri is H or F, begins by reaction of a compound of Formula (2) wherein R3 is H with a methyl metal reagent, for example, methyl lithium to provide an alcohol of Formula (2')

Oxidizing a compound of Formula 2' with an oxidizing agent, for example pyridium dichromate, provides the ketone of Formula (2) as described above wherein R3 is methyl.

This compound is treated with a halogenating agent, for example copper (II) bromide and heated in a suitable solvent to provide the α-halo ketone of Formula (2") wherein X4 is a halogen, for example, bromide.

Formula (2")

Displacement of the halogen of Formula (2") by a metal cyanide, such as sodium cyanide, in a suitable solvent, such as dimethylformamide provides, the α-cyanoketone of Formula (2"), wherein X4 is CN, which is reduced in one or more steps with hydrogen and a catalyst or an appropriate metal hydride to the Formula (5) compound where R3 is OH, and R g, R17, R19 and R24 are H. For example, treatment of the Formula (2") compound with lithium aluminium hydride to provide the Formula (5) compound. To produce compounds wherein R3 is OR5 the compounds of Formula (5), wherein R3 is OH and Rl9 is a sutiable amine protecting can be alkylated by treatment with a strong base followed by using alkyl-L, as described above, or by using the process of W. Sheppard, Journal of Organic Chemistry. Vol. 29, page 1-15, (1964).

Treatment of compounds of Formula (1) where R3 is OH, and Ri8, R17 and R24 are H with an appropriate oxiziding agent, for example, pyridium dichromate in a suitable solvent, such as DMF provides Formula (1) compounds where R3 and Ri8 together form a keto moiety. Treatment of a Formula (1) compound where R3 is OH or a Formula (5) compound wherein R3 is OH and R19 is a removable amine protecting group, such as described in Greene, T., Protective Groups in Organic Synthesis. Wiley Publishers, NY (1981), the contents of which are hereby incorporated by reference; with diethylaminosulfur trifluoride (DAST) provides the corresponding Formula (1) or Formula (5) compounds where R3 or Rig is F; which provides the corresponding Formula (1) compounds when treated by any of the methods indicated herein.

Treatment of Formula (1) or Formula (5) compounds where R3 and Rl8 together form a keto moiety with DAST provides the corresponding Formula (1), or Formula (5) compounds where R3 and Rig are both F; which provides the corresponding Formula (1) compounds when treated by any of the methods indicated herein.

Alternatively, synthesis of some compounds of Formula (1) when X or X3 are other than Br, I, NO2, or formylamine, begins by reaction of a compound of the Formula (2) with a lithium halide and a silyl halide in an appropriate solvent followed by reduction with an appropriate reductant, such as a siloxane, to provide a compound of Formula (6) wherein X5 is halogen.

Formula (6)

Halide displacement of a compound of Formula (6) by, e.g., the anion of a cyano acetate, provides the compound of the Formula (7) wherein R17 is COOR5 and R5 is other than H. Ester saponifcation and acid decarboxylation provides a compound of Formula (7), wherein R3, R17 and Ri8 are H,

which is reduced with an appropriate reductant, such as hydrogen with a suitable catalyst, such as nickel with ammonia or palladium on carbon with an acid, such as perchloric acid, t provide a compound of Formula (5), described above, wherein R 9 is hydrogen.

Alternatively, the R 17 ester group of the above described compounds of Formula (7) may be converted to other compounds of Formula (7) wherein R 7 is, e.g., C(O)OR5, C(O)NR5Ri6, C(Z)H, etc., by standard chemical transformation.

Certain compounds of Formula (1) wherein R17 is other than CH2NR5R16 unless suitably protected, are prepared by reacting a compound of Formula (5) with an appropriately activated oxamic acid derivative of a Formula (8) compound wherein Xg is an activating group, well known to those skilled in the art, such as those disclosed in Bodansky fl al.. Peptide Synthesis. Wiley & Sons, publishers (1976) pages 99-109. More preferred X groups are Cl, Br, OCH2CH3, OC(O)CH ₃ , OC(O)CF ₃ ,O-C(O)-OCH ₂ CH ₃ , O-C(O)- OCH2CH(CH3)2, or O-C(O)-OCH2-C6Hs in the presence of a non-nucleophilic base.

