WO1993019720A2 - Compounds - Google Patents
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- WO1993019720A2 WO1993019720A2 PCT/US1993/002230 US9302230W WO9319720A2 WO 1993019720 A2 WO1993019720 A2 WO 1993019720A2 US 9302230 W US9302230 W US 9302230W WO 9319720 A2 WO9319720 A2 WO 9319720A2
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- alkyl
- cr4r5
- hydrogen
- cyano
- optionally substituted
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- 0 C*CC(C1*)C=C(*)CCC1c1ccc(*)c(*)c1 Chemical compound C*CC(C1*)C=C(*)CCC1c1ccc(*)c(*)c1 0.000 description 3
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- 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).
- TNF Tumor Necrosis Factor
- Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyperreactivity of the respiratory tract to external stimuli. Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma.
- An alternative to the "mediator approach" is to regulate the activity of the cells responsible for the pathophysiology of the disease. One such way is by elevating levels of cAMP (adenosine cyclic 3',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, 17-29, 1973].
- adenylate cyclase is activated, which converts Mg -- ATP to cAMP at an accelerated rate.
- Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation.
- compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.
- PDEs cyclic nucleotide phosphodiesterases
- PDE IV cyclic nucleotide phosphodiesterase
- PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo.
- PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandinE2 and prostacyclin (activators of adenylate cyclase) are elevated.
- Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market
- the compounds of this invention also inhibit the production of Tumor Necrosis Factor
- TNF a serum glycoprotein.
- diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs.
- allograft rejections fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AJDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
- AIDS acquired immune deficiency syndrome
- AJDS AIDS related complex
- keloid formation scar tissue formation
- Crohn's disease Crohn's disease
- ulcerative colitis ulcerative colitis
- pyresis in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
- AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV).
- HIV-1 Human Immunodeficiency Virus
- HTV-2 a ⁇ dHIV-3.
- T-cell-mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms.
- HTV entry into the T lymphocyte requires T lymphocyte activation.
- Viruses such as HTV-1 or HIV- 2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HTV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HTV replication.
- Cytokines are implicated in activated T-cell-mediated HTV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in anHlN-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HTV 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 HTV Infection,
- TNF Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli et al, Proc. Nad. Acad. Sci., 87:782-784, 1990], therefore, inhibition of monokine production or activity aids in limiting HTV progression as stated above for T cells.
- TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
- CMV cytomegalovirus
- influenza virus influenza virus
- adenovirus adenovirus
- herpes virus herpes virus for similar reasons as those noted.
- TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. [See Riipi et al., Infection and Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal of Infectious Diseases, 164:389-95, 1991. See also Wasan etal., Antimicrobial Agents and Chemotherapy, 35,(10):2046-48, 1991; and Luke etal., Journal of Infectious Diseases, 162:211-214,1990]. The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF.
- This invention relates to the novel compounds of Formulas (I) and (II) as shown below, useful in the mediation or inhibition of the enzymatic activity (or catalytic activity) of phosphodiesterase IV (PDE IV). These compounds also have Tumor Necrosis Factor (TNF) inhibitory activity.
- TNF Tumor Necrosis Factor
- This invention also relates to the pharmaceutical compositions comprising a compound of Formulas (I) or (II) and a pharmaceutically acceptable carrier or diluent.
- the invention also relates to a method of mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE IV in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I) or (II) as shown below.
- the invention further provides a method for the treatment of allergic and inflammatory disease which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) or (II).
- the invention also provides a method for the treatment of asthma which comprises administering to a mammal, including humans, in need thereof, an effective amount of a compound of Formula (I) or (II).
- This invention also relates to a method of inhibiting TNF production in a mammal, including humans, which method comprises administering to a mammal in need of such treatment, an effective TNF inhibiting amount of a compound of Formula (I) or (IT).
- This method may be used for the prophylactic treatment or prevention of certain TNF mediated disease states amenable thereto.
