IE913855A1 - Imidazolidinone compounds - Google Patents

Abstract

Novel imidazolidinone derivatives are described which inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease stated mediated or exacerbated by TNF production. The compounds of the present invention are also useful as inhibitors of PDE IV and are therefore useful in the treatment of disease states in need of mediation or inhibition thereof.

Description

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

Background of the Invention Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli.

Identification of novel therapeutic agents for asthma is made difficult by the 0 fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma. An alternative to the mediator approach is to regulate the activity of the cells responsible for the pathophysiology of the disease.

One such way is by elevating levels of cAMP (adenosine cyclic 3',5'2 5 monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, pgs 17-29, 1973). When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated which converts Mg+2-ATP to cAMP at an accelerated rate. 0 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 de-granulation, 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). - 2 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 Antiasthmatic 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. 0 Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.

The compounds of this invention also inhibit the in vivo 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, 0 silicosis, pulmonary sarcoisosis, 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.

AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte activation. 0 Other viruses, such as HIV-1, HIV-2 infect T lymphocytes after T Cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication. 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 inhibition of monokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected ·3· 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 HIV 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 HIV progression as stated above for T-cells. 0 TNF has also been implicated in various roles with other viral infections, such as the cytomegalia virus (CMV), influenza virus, and the herpes virus for similar reasons as those noted.

The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF.

Summary of the Invention This invention relates to the novel compounds of Formula (I), as shown 0 below, having Tumor Necrosis Factor inhibitory activity. This invention also relates to their pharmaceutical compositions comprising a compound of Formula (I), or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which process comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of 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 0 effective TNF inhibiting amount of a compound of Formula (I).

The compounds of 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. 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, HIV-2 and HIV-3 as noted above, Cytomegalovirus (CMV), Influenza, and the Herpes family of viruses, such as Herpes Simplex & Herpes Zoster. -4This invention also relates to the novel compounds and pharmaceutical compositions, of Formula (Ia), a sub-genus of the compounds of Formula (I) having TNF activity but also are useful in the mediation or inhibition of phosphodiesterase IV (PDE IV).

The invention also relates to a method of inhibiting phosphodiesterase IV in a 5 mammal, including humans, which comprises administering to an mammal in need thereof an effective amount of a compound of Formula (Ia), as shown below.

The invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal in need thereof, an effective amount of a compound of Formula (Ia). 0 The invention also provides a method for the treatment of asthma which comprises administering to an a mammal in need thereof, an effective amount of a compound of Formula (Ia).

The compounds of Formula (I) are represented by the structure: O wherein: Rj is - (CR9RlO)n- (C(O)O)r -(CR9RlO)m-R8, -(CR9R10)n- (C(O)NR6)r (CR9RlO)m-R8, θΓ - (CR9RlO)n* (O)s -(CR9Rio)m-R8 wherein the alkyl moieties may be optionally substituted with one or more halogens; n is a number having a value of 0 to 4; 0 m is a number having a value of 0 to 2; r is a number having a value of 0 or 1; s is a number having a value of 0 or 1; R9 and Rio are independently selected from hydrogen or a Ci-2 alkyl; R8 is hydrogen, methyl, hydroxyl, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocylic moietes may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that a) when r is 1, n is 1 to 4; or - 5 b) when s is 1, n is 2 to 4; or c) when Rg is hydroxyl, r is 1, and n is 1 to 4, then m is 2; or d) when Rs is hydroxyl, and r or s is 0, then the sum of n + m is 2 to 6; or e) when m is 0, r is 1 in -(CR9Rio)rr (C(O)O)r -(CR9Rio)m-R8> then n is 1 to 4; or f) when Rs is a 2-tetrahydropyran or 2-tetrahydrothiopyran, 2-tetrahydrofuran or 2 tetrahydrothiophene, and r or s is 0, then the sum of n + m is 1 to 6; or g) when Rs is a 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetrahydrofuran or 2tetrahydrothiophene, n is 1 to 4, and r is 1, then m must be 1 to 2; or h) when R8 is a 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetrahydrofuran or 2tetrahydrothiophene, n is 2 to 4, and s is 1, then m must be 1 to 2; X is YR2, halogen, nitro, NR6R7, or formyl amine; Y is O or S(O)m'; m' is anumber having a value of 0 to 2; R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; R3 is H, CH3, CN, CH2F, CHF2, or CF3; R4 is H, C!-C4 alkyl, OH, OCH3, OCH2CH3, or OAc; R5 is H, OH, -(CH2)qAr, or Cj.g alkyl wherein the (CH2)qAr or Ομ^ alkyl group is optionally substituted one or more times by Br, Cl, F, -N0g,**R6R7,-CO2R6, 0 -OR6, -OC(O)R6, C(O)R6, CN, -C(O)-NR6R7, -C(S)-NR6R7. - NR6-C(O)-NR6R7.

- NR6-C(S)-NR6R7, - NR6-C(O)-R6, - NR6-C(S)-Re, - NR6-C(O)-OR6, C(=NR6)-NR6R7, -C(=NCN)-NR6R7. -C(=NCN)-SR6, -NR6-C(=NCN)-SR6 , - NR6-C(=NCN)-NR6R7, -C(=NR6R7)SR6, -NR6-S(O)2 -R6, - S(O)m'-R6, -NR6SO2-CF3, - NR6C(O)-C(O)-NR6R7, - NR6-C(O)-C(O)-OR6, 1-imidazolyl, or 1-(NR6)-2-imidazolyl; Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, morpholino, 4- or 5thiazolyl, triazolyl, 2- or 3- thienyl, 2-thiaphene, or phenyl; -6R5 and R7 are independently hydrogen, or C 1.4 alkyl optionally substituted by one or more halogens; q is a number having a value of 0 to 2; and the pharmaceutically acceptable salts thereof.

Detailed Description of the Invention The compounds of Formula (la) are represented by the structure: Oa) wherein Rl is -CH2-C3 cylic alkyl, -CH2-C5-6 cylic alkyl, C4-6 cyclic alkyl, tetrahydrofuran, cyclopentenyl,-Ci-7 alkyl optionally substituted by 1 or more fluorines, -(CH2)i_40H for Formula (la), -(CH2)h-C(O)0(^)^-^3,-(CH2) -O-(CH2)rtCH3, all of which may be optionally substituted by one to three mfethyl groupsor one ethyl group; m is a number having a value of 0 to 2; n is a number having a value of 1 to 3; p is a number having a value of 2 or 3; X is YR2; Y is O or S; R2 is -CH3 or CH2CH3 optionally substituted by 1 or more f 1 uori nes; R3 is H, CH3, CN, CH2F, CHF2 or CF3; R4 is H, Cl-4 alkyl, OH, OCH3, OCH2CH3, or OAc; R5 is H, OH, -(CH2)q Ar, Cl-6 alkyl; wherein Ar and Ci-6 alkyl may be unsubstituted or substituted by one or more of the following: Br,Cl,F,N02-,NR6R7. CO2R6, -NH-C(=NCN)-SCH3, -NHC(O)-NR6R7, -C(O)NR6R7, -NHC(O)CH3, -NH-(=NCN)-NR6R7, -NHC(O)C(O)-NR6R7, -NHSO2CH3, -S(O)mCH3, -NHC(O)C(O)-OR6, -OR6, -CN, -C(=NR6)-NR6R7, i.

-NHSO2CF3, 0-0 -7Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, morpholino, or phenyl; Rg and R7 are independently hydrogen, or C1.4 alkyl; q is a number having a value of 0 to 2; or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is the novel compounds of Formula (II), also a sub-genus of Formula (I) having activity as an inhibitor of TNF.

The compounds of Formula (II) are represented by the structure: wherein: Rj, n, m, r, s, q, R8, R3 , R4 , R5, Ar, Rg, and R7 are as defined for Formula (I); Xj is halogen, nitro, NRgR7, or formyl amine; and pharmaceutically acceptable salts thereof.

When Ri for the compounds of Formula (I) and (II) is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a 2 0 Ci-4 alkyl substituted by 1 or more fluorines, more preferably 1 or more times by fluorine The most preferred chain length is one or two carbons, and most preferred is a -CF3, CH2F, -CHF2, -CF2CHF2, CH2CF3, or -CH2CHF2 moiety. More preferred are those — CH2 compounds in which Ri is cyclopentyl, -CF3, -CHF2, or CH3. The Rj term contains the moiety (CR9R10) wherein the R9 and Rio are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR9Rjo)n or (CR9Rio)m; each repeating methylene unit is independent of the other, e.g. (CR9Rio)n wherein n is 2 can be -CH2CH(CH3)- for instance. The individual hydrogen atoms of the repeating methylene unit or the branching hydrocarbon can be substituted by fluorine independent of each other to yield, for instance, the preferred 0 Rl substitutions, as noted above.

Preferred Ri groups for the compounds of Formula (Ia) are -CH2-C3 cycloalkyl, -CH2-C5-6 cycloalkyl, C4-g cycloalkyl, tetrahydrofuran, cyclopentenyl, -Cl.7 alkyl -8optionally substituted by 1 or more fluorines, and for Formula (la). When R. is a Chalky! Optionally substituted by fluOrine the more preferred arouDS are -CF3,-CH2F,CHF2,-CF2CH2CF3, or -CHgCHFg.

Preferred X groups for both Formulas (I) and (Ia) are those wherein X is YR2, Y is oxygen. Preferred R2 groups for the compounds of both Formula (I) and (Π), and (Ia) where applicable is a Ci-2 alkyl optionally substituted by 1 or more halogens. The halogens atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R2 groups those wherein R2 is methyl, or the fluoro-substituted alkyls, specifically a Cj-2 alkyl, such as a -CF3, CHF2» °r -CH2CHF2 moiety. Most preferred are the CHF2 and CHg moieties.

Preferred R5 groups are the optionally substituted -(CH2)qAr moiety, wherein q is preferably 1, or an optionally susbtituted Cl-6 alkyl, more preferably when R5 is an alkyl and more preferred when R5 is a C3_salkyl. Preferred substituent groaps on the alkvl and aryl moieties are Br,Cl,F,NO2» NR6R7,CO2R6,-NH-C(=NCN)-SCH3, -NHC(O)-NR6R7, -C(O)NR6R7, -NHC(O)CH3, -NH-(=NCN)-NR6R7, -NHC(O)C(O)-NR6R7, -NHSO2CH3, -S(O)mCH3, -NHC(O)C(O)-OR6, -OR6. -CN, -n^n N' NR6 or -C(=NR6)-NR6R7, -NHSO2CF3, U=/ , More preferred substitutent groups are -NH2, -N(CH3)2,-S(O)mCH3, -NHC(O)-CH3, -CO2CH3, OCH3, CO2H, NO2,-NH-C(=NCN)-SCH3, -NH-C(=NCN)NH2, -NH-C(O)-NH2, -NH-C(O)-C(O)-OR6> or NH-C(O)-C(O)-NR6R7· Preferably, \=z the Ar moiety is phenyl.

Preferred R4 substituents for the compounds of Formulas (I), (Ia) and (II) are H, Ci-2 alkyl orOCH3.

Preferred are those compounds of Formula (I) and (Ia) wherein R5 is an optionally substituted -(CH2)qAr, q is 0 or 1 or an optionally substituted C3-5 alkyl; Rj is -CH2-C3 cylic alkyl, -CH2-C5-6 cylic alkyl, C4-6 cyclic alkyl, tetrahydrofuran, cycl 0pentenyl, -C^alkyl optional ly substituted by 1 or more fluorines, and -(.CH2)i_4°W for Formula (Ia J fRgis methyl or fluro substituted afayl, R3 is CN,CHF2,CF3, or H; R4 is H.C^.alkyl or OCH.; Y is oxygen.

More preferred compounds are those Rj, f<2» ar>d Y are as described above, and R5 is Ar is optionally substituted -(CH2)qAr, q is 1 and Ar is phenyl; R3, is H, CN, methyl or CHF2 and R4 is H or C1-4 alkyl. The optional substitutuents are selected from -NH-C(O)-CH3, -NH-C(=NCN)-SCH3, -NH-C(=NCN)-NH2, -NH-C(O)-NH2, -nh2, -N(CH3)2, -NH-C(O)-C(O)-NH2, or -NHC(O)CC>2CH3 group.

Most preferred are those compounds wherein R1 is cylopentyl, CF2H or methyl, R3? is H, CN'or CH3, R4 is hydrogen, X is YR2, Y is oxygen, R2 is CF2H or methyl, and Rg -9is benzyl substituted by a -NH-C(O)-CH3, -NH-C(=NCN)-SCH3, -NH-C(=NCN)-NH2, -NH-C(O)-NH2, -NH2, -N(CH3)2, -NH-C(0)-C(0)-NH2, or -NHC(O)CO2CH3 group.

Especially preferred are the following compounds: l-(4-AminobenzyI)-4-(3-cyclopentyloxy-4-methoxyphenyl)-25 imidazolidinone; l-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-2imidazolidinone; 4- (3-Cyclopentyloxy-4-methoxyphenyl)-l-(4-dimethyI-aminobenzyl)-2imidazolidinone; 0 4-(3-CycIopentyloxy-4-methoxyphenyl)-2-imidazolidinone; l-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; R-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidizolidinone - (+)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidiazolidinone S-(-)-1-(4- Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; R-(+)-1-(4- Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; S-(-)-l-(4-Benzylpyridy!)-4-(3-cyclopentyloxy-4-methoxyphenyl)-22 0 imidazolidinone; R-(+)-l-(4-Benzylpyridyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; S-(-)-l-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; R-(+)-1 -(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; S-(-)-l-(4-Oxamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; R-(+)-l-(4-Oxamidobenzyl)-4-(3-cyclopentvloxy-4-methoxyphenyl)-23 0 imidazolidinone; R-(+)-l-(4-Formamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; S-(-)-l-(4-Formamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; l-(4-Acetamido-3-pyridylmethyI)-4-(3-cyclopentyloxy-4-methoxyphenyl)2-imidazolidinone; S-(-)-4-(3-Cyclopentyloxy-4-methoxy pheny 1)-1-(2,4-diaminobenzyl)-2imidazol idinone; - 10S-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1 -(2,4-diacetamidobenzyI)2-imidazolidinone; R-(+)-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(2,4-Diaminobenzyl)-2imidazolidinone; or R-(+)-4-(3-Cyclopenty loxy-4-methoxyphenyl)-1 -(2,4-diacetamidobenzyl)2-imidazolidinone.

Another aspect are the novel intermediates used herein, in particular Formulaes (5) and (6). Preferred exemplified compounds of Formula (5) are (2R)- and 0 (2S)-l-BenzyloxyCarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)menthy loxycarbony lam ino] e th ane.

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.