Formula (8)

Alternatively, the ester moiety of a compound of Formula 9

may be hydrolyzed to give the free acid, followed by activation of the acid moiety by a halogenating agent, such as an acid halide, oxalyl chloride, or phosphorous oxylchloride, etc. or a mixed anhydride and reaction with ammonia, an optionally substituted amine, optionally substituted hydroxylamine, or an optionally substituted hydrazine, produces the compounds of Formula (1) wherein R20 i -NR ₇ Rg, -NR ₇ -NR ₇ Rg, -NR7OH, -NR5OR5, -NR ₅ NR5Rg, -NR5 CH2)qRg; b) or hydrolyzing a compound of Formula (9) as described above, to yield a compound of Formula (9) wherein R is H, and reacting it with ammonia, an optionally substituted amine, optionally substituted hydroxylamine, or an optionally substituted hydrazine and a compound of the formula R28N=C=NR28 wherein R28 is independendy selected from alkyl; cycloalkyl, such as cyclohexyl or dicyclohexyl; alkyl (mono-or dialkyl amino), such as ED AC; aryl or arylalkyl, to produce the compounds of Formula (1) wherein R20 is an amine or substituted amine derivative; or c) for compounds wherein R3 is not H, or CH2NH2 and X and X3 are substituted with other than Br, I, amino, formylamine, and NO2, compounds of Formula (6) wherein X5 is CN, derived by reaction of a compound of the Formula (6) wherein X5 is halide, with e.g., sodium cyanide in DMF, are allowed to react with a strong hindered base, such as lithium dϋsopropylamide (LDA) or hexamethyldisilazylithium (LiHMDS) followed by reaction with, e.g., methyl or t-butyl bromo acetate to provide compounds of Formula (4) wherein R3 is CN and R17 is H and R27 is CH3 or t-butyl; conversion of such a Formula (4) compound to a Formula (4) compound wherein OR27 is NH2 is accomplished as described above. Selective reduction of such a Formula (4) compound to a compound of the Formula (5) wherein R3 is CN and Ri8 and R19 are H may be accomplished using, e.g., sodium bis(2- methoxyethoxy)aluminum hydride or by the method of Y. Mahi et al. Chem. Ind. , 1976, 322. Further elaboration of such a compound of Formula (5) wherein R19 is H to a compound of Formula (5) wherein R19 is other than H, and then to a compound of Formula (1), may be accomplished as described above. d) Compounds of the Formula (a) or Formula (5) wherein R3 and Rig is alkyl or fluoro substituted alkyl may be derived from the corresponding Formula (1) or Formula (5) compound containing an oxo carbon species by deoxygenation or DAST treatment. e) compounds wherein both R3 and Ri8 are cyano are prepared in an analogous manner using a compound of Formula (10)

and reacting with a base or a metal hydride followed by treatment with an appropriately substituted halo alkyl acetate to produce the compound of Formula (4) wherein both R3 and Rl8 are CN; this may be elaborated as described above for other compounds of Formula (4) to produce a compound of Formula (1). f) compounds of Formula (1) wherein X or X3 are is formyl amine are formed at the last step, by formylating a compound wherein X or X3 is NH2, obtained by removal of a protecting group from the amine functionality. Such protective groups are well known to those skilled in the art, See Greene, T., supra. g) compounds of Formula (1) wherein X or X3 are Br or I may be prepared on a deprotected amine, diazotization of the amine, and diazonium displacement. h) compounds of Formula (1) wherein X or X3 are NO2 may be prepared on a deprotected amine by oxidation of the amine to the nitro group. i) compound of Formula (1) wherein R3, R18, R24, R25 and R26 re other than hydrogen can readily be prepared by one skilled in the art using the techniques illustrated above.

In order to use a compound of the 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 composition. Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example orally, parenterally, sublingually, transdermally, rectally, via inhalation or via buccal administration. Those of skill in the formulation arts will be capable of preparing appropriate formulations targeted to one or more of these routes of administration.

Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.