- This invention also relates to a method of treating a human afflicted with a human immunodeficiency virus (HIV), which comprises administering to such human an effective TNF inhibiting amount of a compound of Formula (I) or (J3).
- Compounds of Formula CD or (H) 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.
- compounds of Formula (T) or (II) are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
- R! is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(C 4R5)mR6 5 or-(CR4R5) r R6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; ris 1 to 6;
- R4 and R5 are independently selected from hydrogen or a Ci-2 alkyl;
- R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCl-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl contaixiing one or two unsaturated bonds, wherein the cycloalkyl and eterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then m is 2; or
- Z is S(O) ⁇ VR9, OS(O)2R9, OR9, OC(O)NR7R9, OC(O)(O) q R7, O(CR4R5)nOR9, or NR9R9;
- Z * is O, NR8, NNR8R8, NOR8, NCN, C(-CN)2, CR ⁇ CN, CR8NO2, CR8C(O)OR8, CRsC(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR ⁇ R8; q is 0 or 1;
- R7 is independently hydrogen or R9;
- R8 is independently selected from hydrogen or C ⁇ __ ⁇ alkyl optionally substituted by one to three fluorines, or when R8 and Rio are as -NR ⁇ RlO they may together with the nitrogen form a a 5 to 7 membered ring optionally containing one or more additional heteroatom selected from O, N, or S;
- R8' is R8 or fluorine
- R9 is independendy Cl-lO alkyl, C2-10 alkenyl, C3-7cycloalkyl, C4-6 cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which may be optionally substituted by one or more fluorine atoms, or two R9 terms appearing as NR9R9 may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;
- Rl ⁇ is OR8 orR8; provided that: f) when q is 1 in OC(O)(O)qR7 , then R7 is not hydrogen; g) when Z' is NRs , then R8 is not hydrogen; or the pharmaceutically acceptable salts thereof.
- the other set of compounds of this invmtion are represented by Formula (II):
- Z" is C(Y')Rl4, C(O)ORi4, C(Y')NRi ⁇ Rl4, C(NRifj)NRioRl4, CN, C(NOR8)Rl4, C(NORi4)R8, C(NRg)NRi ⁇ Rl4, C(NRi4)NR ⁇ R8 C(NCN)NRioRl4, C(NCN)SRl l, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[ 1,2,3]), (3- or 5-triazolyl[l,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[l,2,4]), (2-oxadiazolyI[l,3,4]), (2-thiadiazolyl[l,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolid
- R-ll -* s --1-4 a ⁇ c ⁇ optionally substituted by one to three fluorines
- Rl2 is C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2- im ⁇ dazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, mo holinyl, furanyl, (2- or 3-th ⁇ enyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl;
- R13 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these hetero
- Rl4 is hydrogen orR ⁇ 5; orwhen Rio and R14 are as NR 0R14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from Q/N/or S;
- Rj5 is -(CR4R-) r Ri2 or C ⁇ alkyl wherein the R12 or C g alkyl group is optionally substituted one or more times by C ⁇ _2 alkyl optionally substituted by one to three fluorines, -F, -Br, -CI, -NO 2 , -Si(R 4 ) 2 , -NR 8 RlO- -C(O)Rs, -C(O)ORs, -ORs, -CN, -C(O)NRgR 10 , -OC(O)NR 8 R 10 , -OC(O)R8, -NR ⁇ 0 C(O)NR 8 R 10 , -NR ⁇ oC(O)R 8 , -NRi ⁇ C(O)OR 9 , -NR ⁇ oC(O)Ri3, -C(NR ⁇ o)NR 8 R ⁇ 0) -C(NCN)NR 8 R ⁇ 0 , -C(NCN)
- R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N- piperidinyl, orN-morpholinyl, then q is not 1; or the pharmaceutically acceptable salts thereof.
- This invention also relates to a method of mediating or inhibiting the enzymatic activity (or catalytic activity) of PDE IV in a mammal in need thereof and to inhibiting the production of TNF in a mammal in need thereof, which comprises aojninistering to said mammal an effective amount of a compound of Formula (I) or (LI).
