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WO1999034797A1 - Method for treating multiple sclerosis - Google Patents

Method for treating multiple sclerosis Download PDF

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Publication number
WO1999034797A1
WO1999034797A1 PCT/US1999/000126 US9900126W WO9934797A1 WO 1999034797 A1 WO1999034797 A1 WO 1999034797A1 US 9900126 W US9900126 W US 9900126W WO 9934797 A1 WO9934797 A1 WO 9934797A1
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Prior art keywords
cyano
methoxyphenyl
cyclohexane
cyclopropylmethoxy
methyl
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PCT/US1999/000126
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French (fr)
Inventor
Siegfried B. Christensen, Iv
Theodore Torphy
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Priority to AU20262/99A priority Critical patent/AU2026299A/en
Priority to JP2000527246A priority patent/JP2002500187A/en
Priority to CA002317548A priority patent/CA2317548A1/en
Priority to EP99900751A priority patent/EP1043994A4/en
Publication of WO1999034797A1 publication Critical patent/WO1999034797A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to the use of certain compounds for treating multiple sclerosis.
  • MS Multiple sclerosis
  • MS is a disease in which there are patches of demyelination throughout the white matter of the central nervous system, sometimes extending into the gray matter.
  • the symptoms of lesions of the white matter are weakness, incoordination, paresthesias, speech disturbances, and visual complaints.
  • the course of the disease is usually prolonged, with remissions and relapses over a period of many years. It is also called disseminated sclerosis and insular sclerosis.
  • MS The etiology of MS is unknown. Some work implicates an immunologic abnormality. Postulated causes include infection by a slow or latent virus, and myelinolysis by enzymes. IgG is usually elevated in the CSF, and elevated titers have been associated with a variety of viruses, including measles. The significance of these findings and of reported associations with HLA allotypes and altered number of T cells has not been clarified. Women are somewhat more often affected than men. The disease is more common in temperate climates that in the tropics. And while age of onset is usually between 20 and 40, MS has been linked to the geographic area where the patient spend his or hers first 15 years; it appears that relocation after the 15th birthday does not alter risk.
  • the pathology of MS can be summarized as follows: Plaques or islands of demyelination with destruction of oligodendroglia and perivascular inflammation are disseminated through the CNS, primarily in the white matter, with a predilection for the lateral and posterior columns, the optic nerve and periventricular areas. Tracts in the midbrain, pons, and cerebellum also are affected, and gray matter in both cerebrum and cord may be affected. Cell bodies and axons usually are preserved, especially in early lesions. Later, axons may be destroyed, especially in the long tracts, and a fibrous gliosis gives the tracts their "sclerotic" appearance.
  • This invention covers a method for treating MS by administering an effective amount of a compound of Formula (I) alone or in admixture with a pharmaceutically acceptable excipient wherein Formula (I) comprises:
  • Ri is -(CR4R5)nC(O)O(CR4R 5 )mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -
  • 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 aryloxyCi-3 alkyl, indanyl, indenyl, C7-.11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by OH, 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b
  • X is YR2, halogen, nitro, NR4R5, or formyl amine; Y is O or S(O)m . m' is 0, 1, or 2; X2 is O or NR8; X3 is hydrogen or X;
  • X 5 is H, R9, OR 8 , CN, C(O)R 8 , C(O)OR 8 , C(O)NR 8 R8, or NR 8 R8.
  • R2 is independently selected from the group consisting of -CH3 and - CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4;
  • cyclopropyl optionally substituted by R8', CN, OR 8 , CH 2 OR 8 , NR 8 RlO, CH 2 NR8Rl0, C(Z * )H, C(O)OR 8 , C(O)NR 8 Rio, or C ⁇ CR 8 ';
  • Z' is O, NR9, NOR 8 , NCN, C(-CN)2, CR 8 CN, CR 8 NO2, CR 8 C(O)OR 8 , CR 8 C(O)NR 8 R 8 , C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR 8 R8 ;
  • Z is C(y)Ri4.