Each dosage unit for oral administration contains suitably from 0.001 mg to 100 mg/Kg, and preferably from .01 mg to 30 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.001 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt therof calculated as the free base. Each dosage unit for intranasal administration or oral inhalation contains suitably 1-400 mg and preferably 10 to 200 mg per person. A topical formulation contains suitably 001 to 1.0% of a compound of Formula (I). Each dosage unit for rectal administration contains suitably 0.01 mg to 100 mg of a compound of Formula (I).

The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base. The daily dosage regimen for parenteral administration is suitably abut 0.001 mg/Kg to 40 mg/Kg, for example abut 0.001 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 daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 1200 mg/person. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit antiinflammatory activity, or if used as a TNF inhibitor, the active ingredient is administered in an amount sufficient to inhibit TNF production such that normal or subnormal levels are achieved which are sufficient to ameliorate or prevent the disease state.

The biological activity of the compounds of Formula I as in PDE TV inhibitors are demonstrated by the following tests.

Inhibitory Effect of Compounds of Formula I on PDE IV

I. Isolation of PDE Isozymes

Phosphodiesterase inhibitory activity and selectivity of compounds is determined using a battery of five distinct PDE isozymes. The characteristics of these PDEs appear in Table 1. The tissues used as sources of the different isozymes are as follows: 1) PDE la, canine trachealis; 2) PDE lb, porcine aorta; 3) PDE Ic, guinea- pig heart; 4) PDE III, guinea-pig heart; and 5) PDE IV, human monocyte. PDEs la, lb, Ic and JH are partially purified using standard chromatographic techniques (Torphy and Cieslinski, Mol. Pharmacol.21:206-214, 1990). PDE TV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-

Sepharose chromatography (Torphy et al., J. Biol. Chem., 267: 1798-1804 (1992)).

TABLE 1. Characteristics of PDE isozymes. ^a

Peak Isozyme

la cGMP-specific lb Ca^ ⁺ /calmodulin-stimulated

Ic Ca2 ⁺ /calmodulin-stimulated m cGMP-inhibited

TV Ro 20-1724-inhibited

^a Data are from Torphy and Cieslinski, ^D Nomenclature is from Beavo, Adv. Second Messenger Phosphoprotein Res. 22: 1-38, 1988.

π. PPE Assay

Phosphodiesterase activity is assayed as described in Torphy and Cieslinski, Mol. Pharmacol.22:206-214, 1990. IC50S for compounds of this invention range from 25 nM to 500 mM.

III. cAMP Accumulation in U-937 Cells

The ability of selected PDE TV inhibitors to increase cAMP accumulation in intact tissues is assessed using U-937 cells, a human monocyte cell line that has been shown to contain a large amount of PDE IV. To assess the activity of PDE IV inhibition in intact cells, nondifferentiated U-937 cells (approximately 10^ cells/reaction tube) were incubated with various concentrations (0.01-100 mM) of PDE inhibitors for one minute and 1 mM prostaglandin E2 for an additional four minutes. Five minutes after initiating the reaction, cells were lysed by the addition of 1M potassium carbonate and cAMP content was assessed by RIA. A general protocol for this assay is described in Brooker et al., Radioimmunassay of cyclic AMP and cyclic GMP,

Adv. Cyclic Nucleotide Res., 10:1-33, 1979. Data are expressed as both an EC50 for increases in cAMP accumulation as a percentage of the maximum response to rolipram produced by 10 mM of the test compounds. EC50S for compounds of this invention range from 0.3 mM to > 10 mM.

Inhibitory Effect of Compounds of Formula (I) on TNF Production

I. Inhibitory Effect of compounds of the Formula (I) on in vitro TNF production by Human Monocytes.

The inhibitory effect of compounds of the Formula (I) on in vitro TNF production by Human Monocytes may be determined by the protocol as described in Badger et al., EPO published Application 0411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990.

II. In vivo actity

Two models of endotoxin shock have been utilized to determine in vivo TNF activity for the compounds of the Formula (I). The protocol used in these models is described in Badger et al.. EPO published Application 0411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990.

No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention. The following exampled illustrate this invention but are not intended in any way to limit the scope of the invention. Reference is made to the claims for what is reserved to the inventors hereunder.