- Phosphodiesterase IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid a ⁇ hritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
- allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid a ⁇ hritis, s
- PDE IV inhibitors are useful in the treatment of diabetes insipidus and central nervous system disorders such as depression and multi-infarct dementia.
- the viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirecdy, by the TNF inhibitors of Formula (I) or (LI).
- viruses include, but are not limited to HTV-1, HIV-2 and HTV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
- This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) or (II).
- HAV human immunodeficiency virus
- TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
- viruses include, but are not limited to feline immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
- the compounds of this invention are also useful in treating yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
- a preferred disease state for treatment is fungal meningitis.
- the compounds of Formula (I) or (II) may be administered in conjunction with other drugs of choice for systemic yeast and fungal infections.
- Drugs of choice for fungal infections include but are not limited to the class of compounds called the polymixins, such as Polymycin B, the class of compounds called the imidazoles, such as clotrimazole, econazole, miconazole, and ketoconazole; d e class of compounds called the triazoles, such as fluconazole, and itranazole, and the class of compound called the Amphotericins, in particular Amphotericin B and liposomal Amphotericin B.
- polymixins such as Polymycin B
- imidazoles such as clotrimazole, econazole, miconazole, and ketoconazole
- d e class of compounds called the triazoles, such as fluconazole, and itranazole
- Amphotericins in particular Amphotericin B and liposomal Amphotericin B.
- the compounds of Formula (I) or (II) may also be used for inhibiting and/or reducing the toxicity of an anti-fungal, anti-bacterial or anti- viral agent by administering an effective amount of a compound of Formula (I) or (II) to a mammal in need of such treatment.
- a compound of Formula (I) or (II) is administered for inhibiting or reducing the toxicity of the Amphotericin class of compounds, in particular Amphotericin B.
- Preferred compounds are as follows: When Ri for the compounds of the Formula (I) is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a Ci-4 alkyl substituted by 1 or more fluorines.
- the preferred halo-substituted alkyl chain length is one or two carbons, and most preferred are the moieties -CF3, -CH2F, -CHF2, -CF2CHF2, -CH2CF3, and -CH2CHF2.
- Preferred Ri substitutents for the compounds of the Formula (I) are CH2-cycIopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, C7-H polycycloalkyl, (3- or 4- cyclopentenyl), phenyl, tet- ⁇ ⁇ ydrofi ⁇ ran-3-yl, benzyl orCl-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2) ⁇ -2CH3, -(CH2)l-3 ⁇ (CH2)0-2CH3, and -(CH2)2-4OH.
- the Ri term contains the moiety (CR4R5), the R4 and R5 terms are independently hydrogen or alkyl.
- each repeating methylene unit is independent of the other, e.g., (CR4R5)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 optionally be substituted by fluorine independent of each other to yield, for instance, the preferred Ri substitutions, as noted above.
- Ri is a C7-H polycycloalkyl
- examples are bicyclo[2.2J]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2J]octyl, tricyclo[5.2.1.0-> ]decyl, etc. additional examples of which are described in Saccamano etal., WO 87/06576, published 5 November 1987, whose disclosure is incorporated herein by reference in its entirety.
- NR9R9 Zis S(O) m 'R9, OS(O)2R9, OR9, OC(O)NR7R9, OC(O)(O) q R7, 0(CR4R5)nOR9, or NR9R9 in compounds of the Formula (L) and also NHR14 in compounds of the Formula (H).
- q is 0.
- Preferred Z terms are S(O) m 'R9, OS(O)2R9, OR9, OC(O)NR7R9, O(CR4R5) n OR9, or NR9R9 in compounds of the Formula (I) and also NHR14 in compounds of the Formula (II).