By the term Ci-yalkyl or alkyl groups as used herein is meant to include both straight or branched chain radicals of 1 to 7 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.

By the term alkenyl as used herein is meant to include, but not limited to 0 vinyl, 1-propenyl, 2-propenyl, 2-propinyl or 3-methyl-2-propenyl.

By the term cycloalkyl or cycloalkyl alkyl as used herein is meant to include groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl or cyclohexyi.

By the term aryl or aralkyl, unless specificied otherwise, as used herein is meant an aromatic ring or ring system of 6-10 carbon atoms, preferably monocycle, such as phenyl, benzyl, phenethyl or naphthyl.

By the term halo as used herein is meant all halogens, i.e., chloro, fluoro, bromo and iodo.

By the term l-(NR6)-2-imidazolyl or 1-imidazolyl or is meant N^N - R6 —N^N 0 \=/ or \=J respectively.

By the term inhibiting the production of IL-1 or inhibiting the production of TNF is meant a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of the in vivo release of IL-1 by all cells, including but not limited to monocytes or macrophages; - 11 b) a down regulation, at the translational or transcription level, of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of the direct synthesis of IL-1 or TNF levels as a postranslational event.

By the term TNF mediated disease or disease states is meant 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 secreted in response to TNF, would therefore be considered a disease state 0 mediated by TNF. As TNF-Β (also known as lymphotoxin) has close structural homology with TNF-α (also known as cachectin) and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-α and TNF-Β are inhibited by the compounds of the present invention and thus are herein referred to collectively as TNF unless specifically delineated otherwise. Preferably TNF-α is inhibited.

By the term cytokine as used herein is meant any secreted polypeptide that affects the functions of 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 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 B- lymphocytes. Lymphokines are generally referred to as being produced by lymphoctye cells. Examples of cytokines for the present invention include, but are not limited to, Interleukin-1 (EL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF~e) and Tumor Necrosis Factor beta (TNFp).

The inhibition of a cytokine, contemplated by the present invention, for use in the treatment of a HIV-infected human, must be a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HIV gene 0 expression and/or replication, and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration. The cytokine specifically desired to be inhibited is TNF a.

All of the compounds of Formula (I) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes in a human in need thereof. All of the compounds of Formula (Ia) are useful in the method of inhibiting PDE IV and in treatment of disease states mediated thereby.

The mammal is preferably a human, afflicted with a disease state selected from endotoxic shock, adult respiratory distress syndrome, cachexia secondary to infection - 12or malignancy, cachexia secondary to acute immune deficiency syndrome (AIDS), AIDS, reperfusion injury, pulmonary inflammatory disease, cerebral malaria, graft vs. host reaction, bone resorption diseases, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, eczema, psoriasis, sunburn, conjunctivitis, or pyresis.

METHODS OF PREPARATION: Preparation of the compounds of Formula (I) 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 (I) not described therein may be prepared by the 0 analogous processes disclosed herein which comprise: For compounds wherein R3 is other than CN and X is other than Br, I, NO2 , amine, formyl amine or S(O)m' when m1 is 1 or 2, reacting a compound of the Formula (2) wherein Rj represents Rj as defined in relation to a compound of Formula (I) or a group convertable to Ri and X represents X as defined in relation to a compound of Formula (I) or a group convertable to X, with trimethylsilyl cyanide and a suitable catalyst, such as anhydrous zinc iodide, either neat or in the presence of a suitable non-reacting solvent, such as a halocarbon, at ambient temperature under an inert atmosphere. Upon complete formation of the intermediate trimethylsilyl cyanohydrin, the solvent, if present, is removed and the residue is reacted with the amine (NH2R4), in which R4 represents R4 as defined in relation to a compound of Formula (I) or a group convenable to R4, in a suitable solvent, such as an alcohol, at about 40°C under an inert atmosphere in a sealed vessel to provide a compound of the Formula (3) which may be converted to an appropriate acid salt form, such as a hydrochloride. Alternatively, compounds of Formula (3) may be prepared by a Strecker synthesis in which a compound of Formula (2) is reacted with sodium cyanide and the amine as its hydrochloride salt in an appropriate non-reacting solvent, such as an alcohol, at ambient temperature. Reaction of a compound of Formula (3) or its salt with a suitable alkyl or aralkyl haloformate, such as ethyl, benzyl or menthyl chlorofonnate, in a non-reacting - 13solvent, such as methylene chloride, in the presence of an appropriate acid scavenger, such as saturated aqueous sodium bicarbonate, provides a compound of the Formula (4) in which Rg is alkyl, optionally substituted benzyl, or (-)-menthyl.

ORo (4) Reduction of the nitrile of a compound of Formula (4), wherein Rs is not optionally substituted benzyl, with, for example, hydrogen and a catalyst, such as Raney nickel catalyst in the presence of excess ammonia, provides a compound of Formula (5) in which R5 is H.

NHRC (5) Cyclization of a compound of Formula (5) wherein R5 is H in the presence of an appropriate base, such as aqueous sodium hydroxide, in an appropriate solvent, such as an alcohol or dimethyl sulfoxide (DMSO), then provides a compound of Formula (I) wherein R5 is H and R3 is other than CN.

Alternatively, these compounds may be obtained by reduction of the nitrile of a compound of the Formula (3) with an appropriate reductant, such as lithium aluminum hydride in a non-reacting solvent, such as ethyl ether, THF, or hydrogen in the presence of a suitable catalyst, such as a noble metal or Raney nickel, in an alcoholic solvent to provide a diamine of the Formula (6) in which R5 is H.

Reaction of a diamine of Formula (6) in which R5 is H, with phosgene in a (6) solvent, such as toluene, at reduced temperature in the presence of an acid scavenger, such as saturated aqueous sodium bicarbonate, then provides these compounds of Formula (I) wherein R5 is H and R3 is other than CN; alternatively, use of N,N'-carbonyldiimidazole - 14or l,l-carbonyl-di-l,2,4-triazole in an appropriate solvent avoids the use of phosgene and acid scavenger to provide these compounds in comparable quantities.

Alternatively, sSlective protect! otf of thea-NH in a compound of the Formula (6) wherein R5 is H, and R3 is not CN, withr for example a t-butyloxy carbonyl or benzyloxy carbonyL group» followed by imine formation.with .the.apprQpriate aldehyde and imine or imminium ion reduction as described below, followed by α-N protecting group removal, provides a compound of Formula (6) in which R5 is other than H and R3 is other than CN.

Reaction of the diamine of the compound of Formula (6) when R5 is other then H, as described above for the compound of Formula (6) when R5 is H, then provides the compound of Formula (I), in which R5 is other then H.

For compounds of Formula (I) wherein R5 is OH are prepared by oxidation of the corresponding Formula (5) compound where R5 is H to an aldehyde oxime with, e.g., sodium tungstate and hydrogen peroxide at 0°C followed by reduction of the oxime intermediate with, e.g., sodium ς-yanoborohydride .in presence of acid to give the corresponding Formula (5) compound wherein R5 is hydroxyl.

Compounds of Formula (I) wherein R3 is CF3, CHF2 or CH2F, are prepared from the corresponding Formula (2) compounds using the methods decribed below. The Formula (2) compounds where R3 is CF3 are obtained by the method of Shono et al.. J. Org. Chem.. Vol. 56, pages 204 (1991) electrochemically from the 0 Formula (2) compounds where R3 is H.

Formula (2) compounds where R3 is CF3 or CHF2, are obtained by treatment of the Formula (2a) compound with a metalling agent at -78°C followed by trifluoroacetic acid or difluoroacetic acid by the method of Nad et al., Izvest, (1959) page formula (2a) compound with a metalling agent at -78 °C followed by trifluroacetic acid or difluroacetic acid by the method of Nad et al., Izvest, (1959) page 71; Chem. Abstract., Vol. 53, No. 14877; and Vol. 53, No. 17933 (1959).

R,C) XL Br or I x Formula (2a) Formula (2) compound where R3 is ClbF are obtained by treatment of the 3 0 Formula (2) compounds where R3 is CH3 according to the method of Rozen et al., Synthesis (6) 665, (1985).

Formula (2) compounds where X is R2S and R3 is H are prepared by alkylation of 3-hydroxy 4-nitrobenzaldehyde with the desired Ri-halide, where Rl is as described above, followed by treatment with sodium SR2 in DMF.

Formula (2) compounds wherein X is F or Cl and R3 is H are prepared by alkylation of the (2-fluoro or chloro)-5-methyl phenol with the desired Rl-halide, followed - I5by formation of the benzyl bromide with N-bromo succinimide and subsequent transformation to the required aldehyde with 2-nitropropane and sodium ethoxide in ethanol.

Novel Formula (2) compounds where R3 is CH3 can be made by addition 5 of a methyl metal to the Formula (2) compounds where R3 is hydrogen, followed by oxidation, e.g. with pyridinium dichromate.

For compounds of Formula (I) wherein RiO and X are as described in Formula (I) are prepared by alkylation of the corresonding Formula (2) compounds where either both of Ri and R2 (where X is YR2) are hydrogen with a base, e.g. a metal 0 carbonate, metal hydroxide, metal hydride, and an alkylating agent Q-L, where Q is Ri or R2 as described above and L is an appropriate leaving group known in the art, e.g. Cl, Br, I, tosyl, mesyl, or triflyl or with a fluorinated ethylene, e«a« tetraflooroethy 1 ene. Alternatively the Formula (I) compounds may be prepared f ronr other Formula (I) compounds where Rj and/or R2 are protecting groups such as benzyl or methoxymethyl, ethoxymethyl or acetonide, and are removed by methods well known in the art and subsequently alkylated as described above for the Formula (2) compounds. For compounds of Formula (I) wherein X is amine, monoakylamine or formylamine, such alkylation is performed on Formula (2) or protected R1/R2 Formula (I) compounds, where X is nitro or a protected amine, e.g. a mono- or di-Nrt-butoxycarbonyl or a mono- or di-N benzyloxycarbonyl and the protecting group removed subsequently by methods known to those skilled in the art.

For those compounds of the Formula (I) in which R3 is other than CN, when X is other than Br, I, NO2, amine, formyl amine or S(O)m' and m' is 1 or 2, and R5 is other than H, reaction of an amine of the Formula (5) wherein R5 is H with a suitably substituted aryl or alkyl aldehyde in a suitable solvent, such as chloroform at reflux temperature, followed by suitable acid salt formation, such as a hydrochloride or acetate, and reduction of the iminium salt with, for example, sodium cyanoborohydride in methanol, provides a compound of the Formula (5) in whjeh-R3 is oiher than CN and Rc is other than H; alternatively nobel methl catalytic reduction of the imine or iminium function may 0 also be employed. For most of these compounds, cyclization as described above provides compounds of Formula (I) in which R5 is other than H. In the case of certain compounds of Formula (5) which contain a base-sensitive functionality in R5, such as a nitro group, conversion to a base stable functionality, such as an amine, is conducted prior to cyclization; such amines may then be functionalized as desired.

For those compounds of Formula (I) in which R3 is CN, and X is other than Br, I, NO2 or formyl amine, a sequence beginning with reaction of a compound of the Formula (2) wherein R3 is H with a lithium halide and a silyl halide in an appropriate solvent followed by reduction with an appropriate reductant, such as a siloxane, provides a - 16compound of the Formula (7) wherein Xj is a halide. Alternatively, reduction of a compound of the Formula (2) wherein R3 is H with a suitable reductant, such as sodium borohydride, provides a compound of the Formula (7) wherein X] is OH. Reaction of such a compound of the Formula (7) with, for example, phosphorous trichloride, thionyl chloride, phosphorous tribromide, cupric bromide or carbon tetrabromide and triphenylphosphine, also provides a compound of the Formula (7) wherein Xj is a halide; 0 halide displacement by cyanide provides a compound of the Formula (8) wherein R3 and R9 is H which is allowed to react with a strong base, such as LDA or an alkyl lithium or lithium hexamethyldisilazide, at reduced temperature under an inert atmosphere followed by reaction with, for example, trimethylsilyl isocyanate and appropriate workup to produce a compound of Formula (8) wherein R3 is CONH2 and R9 is H; or followed by reaction with for example an alkyl or aryl haloformate, such as methyl chlorofonnate, to produce a compound of Formula (8) wherein R3 is COORg and R9 is H; this COORs group of such a compound may be transformed either at this stage or at a later stage to a CONH2 group by 0 any of the standard techiniques well known to those skilled in the an. Alternatively, a compound of Formula (8) wherein R3 is COORg and R9 is H may also be obtained by reaction of a compound of Formula (8) wherein R3 and R9 are H with a metal hydride, such as sodium or potassium hydride, at ambient or elevated temperature under an inert atmosphere in the presence of an alkyl or aryl dicarbonate, for example methyl dicarbonate.

Also a compound of Formula (2) wherein R3 is H may be homologated to a compound of the Formula (7) wherein Xi is COOR4 by any number of known processes, such as reaction with a methyl methyl sulfinylmethyl sulfide and a base, such as sodium hydroxide, followed by treatment with, for example, alcoholic acid; generation of an anion of a compound of Formula (7) wherein Xi is COOR4 with a suitable base, followed by reaction 0 with, for example, cyanogen chloride or 2-chlorobenzyl thiocyanate, provides a compound of Formula (8) wherein R3 is COOR4 and R9 is H.

Generation of a third anion with the appropriate base in an appropriate solvent followed by reaction with, e.g. 2,4,6-triisopropyl-benzenesulfonyl azide or other - 17 electrophilic source of azide, produces a compound of the Formula (8) wherein R3 is CONH2 and R9 is N3. Reduction of both the azido and nitrile moieties by, for example, hydrogenation with a noble metal or Raney nickel catalyst provides a compound of the Formula (6) wherein R4 is H and R3 is CONH2. Cyclization of this diamine as described above followed by amide dehydration, with for example, trifluoroacetic anhydride provides a compound of the Formula (I) wherein R4 and R5 are H and R3 is CN.

Alternatively, for a compound of the Formula (8) wherein R3 is CONH2 and R9 is N3, selective reduction of the azido moiety to an amine, using e.g., catalytic hydrogenation with 10% palladium on carbon and one equivalent of acetic acid or 0 alternatively triphenyl phosphine in a suitable solvent such as tetrhydrofuran/water, followed by reaction with a suitable alkyl or aralkyl haloformate as described above produces a compound of the Formula (4) wherein R4 is H and R3 is CONH2. Nitrile reduction as described above provides a compound of the Formula (5) wherein R4 and R5 are H and R3 is CONH2. Cyclization of the ring and dehydration of the R3 amide to a nitrile then provides a compound of the Formula 1 wherein R4 and Rg are H and R3 is CN.