  • R7 is -(CR4R5)qRi2 or C . alkyl wherein the R12 or C ⁇ . alkyl group is optionally substituted one or more times by Ci-2 alkyl optionally substituted by one to three fluorines, -F, -Br, -Cl, -NO 2 , -NRIQRH , -C(O)R 8 , -C(O)OR 8 , -ORS, -CN, -C(O)NR ⁇ oRl l, -OC(O)NR ⁇ oRl l, -OC(O)R 8 , -NR ⁇ 0 C(O)NR ⁇ 0 Rl l, -NRi ⁇ C(O)R ⁇ , -NRi 0 C(O)OR 9 , -NRi 0 C(O)R i3 , -C(NRi 0 )NRi 0 Rl l,
  • Rl2 is C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2- imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl;
  • R 8 is independently selected from hydrogen or R9; R 8 ' is R 8 or fluorine;
  • R9 is C -.4 alkyl optionally substituted by one to three fluorines
  • Rl ⁇ is OR 8 or R ⁇
  • Rj j is hydrogen, or C1-.4 alkyl optionally substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S;
  • Rl3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two Cj_2 alkyl groups;
  • R]4 is hydrogen or R7; or when Rio and R 14 are as NR10R14 they 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; provided that: f) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N- piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1 ; or g) when X2R1 is OCF2H or OCF3, X is F, OCF2H or OCF3, X3 is H, s is zero, X5 is H, Z is C(O)ORi4 and R14 is Ci-7 unsubstituted alkyl, then R3 is other than H; or the pharmaceutically acceptable salts thereof.
  • this invention relates to a method for treating MS by administering an effective amount of a compound of Formula (II) to a mammal in need thereof, wherein Formula (II) is:
  • Rl is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R 5 )nC(O)NR4(CR4R5)mR6, -(CR4R5) n O(CR4R5) m R6, or -(CR4R5) r R6 wherein the alkyl moieties unsubstituted or substituted with one or more halogens; m is 0 to 2; n is 0 to 4; r is 0 to 6;
  • R4 and R5 are independently selected hydrogen or Ci-2 alkyl
  • R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-.11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group, or an hydroxyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R is hydroxyl, then r is 2 to
  • X is YR2, fluorine, NR4R5, or formyl amine; Y is O or S(O) m '; m' is 0, 1, or 2; X2 is O or NR 8 ; X3 is hydrogen or X;
  • X 4 is H, R9, OR 8 , CN, C(O)R 8 , C(O)OR 8 , C(O)NR 8 R8, or NR 8 R 8 ;
  • R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4;
  • W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
  • R3 is COOR14, C(O)NR4Ri4 or R7;
  • Z is OR14, OR15, SR14, S(O) m 'R7, S(O)2NR ⁇ 0 Rl4, NR10R14, NR ⁇ 4 C(O)R 9 , NR ⁇ 0 C(Y-)Rl4, NR ⁇ 0 C(O)OR 7 , NR ⁇ 0 C(Y')NR ⁇ oRl4, NRioS(O) 2 NRioRl4, NR ⁇ 0 C(NCN)NR ⁇ 0 Rl4, NR ⁇ 0 S(O) 2 R7, NRioC(CR4NO2)NRioRl4, NRioC(NCN)SR9, NRioC(CR4NO2)SR9, NRioC(NR ⁇ )NRi 0 Rl4, NR ⁇ 0 C(O)C(O)NR ⁇ 0 Rl4,or NRi 0 C(O)C(O)ORi4;
  • Y' is O or S;
  • R7 is -(CR4R5)qRl2 or C ⁇ _6 alkyl wherein the R12 or C ⁇ . alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -F, -Br, -Cl, -NO2, -NRIQRH , -C(O)R 8 , -CO2R 8 , -O(CH 2 ) 2 -4 ⁇ R 8 , -O(CH 2 ) q R 8 , -CN, -C(O)NR ⁇ 0 Rl l.