- Z" in Formula (LI) is preferably C(O)Rl4, C(O)ORi4, C(O)NRioRl4, C(NRio)NRl ⁇ Rl4, CN, C(NOR ⁇ )Rl4, C(NR8)NR ⁇ oRl4, C(NCN)NR8Rl4, C(NCN)SRn, (1-, 4- or 5- ⁇ Ri4 ⁇ -2-imidazolyl), (1-, 4- or 5- ⁇ Ri4 ⁇ -3-pyrazolyl), (1-, 2- or 5- ⁇ Ri4 ⁇ -4-triazolyl[l,2,3]), (1-, 2-, 4- or 5- ⁇ Rl4.-3-triazolyl[l,2,4]), (1- or 2- ⁇ Ri4 ⁇ -5- tetrazolyl), (4- or 5- ⁇ Ri4 ⁇ -2-oxazolyl), (3- or 4- ⁇ Ri4)-5-isoxazolyl), (3- ⁇ Rl4 ⁇ -5-oxadiazolyl[l,2,4]), (5- ⁇ Ri4 ⁇
- Preferred X groups for Formulas (I) and (It) are those wherein X is YR2 and Y is oxygen.
- the preferred X2 group Formulas (I) and (II) is that wherein X2 is oxygen.
- the preferred X3 group is hydrogen.
- Preferred R2 groups, where applicable, are a C ⁇ _2 alkyl optionally substituted by 1 or more halogens.
- the halogen atoms are preferably fluorine and chlorine, more preferably fluorine.
- More preferred R2 groups are those wherein R2 is methyl, or the fluoro-substituted alkyls, specifically a Ci_2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 arid -CH3 moieties.
- R3 moieties are C(O)NH2, OCRs, CN, C(Z')H, CH2OH, CH2F, CF2H, and CF3: Z is preferably O or NOR8- More preferred are C ⁇ CH and CN.
- R15 moieties include optionally substituted -(CH2)l-2(cyclopropyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopentyl), -(CH2)0-2(cyclohexyl), -(R4R5)0-2(2-, 3- or4-pyridyl), (R4R5)i-2(2-imidazolyl), (R4R5)2(4-morpholinyl), (R4R5)2(4-piperazinyl), (R4R5)l-2(2-thienyl), (R4R5)i-2(4-thiazolyl), and (R4R5) ⁇ -2phenyl; Preferred rings when the two R9 terms in the moiety NR9R9 together with the nitrogen to which they are attached form a a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N or S include, but are not Umited to, the morpholinyl, piperazinyl
- Preferred rings when R8 and Rio in the moiety -NR ⁇ RlO together with the nitrogen to which they are attached form a a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R8)-l-imidazolyl, 1-pyrazolyl, 3-(R8)-l -pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)-l-triazolyl, 5-(Rs)-2-triazolyl, 5-(R8)-l-tetrazolyl, 5-(R8)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl, morpholinyl, piperazinyl, 4-(R8)-l-piperazinyl, or pyrrolyl ring.
- the respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R15 as described herein for Formula (IT).
- Illustrations of such carbon substitutions includes, but is not limited to, 2-(Ri5)-l-imidazolyl, 4-(Rl5)-l-imidazolyl, 5-(Rl5)-l-imidazolyl, 3-(Rl5)-l-pyrazolyl, 4-(Ri5)-l-pyrazolyl, 5-(Rl5)-l-pyrazolyl, 4-(Ri5)-2-triazolyl, 5-(Ri5)-2-triazolyl, 4-(R ⁇ 5)- 1 -triazolyl, 5-(Rl 5)- 1 -triazolyl, 5-(Rl 5)- 1 -tetrazolyl, and 5-(Ri5)-2-tetrazolyl.
- R15 includes, but is not limited to, l-(Ri5)-2-tetrazolyl, 2-(Ri5)-l-tetrazolyl, 4-(Rl5)-l-piperazinyl. Where applicable, the ring may be substituted one or more times by
- Preferred groups for -NR10R14 which contain a heterocyclic ring are 5-(Ri4)-l- tetrazolyl, 2-(R ⁇ 4)- 1 -imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(R ⁇ 4)- 1 -piperazinyl, or 4-(Ri5)-l-piperazinyl.