Alternatively, the amino moiety of a compound of the Formula (5) wherein R4 and R5 are H and R3 is CONH2 may be suitably protected, e.g. with a carbobenzyloxy or t-butyloxycarbonyl group, prepared as known in the art, dehydration of the R3 amide to the nitrile is conducted, and the amine deprotected, by methods well known to those skilled 20 in the art, to provide a compound of the Formula (5) wherein R4 and R5 are H and R3 is CN. The amine moiety of such a compound of Formula (5) may be homologated as described above to provide a compound of the Formula (5) wherein R5 is other than H. Cyclization followed by any appropriate functional group manipulations (such as reductions, acylations, deprotections, oxidations, etc.) then provides a compound of the Formula (I) wherein R3 is CN, R4 is H and R5 is other than H.

Compounds of Formula (I) may be prepared from other Formula (I) compounds and functionally modified, as known in the art, e.g. where R4 is O-acetate, by acetylation from R4 as hydroxyl. Compounds where R5 is (CH2)qAr or C2-6 alkyl substituted by: NO2 from the NH2 derivative by oxidation, e.g. with a peracid; C(O)NR6R7 0 from the -CO2CH3 by heating with or without catalytic metal cyanide, e.g. NaCN, and HNR6R7 in CH3OH; -OC(O)R6 from the -OH with e.g.,ClC(O)R6 in pyridine; -NRgC(S)NR6R7 from -NHR^ with an alkylisothiocyante or thiocyanic acid; NR6C(O)OR6 from -NHR6 with the alkyl chloroformate; -NR6C(O)NR6R7 from the -NHR6 by treatment with an i socyanate, e.g. HN=C=O or R6N=C=O; -NR6-C(O)R6 from the -NHR6 by treatment with C1-C(O)R6 in pyridine; -C(=NR6)NR6R7 from -C(NR6R7)SR6 with H3NR6+OAc' by heating in alcohol; -C(NR6R7)SR6 from -C(S)NR6R7 with Rg-I in an inert solvent, e.g. acetone; -C(S)NR6R7 where R6 or R7 is not hydrogen from C(S)NH2 with HNR6R7, C(=NCN)-NR6R7 from -C(feNR6R7)-SRb with NH2CN by heating in anhydrous alcohol, - 18 alternatively from C(=NHV-NRgR7 by treatment with Br-CN and NaEtO- in EtOH; NRg-C(=NCN)SRg from NHRg by .treatment with (RgS)2C=NCN;-NRgSO2Rg from NHRg by treatment with ClSO2Rg by heating in pyridine; -NRgC(S)Rg from -NRgC(Q)Rg by treatment with Lawesson's reagent [2,4-bis(4-methoxyphenyl)-T,2,3,4-ditiadiphosphetane-2,4-disulfide]; -NRgS02CF3 from NHRg with triflic anhydride and base; NRgC(O)-C(O)-ORg from -NHRg with, e.g. methyloxalyl chloride and a base such as triethylamine; -NRgC(O)C(O)-NRgR7 from -NRgC(0)-C(0)-0R6 with HNRgR?; 1-(NRg)-2-imidazolyl from -CC=NH)NHRg by heating with 2-chloroacetaTdehyde in chloroform, For compounds wherein X is S(O)m'-Ci-6 alkyl, and m is 1 or 2 the final compound is made from the -S-Ci-6 alkyl moiety by oxidizing the intermediate -S-alkyl product with, e.g. a peracid such as 3-chloroperbenzoic acid, under conditions-well known those skilled in the art, after the CONH2 moiety in synthesis step (c) is dehydrated to the cyano moiety. For compounds wherein X is Br, I, NO2, amine or formyl amine synthesis of these compounds is accomplished by any of the steps described above using a suitably protected amine. Such protecting groups are known to those skilled in the art and are readily disclosed in Greene, T., Protective Groups in Organic Synthesis. Wiley Publishers, NY (1981), the contents of which are hereby incorporated by reference.

In particular, for Compounds of Formula (I) wherein X is formyl amine are formed at the last step, by formylating a compound wherein X is NH2, obtained by removal of a protecting group from the amine functionality. Use of the deprotected amine in many instances allows for appropriately acyleting the moiety to the NHCHO moiety, or oxidiz ing i t to the NO2 moiety; diazotization and displacement by methods well known to those skilled in the art produces the desired Br or I moiety. For instance, compounds of Formula (I) wherein X is Br or I may be prepared using the techniques of PCT/US91/04795 on a similarly deprotected amine, diazotization of the amine, and diazonium displacement; or for compounds of Formula (I) wherein X is NO2 may be prepared using the techniques of PCT/US91/04795 on a similarly deprotected amine by oxidation of the amine to the nitro 0 group.

METHODS OF TREATMENT 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.

The compounds of Formula (1) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment - 19of any disease state in a human, or other mammal, which is exacerbated or caused by TNF production by such human's cell, such as but not limited to monocytes and/or macrophages, especially caused by excessive or unregulated TNF production. The compounds of Formula (I) are administered in an amount sufficient to inhibit TNF production such that it is regulated down to normal levels, or in some case to subnormal levels, so as to ameliorate or prevent the disease state. Abnormal levels of TNF, for the present invention, constitute levels of 1) free (not cell bound) TNF, greater than or equal to 1 picogram per ml; 2) any cell associated TNF; or 3) the presence of TNF mRNA above basal levels in cells or tissues in which TNF is produced. 0 The compounds of Formula (Ia), or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylatic or therapeutic treatment of any disease state, in a human, or other mammal, which is mediated by inhibition of PDE IV, such as but not limited to asthma, allergic or inflammatory diseases. The compounds of Formula (Ia) are administered in an amount sufficient to treat such a disease in a human or other mammal.

No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.

The compounds of Formula (I) may be used in the treatment of any disease states mediated by excessive or unregulated TNF production, such as but not limited to 0 arheumatoid 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 sarcoisosis, 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, pyresis, AIDS and other viral infections, such as cytomegalia virus (CMV), influenza virus, and the Adenovirus herpes family of viruses. 0 The compounds of Formula (I) may also be used topically as well in the treatment or prophylaxis of inflammatory topical disease states mediated or exacerbated by excessive TNF production respectively, such as for rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.

The compounds of Formula (I) may also be used in association with the veterinary field for treatment of TNF mediated diseases such as viral infections. Examples of -2(1such viruses include but are not limited to, feline immunodefincency virus (FIV) or other retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.

It further appears that among the cytokines, while TNF production precedes 5 and augments the function of IL-1 and other cytokines, there is no clear data on how the relationship among these molecules contributes to inflammation-related disease states. The present invention attributes many of the biological disease states attributable to interleukin-1 (IL-1) activity as being attributable to that of TNF activity as well. A comprehensive listing of IL-1 activities can be found in Dinarello, J. Clinical Immunology. 5 (5), 287-297 (1985).

It should be noted that some of these effects have been described by others as indirect effects of IL-1. The myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels. These disease states are also considered appropriate disease states of TNF activity and hence compounds of Formula (I) are also useful in their treatment as well, and the use of the compounds of Formula (I) should not be considered solely limited to the specifically described TNF mediated disease states herein. The compounds of Formula (I) should be efficacious in an IL-1 mediated disease state as TNF and IL-1 act in a synergistic manner. TNF as well mediates the release, in some instances, of IL-1, therefore a reduction in the 0 levels of TNF may be useful in the treatment of a disease state wherein IL-1 is a major component. The present invention relates therefore, to an effective, TNF production inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof is useful in treating, prophylactically or therapeutically, any disease state in a human which is exacerbated or caused by excessive or unregulated IL-1 production, i.e., where IL-1 is a major component, by such human's monocytes and/or macrophages.

The method of treatment and monitoring for an HIV-infected human manifesting immune dysfunction or cytokine-mediated disease associated problems is taught in Hanna, WO 90/15534, December 27, 1990. In general, an initial treatment regimen can be copied from that known to be effective in interfering with TNF activity for other TNF 0 mediated disease states by the compounds of Formula (1). Treated individuals will be regularly checked for T cell numbers and T4/T8 ratios and/or measures of viremia such as levels of reverse transcriptase or viral proteins, and/or for progression of monokine-mediated disease associated problems such as cachexia or muscle degeneration. If no effect is seen following the normal treatment regimen, then the amount of the monokine activity interfering agent administered is increased, e.g., by fifty percent per week.

The compounds of Formula (I) may be administered orally (when active by this route), topically, parenterally or by inhalation in conventional dosage forms prepared by combining such agent with standard pharmaceutical carriers according to conventional - 21 procedures in an amount sufficient to produce the desired therapeutic activity for treatment of a TNF mediated disease state or in the case of a compound of Formula (Ia) in their use as a PDE IV inhibitor.

In order to use a compound of the Formula (I) or a pharmaceutically 5 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.

The pharmaceutical composition of the present invention will comprising an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically 0 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 produce TNF production inhibiting activity, respectively, with standard pharmaceutical carriers according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may 0 include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

Compounds of Formula (I) and their pharmaceutically acceptable salts (when possible), some of which are orally active, can be employed in a wide variety of pharmaceutical forms. The preparation of a pharmaceutically acceptable salt will be determined by the nature of the compound itself, and can be prepared by conventional techniques readily available to one skilled in the art. 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 the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 gram. When a liquid carrier is used, the preparation 0 will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent. • 22The amount of a compound of Formula (I) required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the condition and the animal undergoing treatment, and is ultimately at the discretion of the physician.

By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.

By 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 0 not significantly enter the blood stream.

The term '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. Appropriate dosage forms for such administration may be prepared by conventional techniques.

Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil. The daily dosage regimen for inhibition of TNF production, via 0 parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (1) or a pharmaceutically acceptable salt thereof calculated as the free base.

The compounds of Formula (1) may be administered orally. Each dosage unit for oral administration contains suitably from 1 mg to 100 mg, and preferably from 10 mg to 30 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.

The daily dosage regimen for oral administration is suitably about .001 mg/kg to lOOmg/kg, preferably 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 active ingredient 0 may be administered from 1 to 6 times a day, sufficient to exhibit activity.

The compounds of Formula (I) may also be administered by inhalation. By inhalation is meant intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques. The daily dosage regimen for a compound of Formula (I) for intranasal administration and oral inhalation is suitably about 10 to about 1200 mg. -23Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.

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.

The compounds of Formula (I) may also be administered topically. Thus, the compounds of Formula (I) may be administered topically in the treatment or prophylaxis of inflammatory topical disease states mediated or exacerbated by excessive TNF production, respectively, such as rheumatoid arthritis, rheumatoid spondylitis, 0 osteoarthritis, gouty arthritis and other arthritic conditions, inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.

A suitable dose of a TNF production inhibiting compound of Formula (I) is from about .01 mg to about 100 mg of base for topical administration, the most preferred dosage being about .01 mg to about 30 mg, for example, .003 mg to 10 mg administered two or three times daily.

While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The active 0 ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.

The formulations of the present invention comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s). The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as 0 liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.

Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-l(X)°C.for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic -24technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (O.(X)2%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a 0 moisturizer such as glycerol or an oil such as castor oil or arachis oil.

Creams, ointments or pastes according to the present invention are semisolid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis. The basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, com, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as prolylene glycol or macrogols. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or 0 non-ionic sulfactant such as sorbitan esters or polyoxyethylene derivatives thereof.

Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.

It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient, with which it is to be combined, the route of administration and other wellknown variables.

It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being 0 treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

UTILITY EXAMPLES Example A - 25 Inhibitory Effect of compounds of Formula (I) on in vitro TNF production by Human Monocytes The inhibitory effect of compounds of Formula (I) on in vitro TNF production by Human Monocytes can be determined by the protocol as described in Badger et al.. EPO published Application 0 411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990. The compounds of Formula (I) displayed an IC50 value of 0.01- to about >3.0 for Inhibition of LPS-Induced Human Monocyte TNF Production in the above noted assay. For instance, 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone demonstrated an IC50 of .2μΜ in the in-vitro assay system described above. 0 UTILITY EXAMPLE B MODELA Two models of endotoxin shock have been utilized to determine in vivo TNF activity for the compounds of Formula (1). The protocol used in these models is described in Badger et al., EPO published Application 0 411 754 A2, February 6, 1991, and in Hanna, WO 90/15534, December 27, 1990. 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone demonstrated a positive in-vivo response of about 57 % reduction in serum levels of TNF which were induced by the injection of endotoxin. 0 The data shown herein demonstrate that the compounds of the present invention inhibit TNF production in a mammal. Therefore, the compounds of Formula (I) are useful in inhibiting the production of tumor necrosis factor (TNF) by monocytes or macrophages in a human.

UTILITY MODEL B The phosphodiesterase inhibitory activity and selectivity of the compounds of Formula (la) can be determined using a battery of five distinct PDE isozymes. 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) 0 PDE IV, human monocyte. PDEs la, lb, Ic and III are partially purified using standard chromatographic techniques (Torphy and Cieslinski, Mol. Pharmacol. 37: 206-214, 1990). PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography (White et al., FASEB J. 4: A1987 1990).

Phosphodiesterase activity is assayed as described in the protocol of Torphy and Cieslinski. Mol. Pharmacol. 37: 206-214. 1990. IC5()'s for compounds of Formula (la) range from 0.1 μΜ to 30 μΜ.

UTILITY MODEL C -26The ability of selected PDE IV 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 1()5 cells/reaction tube) were incubated with various concentrations (0.01-100 μΜ) of PDE inhibitors for one minute and ΙμΜ prostaglandin E2 for an additional four minutes. Five minutes after initiating the reaction, cells were lysed by the addition of 17.5% perchloric acid, the pH was neutralized 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 0 cyclic GMP., Adv. Cyclic Nucleotide Res., 10:1-33, 1979. ECso's for compounds of Formula (Ia) range from 0.3 μΜ to >10 μΜ.

SYNTHETIC EXAMPLES The following examples are illustrative and are not limiting of the compounds of this invention.

EXAMPLE 1 4-(3-Cvclopentyloxy-4-methoxyphenyl)-2-imidazolidinone 0 A) 2-Amino-2-(3-cyclopentyloxv-4-methoxyphenyl)acetonitrile hydrochloride.

A mixture of 3-cyclopentyloxy-4-methoxybenzaldehyde (10.0 g, 45.4 mmol), trimethyl-silylcyanide (7.6 ml, 57 mmol) and a trace of anhydrous zinc iodide under an argon atmosphere was stirred at room temperature. After 30 min, a cold solution of anhydrous ammonia in methanol (6.2 M, 36 ml, 223 mmol) was added and the mixture was heated in a sealed reaction vessel at 40°C for 3 hours. The vessel was vented and the liquids were removed in vacuo. The resulting oil was redissolved in methanol, concentrated hydrochloric acid (5 ml, 60 mmol) and ether were added to produce a solid, which was washed well with ether and dried to produce the hydrochloride salt of 2-amino2-(3-cyclopentyIoxy-4-methoxyphenyl)acetonitrile as an off-white powder (11.8 g, 92%): 0 m.p. 164-166°C (dec).