  • Rl2 is R13, C3-C7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl;
  • R 8 is independently selected from hydrogen or R9;
  • R9 is C ⁇ _4 alkyl optionally substituted by one to three fluorines
  • Rl 1 is hydrogen, or C 1.4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S;
  • R13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R 13 is substituted on R 12 or R 1 the rings are connected through a carbon atom and each second R 1 ring may be unsubstituted or substituted by one or two C1-.2 alkyl groups unsub
  • Rl4 is hydrogen or R7; or when R 8 and R 14 are as NR 8 Ri4 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S; R15 is C(O)R 14 , C(O)NR 8 R 14 , S(O) q NR 8 R 14 or S(O) q R 7 where q is 0, 1 or 2; provided that: (f) R7 is not C ⁇ _4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.
  • This invention relates to the use of compounds of Formulas (I) and (II), and to pharmaceutical compositions comprising a compound of Formulas (I) and (II) and a pharmaceutically acceptable carrier or diluent, for treating MS.
  • the mechanism of action may be one of the action of cells such as macrophages and lymphocytes and supressing the production of IL-2, TNF- ⁇ , TNF2, and other pro-inflammatory cytokines and mediators.
  • EAE experimental autoimmune encephalomyelitis
  • rolipram another regulator of TNF- is effective in treating experimental autoimmune encephalomyelitis (EAE) in animals. See for example Raine, C.S., Nature Medicine, Nol 1, No 3, pp211-214, 1995; Sommer, N. et al, Nature Medicine, Vol. 1, No. 3, pp. 244-248, 1995; Genin, C. P., et al, Proc. Natl. Acad. Sci., Vol. 92, pp. 3601-3605, April 1995; and Takusuka, N., et al, The J. of Immunology, 1995, 154: 4803-4812, 1995. Accordingly the compounds of Formulas (I) and (II) are useful in treating MS.
  • the preferred compounds for use in this invention are defined as follows:
  • 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 C ⁇ _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-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl optionally substituted by OH, C7-11 polycycloalkyl, (3- or 4- cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2) ⁇ -2CH3, -(CH 2 )1-3O(CH 2 )0-2CH 3 , and -(CH 2 )2-4OH.
  • the R4 and R5 terms are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5)n or (CR4R5) m ; 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.
  • R] is a C7-11 polycycloalkyl
  • examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0 > 6 ]decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987, which disclosure is incorporated herein by reference in its entirety.
  • Z is preferably C(O)R8, C(O)OR 8 , C(O)NR 8 R 8 , C(NR 8 )NR 8 R8, CN,
  • Preferred X groups for Formula (I) are those wherein X is YR2 and Y is oxygen.
  • the preferred X2 group for Formula (I) is that wherein X2 is oxygen.
  • the preferred X3 group for Formula (I) is that wherein X3 is hydrogen.
  • Preferred R2 groups, where applicable, are 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 and -CH 3 moieties.
  • Preferred R3 moieties are C(O)NH2, C ⁇ CR 8 , CN, QZ ⁇ H, CH2OH, CH2F,
  • CF2H and CF3. More preferred are -C ⁇ CH and CN.
  • Z' is preferably O or NOR 8 .
  • R7 moieties include optionally substituted -(CH2)l-2(cyclopropyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopentyl), -(CH2)0-2(cyclohexyl), -(CH2)0-2(2-, 3- or 4-pyridyl), -(CH2)l-2(2-imidazolyl), -(CH2)2(4-morpholinyl), -(CH2)2(4-piperazinyl), -(CH2)l-2(2-thienyl), -(CH2)l-2(4-thiazolyl), and -(CH2)0-2phenyl;
  • Preferred rings when Rio and Rl l in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R8)-l-imidazolyl, 1 -pyrazolyl,
  • the respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I). Illustrations of such carbon substitutions includes, but are not limited to, 2-(R7)-l-imidazolyl,
  • R7 Applicable nitrogen substitution by R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l -tetrazolyl, 4-(R7)-l -piperazinyl. Where applicable, the ring may be substituted one or more times by R7.