- Preferred rings for R13 include (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[l,2,3]), (3- or 5-triazolyl[l,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5- isoxazolyl), (3- or 5-oxadiazolyl[l,2,4]), (2-oxadiazolyl[ 1,3,4]), (2-thiadiazolyl[l,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazohdinyl).
- the heterocyclic ring itself may be optionally substituted by R 8 either on an available nitrogen or carbon atom, such as l-(Rg)-2-imidazolyl, l-(R8)-4-imidazolyl, l-(R8)-5-imidazolyl, l-(R8)-3-pyrazolyl, l-(R8)-4-pyrazolyl, l-(R8)-5-pyrazolyl, l-(R8)-4-triazolyl, or l-(R8)-5-triazolyl.
- the ring may be substituted one or more times by R .
- R2 is methyl or fluoro-substituted alkyl
- R3 is CN or C ⁇ CR ⁇
- X is YR2.
- Ri is -CH2-cyclopropyl, cyclopentyl, methyl or CF2H
- R3 is CN or C ⁇ CH
- X is YR2
- Y is oxygen
- X2 is oxygen
- X3 is hydrogen
- R2 is CF2H or methyl.
- a preferred subgenus of the compounds of the Formula (I) is the compounds of the
- Ri is CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, C7- 11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or Cl-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2) ⁇ -2CH3, -(CH2)1-3O(CH2)0-2CH3, and -(CH2)2-4OH;
- X is YR2, halogen, nitro, NR4R5, or formyl amine; Yis O or S(O)n ⁇ ; m' is 0, 1, or 2;
- R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens
- R3 is hydrogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, CN, CH2OR8, C(Z * )H, C(O)OR8, C(O)NR8Rl0, orC ⁇ CR ⁇ ;
- Z is S(O) m 'R9, OS(O)2R9. OR9, OC(O)NR7R9, OC(O)(O) q R7, 0(CR4R5) n OR9, or
- Z' is O orNORs; qis O or l;
- R7 is independendy hydrogen orR9;
- R8 is independendy selected from hydrogen or C _4 alkyl optionally substituted by one to ⁇ iree fluorines;
- Rg 1 is R8 or fluorine
- R9 is independendy Ci-io alkyl, C2-10 alkenyl, C3-7cycloalkyl, C4-6 cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which may be optionally substituted by one or more fluorine atoms, or two R9 terms appearing as NR9R9 may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O/N/orS;
- Rl is OR8 orR8; provided that: f) when q is 1 in OC(O)(O)qR7 , then R7 is not hydrogen; g) when Z' is NR8 then R8 is not hydrogen; or the pharmaceutically acceptable salts thereof.
- Exemplified compounds of Formula (I) are:
- Exemplified compounds of Formula (II) are: 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 -
- Compounds of Formula (U) may exist in a tautomeric form, such as the imine form. ylidine bond) being exocyclic to die cyclohexane ring
- C1.3 alkyl includes both straight or branched chain radicals of 1 to 10, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, rerr-butyl, and die like.
- Alkenyl means both straight or branched chain radicals of 1 to 6 carbon lengths, unless the chain length is limited thereto, including but not limited to vinyl, 1-propenyl, 2- propenyl, 2-propynyl, or 3-methyl-2-propenyl.
- cycloalkyl or “cycloalkyl alkyl” means groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, or cyclohexyl.
- Aryl or “aralkyl”, unless specified otherwise, means an aromatic ring or ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, or naphthyl.
- the aryl is monocyclic, i.e, phenyl.
- the alkyl chain is meant to include both straight or branched chain radicals of 1 to 4 carbon atoms.
- Heteroaryl means an aromatic ring system containing one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl.
- Hetero means all halogens, i.e., chloro, fluoro, bromo, or iodo.