EXAMPLE 1 3-Cvclopentyloxy-4-methoxybenzaldehvde 3-Cvclopeπtyloxy-4-methoxybenzaldehvde A mixture of 3-hydroxy-4-methoxy- benzaldehyde (40 g, 0.26 mol), potassium carbonate (40 g, 0.29 mol) and bromocyclo- pentane (32 mL, 0.31 mol) in dimethylformamide (0.25 L) was heated under an argon atmosphere at 100°C. After 4h, additional bromocyclopentane (8.5 mL, 0.08 mol) was added and heating was continued for 4h. The mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between ether and aqueous sodium bicarbonate. The organic extract was washed witii aqueous sodium carbonate and was dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 2:1 hexanes ether, to provide a pale yellow oil- Analysis Calc. for Cι ₃ H ₁₆ θ3: C 70.89, H 7.32; found: C 70.71, H 7.33.

EXAMPLE 2

N-r3-G-Cvclopentyloxy-4-methoxyphenyl).propyπoxamide 2a. 3-f3-Cyclopentyloxy-4-methoxyphenyl ^' .prop-2-enoic acid A mixture of 3- cyclopentyloxy-4-methoxybenzaldehyde (4.4 g, 20 mmol), malonic acid (4.16 g, 40 mmol) and piperidine (0.3 mL) in pyridine (8 mL) under an argon atmosphere was heated at 80°C for 4h. The mixture was cooled, the residue was poured into ice water and was acidified with concentrated hydrochloric acid (10 mL). The solid was collected by filtration, was washed well with acidic water and was dried.

2b. 3-f3-Cvclopentyloxy-4-methoxyphenyl'-prop-2-enamide To a solution of 3-(3- cyclopentyloxy-4-methoxyphenyl)prop-2-enoic acid (0.3 g, 1.14 mmol) in chloroform (5.2 mL) under an argon atmosphere was added triethylamine (0.16 mL, 1.14 mmol). The solution was cooled to 0 C and ethyl chloroformate (0.11 mL, 1.14 mmol) was added. The resulting mixture was stirred at 0 C for 20 min. Ammonia was bubbled into the solution, the solution was allowed to warm to room temperature, was stirred for lh and was allowed to stand overnight The mixture was partitioned between methylene chloride and water, the organic extract was dried (potassium carbonate) and was concentrated under reduced pressure to provide a solid-

2c. 3- 3-Cyclopentyloxy-4-methoxyphenyl ^' )propanamide A solution of 3-(3- cyclopentyloxy-4-methoxyphenyl)prop-2-enamide (0.215 g, 0.82 mmol) and 10% palladium on carbon (0.2 g) in methanol (10 mL) was hydrogenated at 50 psi for 1.5h. The mixture was filtered through Celite, the filtrate was evaporated and was partitioned between methylene chloride and water. The organic layer was dried (potassium carbonate) and was evaporated to a solid.

2d. 3-G-Cyclopentyloxy-4-methoxyphenvDpropylamine To a suspension of lithium aluminum hydride (0.043 g, 1.13 mmol) in ether (10 mL) at room temperature under an argon atmosphere was added dropwise a solution of 3-(3-cyclopentyIoxy-4-

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SϋBSTiTϋTE SHEET

methoxyphenyl)propanamide (0.19 g, 0.71 mmol) in tetrahydrofuran/ether. The resulting mixture was heated at reflux for 2h and then stirred at room temperature overnight. The reaction mixture was quenched by the successive dropwise addition of water (0.043 mL), 15% sodium hydroxide (0.043 mL) and water (0.13 mL). The mixture was filtered and was diluted with methylene chloride, the filtrate was washed with water and was dried (potassium carbonate). Removal of the solvent in vacuo provided the amine.

2e. Methyl N-r3- 3-cvclopentyloxy-4-methoxyphenyπpropynoxamate A solution of 3- (3-cyclopentyloxy-4-methoxyphenyl)propylamine (0.14 g, 0.57 mmol) in tetrahydrofuran (2 mL) was cooled to 0°C and was treated with triethylamine (0.09 mL, 0.57 mmol) and methyl oxalyl chloride (0.065 mL, 0.57 mmol). The reaction was stirred under an argon atmosphere for 0.5h, then partitioned between acidic water and methylene chloride. The extract was dried (potassium carbonate) and was evaporated.