Analysis Calc, for Ci4Hi8N2O2.HCl: C 59.47, H 6.77, N 9.91; found: C 59.30, H 6.91, N 9.87.

B) 2-Ethoxvcarbonylamino-2-(3-cyclopentyloxv-4-methoxy-phenvl)acetonitrile. 2-Amino-2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile hydrochloride (2.83 g, mmol) was suspended in saturated aqueous sodium bicarbonate (25 ml) and methylene chloride (25 mi) was added. The mixture was stirred vigorously under an argon atmosphere until all solid dissolved and then ethyl chloroformate (1.9 ml, 19.9 mmol) was -27added in one portion. Additional ethyl chloroformate (0.5 ml, 5.2 mmol) was added at 1, 2 and 3 hours. After 4 hours, the mixture was partitioned, the methylene chloride was washed with dilute hydrochloric acid and dried (potassium carbonate). Recrystallization from ether/hexanes provided a solid of the title compound (3.0 g, 93%): m.p. 100-101°C.

Analysis Calc, for C 64.13.

H 6.97, N 8.80; found: C 63.89, H 7.04, N 8.72.

C) 2-Ethoxvcarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine. 2-Ethoxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (3.0 0 g,9.4 mmol) and concentrated ammonium hydroxide (2.5 ml) were added to a suspension of Raney nickel (3.0 ml of 50% suspension in water, washed three times with ethanol) in ethanol (70 ml). The mixture was hydrogenated at 60 psi for 3 hours, diluted with methylene chloride, filtered through celite and evaporated. The residue was partitioned between methylene chloride and dilute aqueous hydrochloric acid and the organic layer was discarded. The aqueous layer was basified with saturated aqueous sodium carbonate, extracted with methylene chloride and dried (potassium carbonate). Solvent evaporation provided 2-ethoxycarbonylamino-2-(3-cyclopentyloxy-4-methoxy-phenyl)ethylamine (3.0 g, 100%): m.p. 79-84°C.

Analysis Calc, for C17H26N2O4 -1/8 H2O: C 62.89, H 8.15, N 8.63; found: C 62.70, H 8.17, N 8.47.

D) 4-(3-Cyclopentvloxv-4-methoxyphenyl)-2-imidazo1idinone.

A solution of 2-ethoxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyI)ethylamine (40 mg, 0.12 mmol) in ethanol (1 ml) and aqueous sodium hydroxide (2.5 N, 0.5 ml) under an argon atmosphere was heated at reflux for 5 hours. The mixture was cooled and partitioned between ether and water. The ether layer was washed with dilute acid, dried (potassium carbonate) and evaporated to a solid of 4-(3-cyclo-pentyloxy-4methoxy-phenyl)-2-imidazolidinone (16 mg,48%): m.p. 116-118°C.

Analysis Calc, for C15H20N2O3* C 65.20, 0 H 7.30, N 10.14; found: C 65.04, H 7.19, N 10.28.

EXAMPLE 2 l-(4-Aminobenzvl)-4-(3-cvclopentyloxy-4-methoxyphenyO-2-imidazolidinone A) 2-Ethoxycarbonvlamino-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(4nitrobenzylaminolethane. - 28 A solution of 2-ethoxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)-ethyIamine (1.25 g, 3.9 mmol), prepared as in Example 1, and 4-nitrobenzaldehyde (0.59 g, 3.9 mmol) in chloroform under an argon atmosphere was heated at reflux for 2 hours. The mixture was cooled, the solvent was removed in vacuo and a solution of anhydrous hydrochloric acid in ether (1.0 M, 4 ml) was added. The solution was evaporated to dryness, the residue was redissolved in absolute methanol and sodium cyanoborohydride (0.25 g, 4.0 mmol) was added. The mixture was stirred at room temperature for 2 hours, partitioned between methylene chloride and saturated sodium bicarbonate and the organic layer dried (potassium carbonate). The residue was purified by flash chromatography, 0 eluting with ether to provide a solid of 2-ethoxycarbonylamino-2-(3-cyclopentyloxy-4methoxyphenyl)-l-(4-nitrobenzylamino)ethane. (0.7 g, 40%); m.p. 112-113°C.

B) l-(4-Aminobenzyl)-4-(3-cvc1openty1oxy-4-methoxyphenyl)-2-imidazolidinone.

A solution of 2-ethoxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)-l-(4-nitrobenzylamino)ethane (0.4 g, 0.9 mmol) in acetic acid (2.5 ml) and water (2.5 ml) was treated with an aqueous solution of titanium trichloride (20%, 4.5 ml). After 15 min, concentrated ammonium hydroxide (6 ml) and 9:1 methylene chloride/methanol were added and the mixture was filtered through a glass fiber filter. The methylene chloride layer was 0 separated and dried (sodium sulfate). The solvent was evaporated. The residue (0.31 g) in ethanol (10 ml) and aqueous sodium hydroxide (2.5 M, 5 ml) was heated at reflux for 5 hours. The mixture was cooled, partitioned between methylene chloride and water and the aqueous layer extracted with both methylene chloride and ether. The combined organic layers were dried (potassium carbonate) and evaporated. The residue was purified by recrystallization from methylene chloride/ether to provide a solid of l-(4-amino-benzyl)-4(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone (0.22 g, 66%): m.p. 127-128°C.

Analysis Calc, for C22H27N3O3: C 69.27, H7.13, N 11.02; found: C 69.51, H 7.23, N 11.16.

EXAMPLE 3 4-(3-Cyclopentyloxv-4-methoxyphenvl)-l-(4-dimethylaminobenzvl)-2-imidazolidinone.

A) 2-Ethoxvcarbonylamino-2-(3-cyclopentvloxy-4-methoxy-phenyl)-1-(43 5 dimethylaminobenzylamino)ethane.

A solution of 2-ethoxycarbonylamino-2-(3-cyciopentyloxy-4-methoxyphenyl)-ethylamine, prepared as in Example 1, (0.725 g, 2.25 mmol) and 4-dimethylamino-benzaldehyde (0.34 g, 2.25 mmol) in chloroform under an argon atmosphere was heated at reflux for 2 hours -29and the solvent was removed by distillation. Additional chloroform (10 ml) was added and reflux was continued for an additional hour. The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran (15 ml) and a solution of anhydrous hydrochloric acid in ether (1.0 M, 5 ml) was added. The solution was evaporated to dryness, the residue was redissolved in absolute methanol (10 ml), cooled to 0°C and sodium cyanoborohydride (0.28 g, 4.5 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. The colorless mixture was partitioned between methylene chloride and 10% sodium hydroxide and the organic layer dried (potassium carbonate). The residue was purified by flash chromatography, eluting 0 first with ether and then with 5% methanol/ether to provide a solid of the title compound (0.82 g, 80%); m.p. 94-96°C.

B) 4-(3-Cvclopentvloxy-4-methoxyphenyl)-1 -(4-dimethylam inobenzyl)-2imidazolidinone.

A solution of 2-ethoxycarbonylamino-2-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(4dimethylaminobenzylamino)ethane (0.40 g, 0.88 mmol) in ethanol (10 ml) and aqueous sodium hydroxide (2.5 Μ, 1 ml) was heated at reflux under an argon atmosphere for 6 hours. The mixture was cooled, partitioned between methylene chloride and water and the aqueous layer extracted with methylene chloride. The organic layer was dried (potassium 0 carbonate) and evaporated. The residue was purified by flash chromatography, eluting with 2% methanol/methylene chloride, and the resulting solid was purified by recrystallization from chloroform/ether to provide a solid of the title compound (0.29 g, 80%): m.p. 171-172°C.

Analysis Calc, for C24H31N3O3 · 3/8 H2O: C 69.25, H 7.69, N 10.09; found: C 69.29, H 7.50, N 9.95.

EXAMPLE 4 l-(4-Acetamidobenzyl)-4-(3-cyclopentvloxy-4-methoxyphenyl)-2-imidazolidinone A) l-(4-Acetamidobenzylamino)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2(ethoxvcarbonvlamino)ethane.

A solution of 2-ethoxycarbonylamino-2-(3-cyclo-pentyloxy-4-methoxyphenyl)ethylamine prepared as in Example 1 (0.725 g, 2.25 mmol) and 4-acetamido-benzaldehyde (0.37 g, 2.25 mmol) in chloroform (15 ml) under an argon atmosphere was heated at reflux for 3 hours and the solvent was removed by distillation. Additional chloroform (10 ml) was added and reflux was continued for an additional hour. The mixture was cooled, the solvent was removed in vacuo, the residue was redissolved in tetrahydrofuran (15 ml) and a - 30solution of anhydrous hydrochloric acid in ether (1.0 M, 2.5 ml) was added. The solution was evaporated to dryness, the residue was redissolved in absolute methanol (10 ml), cooled to 0°C and sodium cyanoborohydride (0.28 g, 4.5 mmol) in methanol (5 ml) was added. The mixture was allowed to warm to room temperature and stirred overnight. The colorless mixture was partitioned between methylene chloride and 10% sodium hydroxide and the organic layer dried (potassium carbonate). The residue was purified by flash chromatography, eluting with 3% methanol/methylene chloride to provide a foam of the title compound (0.84 g, 80%).

B) l-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone. A solution of 2-ethoxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(4acetamidobenzylamino)ethane (0.08 g, 0.17 mmol) in ethanol (3 ml) and aqueous sodium hydroxide (2.5 M, 0.2 ml) was heated at reflux under an argon atmosphere for 48 hours. The mixture was cooled, partitioned between methylene chloride and water and the aqueous layer extracted with methylene chloride. The organic layer was dried (potassium carbonate) and evaporated. The residue was purified by flash chromatography, eluting with a gradient of 2-5% methanol/chloroform, and the resulting solid was purified by recrystallization from chloroform/ether to provide a solid of the title compound (0.05 g, 65%): m.p. 191 °C. Analysis Calc, for C24H29N3O4: C 68.06, 0 H 6.90, N 9.92; found: C 67.90, H 7.21, N 9.86.

EXAMPLE 5 l-(4-Aminobenzvl)-4-(3-cyclopentyloxv-4-methoxyphenyl)-3-methvI-2-imidazolidinone A) 2-(3-Cvclopentyloxv-4-methoxyphenyl)-2-methvlamino-acetonitrile hydrochloride.

A mixture of 3-cyclopentyloxy-4- methoxybenzaldehyde (5.5 g, 25 mmol), trimethylsilylcyanide (4.2 mL, 31.3 mmol) and a trace of anhydrous zinc iodide under an argon atmosphere was stirred at room temperature. After 30 min, a cold solution of anhydrous methylamine in methanol (5 M, 25 mL, 125 mmol) was added and the mixture was heated 0 in a sealed reaction vessel at 40°C for 3 hours. The vessel was vented and the liquids were removed in vacuo. The resulting oil was redissolved in methanol, concentrated hydrochloric acid (2.3 mL, 27 mmol) and ether were added to produce a solid, which was washed well with ether and dried to produce the hydrochloride salt as an off-white powder (6.5 g, 85%); m.p. 123 - 127°C (dec).

Analysis Calc, for C14H jg^Cb.HCl: C 59.47, H 6.77, N 9.91; found : C 59.30, H 6.91, N 9.87.

B) 2-Ethoxvcarbonylmethylamino-2-(3-eyelopentyloxy-4-methoxyphenyl)-acetonitrile. -3l 2-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylamino-acetonitrile hydrochloride (2.0 g, 6.7 mmol) was suspended in saturated aqueous sodium bicarbonate (15 mL) and methylene chloride (25 mL) was added. The mixture was stirred vigorously under an argon atmosphere until all solid dissolved and then ethyl chloroformate (1.35 mL, 14 mmol) was added in one portion. After 3 h at room temperature, the mixture was partitioned, the methylene chloride was dried (potassium carbonate) and the solvent removed in vacuo to provide an oil (2.6 g, 100%).

C) 2-Ethoxycarbonvlmethylamino-2-(3-cyclopentyloxv-4-methoxvphenyl)-ethylamine. 1 0 2-Ethoxycarbonyl-methylamino-2-(3-cyclopentyloxy-4-methoxyphenyI)-acetonitrile (2.4 g, 7.2 mmol) and concentrated ammonium hydroxide (2 mL) were added to a suspension of Raney nickel (2.4 mL of 50% suspension in water, washed three times with ethanol) in ethanol (70 mL). The mixture was hydrogenated at 60 psi for 3 h, diluted with methylene chloride, filtered through celite and evaporated to an oil. The residue was partitioned between methylene chloride and dilute aqueous hydrochloric acid and the organic layer was discarded. The aqueous layer was basified with saturated aqueous sodium carbonate, extracted with methylene chloride and dried (potassium carbonate). Solvent evaporation provided the amine (3.0 g, 100%): m.p. 79 - 84°C.

Analysis Calc, for C17H26N2O4 »1/8 H2O: 0 C 62.89, H 8.15, N 8.63; found : C 62.70, H 8.17, N 8.47.

D) 2-Ethoxycarbonylmethylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(4nitrobenzylamino)ethane.

A solution of 2-ethoxycarbonylmethylamino-2-(3-cyclopentyloxy-42 5 methoxyphenyl)ethylamine (1.88 g, 5.6 mmol) and 4-nitrobenzaldehyde (0.89 g, 5.9 mmol) in chloroform (25 mL) under an argon atmosphere was heated at reflux for 6 h. The mixture was cooled, the solvent was removed in vacuo and a solution of anhydrous hydrochloric acid in ether (1 M, 5.7 mL) was added. The solution was evaporated to dryness, the residue was redissolved in absolute methanol (25 mL) and sodium 0 cyanoborohydride (0.71 g, 11.3 mmol) was added. The mixture was stirred at room temperature for 2 h, partitioned between ethyl acetate and ten percent aqueous sodium hydroxide and the organic layer dried (sodium sulfate). The residue was purified by flash chromatography, eluting with 50% hexanes/ethylacetate to provide the amine (1.11 g, 42%).

E) l-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxvphenyl)-3-methyl-2imidazolidinone. -32A solution of 2-ethoxycarbonylmethylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)-l-(4-nitrobenzylamino)ethane (1.11 g, 2.4 mmol) in acetic acid (6.5 mL) and water (6.5 mL) was treated with an aqueous solution of titanium trichloride (20%, 12.2 mL). After 30 min, concentrated ammonium hydroxide (16 mL) and 97:3 methylene chloride/methanol were added and the mixture was filtered through a glass fiber filter. The methylene chloride layer was separated and dried (sodium sulfate). The solvent was evaporated. The residue (0.99 g, 2.1 mmol) in ethanol (55 mL) and aqueous sodium hydroxide (2.5 M, 2.6 mL) was heated at reflux for 48 h. The mixture was cooled, partitioned between ethyl acetate and water and the aqueous layer extracted with both ethyl 0 acetate and ether. The combined organic layers were dried (sodium sulfate) and evaporated. The residue was purified by flash chromatography, eluting with 10% ether/methylene chloride, followed by recrystallization from methylene chloride/ether, to provide a solid of l-(4-aminobenzyl)-l-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-2-imidazolidinone (0.7 g, 88%): m.p. 143°C.