- Inhibiting the production of IL-1 or “inhibiting the production of TNF” means: a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels by inhibition of the in vivo release of LL-1 by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the translational or transcriptional level, of excessive in vivo IL-1 or TNF levels, respectively, in a human to normal levels or below normal levels; or c) a down regulation, by inhibition of die direct synthesis of IL-1 or TNF levels as a postranslational event
- TNF mediated disease or disease states means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to LL-1 or LL-6.
- TNF- ⁇ also known as lymphotoxin
- TNF- ⁇ also known as cachectin
- TNF- ⁇ also known as cachectin
- both TNF- ⁇ and TNF- ⁇ are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF” unless specifically delineated otherwise.
- TNF- ⁇ is inhibited.
- Cytokine means any secreted polypeptide that affects die functions of cells, and is a molecule which modulates interactions between cells in immune, inflammatory, or hematopoietic responses.
- a cytokine includes, but is not limited to, monokines and lymphokines regardless of which cells produce them.
- the cytokine inhibited by the present invention for use in the treatment of a HTV- 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 HTV gene expression and/or replication, and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.
- his cytokine is TNF- ⁇ .
- All of the compounds of Formulas (I) and (II) are useful in the method of inhibiting the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal, including humans, in need thereof. All of the compounds of Formulas (I) and (II) are useful in the method of inhibiting or mediating me enzymatic or catalytic activity of PDE IV and in treatment of disease states mediated thereby.
- Ri represents Ri as defined in relation to Formula (I) or a group convertable to Ri and X
- X2 and X3 represent X, X2 and X3 as defined in relation to Formula (I) or a group convertable to X
- X2 or X3 and R2 and R3 represent R2 and R3 as defined in relation to Formula ⁇ or a group convertable to R2 or R3, with a suitable base in a suitable non-reacting solvent followed by reaction with a suitable alkylating or acylating agent ⁇ LS(O)2R9, LR9- L(CR4R5) n OR9, LC(O)(O)qR7, or LC(O)NR7R ⁇ , wherein L is a leaving group] to provide compounds of the Formula (I) wherein Z is OS(O)2R9, OR9, 0(CR4R5)nOR9, OC(O)(O)qR7, or OC(O)NR7R7 and R3 is other than
- Z is an aldehyde protecting group, such as a dimethylacetal or a dioxolane
- Some compounds of the Formula (H) may be prepared by processes analogous to those above by reacting the appropriate reagent with a compound of die Formula (3)
- Ri represents Ri as defined in relation to Formula (I) or a group convertable to Ri and X
- X2 and X3 represent X, X2 and X3 as defined in relation to Formula (I) or a group convertable to X
- X2 or X3 and R3 represents R3 as defined in relation to Formula (I) or a group convertable to R3 and Ri6 is an alkyl, phenyl or benzyl group.
- Compounds of the Formula (3) may be prepared in turn by the processes described in co-pending U.S. application serial number 07/862,083 filed 2 April 1992 and its corresponding continuation-in-part application filed on even date herewitfi.
- some compounds of die Formula (LI) may be prepared by reacting a compound of the Formula (4)
- Rl represents Ri as defined in relation to Formula (I) or a group convertable to Ri and X
- X2 and X3 represent X, X2 and X3 as defined in relation to Formula (I) or a group convertable to X
- X2 or X3 and R3 represents R3 as defined in relation to Formula (I) or a group convertable to R3, and
- X4 is CN with an excess of acrylonitrile in the presence of a base, such as excess metal hydride, or catalytic or excess quaternary amine base, such as benzyltrimethylammonium hydroxide, in a suitable non-reacting solvent, such as tetrahydrofuran or 1,2-dimethoxyethane when a metal hydride base is used or these sovents or acetonitrile when a quaternary amine base is used, to provide a compound of the Formula (5)
- X4 is CN and X5 and X6 are bodi H; alternatively, a compound of the Formula (6) [a subset of die compounds of the Formula (II)] may be obtained direcdy from a compound of Formula (5) wherein X4 is as described above by reaction with an excess of optionally R2-substituted acrylonitrile, with excess base, such as a metal hydride, in a suitable non- reacting solvent, such as tetrahydrofuran or 1,2-dime oxyethane, at an elevated temperature.