  • Preferred groups for NR10R14 which contain a heterocyclic ring are 5- (Rl 4)- 1 -tetrazolyl, 2-(Ri4)-l-imidazolyl, 5-(Ri4)-2-tetrazolyl, or 4-(R ⁇ _ -l- piperazinyl.
  • Preferred rings for R13 include (2-, 4- or 5-imidazolyl), (3-, 4- or
  • 5-pyrazolyl (4- or 5-triazolyl[ 1,2,3]), (3- or 5-triazolyl[ 1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[l,2,4]), (2-oxadiazolyl[ 1,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).
  • the heterocyclic ring itself may be optionally substituted by R 8 either on an available nitrogen or carbon atom, such as l-(R8)-2-imidazolyl, l-(R 8 )-4-imidazolyl, l-(R 8 )-5-imidazolyl, l-(R 8 )-3-pyrazolyl, l-(R 8 )-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 8 .
  • R is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl optionally substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Ci-2 alkyl optionally substituted by 1 or more fluorines, and -(CH2)2-4 OH;
  • R2 is methyl or fluoro- substituted alkyl, R3 is CN or C ⁇ CRs;
  • X is YR2-
  • Ri is -CH2-cyclopropyl, cyclopentyl, methyl or CF2H;
  • R3 is CN or C ⁇ CH;
  • X is YR2;
  • Y oxygen;
  • X2 is oxygen;
  • X3 is hydrogen; and R2 is CF2H or methyl.
  • a preferred subgenus of the compounds of Formula (I) are the compounds of Formula (la)
  • Rl is CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl optionally substituted by OH, C7 1 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl optionally substituted by 1 or more fluorines,-(CH2)l-3C(O)O(CH 2 )0-2CH3, -(CH 2 )l-3 ⁇ (CH2)0-2CH 3 , and -(CH 2 )2-4OH;
  • X is YR2, halogen, nitro, NR4R5, or formyl amine; X4 is
  • X 5 is H, R 9 , OR 8 , CN, C(O)R 8 , C(O)OR 8 , C(O)NR 8 R 8 , or NR 8 R 8 ;
  • Y is O or S(O) m '; m' is 0, l, or 2;
  • R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens;
  • R3 is hydrogen, -4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, CN, CH2OR8, C(Z')H, C(O)ORs, C(O)NRsRl ⁇ , or C ⁇ CR 8 ;
  • Z' is O or NOR 8 ;
  • Z is C(O)Ri4, C(O)ORi4, C(O)NR ⁇ oRl4, C(NR ⁇ o)NR ⁇ oRl4.
  • R7 is -(CR4R5)qRi2 or Ci.g alkyl wherein the R12 or C ⁇ . alkyl group is optionally substituted one or more times by C ⁇ _2 alkyl optionally substituted by one to three fluorines, -F, -Br, -Cl, -NO , -NR QRI 1, -C(O)R 8 , -C(O)OR 8 , -OR 8 , -CN, -C(O)NR ⁇ oRl l, -OC(O)NR ⁇ oRl l, -OC(O)R 8 , -NR ⁇ 0 C(O)NR ⁇ 0 Rl l, -NRi ⁇ C(O)Rn, -NR ⁇ oC(O)OR 9 , -NRl ⁇ C(O)R ⁇ 3 , -C(NRio)NRi 0 Rl l, -C(NCN)NR ⁇ oRl l, -C(NCN)SR
  • Rl2 is C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), (1- or 2-imidazolyl), piperazinyl, mo ⁇ holinyl, (2- or 3-thienyl), (4- or 5-thiazolyl), or phenyl; the dotted line formula (a) represents a single or double bond; R 8 is independently selected from hydrogen or R9;
  • R9 is C1-.4 alkyl optionally substituted by one to three fluorines
  • Rl ⁇ is OR 8 or Rn
  • Rl 1 is hydrogen or C1-.4 alkyl optionally substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S;
  • Rl3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C -.2 alkyl groups;
  • Rl4 is hydrogen or R7; or when Rio and R 14 are as NR10R14 they 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; provided that: a) when R12 is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, or N- mo ⁇ holinyl, then q is not 1; or b) when Ri is CF2H or CF3, X is F, OCF2H, or OCF3, X5 is H, Z is C(O)ORi4 and R14 is Ci-7 unsubstituted alkyl, then R3 is other than H; or the pharmaceutically acceptable salts thereof.