Analysis Calc, for C23H29N3O3 : C 69.85, H 7.39, N 10.62; found : C 69.82, H 7.46, N 10.52.

EXAMPLES 6 and 7 (2R)- and (2S)-l-Benzyloxycarbonylamino-2-(3-cyclopentyloxy-4-methoxvphenyl)-2-f(-)2 0 menthyloxycarbonylaminolethane A} 2-(3-Cyclopentyloxy-4-methoxvphenyl)-2-|(-)-menthyloxycarbonylaminolacetonitrile A solution of 2-Amino-2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile hydrochloride (as prepared in Example 1, part A) (39 g, 137.9 mmol) in methylene chloride (450 mL) was treated with saturated aqueous sodium bicarbonate (350 mL) and stirred under argon until the amine had dissolved. To the mixture was added (-)-menthyl chloroformate (44.4 mL, 206.9 mmol) and the mixture was stirred vigorously for 18 h.

The organic layer was separated, dried (potassium carbonate) and evaporated. The product 0 was recrystallized from methylene chloride and hexanes, washing the filtered solid with 9:1 hexanes/ether (34.7 g, 59%): m.p. 124 - 141°C. The mother liquor was evaporated and purified by flash chromatography, eluting with 6:1:2 hexanes/ether/methylene chloride, to provide a solid (21.2 g, 36%); m.p. 114 - 125°C.

Analysis Calc, for C25H36N2O4»1/1()H2O : C 69.77, H 8.48, N 6.51; found : C 70.14, H 8.41, N 6.66. - 33 B) 2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylaminolethvlamine A solution of 2-(3-cyclopenty loxy-4-methoxypheny 1)-2-( (-)-menthyloxycarbonylaminolacetonitrile (27.5 g, 64.2 mmol) in hot ethanol (650 mL) was treated with Raney nickel (28 mL of a 50% suspension washed three times with ethanol) and concentrated ammonium hydroxide (30 mL). The mixture was hydrogenated at 50 psi for 2 h and filtered through celite washing with methylene chloride. The solvent was evaporated in vacuo to provide a solid (27.5 g, 99%).

Analysis Calc, for C25H40N2O4 : C 69.41, H 9.32, N 6.48; 0 found : C 68.21, H 9.73, N 5.06.

C) l-Benzvloxycarbonvlamino-2-(3-cycIopentyloxy-4-methoxyphenyl)-2-f(-)menthvloxycarbonylaminolethane To a solution of 2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)1 5 menthyloxycarbonylamino]ethylamine (27.2 g, 62.9 mmol) in methylene chloride (500 mL) was treated with triethylamine (9.2 mL, 66.2 mmol) under an argon atmosphere, and cooled to 0°C. Over a period of 10 min, benzyl chloroformate (9.1 mL, 63.7 mmol) was added, and the reaction was stirred for 16 h, slowly coming to room temperature. The mixture was partitioned between methylene chloride and dilute hydrochloric acid. The 0 organic extracts were dried (magnesium sulfate) and evaporated. Purification by flash chromatography, eluting with 97:3 methylene chloride/ether, provided a solid which was recrystallized from methylene chloride/ether/hexanes to provide a solid (27.1 g, 76%): m.p. 154-164°C.

D) (2R)- and (2S)-l-Benzyloxvcarbonylamino-2-(3-cyclopentyloxy-4methoxyphenyl)-2-[(-)-menthyloxvcarbonvlaminolethane Diastereomeric separation of l-benzyIoxycarbonyIamino-2-(3-cyclopentyloxy-4methoxyphenyl)-2-[(-)-menthyloxycarbonylamino]ethane was accomplished with preparative HPLC conditions using a JY-l(X) chromatospac apparatus equipped with a 8cm 0 x 100cm column packed with 1.8 kg YMC sperical silica gel (15-30μ). The mobile phase of 95:5 methylene chloride/ether eluted at a flow rate of 200 mL/min and a load of 13 g per run. The total amout of mixed sample run was 51 g (54% 2R, 46% 2S). Refractive index detection of the eluting product was employed. Recovery of the 2R-isomer was 25.2 g (92%); 99.9% HPLC, and recovery of the 2S-isomer was 20.7 g (88%); 99.3% HPLC: m.p. (2R): 178-179°C; (2S): 167-169°C.

Analysis Calc, for C33H46N2O6 : C 69.94, H 8.18, N 4.94; found : 2R: C 69.95, H 8.19, N 4.92; 2S: C 69.55, H 7.89, N 4.84. -342R: [α)θ (0.5, methanol) = -67.2° 2S: [α]θ5 (0.5, methanol) = +9.2° EXAMPLE 8 R-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidizolidinone A) (2R)-2-(3-CycloDentyloxy-4-methoxyDhenyl)-2-in-menthvloxycarbonylaminolethvlamine A solution of (2R)-l-benzyloxycarbonylamino-2-(3-cyclopentyloxy-41 0 methoxyphenyl)-2-[(-)-menthyloxycarbonylamino]ethane ( 293 mg, 0.52 mmol) in methanol (20 mL) was treated with 10% palladium on carbon (306g) and ammonium formate (168 mg, 2.6 mmol). The reaction was allowed to stir at 50-55°C for 0.5 h, basified with concentrated ammonium hydroxide and then filtered through Celite. The solvent was removed in vacuo and the residue was partitioned between 95:5 methylene chloride/methanol and water. The organic extracts were dried (sodium sulfate) and evaporated to a white solid (222 mg, 99%).

B) R-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidazol idinone A solution of (2R)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)2 0 menthyloxycarbonylamino]ethylamine (149 mg, 0.34 mmol) in dimethylsulfoxide (3 mL) was treated with 10% aqueous sodium hydroxide (0.15 L, 0.41 mmol) and stirred under an argon atmosphere for 1.5 h. The mixture was diluted with ethyl acetate and the pH was adjusted to ~ 6 with ammonium chloride. The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed five times with water. The organic extracts were dried (sodium sulfate) and evaporated. Purification by flash chromatography, eluting with 97:3 methylene chloride/methanol, provided a white solid (70 mg, 74%): m.p. 135-137°C.

Analysis Calc, for C15H20N2O3 : C 65.20, H 7.30, N 10.14; found : C 65.26, H 7.39, N 10.14. 0 [α]θ^ (1.13, methanol) =-25.2° EXAMPLE 9 S-(+)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidiazolidinone - 35 A) 2S)-2-(3-Cvclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylaminolethylamine A solution of (2S)-l-benzyloxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyhenyl)-2-[(-)-menthyloxycarbonylamino]ethane (1.65 g, 2.91 mmol) in methanol (100 mL) was treated with 10% palladium on carbon (1.65 g) and ammonium formate (1.0 g, 15.8 mmol). The reaction was allowed to stir at 50-55°C for 0.25 h and then filtered through Celite. The solvent was removed in vacuo and the residue was partitioned between 95:5 methylene chloride/methanol and 95:5 water/concentrated ammonium hydroxide. The organic extracts were dried (sodium sulfate) and evaporated to a white 0 solid (1.21 g, 96%).

B) S-(+)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone A solution of (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylaminolethylamine (147.3 mg, 0.34 mmol) in dimethylsulfoxide (3 mL) was treated with 10% aqueous sodium hydroxide (0.15 mL, 0.41 mmol) and stirred under an argon atmosphere for 1.5 h. The mixture was diluted with ethyl acetate and the pH was adjusted to ~ 6 with ammonium chloride. The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed 5 times with water. The organic extracts were dried (sodium sulfate) and evaporated. Purification by flash 0 chromatography, eluting with 97:3 methylene chloride/methanol, provided a white solid (80.4 mg, 84%): m.p. 134-136θΟ Analysis Calc, for ^Η2θΝ2θ3·5/4ΗοΟ : C 60.28, H 6.75, N 9.37; found : C 60.35, H 6.60, N 9.42. [ot]p)5 (1.30, methanol) = +22° EXAMPLE 10 S-(-)-1-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone (A) 2S)-l-(4-Nitrobenzylamino)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-l (-)3 0 menthyloxycarbonylaminolethane A solution of (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylamino]ethylamine (553 mg, 1.27 mmol) and 4-nitrobenzaldehyde (202 mg, 1.33 mmol) in chloroform (10 mL) under an argon atmosphere was stirred for 8 h at reflux and for 18 h at room temperature. The solvent was removed in vacuo and the residue was redissolved in tetrahydrofuran (10 mL) and methanol (15 mL). Sodium cyanoborohydride (242 mg, 3.85 mmol) was added and the solution was stirred for 0.5 h. Addition of acetic acid (150 pL, 2.5 mmol) was followed by stirring at room temperature for 2 h under an -36argon atmosphere. Aqueous sodium bicarbonate was added, and the solution was evaporated to dryness. The residue was partitioned between methylene chloride/methanol and water several times, and the organic extracts were dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate/hexanes, provided a yellow solid (293 mg, 41 %): m.p. 76-77.5°C.

B) (2S)-1-(4-Aminobenzvlamino)-2-(3-cyclopentvloxy-4-methoxyphenvl)-2-r(-)menthyloxycarbonylaminolethane A solution of (2S)-l-(4-nitrobenzylamino)-2-(3-cyclopentyloxy-41 0 methoxyphenyl)-2-(-)-menthyloxycarbonylamino|ethane (270 mg, 0.5 mmol) in methanol (1.5 mL) was treated with acetic acid (1.45 mL), water (1.45 mL) and titanium trichloride (2.6 mL of a 20% aqueous solution). The reaction was stirred for 15 min, at which time water (1.45 mL) and concentrated ammonium hydroxide (3.5 mL) were added. The reaction was diluted with 1:1:2 aqueous sodium carbonate/methanol/methylene chloride (100 mL) and stirred for 1 h. The mixture was filtered through Celite, washing well with %methanol/methylene chloride and evaporated. The residue was partitioned between water and methylene chloride, and the organic extracts were dried (potassium carbonate) and evaporated to provide a yellow solid (237 mg, 93%): m.p. 74-75°C. 0 C) S-(-)-1-(4-Aminobenzvl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone A solution of (2S)-l-(4-aminobenzylamino)-2-(3-cyclopentyloxy-4methoxyphenyl)-2-[(-)-menthyloxycarbonylamino]ethane (232 mg, 0.43 mmol) in dimethylsulfoxide (5 mL) was treated with 10% sodium hydroxide (210 pL, 0.54 mmol) and stirred for 1 h under an argon atmosphere at 80-85°C. The reaction mixture was cooled and extracted twice with ethyl acetate. The organic extracts were washed 5 times with water, dried (potassium carbonate) and evaporated. Purification by flash chromatography, first eluting with 7:3 ethyl acetate/hexanes, then a second column, eluting with 98.5:1.5 methylene chloride/methanol, provided a off-white solid (119 mg, 63%): 0 m.p. 72-74°C.

Analysis Calc, for C22H27N3O3· 1/4Η?Ο : C 68.46, H 7.18, N 10.89; found : C 68.35, H 7.07, N 10.52. [α]θ (0.99, methanol) = -85° EXAMPLE 11 R-(+)-1-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone A) (2R)-l-(4-Nitrobenzylamino)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-((-)menthyloxycarbonylaminolethane A solution of (2R)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-I(-)-menthyloxycarbonylamino]ethylamine (843 mg, 1.95 mmol) and 4-nitrobenzaldehyde (311 mg, 2.04 mmol) in chloroform (15 mL) under an argon atmosphere was stirred for 18 h at reflux. The solvent was removed in vacuo and the residue was redissolved in tetrahydrofuran (10 mL) and methanol (10 mL). Sodium cyanoborohydride (371 mg, 5.8 mmol) was added and the solution was stirred for 1 h. Addition of acetic acid (225 μί, 3.7 mmol) was followed by stirring at room temperature for 48 h under an argon 0 atmosphere. Aqueous sodium bicarbonate was added, and the solution was evaporated to dryness. The residue was partitioned between methylene chloride/methanol and water several times, and the organic extracts were dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate/hexanes, provided a yellow solid (704 mg, 64%): m.p. 62-64°C.

B) (2R)-l-(4-Aminobenzvlamino-2-(3-cvclopentyloxy-4-methoxyphenyl)-2-r(-)menthvloxycarbonylaminolethane A solution of (2R)-l-(4-nitrobenzylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)2-[(-)-menthyloxycarbonylamino]ethane (683 mg, 1.2 mmol) in methanol (5 mL) was 0 treated with acetic acid (4.5 mL), water (4.5 mL) and titanium trichloride (7.8 mL of a % aqueous solution). The reaction was stirred for 15 min, at which time water (4.5 mL) and concentrated ammonium hydroxide (10.5 mL) were added. The reaction was diluted with 1:1:2 aqueous sodium carbonate/methanol/methylene chloride (300 mL) and stirred for 1.5 h. The mixture was filtered through Celite, washing well with 5% methanol/methylene chloride and evaporated. The residue was partitioned between water and methylene chloride, and the organic extracts were dried (potassium carbonate) and evaporated to provide a yellow solid (625 mg, 97%): m.p. 71-73°C.

C) R-(-l·)-1-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-23 0 imidazolidinone A solution of (2R)-l-(4-aminobenzylamino)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylaminojethane (615 mg, 1.2 mmol) in dimethylsulfoxide (3 mL) was treated with 10% sodium hydroxide (600 μί, 2.5 mmol) and stirred for 2 h under an argon atmosphere at 85-90°C. The reaction was cooled, water added and extracted twice with ethyl acetate. The organic extracts were washed 5 times with water, dried (potassium carbonate) and evaporated. Purification by flash chromatography, first eluting with 98.5:1.5 methylene chloride/methanol, then a second column, eluting with !E 913855 - 3898:2 methylene chloride/methanol, provided a yellow solid (310 mg, 68%); m.p. 7173°C.