- a suitable non- reacting solvent such as tetrahydrofuran or 1,2-dime oxyethane
- X5 is H
- compounds of the Formula (7) are prepared by heating compounds of the Formula (7) in a solution of hydrazoic acid generated in situ by, e.g., ad ⁇ iixture of an alkalai metal azide, such as sodium azide, with an ammonium halide, such as triethylamine hydrochloride, in a polar non-protic solvent such as N-meu ylpyrrolidinone such compounds may be converted to compound of Formula (LQ by processes analogous to those described above.
- Some compounds of Formula (II) may be prepared from other compounds of the
- Formula (H) by, e.g., functional group manipulation of the Z" group either proceeding functional group manipulation of the Z group or, in some cases, widi appropriate protection and deprotection of chemically sensitive Z group functionality during functional group manipulation of the Z" group.
- Some such manipulations of die Z" group may be accomplished by die processes described in co-pending U.S . application serial number 862,030 filed 2 April 1992 and its corresponding continuation-in-part application USSN 968,762 filed 30 October 1992.
- EXAMPLE 3 1 -Amino-4-(3-cyclopropylmethoxy-4-difluorome oxyphen yll)-2.4-dicyanocyclohex- 1 -ene 3a. 4-Cyano-4-(3-cyclopropylmed ⁇ oxy-4-difluoromethoxypheny pimelonitrile To a stirred solution of 3-cyclopropylmethoxy-4-difluoromethoxyphenylacetonitrile (1.0 g, 3.95 mmol) in dry acetonitrile (25 mL) under an argon atmosphere was added a 40% solution of Triton-B in methanol (0J86 mL, 0.40 mmol) followed by acrylonitrile (2.9 mL, 44 mmol).
- A a white foamy solid (0.44 g, 30 %), further purified by trituration from methanol-water, to provide a white solid: m.p. 55-58°C; TLC Rf (20% ethyl acetate/hexanes): 0.33.
- A a solid: m.p. 121-122°C.
- the compounds of Formula (I) or (LI), or a pharmaceutically acceptable salt tiiereof can be used in die manufacture of a medicament for the prophylatic or dierapeutic 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 (I) or (U) are administered in an amount sufficient to treat such a disease in a human or other mammal.
- the amount of a compound of Formula (I) or (II) required for tiierapeutic effect on topical administration will, of course, vary widi die compound chosen, die nature and severity of the condition and the animal undergoing treatment, and is ultimately at the discretion of the physician.
- 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 (II) or a pharmaceutically acceptable salt tiiereof calculated as the free acid or base, which ever is appropriate.
- the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity.
- Example 1 demonstrated a positive in vivo response in reducing serum levels of TNF induced by the injection of endotoxin.
- PDE Isozvmes The phosphodiesterase inhibitory activity and selectivity of die compounds of of t is invention.s can be determined using a battery of five distinct PDE isozvmes.
- the tissues used as sources of die different isozymes are as follows: 1) PDE lb, porcine aorta; 2) PDE Ic, guinea-pig heart; 3) PDE III, guinea-pig heart; 4) PDE TV, human monocyte; and 5) PDE V (also called "la”), canine trachealis.
- PDEs la, lb, Ic and III are partially purified using standard chromatographic techniques [Torphy and Cieslinski, Mol.
- PDE IV is purified to kinetic homogeneity by the sequential use of anion-exchange followed by heparin-Sepharose chromatography [Torphy etal., J. Biol. Chem., 267:1798- 1804, 1992]. Phosphodiesterase activity is assayed as described in the protocol of Torphy and
- U-937 cells a human monocyte cell line that has been shown to contain a large amount of PDE IV.