2f. N-r3-( ^" 3-Cvclopentyloxy-4-methoxyphenyl).propylloxamide A solution of methyl N- [3-(3-cyclopentyloxy-4-methoxyphenyl)propyl]oxamate (0.18 g, 0.54 mmol) in methanol (2 mL) in a pressure vessel was cooled to -78°C and ammonia (2 mL) was condensed into the vessel. The vessel was sealed, was allowed to come to room temperature and was stirred overnight. The ammonia was evaporated, the residue was dissolved in chloroform, the solution was washed with water and was dried (potassium carbonate). The resultant solid was triturated with ether/methylene chloride, was filtered and was dried : m. p. 163 C. Analysis Calc. for CπH ₂ 4N ₂ θ4-l/8 H ₂ 0: C 63.29, H 7.58, N 8.61; found: C 63.16, H 7.34, N 8.75.

EXAMPLE 3 Methyl N-r3-G-Cvclopropylmethoxy-4-difluoromethoxyphenyl)propylloxa mate 3a. 4-Difluoromethoxy-3-hydroxybenzaldehyde A vigorously stirred mixture of 3,4- dihydroxybenzaldehyde (50 g, 362 mmol) and potassium carbonate (50 g, 362 mol) in dimethylformamide (250 mL) was heated under an atmosphere of chlorodifluoromethane using a -78 C condenser at 100 C for 5.5h. An additional quantity of potassium carbonate (10 g) was added and the reaction was continued for another 0.5h. . The mixture was allowed to cool, was acidified to pH 5-6 with concentrated hydrochloric acid and was concentrated under reduced pressure. The residue was partitioned between ether and 3N aqueous hydrochloric acid and was extracted five times with ether. The organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, to provide a yellow solid, which was triturated with ethyl acetate/hexanes to provide, in three crops, a white solid: m.p. 84-86°C.

3b. 3-Cyclopropylmethoxy-4-difluoromethoxybenzaldehvde To a mixture of 3-hydroxy- 4-difluoromethoxybenzaldehyde (19.55 g, 104 mmol) and potassium carbonate (21.56 g, 156 mmol) in dimethylformamide (150 mL) under an argon atmosphere at 60°C was added bromomethylcyclopropane (15.13 mL, 156 mmol) and the mixture was stirred and heated at

- 19 -

65°C. After 1.5h, the mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure, water was added and the mixture was extracted four times with ethyl acetate. The organic extract was washed twice with water and was dried (sodium sulfate). The solvent was removed in vacuo to provide an oil. 3e. 3-G-Cy opropylmethoxy-4-difluoromethoxyphenyDprop-2-enoic acid A mixture of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (0.4 g, 1.65 mmol), malonic acid (0.34 g, 3.3 mmol) and piperdine (10 drops) in pyridine (0.66 mL) under an argon atmosphere was heated at 80°C for 4.5h. The mixture was cooled, the residue was acidified with 3N hydrochloric acid, the solid was collected by filtration, was washed well with 3ϋ hydrochloric acid and was dried: m.p. 161-163 C.

3f. 3-G-CycIopropylmethoxy-4-difluoromethoxyphenyl)prop-2-enarni de To a solution of 3-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)prop-2-enoic acid (0.55 g, 1.93 mmol) in chloroform (10 mL) under an argon atmosphere was added triethylamine (0.27 mL, 1.93 mmol). The solution was cooled to 0°C and ethyl chloroformate (0.18 mL, 1.93 mmol) was added. The resulting mixture was stirred at 0°C for 15 min. Ammonia was bubbled into the solution, the solution was allowed to warm to room temperature and was stirred for 3 days. The mixture was partitioned between ethyl acetate and acidic brine, was extracted twice, the organic extract was washed with acidic brine, was dried (magnesium sulfate) and was concentrated under reduced pressure. Purification by flash chromatography, eluting with 10-20% me anol/methylene chloride, provided a solid: m.p. 134-136°C.