Analysis Calc, for C22H27N3C>3«5/8H2O : C 67.28, H 7.25, N 10.70; found : C 67.24, H 7.02, N 10.34. [ot]^ (1.12, methanol) =+80° EXAMPLE 12 S-(-)-l-(4-Benzylpyridyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone 0 A) (2S)-1-(4-Benzylpvridylamino)-2-(3-cyclopentyloxy-4-methoxvphenyl)-2[(-)-menthyloxycarbonylaminolethane A solution of (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylaminojethylamine (444 mg, 1.03 mmol) and 4-pyridine-carboxaldehyde (105 pL, 1.08 mmol) in chloroform (10 mL) under an argon atmosphere was stirred for 4.5 h at reflux and then allowed to stir at room temperature for 18 h. The solvent was removed in vacuo and the residue was redissolved in tetrahydrofuran (8 mL) and methanol (5 mL). Sodium cyanoborohydride (198 mg, 3.1 mmol) was added and the solution was stirred for 0.5 h. Addition of acetic acid (120 pL, 2.1 mmol) was followed by stirring at room temperature for 2 h under an argon atmosphere. Aqueous sodium bicarbonate was added, 0 and the solution was evaporated to dryness. The residue was partitioned between methylene chloride/methanol and water, and the organic layer was dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 98:2 methanol/methylene chloride, provided the product (353 mg, 66%).

B) S-(-)-l-(4-Benzylpyridyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazol idinone A solution of (2S)-l-(4-benzylpyridylamino)-2-(3-cyc!opentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylamino|ethane (322 mg, 0.62 mmol) in dimethylsulfoxide (5 mL) was treated with 10% sodium hydroxide (300 pL, 0.74 mmol) 0 and stirred for 0.5 h under an argon atmosphere at 10()-105°C. The reaction was cooled and extracted twice with ethyl acetate. The organic extracts were washed 5 times with water, dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 97.5:2.5 methylene chloride/methanol, provided a pale yellow solid (162 mg, 71%), which was triturated with ether and dried (143 mg): m.p.l46-147°C.

Analysis Calc, for C21 Η25Ν3θ3·3/8Η7θ : C 67.40, H 6.94, N 11.23; found : C 67.71, H 6.82, N 11.05. -39[a]j~) (0.95, methanol) = -64.6° EXAMPLE 13 R-(+)-l-(4-Benzylpyridyl)-4-(3-cvclopentyloxy-4-methoxyphenyl)-2-imidazolidinone A) (2R)-l-(4-Benzylpyridylamino')-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-((-)menthyloxycarbonvlaminolethane A solution of (2R)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylaminojethylamine (358 mg, 0.83 mmol) and 4-pyridinecarboxaldehyde (85 0 gL, 0.87 mmol) in chloroform (8 mL) under an argon atmosphere was stirred for 6 h at reflux and then allowed to stir at room temperature for 18 h. The solvent was removed in vacuo and the residue was redissolved in tetrahydrofuran (5 mL) and methanol (5 mL). Sodium cyanoborohydride (161 mg, 2.5 mmol) was added and the solution was stirred for 1 h. Addition of acetic acid (95 gL, 1.7 mmol) was followed by stirring at room temperature for 18 h under an argon atmosphere. Aqueous sodium bicarbonate was added, and the solution was evaporated to dryness. The residue was partitioned between methylene chloride/methanol and water, and the organic layer was dried (potassium carbonate) and evaporated. Purification by flash chromatography, first eluting with 97:3 methanol/methylene chloride, followed by a second separation using flash 0 chromatography, eluting with 98:2 methanol/methylene chloride, provided the product (120 mg, 28%).

B) R-(+~)-l-(4-Benzylpyridyl~)-4-(3-cyclopentyloxy-4-methoxyphenyl~)-2imidazolidinone A solution of (2R)-l-(4-benzylpyridylamino)-2-(3-cyclopentyloxy-4methoxyphenyl)-2-[(-)-menthyloxycarbonyIamino]ethane (112 mg, 0.21 mmol) in dimethylsulfoxide (3 mL) was treated with 10% sodium hydroxide (110 gL, 0.26 mmol) and stirred for 1 h under an argon atmosphere at 8O-85°C. The reaction was cooled, water added and extracted twice with ethyl acetate. The organic extracts were washed 5 times 0 with water, dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 97:3 methylene chloride/methanol, provided a white solid (41 mg, 52%); m.p. 135-137°C.

Analysis Calc, for C2lH25N3O3«0.55SiO2 : C 60.33, H 6.03, N 10.05; found : C 60.32, H 6.14, N 9.92.

EXAMPLE 14 S-(-)-l-(4-Acetamidobenzyl)-4-(3-cyclopentyloxv-4-methoxyphenvl)-2-imidazolidinone - 40 A) S-(-)~ 1-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazol idi none To S-(-)-1 -(4-aminobenzyl)-4-(3-cyclopentyloxy-4-methoxypheny 1)-25 imidazolidinone (50 mg, 0.13 mmol) was added a solution of acetic anhydride (37 μί,, 0.39 mmol) and pyridine (one-half drop) in methylene chloride (1 mL) and the mixture was stirred at ambient temperature for 0.5 h under an argon atmosphere. The reaction mixture was purified by flash chromatography, eluting with 98:2 methylene chloride/methanol, to provid a white solid (51 mg, 93%): m.p. 98-100°C. 0 Analysis Calc, for C24H29N3O4*1/2H2O : C 66.65, H 6.99, N 9.72; found : C 66.94, H 6.89, N 9.58. [α]θ (0.90, methanol) = -72.9° EXAMPLE 15 R-(+)-l-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone R-(+)-l-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone To R-(+)-l-(4-aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone (50 mg, 0.13 mmol) was added a solution of acetic anhydride (37 μί, 0.39 mmol) and 0 pyridine (one-half drop) in methylene chloride (1 mL).and the mixture was stirred at ambient temperature for 0.5 h under an argon atmosphere. The reaction mixture was purified by flash chromatography, eluting with 98:2 methylene chloride/methanol, to provid a white solid (51 mg, 93%): m.p. 99-102°C.

Analysis Calc, for C24H29N3O4-1/2H2O : C 66.65, H 6.99, N 9.72; found : C 66.89, 2 5 H 6.60, N 9.38. [α]θ5 (0.99, methanol) = +75.6° EXAMPLE 16 0 S-(-)-l-(4-Oxamidobenzyl)-4-(3-cyclopentyloxy-4-methoxvphenyl)-2-imidazolidinone S-(-)-l-(4-Oxamidobenzyl)-4-(3-cvclopentvloxy-4-methoxyphenyl)-2-imidazolidinone To a solution of S-(-)-l-(4-aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)2-imidazolidinone (76 mg, 0.2 mmol) in methylene chloride (1.5 mL) at 0°C under an argon atmosphere was added triethylamine (0.03 mL, 0.22 mmol) and methyl oxalyl chloride (0.04 mL, 0.22 mmol). After 0.5 h, aqueous ammonium chloride was added, the -41 mixture was poured into water and extracted three times with methylene chloride. The organic extracts were dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 4:1 ethyl acetate/hexanes, provided a white foamy solid (89 mg, 93%): m.p. 77-80°C. This methyl oxamate (89 mg, 0.19 mmol) in methanol (1 mL) in a pressure tube under an argon atmosphere was cooled to -78°C and amhydrous ammonia (3 mL) was condensed into the tube. The tube was sealed and the mixture was allowed to come to ambient temperature. After 20 h, the tube was cooled to -78°C, unsealed and allowed to come to ambient temperature under a stream of argon. The residue was dissolved, filtered and evaporated. Trituration with methylene chloride provided a white solid (79 mg, 91 %): m.p. 191-193°C.

Analysis Calc, for C24H28N4O5»0.6H2O : C 62.22, H 6.35, N 12.09; found : C 62.25, H 6.22, N 11.97. [α]β> (0.99, dimethylsulfoxide) = -47.7° EXAMPLE 17 R-(+)-l-(4-Oxamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone R-(+)-l-(4-Oxamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone To R-(+)-l-(4-aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-22 0 imidazolidinone (51 mg, 0,13 mmol) at 0°C under an argon atmosphere was added a solution of triethylamine (0.02 mL, 0.14 mmol) in methylene chloride (0.5 mL) and a solution of methyl oxalyl chloride (0.014 mL, 0.14 mmol) in methylene chloride (0.5 mL). After 0.5 h, aqueous ammonium chloride was added, the mixture was poured into water and extracted three times with methylene chloride. The organic extracts were dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 3:1 ethyl acetate/hexanes, provided a sticky white solid (58 mg, 96%): m.p. 127-131°C. This methyl oxamate (58 mg, 0.12 mmol) in methanol (1 mL) in a pressure tube under an argon atmosphere was cooled to -78°C and anhydrous ammonia (2 mL) was condensed into the tube. The tube was sealed and the mixture was allowed to come to ambient 0 temperature. After 18 h, the tube was cooled to -78°C, unsealed and allowed to come to ambient temperature under a stream of argon. The residue was dissolved, filtered and evaporated. Trituration with methylene chloride provided a white solid (35 mg, 61%): m.p. 192-193°C.

Analysis Calc, for C24H28N4O5-1/3H2O : C 62.88, H 6.30, N 12.22; found : C 63.23, H 6.27, N 11.78. [a||)5 (0.99, dimethylsulfoxide) = +49.1° -42EX AMPLE 18 R-(+)-l-(4-Formamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone R-(+)-l-(4-Formamidobenzyl)-4-(3-cvclopentvloxy-4-methoxyphenyl)-2-imidazolidinone Acetic formic anhydride was prepared by heating a mixture of acetic anhydride (5.0 mL, 53 mmol) and formic acid (2.1 mL, 56 mmol) at 40-45°C for 3 h. To acetic formic anhydride (37 pL, 0.39 mmol) at 0°C under an argon atmosphere was added dropwise a solution of R-(+)- l-(4-aminobenzyl)-4-(3-cyclopentyIoxy-4-methoxyphenyl)-21 0 imidazolidinone (66 mg, 0.17 mmol) in dry tetrahydrofuran (1.5 mL), the mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was partitioned between methylene chloride and aqueous sodium bicarbonate, the organic extracts were washed with water, dried and evaporated. Purification by flash chromatography, eluting with 98:2 methylene chloride/methanol, provided a white solid (57 mg, 82%); m.p. 92-95°C.

Analysis Calc, for C23H27N3O4 : C 67.46, H 6.65, N 10.26; found : C 67.09, H 6.64, N 10.06. [a]^5 (0.90, methanol) = +89.3° 0 EXAMPLE 19 S-(-)-l-(4-Formamidobenzyl)-4-(3-eyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone S-(-)-l-(4-Formamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone Acetic formic anhydride was prepared by heating a mixture of acetic anhydride (5.0 mL, 53 mmol) and formic acid (2.1 mL, 56 mmol) at 40-45°C for 3 h. To acetic formic anhydride (25 gL, 0.27 mmol) at 0°C under an argon atmosphere was added dropwise a solution of S-(-)- l-(4-aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone (65 mg, 0.17 mmol) in dry tetrahydrofuran (1.5 mL), the mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was 0 partitioned between methylene chloride and aqueous sodium bicarbonate, the organic extracts were washed with water, dried and evaporated. Purification by flash chromatography, eluting with 98:2 methylene chloride/methanol, provided a foamy white solid (43 mg, 62%): m.p. 103-106°C.

Analysis Calc, for C23H27N3O4LIH2O : C 64.35, H 6.86, N 9.79; found : C 64.72, H 6.53, N 9.31. [a]!)5 (0.90, methanol) = -90.6° -43EXAMPLE 20 l-(4-Acetamido-3-pvridvlmethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone A) l-(4-Acetamido-3-pyridylmethylamino)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone A solution of (2R,2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)menthyloxycarbonylaminojethylamine (409 mg, 0.95 mmol) and 4-pyridine1 0 carboxaldehyde (155 mg, 0.95 mmol) in chloroform (15 mL) under an argon atmosphere was stirred for 4 h at reflux and cooled. The solvent was removed in vacuo and a portion of the residue (195 mg, 0.34 mmoles) was redissolved in tetrahydrofuran (2 mL) and methanol (2 mL). Sodium cyanoborohydride (65 mg, 1.0 mmol) was added and the solution was stirred for 0.5 h. Addition of acetic acid (40 pL, 0.7 mmol) was followed by stirring at room temperature for 1 h under an argon atmosphere. Aqueous sodium bicarbonate was added, and the solution was evaporated to dryness. The residue was partitioned between methylene chloride/methanol and water, and the organic layer was dried (potassium carbonate) and evaporated. Purification by flash chromatography, first eluting with 3:97 methanol/methylene chloride, provided the amine (128 mg, 65%); m.p. 0 78-81°C.

B) 1-(4-Amino-3-pyridylmethy l)-4-(3-cyclopentv loxy-4-methoxypheny 0-2imidazolidinone A solution of l-(4-acetamido-3-pyridylmethylamino)-4-(3-cycIopentyIoxy-42 5 methoxyphenyl)-2-imidazolidinone (121 mg, 0.21 mmol) in dimethylsulfoxide (3 mL) was treated with 10% sodium hydroxide (0.42 mL, 1.05 mmol) and stirred for 2.5 h under an argon atmosphere at 90-95°C. The reaction was cooled, water added and extracted twice with ethyl acetate. The organic extracts were washed 5 times with water, dried (potassium carbonate) and evaporated. Purification by flash chromatography, eluting with 96:4 0 methylene chloride/methanol, provided a white solid (63 mg, 79%): m.p. 69-71°C.

Analysis Calc, for C21H26N4O3O.5H2O : C 64.43, H 6.95, N 14.31; found: C 64.30, H 6.86, N 14.05.

C) l-(4-Acetamido-3-Pvridylmethyl)-4-(3-cyclopentvloxy-4-methoxyphenyl)-23 5 imidazolidinone A solution of 1-(4-amino-3-pyridylmethyl)-4-(3-cyclopentyloxy-4-methoxyhenyl)-2-imidazolidinone (36 mg, 0.09 mmol) in pyridine (2 mL) was treated with a solution of acetyl chloride (0.0075 mL, 0.11 mmol) in methylene chloride (0.5 mL) and -44the mixture was stirred for l h under an argon atmosphere at ambient temperature. An additional aliquot of acetyl chloride (0.0075 mL, 0.11 mmol) in methylene chloride (0.5 mL)was added and stirring was continued for 1.5 h. Water was added and the mixture was extracted three times with methylene chloride. The organic extracts dried (sodium sulfate) and evaporated. Purification by flash chromatography, eluting with 96:4 methylene chloride/methanol, provided an off-white solid (39 mg, 99%); m.p, 184187°C. the solid was triturated with methylene chloride and ether to provide a white solid (10 mg).

Analysis Calc, for C23H28N4C>4«().65H2O : C 63.33, H 6.77, N 12.84; found : C 0 63.34, H 6.52, N 12.44.