  • the most perferred compounds of Formula (I) are: methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex- 1 -ene- 1 - carboxylate; 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex- 1 -ene- 1 -carboxylic acid; methyl cw-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 - carboxylate]; methyl tr ⁇ ns-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane- 1 -carboxylate] ; methyl cis- [4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane- 1 - carboxylate]; methyl trans- [4-(3,4-bisdi
  • the preferred compounds are as follows:
  • Ri is an alkyl substituted by 1 or more halogens
  • the halogens are preferably fluorine and chlorine, more preferably a C1-.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 Formula (I) are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-.6 cycloalkyl unsubstituted or substituted with OHC7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or Ci-2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2) ⁇ -2CH3, -(CH2)l-3O(CH2)0-2CH3, and -(CH 2 )2-4OH.
  • Ri term contains the moiety (CR4R5)
  • the R4 and R5 terms are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5) n or (CR4R5)m. 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 unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred Ri substitutions, as noted above.
  • Ri is a C7.1 polycycloalkyl
  • examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0 2 > 6 ]decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987.
  • W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and where it is alkenyl or alkynyl, that one or two double or triple bonds be present. It is most preferred that W is ethynyl or 1,3-butadiynyl.
  • Z is preferably OR14, OR15, SR14, S(O) m 'R7, S(O)2NR ⁇ oRl4, NR10R14,
  • NR ⁇ 4 C(O)R 9 NRl ⁇ C(O)Ri4, NRi 0 C(O)OR 7 , NRi 0 C(O)NRi 0 Rl4, NR ⁇ oS(O) 2 NR ⁇ oRl4.
  • Preferred X groups for Formula (I) are those wherein X is YR2 and Y is oxygen.
  • the preferred X2 group for Formula (I) is that wherein X2 is oxygen.
  • the preferred X3 group for Formula (I) is that wherein X3 is hydrogen.
  • Preferred R2 groups, where applicable, is a Ci-2 alkyl unsubstituted or 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.
  • R7 moieties include unsubstituted or substituted -(CH2)0-2(2-, 3- or 4-pyridyl), (CH2)l-2(2-imidazolyl), (CH2)2(4-mo ⁇ holinyl), (CH2)2(4- piperazinyl), (CH2)l-2(2-thienyl), (CH2)l-2(4-thiazolyl), unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH2) ⁇ -2phenyl.
  • Preferred rings when Rio and Rl l in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1 -imidazolyl, 2-(R 8 )-l -imidazolyl, 1 -pyrazolyl, 3-(R8)-l -pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)-l -triazolyl, 5-(R 8 )-2-triazolyl, 5-(R 8 )-l -tetrazolyl, 5-(R 8 )-2-tetrazolyl, 1 -tetrazolyl, 2-tetrazloyl, mo ⁇ holinyl, piperazinyl, 4-(R 8 )-l -piperazinyl, or pyrrolyl ring.
  • Preferred rings when Rio and R14 in the moiety -NR10R14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1 -imidazolyl, 1 -pyrazolyl, 1 -triazolyl, 2-triazolyl, 1 -tetrazolyl, 2-tetrazolyl, mo ⁇ holinyl, piperazinyl, and pyrrolyl.
  • the respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I).
  • Illustrations of such carbon substitutions includes, but is not limited to, 2-(R7)-l -imidazolyl, 4-(R7)-l -imidazolyl, 5-(R7)-l -imidazolyl, 3-(R7)-l -pyrazolyl, 4-(R7)-l -pyrazolyl, 5-(R7)-l -pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-l -triazolyl, 5-(R7)-l -triazolyl, 5-(R7)-l -tetrazolyl, and 5-(R7)-2-tetrazolyl.
  • R7 Applicable nitrogen substitution by R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l -tetrazolyl, 4-(R7)-l -piperazinyl. Where applicable, the ring may be substituted one or more times by R7.