3g, 3-G-Cyclopropylmethoxy-4-difluoromethoxyphenyI'.propanaιnid e A solution of 3- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl)prop-2-enamide (0.36 g, 1.27 mmol) and 10% palladium on carbon in methanol (20 mL) was hydrogenated at 50 psi for 1.5h. The mixture was filtered through Celite, the filtrate was evaporated and the residue was redissolved, was filtered through a short pad of silica gel and was evaporated to a solid: m.p. 103-105°C.

3h. 3-G-Cvclopropylmethoxy-4-difluoromethoxyphenyl ^' )propyl- amine. To a suspension of lithium aluminum hydride (0.066 g, 1.74 mmol) in ether (20 mL) at room temperature under an argon atmosphere was added dropwise a solution of 3-(3- cyclopropylmethoxy-4-difluoromethoxy-phenyl)propanamide (0.31 g, 1.09 mmol) in tetrahydro-furan/ether (10 mL). The resulting mixture was heated at reflux for 2h and then was stirred at room temperature overnight. The reaction mixture was quenched by the successive dropwise addition of ethyl acetate and then aqueous sodium potassium tartrate, was poured into brine and was extracted twice with methylene chloride. The organic extract was dried (potassium carbonate) and d e solvent was revoved in vacuo to provide the amine.

3i. Methyl N-G-G-cyclopropylmethoxy-4-difluoromethoxyphenyl ^" )propyl]oxamate A solution of 3-(3-cyclopropylmethoxy-4-difluoromeΛoxyphenyl)propylamine (0.31 g, 1.14 mmol) in tetrahydrofuran (20 mL) was cooled to 0 C and was treated with triethylamine (0.18 mL, 1.25 mmol) and methyl oxalyl chloride (0.11 mL, 1.14 mmol). The reaction was

- 20 -

T TE SHEET

stirred under an argon atmosphere for 0.5 h, was partitioned between acidic water and methylene chloride and was extracted twice. The organic extract was dried (magnesium sulfate) and evaporated. Purifi-cation by flash chromatography, eluting with 1:1 hexanes/ethyl acetate, provided a tan solid: m.p. 33-35 C. Analysis Calc. for C17H21F2NO5: C 57.14, H 5.92, N 3.92; found: C 57.39, H 6.00, N 3.90.

EXAMPLE 4 N-r3-C3-Cvclopropvlmethoxv-4-difluoromethoxvphenvnpropylloxa mide N-f3-f3-Cyclopropylmethoxy-4-difluoromethoxyphenvI')-propyll oxamide A solution of methyl N-[3-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)propyl]-o xamate (0.1 g, 0.28 mmol) in methanol (3 mL) was cooled to -78 C and ammonia (2 mL) was condensed into die vessel. The the mixture was allowed to come to room temperature and the ammonia was evaporated under a stream of argon. The residue was partitioned between methylene chloride and brine, was extracted twice with methylene chloride, die organic extract was dried (magnesium sulfate) and was evaporated. The solid product was precipitated from ethyl acetate with hexane: m. p. 151-152 C.

Analysis Calc. for C16H20F2N2O4: C 56.14, H 5.89, N 8.18; found: C 56.22, H 5.85, N 8.08.

EXAMPLE 5 N 3-f3-Cvclopropvlmethoxv-4-difluoromethoxvphenvttpropvlloxami c acid N-r3-('3-Cvclopropvlmethoxv-4-difluoromethoxvphenvn-proρvno xamic acid To a solution of methyl N-[3-(3-cyclopropylmethoxy-4-difluoromethoxyρhenyl)propyl]- oxamate (0.05 g, 0.14 mmol) in 5:5:2 tetrahydrofuran/methanol/water (2 mL) at room temperature under an argon atmosphere was added powdered sodium hydroxide (0.02 g, 0.42 mmol). After 3h, the mixture was acidified with 3M hydrochloric acid, was extracted three times with methylene chloride, the organic extract was dried (magnesium sulfate) and was evaporated to a tan solid: m.p. 134-135 C. Analysis Calc. for C16H19F2NO5: C 55.97, H 5.58, N 4.08; found: C 55.81, H 5.69, N 3.95.