EXAMPLE 21 S-(-)-4-(3-Cvclopentvloxv-4-methoxyphenvl)-l-(2,4-diaminobenzyl)-2-imidazolidinone A) (2S)-2-(3-cycIopentyloxy-4-methoxyphenyl)-l-(2,4-DinitrobenzyIamino)-2-i(-)menthyloxycarbonylaminolethane A solution of (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylaminojethylamine, obtained as described above from (2S)-l-benzyloxycarbonylamino-2(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylamino]ethane (2.00 g, 0 3.53 mmol), and 2,4-dinitrobenzaldehyde (762 mg, 3.88 mmol) in chloroform (40 mL) under an argon atmosphere was stirred for 5 h at reflux. The solvent was removed in vacuo and the residue was redissolved in tetrahydrofuran (38 mL) and methanol (40 mL) under an argon atmosphere. Sodium cyanoborohydride (664 mg, 10.6 mmol) was added and the solution was stirred for 1 h. Addition of acetic acid (404 pL, 7.1 mmol) was followed by stiring at room temperature for 72 h . Aqueous sodium bicarbonate was added, and the mixture was evaporated to dryness. The residue was partitioned between methylene chloride and water, and the organic extract was dried (sodium sulfate) and evaporated in vacuo. Purification by flash chromatography, eluting with from 40 to 60% ethyl acetate in hexane, provided a semi-solid (1.7 g, 79%).

B) (2S)-2-(3-cyclopentyloxy-4-methoxyphenyD-1-(2,4-diaminobenzylamino)-2-K-)menthyloxycarbonylaminolethane A solution of (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(2,4-dinitrobenzyl)2-[(-)-menthyloxycarbonylamino]ethane (1.7 g, 2.8 mmol) in methanol (16.6 mL) containing acetic acid (16.6 mL), was treated with water (16.6 mL) and titanium trichloride (35 mL of a 20% aqueous solution). The reaction was stirred for 90 min, chilled in an ice bath and a solution of water (24 mL) and concentrated ammonium hydroxide (47 mL) were added. The reaction was diluted with 5% sodium carbonate/methanol/methylene chloride -45 (1:1:2) and stirred for 1 h. The mixture was separated and the aqueous phase extracted with methylene chloride. The organic extract was dried (potassium carbonate) and evaporated in vacuo. Purification by flash chromatography, eluting the product with chloroform (saturated with ammonium hydroxide and dried) provided a solid (1.04 g, 68%): m.p. 150-154°C.

C) S-(-)-4-(3-cyclopentyIoxv-4-methoxyohenyl)-l-(2,4-diaminobenzvl)-2imidazolidinone A solution of (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(2,4-diamino1 0 benzylamino)-2-[(-)-menthyloxycarbonylamino]ethane (1.0 g, 1.81 mmol) in dimethylsulfoxide (8 mL) was treated with 10% sodium hydroxide (1.0 mL, 2.5 mmol) and stirred for 3 h under an argon atmosphere at 80-85°C. The reaction mixture was cooled, partitioned between cold water and ethyl acetate, and the organic extract was washed with water, dried (sodium sulfate) and evaporated in vacuo. Purification by flash chromatography, eluting the product with chloroform (saturated with ammonium hydroxide and dried) containing 0.5 to 2% methanol, provided a granular resin (459 mg, 64%); [α]θ (0.609, methanol) = -83.6°.

Analysis Calc, for C22H28N4O3 : C 66.65, H 7.12, N 14.13; found : C 66.40, H 7.04, N 13.96.

EXAMPLE 22 S-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-l -(2,4-diacetamidobenzy 1)-2imidazolidinone.

To a solution of S-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(2,42 5 diaminobenzyl)-2-imidazolidinone (240 mg, 0.605 mmol) in anhydrous pyridine (5 ml) was added acetic anhydride (340 pL, 3.60 mmol) and the mixture was stirred at ambient temperature for 18 h under an argon atmosphere. The reaction mixture was concentrated in vacuo, and the residue partitioned between cold 3N HCI and ethyl acetate. The organic extract was washed with water, 5% aqueous sodium bicarbonate, water, dried over 0 sodium sulfate and concentrated in vacuo. Purification by flash chromatography,eluting the product with chloroform (saturated with ammonium hydroxide and dried) containing 1 25 to 2% methanol, provided a resin (180 mg, 62%); [a]q (0.600, methanol) = -61°.

Analysis Calc, for C26H32N4O5«1/4H2O : C 64.38, H 6.75, Ν 11.55; found : C 64.61, H 6.77, Ν 11.38. -46EXAMPLE 23 R-(+)-4-(3-cyclopentvloxy-4-methoxyphenyl)-l-(2,4-Diaminobenzyl)-2-imidazolidinone A) (2R)-2-(3-cyclonentyloxv-4-methoxyphenvl)-l-(2,4-Dinitrobenzylamino)-2-f(-)5 menthyloxycarbonylarninolethane A solution of (2R)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylamino]ethylamine, obtained as described above from (2R)-l-benzyloxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-((-)-menthyloxycarbonylamino)e thane (2.00 g, 3.53 mmol), and 2,4-dinitrobenzaldehyde (762 mg, 3.88 mmol) in chloroform 0 (40 mL) under an argon atmosphere was stirred for 5 h at reflux. The solvent was removed in vacuo and the residue was redissolved in tetrahydrofuran (10 mL) and methanol (15 mL). Sodium cyanoborohydride (665 mg, 10.6 mmol) was added and the solution was stirred for 1 h. Addition of acetic acid (405 gL, 7.1 mmol) was followed by stiring at room temperature for 72 h under an argon atmosphere. Aqueous sodium bicarbonate was added, and the solution was evaporated to dryness. The residue was partitioned between methylene chloride and water, and the organic extract was dried (sodium sulfate) and evaporated in vacuo. Purification by flash chromatography, eluting with from 30 to 50% ethyl acetate in hexane, provided an orange solid (1.25 g, 62%), mp 119-125°C.

B) (2R)-2-(3-cyclopentvloxv-4-methoxyphenyl)-l-(2,4-diaminobenzylamino)-2-r(-)menthyloxycarbonylaminolethane A solution of (2R)-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(2,4-dinitrobenzyIamino)-2-[(-)-menthyloxycarbonylaminojethane (1.2 g, 2.0 mmol) in methanol (12 mL) containing acetic acid (12 mL), was treated with water (10 mL) and titanium trichloride (20.8 mL of a 20% aqueous solution). The reaction was stirred for 60 min, chilled in an ice bath and a solution of water (12 mL) and concentrated ammonium hydroxide (28 mL) were added. The reaction was diluted with 5% sodium carbonate/methanol/methylene chloride (1:1:2) and stirred for 1 h. The mixture was 0 separated, the aqueous phase extracted with methylene chloride containing 5% methanol and the combined organic extracts were washed with water, dried (potassium carbonate), and evaporated in vacuo. Purification by flash chromatography, eluting with chloroform (saturated with ammonium hydroxide and dried) provided a tan solid (0.59 g, 54%): m.p 139-143°C.

C) R-(+)-4-(3-cyclopcntyloxy-4-melhoxypheny1)-l-(2,4-Diaminohenzyl)-2imidazolidinone -47 A solution of (2R)-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(2,4diaminobenzylamino)-2-[(-)-menthyloxycarbonylamino]ethane (0.59 g, 1.07 mmol) in dimethylsulfoxide (4 mL) was treated with 10% sodium hydroxide (0.53 mL, 1.3 mmol) and stirred for 3.5 h under an argon atmosphere at 80-85°C. The reaction mixture was cooled, partitioned between cold water and ethyl acetate, and the organic extract was washed with water, dried (potassium carbonate) and evaporated in vacuo. Purification by flash chromatography, eluting the product with chloroform (saturated with ammonium hydroxide and dried) containing 1 to 2% methanol, provided a resin (352 mg, 83%): [a]^ (0.564, methanol) = *84°. 0 Analysis Calc, for C22H28N4O3 : C 66.65, H 7.12, N 14.13; found: C 66.43, H 7.03, N 14.11.

EXAMPLE 24 R-(+)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(2,4-diacetamidobenzyl)-215 imidazolidinone.

To a solution of R-(+)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,4diaminobenzyl)-2-imidazolidinone (176 mg, 0.44 mmol) in anhydrous pyridine (4 ml) was added acetic anhydride (250 pL, 2.64 mmol) and the mixture was stirred at ambient temperature for 18 h under an argon atmosphere. The reaction mixture was concentrated in 0 vacuo, and the residue partitioned between cold 3N HCl and ethyl acetate. The organic extract was washed with water, 2% aqueous sodium carbonate, water, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography,eluting the product with chloroform (saturated with ammonium hydroxide and dried) containing 1 to 25 2% methanol, provided a resin (140 mg, 66%): [α]θ (0.591, methanol) = 59°.

Analysis Calc, for C26H32N4O5«1/4H2O : C 64.38, H 6.75, Ν 11.55; found : C 64.20, H 6.70, N 11.43.

By the methods given above, the following compounds may be prepared: Example No. Compound 30 25 1- (4-Cyanobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)- 2- imidzoIidinone 26 1- (4-Amidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)- 2- imidzolidinone 27 4-(3-Cyclopentyloxy-4-methylphenyl)-1-(4-(2- 35 imidazo)benzyl}-2-imidazolidinone 28 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone -48 29 4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(4-(1 imidazo)benzyl|-2-imidzolidinone 4-(3-[4-Butoxy(-4-methoxyphenyl)-2-imidazolidinone EXAMPLE 31 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below. 0 Inhalant Formulation A compound of Formula (I), (lpg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.

Tablets/Ingredients 1. Active Ingredients Per Tablet 1 5 (cpd. of Formula (I) 40 mg 2. Corn Starch 20 mg 3. Alginic Acid 20 mg 4. Sodium Alginate 20 mg 5. Mg Stearate 1.3 mg 20 101.3 mg EXAMPLE 32 A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of Formula (I) in polyethylene glycol with heating. This solution is then diluted with water for injection (to 100ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

The above description fully discloses the invention including preferred embodiments 0 thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is belived that one skilled in the are can, using the preceding description, utilize the present invention to its fuillest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims (40)

What is Claimed is

1. A compound of the formula: O wherein: Rl is - (CR 9 RlO)n- (C(O)O) r -(CR9Rl0)m-R8, -(CRgE^ θ (C(O)NRg ) r (CR9Rl0)m-R8, or - (CR9RlO)n- (O)s -(CR9Rl0)m- R 8 wherein the alkyl moieties may be optionally substituted with one or more halogens; n is a number having a value of 0 to 4; m is a number having a value of 0 to 2; r is a number having a value of 0 or 1; s is a number having a value of 0 or 1; R9 and Rio are independently selected from hydrogen or a Ci-2 alkyl; R8 is hydrogen, methyl, hydroxyl, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocylic moietes may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that a) when r is 1, n is 1 to 4; or b) when s is 1, n is 2 to 4; or c) when R8 is hydroxyl, r is 1, and n is 1 to 4, then m is 2; or d) when Rs is hydroxyl, and r or s is 0, then the sum of n + m is 2 to 6; or e) when m is 0, r is 1 in -(CR9Rio)n* (C(O)O)r -(CR9RiO)m-R8, then n is 1 to 4; or f) when R8 is a 2-tetrahydropyran or 2-tetrahydrothiopyran, 2-tetrahydrofuran or 2tetrahydrothiophene, and r or s is 0, then the sum of n + m is 1 to 6; or - 50g) when Rs is a 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetrahydrofuran or 2tetrahydrothiophene, n is 1 to 4, and r is 1, then m must be 1 to 2; or h) when R8 is a 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetrahydrofuran or 2tetrahydrothiophene, n is 2 to 4, and s is 1, then m must be 1 to 2; 5 X is YR2, halogen, nitro, NR6R7, or formyl amine; Y is O or S(O) m ’; m' is anumber having a value of 0 to 2; R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; R3 is H, CH3, CN, CH2F, CHF2, or CF3; 10 R4 is H, C1-C4 alkyl, OH, OCH3, OCH2CH3, or OAc; R5 is H, OH, -(CH2)qAr, or Cj.g alkyl wherein the (CH2)qAr or Cj.g alkyl group is optionally substituted one or more times by Br, Cl, F ,-Νί^ ,-NRgR? j-CC^Rg, -OR6, -OC(O)R6, C(O)R6, CN, -C(O)-NR6R7. -C(S)-NR6R7, - NR6-C(O)-NR6R7, - NR6-C(S)-NR6R7> - NR6-C(O)-R6, - NR6-C(S)-R6, - NR6-C(O)-OR6, 1 5 C(=NR6)-NR6R7. -C(=NCN)-NR6R7. -C(=NCN)-SR6, -NR6-C(=NCN)-SR6 , - NR6-C(=NCN)-NR6R7, -C(=NR6R7)SR6. -NR6-S(O)2 -R6, - S(O) m '-R6, -NR6SO2-CF3, - NR6C(O)-C(O)-NR6R7, - NR6-C(O)-C(O)-OR6, 1-imidazolyl, or l-(NR6)-2-imidazolyl; Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, morpholino, 4- or 52 0 thiazolyl, triazolyl, 2- or 3- thienyl, 2-thiaphene, or phenyl; Rg and R7 are independently hydrogen, or C 1.4 alkyl optionally substituted by one or more halogens; q is a number having a value of 0 to 2; and the pharmaceutically acceptable salts thereof.

2. The compound according to Claim 1 wherein the halogens are fluorine.

3. The compound according to Claims 1 or 2 wherein X is YR230

4. The compound according to Claim 3 wherein Y is oxygen. -51 5. The compound according to Claims 1,2 or 3 wherein -(CH2)qAr.

5.CH.

6. The compound according to Claims I to 5 wherein Rj is cyclopentyl, !_ O. , “O. -CF3, CH2F, -CHF2, -CF2CHF2, CH2CF3, or -CH2CHF2 or CH3.

7. The compound according to Claim 6 wherein R2 is methyl, -CF3, CHF2, or -CH2CHF2.

8. The compound according to Claim 7 wherein R4 is hydrogen, methyl, methoxy;, and Rg is CN,CHF 2 »CF 3 or H. 15

9. The compound according to Claim 1 or 2 wherein R5 is H, optionally susbtituted Ci-6 alkyl or -(CH2)qAr.

10. The compound according to Claim 8 or 9 wherein Ar is a phenyl or substituted phenyl and q is 1.

11. The compound according to Claim 10 wherein optionally substitutents are selected from -NH2, -N(CH3)2, - S(O) m CH3, -NH-C(O)CH3, NHC(O)NH2, CO2CH3. OCH3, NO2, -NHC(=NCN)NH2, -NHC(=NCN)SCH3, - NHC(O)-C(O)-OCH3, -NHC(O)-C(O)-NH2 or COOCH3.