- nondifferentiated U-937 cells approximately 10- cells/reaction tube
- PDE inhibitors were incubated widi various concentrations (0.01-1000 ⁇ M) of PDE inhibitors for one minute and l ⁇ M prostaglandin E2 for an additional four minutes.
- cells were lysed by die addition of 17.5% perchloric acid, me pH was neutrahzed by the addition of IM potassium carbonate and cAMP content was assessed by RIA.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP51745993A JP3199380B2 (en) | 1992-04-02 | 1993-03-12 | Compound |
EP93907430A EP0633771A4 (en) | 1992-04-02 | 1993-03-12 | Compounds. |
MA23151A MA22860A1 (en) | 1992-04-02 | 1993-04-01 | PROCESS FOR THE PREPARATION OF NEW COMPOUNDS. |
SI9300166A SI9300166A (en) | 1992-04-02 | 1993-04-02 | New compounds useful for treating or inhibiting phosphodiesterase iv (pde iv) enzyme activity |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US86211492A | 1992-04-02 | 1992-04-02 | |
US07/862,114 | 1992-04-02 | ||
US96880692A | 1992-10-30 | 1992-10-30 | |
US07/968,806 | 1992-10-30 | ||
US9302046 | 1993-03-05 | ||
USPCT/US93/02046 | 1993-03-05 |
Publications (2)
Publication Number | Publication Date |
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WO1993019720A2 true WO1993019720A2 (en) | 1993-10-14 |
WO1993019720A3 WO1993019720A3 (en) | 1993-11-25 |
Family
ID=27377344
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1993/002230 WO1993019720A2 (en) | 1992-04-02 | 1993-03-12 | Compounds |
Country Status (3)
Country | Link |
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EP (1) | EP0633771A4 (en) |
JP (1) | JP3199380B2 (en) |
WO (1) | WO1993019720A2 (en) |
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EP0633776A1 (en) * | 1992-04-02 | 1995-01-18 | Smithkline Beecham Corporation | Compounds useful for treating allergic and inflammatory diseases |
WO1996020175A1 (en) * | 1994-12-23 | 1996-07-04 | Smithkline Beecham Corporation | 1,4,4-(trisubstituted)cyclohex-1-ene derivatives as pde iv- and tnf-inhibitors |
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EP0841908A4 (en) * | 1994-12-23 | 1998-05-20 | ||
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EP0919544A1 (en) * | 1992-04-02 | 1999-06-02 | Smithkline Beecham Corporation | Compounds useful for treating allergic and inflammatory diseases |
EP1051172A2 (en) * | 1998-01-07 | 2000-11-15 | Smithkline Beecham Corporation | Method for treating copd |
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Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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PL377478A1 (en) * | 2002-12-23 | 2006-02-06 | 4Sc Ag | Cycloalkene dicarboxylic acid compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
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US4795757A (en) * | 1984-09-04 | 1989-01-03 | Rorer Pharmaceutical Corporation | Bisarylamines |
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1993
- 1993-03-12 EP EP93907430A patent/EP0633771A4/en not_active Withdrawn
- 1993-03-12 WO PCT/US1993/002230 patent/WO1993019720A2/en not_active Application Discontinuation
- 1993-03-12 JP JP51745993A patent/JP3199380B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US4795757A (en) * | 1984-09-04 | 1989-01-03 | Rorer Pharmaceutical Corporation | Bisarylamines |
Non-Patent Citations (2)
Title |
---|
CHEMICAL ABSTRACTS 2, July 1990, (MUKHERJEE, A. et al.), Vol. 113, No. 1, Abstract 5823S, see Formula II. * |
See also references of EP0633771A1 * |
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Also Published As
Publication number | Publication date |
---|---|
WO1993019720A3 (en) | 1993-11-25 |
EP0633771A1 (en) | 1995-01-18 |
JPH08500815A (en) | 1996-01-30 |
EP0633771A4 (en) | 1995-02-22 |
JP3199380B2 (en) | 2001-08-20 |
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