12. The compound according to Claim 1 wherein Rs is methyl.

13. The compound according to Claim 1 which is 4-(3-Cyclopentyloxy-4methoxy-phenyl)-2-imidazolidinone.

14. The compound according to Claim 1 which is l-(4-Aminobenzyl-4-(3cyclopentyl-oxy-4-methoxyphenyl)-2-imidazolidinone.

15. The compound according to Claim 1 wherein the compound is selected 3 5 from l-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; -52 l-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-2imidazolidinone; 4- (3-Cyclopentyloxy-4-methoxyphenyl)-l-(4-dimethyl-aminobenzyl)-2imidazolidinone; 5. 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone; l-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; R-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidizolidinone 5- (+)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidiazolidinone 6. 1 0 S-(-)-1-(4- Aminobenzyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-2imidazolidinone; R-(+)-1-(4- Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; S-(-)-l-(4-Benzylpyridyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-21 5 imidazolidinone; R-(+)-l-(4-Benzylpyridyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; S-(-)-1-(4- Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; 2 0 R-(+)-1-(4- Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; S-(-)-l-(4-Oxamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyI)-2imidazolidinone; R-(+)-l-(4-Oxamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-22 5 imidazolidinone; R-(+)-l-(4-Formamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; S-(-)-l-(4-Formamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; 3 0 1-(4-Acetamido-3-pyridylmethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl) 2-imidazolidinone; S-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,4-diaminobenzyl)-2imidazolidinone; S-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,4-diacetamidobenzyl)3 5 2-imidazolidinone; R-(+)-4-(3-cyclopentyloxy-4-methoxy phenyl)-1-(2,4-Diaminobenzyl)-2imidazolidinone; or -53R-(+)-4-(3-CyclopentyIoxy-4-methoxyphenyl)-1-(2,4-diacetamido benzyl)2-imidazolidinone.

16. A method of inhibiting the production of tumor necrosis factor (TNF) in an animal in need thereof, which comprises administering to such animal an effective, TNF production inhibiting amount of a compound according to Claim 1.

17. The method of claim 16 wherein X is YR2.and the halogens are all fluorine.

18. The method of claim 17 wherein Y is oxygen, and R5 is H or -(CH 2 )qAr.

19. The method of claim 18 wherein Rj is cyclopentyl, CHi O. , Ο CH3, or halo substituted alkyl; R 2 is methyl or halo-substituted alkyl.

20. The method of claim 19 wherein Ar is a phenyl or substituted phenyl, q is 1 and the Ar is optionally substituted by -NH2, -N(CH3) 2 , - S(O) m CH 3 , -NH2 0 C(O)CH3, NHC(O)NH2, CO2CH3, OCH3, NO 2 , -NHC(=NCN)NH2, -NHC(=NCN)SCH3, - NHC(O)-C(O)-OCH3, -NHC(O)-C(O)-NH2 or C(O)OCH 3 ., and Rg is methyl.

21. The method of claim 16 wherein the compound is selected from 2 5 l-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; 1-(4- Aminobenzyl)-4-(3-cyclopentyloxy-4-meth0xyphenyl)-3-methyl-2imidazolidinone; 4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(4-dimethyl-aminobenzyl)-23 0 imidazolidinone; 4- (3-Cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone; l-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; R-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidizolidinone 3 5 S-(+)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidiazolidinone 5- (-)-l-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; -54R-(+)-1 -(4-Am inobenzyl)-4-(3-cyclopenty loxy-4-methoxyphenyl)-2imidazolidinone; S-(-)-l-(4-Benzylpyridyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; 5 R-(+)-1 -(4-Benzylpyridyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; S-(-)-l-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; R-(+)-l-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-210 imidazolidinone; S-(-)-l-(4-Oxamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; R-(+)-l-(4-Oxamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; 1 5 R-(+)-1 -(4-Formamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; S-(-)-l-(4-Formamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2imidazolidinone; 1-(4- Acetamido-3-pyridylmethyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)2 0 2-imidazolidinone; S-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,4-diaminobenzyl)-2imidazolidinone; S-(-)-4-(3-CyclopentyIoxy-4-methoxyphenyl)-1-(2,4-diacetamidobenzyl)2-imidazolidinone; 2 5 R-(+)-4-(3-cyclopentyloxy-4-methoxyphenyl)-1 -(2,4-Diaminobenzyl)-2imidazolidinone; or R-(+)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,4-diacetamidobenzyl)2-imidazolidinone. 3 0

22. The method of Claim 16 wherein the inhibition of TNF mediates the disease states of septic shock, endotoxic shock, gram negative sepsis, or toxic shock syndrome.

23. The method of Claim 16 wherein the inhibition of TNF mediates the 3 5 disease states of cachexia secondary to AIDS, or cachexia secondary to cancer, acute immune deficency syndrome (AIDS), AIDS Related Complex (ARC) or any other disease state associated with an HIV infection, or a viral infection selected from the group consisting of influenza, CMV or adenovi rus.

24.-5524. The method of Claim 16 wherein the inhibition of TNF mediates the disease states of adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory diseases, Crohn's disease, or ulcerative colitis.

25. The method of Claim 16 wherein the inhibition of TNF mediates the disease states of bone resorption, or graft vs. host reaction.

26. A pharmaceutical composition comprising an effective amount of a 1 0 compound according to Claim 1 and a pharmacuetically acceptable carrier or diluent.

27. A compound of the formula: wherein O (Ia) -Cl^-Cg cylic alkylcyVic alkyl, cylic alkyl, tetrahydrofuran, cyclopentenyl, -Ci_ 7 alkyl optionally substituted by 1 or more fluorines, -4OH for Formula (Ia), -,- -(CH2)n-C(O)O(CH2)m-CH3, - (CH2)p-O-(CH2) m CH3, all of which may be optionally substitued by one to three methyl groups or one ethyl group; m is a number having a value of 0 to 2; n is a number having a value of 1 to 3; is p is a number having a value of 2 or 3; X is YR2; Y is O or S; R2 is -CH3 or CH2CH3 optionally substituted by 1 or more f 1 uorines; R3 is H, CH 3 , CN, CH2F, CHF2 or CF3; R4 is H, Ci-4 alkyl, OH, OCH3, OCH2CH3, or OAc; R5 is H, OH, -(CH2)q Ar, Ci-6 alkyl; wherein Ar and C1-6 alkyl may be unsubstituted or substituted by one or more of the following: Br, Cl, NO2, NR6R7, CO2R6, -NH-C(=NCN)-SCH3, -NHC(O)-NR6R7, -C(O)NR6R7, -NHC(O)CH3, -NH-(=NCN)-NR6R7, -NHC(O)C(O)-NR6R7, -NHSO2CH3, -S(O) m CH3, -NHC(O)C(O)-OR6, -OR6, -CN, -C(=NR6)-NR6R7, -561. N^NR 6 or - ^^ -NHSO2CF3, \=4 ^= 7 Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, morpholino, or phenyl; Rg and R7 are independently hydrogen, or Cj_4 alkyl; 5 q is a number having a value of 0 to 2; or a pharmaceutically acceptable salt thereof.

28. CH 2The compound according to Claim 27 wherein R j is -ch 2 —<1 — θ “0 -0° N · '—,. \ I , -CF 3 , CHF2, C1-7 alkyl, -Cj-4 alkyl OH, or a C4-C5 cyclic alkyl optionally substituted by one to three methyl groups or one ethyl group.

29. A pharmaceutical composition comprising an effective amount of a compound according to Claim 27 and a pharmaceutically acceptable carrier or diluent. 1 5

30. A method of inhibiting PDE IV which comprises administering to a mammal in need thereof, an effective amount of a compound acccording to Claim 27 sufficent to inhibit PDE IV. 2 0

31. The method according to Claim 30 wherein the inhibition of PDE IV mediates the disease state of asthma, or an allergic or inflammatory disease.

32. A method of inhibiting PDE IV which comprises administering to a mammal in need thereof, an effective amount to inhibit PDE IV of a compound according to 2 5 Claim 15.

33. A process of making a compound of Formula (I): X (1) -57 10 wherein* -CCRgR, 0 ) n -(C(O)O) r -(CR g R l0 ) nl -R 8 -(CRgR 10 ) n -(C(O)N R 6> r ( CR 9 R 1C>n,- R 8· or -< CR 9 R 10’n-< 0 > S -< CR 9 R 10>m- R 8 wherein the alkyl moieties may be optionally substituted with one or more halogens; n is a number having a value 0 to 4; m is a nufnber having a value 0 to 2; r is a number having a value 0 or 1; s is a number having a value 0 or 1; R g apd Rjp are independently selected from hydrogen or a C-, _ 2 al kyl; Rg is methyl, hydroxyl, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, C3-6 cycloalkyl, C4-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocylic moietes may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that a) when r is 1, n is 1 to 4; or b) when s is 1, n is 2 to 4; or c) when Rs is hydroxyl, r is 1, and n is 1 to 4, then m is 2; or d) when Rs is hydroxyl, and r or s is 0, then the sum of n + m is 2 to 6; or e) when m is 0, n is 1 to 4, Ri is (C(O)O) r and r is 1, then Rs may be hydrogen; or 2 0 f) when R8 is a 2-tetrahydropyran or 2-tetrahydrothiopyran, 2-tetrahydrofuran or 2 tetrahydrothiophene, and r or s is 0, then the sum of n + m is 1 to 6; or g) when Rs is a 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetrahydrofuran or 2tetrahydrothiophene, n is 1 to 4, and r is 1, then m must be 1 to 2; or h) when Rs is a 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetrahydrofuran or 22 5 tetrahydrothiophene, n is 2 to 4, and s is 1, then m must be 1 to 2; X is YR2, halogen, nitro, NRgR? > -58πϊ is 0 to 2; R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; R3 is H, CH3, CN, CH2F, CHF2, or CF3; R4 is H, C1-C4 alkyl, OH, OCH3, OCH2CH3, or OAc; 5 R5 is H, OH, -(CH2)qAr, or Cj.g alkyl wherein the (CH2)qAr or Cj.g alkyl group is optionally substituted one or more times by Br, Cl,F,-NOg ,-NRgRy j-CC^Rg, -ORg, -OC(O)R6, C(O)Rg, CN, -C(O)-NRgR7, -C(S)-NRgR7, - NRg-C(O)-NRgR7, - NRg-C(S)-NRgR7, * NR6-C(O)-R6, - NR6-C(S)-R6, - NR6-C(O)-OR6, C(=NR6)-NR6R7, -C(=NCN)-NR6R7, -C(=NCN)-SRg, -NR6-C(=NCN)-SR6 , 1 0 - NRg-C(=NCN)-NRgR7, -C(=NRgR 7 )SRg, -NR6-S(O)2 -R6, - S(O) m --Rg, -NR6SO2-CF3, - NRgC(O)-C(O)-NRgR7, - NR6-C(O)-C(O)-OR6, 1-imidazolyl, or l-(NRg)-2-imidazolyl; Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, morpholino, 4- or 5thiazolyl, triazolyl, 2- or 3- thienyl, 2-thiaphene, or phenyl; 7. 15 Rg and R7 are independently hydrogen, or C 1.4 alkyl optionally substituted by one or more halogens; q 1s a number having a value of 0, 1 or 2, and the pharmaceutically acceptable salts thereof. 8. 2 0 which process comprises A. Oxidizing a compound of Formula (5) O wherein 9. 25 Rj, X, R3, R4, R8 are as defined for Formula (1); and R5 is H to an aldehyde oxime followed by reduction of the oxime to yield the corresponding Formula (5) -59compound wherein R5 is hydroxyl; followed by cyclization with a base and solvent to provide a compound of Formula (I) wherein R5 is H and R3 is other than CN; or B. Reacting a compound of Formula (5), as described above, wherein R5 is H with an 5 aldehyde followed by acid salt formation and reduction of the resulting iminium salt to provide a compound of Formula (5) wherein R3 is other than CN, R5 is other than H, followed by cyclization with base to yield a compound of Formula (I) wherein R3 is other than CN, R5 is other than H and X is other than Br, I, NO2, amine, formylamine, or S(O)m' and m is 1 or 2; or 1 0 C. Cyclizing a compound of Formula (5), as described above, wherein R4 and R5 are H and R3 is CONH2; followed by dehydration of the R 3 amide to a nitrile provides a compound of Formula (I) wherin R4 and R5 are H and R3 is CN; or 15 D. Reacting a suitably protected amino moiety of Formula (5) wherein R4 and R5 are H and R3 is CONH2, dehydrating the R3 amide to a nitrile, deprotecting the amine functionality to provide a compound of Formula (5) wherein R4 and R5 are H and R3 is CN; followed by acyclization to provide a compound of Formula (I) wherein is hydrogen, Rg is other than H and Rg is CN; F. Homologating the deprotected amine functionality of Formula(5) produced in step E. above; followed by acyclization to provide β compound of Formula (I) wherein R4 is hydrogen, Rg ts other than H-and R 3 is CN; 2 5 F. Reacting a compound of Formula (6) with phosgene in a solvent in the presence of an acid scavenger to provide a compound of Formula (I) wherein R5 is H and R3 is other than CN; or G. Reacting a compound of Formula (6) with Ν,Ν'-carbonyldi-imidazole or 1,1,carbonyldi-1,2,4-triazole in solvent to yield a compound of Formula (I) wherein R5 is H and R3 is other than CN; or -60H. Reacting a compound of Formula (6) wherein R4 is H and R3 is CONH2 by cycliziation followed by amide dehydration provides a compound of Formula (I) wherein R4 and R5 are H and R3 is CN; or 5 I. Reacting a compound of the Formula (6), as described above, wherein the α-NH is protected, R5 is H, and R3 is not CN, followed by imine formation with the appropriate aldehyde, followed by imine or imminium ion reduction and deprotection of the α-NH, to provide a compound of Formula (6) in which R5 is other than H and R3 is other than CN; followed by any of steps F. to H. above to yield a compound of Formula (I). 1 0

34. A compound of the formula wherein 15 Rl, X, R3, R4, R5 and Rs are as defined for Formula (I).

35. The compounds according to Claim 33 which are: (2R)-l-Benzyloxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)2-[(-)-menthyloxycarbonylamino]ethane; or 2 0 (2S)-l-Benzyloxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)2-[(-)-menthyloxycarbonylamino]ethane.

36. A compound of the formula: wherein X, Rj, R4, R3, and R5 are as defined for Formula (1). - 61

37. A process for the preparation of a compound of formula I as defined in claim 33 substantially as described herein by way of example. 5

38. A compound as prepared by a process as claimed in any of claims 33 to 37.

39. Use of a compound of formula I as defined in claim 1 in the preparation of a medicament for inhibition of tumor necrosis IQ factor (TNF).

40. Use of a compound of formula Ia as defined in claim 27 in the preparation of a medicament for inhibiting PDE IV.