  • Preferred groups for NR10R14 which contain a heterocyclic ring are 5- (R 14)- 1 -tetrazolyl, 2-(R 14)- 1 -imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(Ri4)-l- piperazinyl, or 4-(R ⁇ 5)- 1 -piperazinyl.
  • Preferred rings for R13 include (2-, 4- or 5 -imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[ 1,2,3]), (3- or 5 -triazolyl [1,2, 4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[ 1,2,4]), (2-oxadiazolyl[ 1,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).
  • the heterocyclic ring itself may be unsubstituted or substituted by R 8 on an available nitrogen or carbon atom, such as l-(R 8 )-2-imidazolyl, l-(R 8 )-4-imidazolyl, l-(R )-5-imidazolyl, l-(R 8 )-3-pyrazolyl, l-(R 8 )-4-pyrazolyl, l-(R 8 )-5-pyrazolyl, l-(R8)-4-triazolyl, or l-(R 8 )-5-triazolyl.
  • the ring may be substituted one or more times by R 8 .
  • Ri is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H
  • X is YR2
  • Y is oxygen
  • X2 is oxygen
  • X3 is hydrogen
  • R2 is CF2H or methyl
  • W is ethynyl or 1,3-butadiynyl
  • R3 is a substituted or unsubstituted pyrimidinyl ring.
  • the most preferred compounds of Formula (II) are: c._.-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -ol] , s-[4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-cyclohexan- 1 -ol] , tr ⁇ «_.-[4-(2-acetamidopyrimidin-5-ylethynyl)-4-(3-cyclopentyloy-4- methoxyphenyl)cyclohexan- 1 -ol] , tr ⁇ n5-[4-(2-aminopyrimidin-5-yl-ethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-cyclohexan
  • Some compounds of Formula (I) and Formula (II) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. All of these compounds are considered to be within the scope of the present invention. Therefore another aspect of the present invention is the administration of either a racemate, a single enantiomeric form, a single diastereomeric form, or mixtures thereof.
  • C ⁇ _ 3 alkyl 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, tert-butyl, and the like.
  • Alkenyl includes 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” includes 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. Preferably the aryl is monocyclic, i.e, phenyl.
  • the alkyl chain includes both straight or branched chain radicals of 1 to 4 carbon atoms.
  • Heteroaryl as used herein, is meant an aromatic ring system containing one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl.
  • Halo as used herein is meant all halogens, i.e., chloro, fluoro, bromo, or iodo.
  • down regulating or inhibiting the production of TNF means: a) a decrease of excessive in vivo 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; b) a down regulation, at the translational or transcriptional level, of excessive in vivo 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 TNF levels as a postranslational event.
  • All of the compounds of Formula (I) are useful in the method of treating MS; the mechanism of which may be that of inhibiting or down regulating the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal. Mammals includes humans.
  • a compound of Formula (I) and (II) or a pharmaceutically acceptable salt thereof for the treatment of MS, it will be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the compounds of Formula (I) and (II) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylatic or therapeutic treatment of MS.
  • the pharmaceutical composition of the present invention will comprise an effective, non-toxic amount of a compound of Formula (I) or (II) and a pharmaceutically acceptable carrier or diluent.
  • the compounds of Formula (I) and (II) are administered in conventional dosage forms prepared by combining a compound of Formula (I) and (II) 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.
  • 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.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates, or oils and are inco ⁇ orated 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 flavoring or coloring agent.
  • 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) and (II) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity.
  • an active ingredient may be administered neat, it is preferable to present it as a pharmaceutical formulation.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of 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 Formulation.
  • Formulations of the present invention comprise an active ingredient together with one or more acceptable carrier(s) thereof and optionally any other therapeutic ingredient(s).
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of Formulation and not deleterious to the recipient thereof.
  • 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 well-known variables.

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Abstract

A method for treating multiple sclerosis comprising administering compounds of Formula (I) where X4 is a 1-substituted cyclohexyl group and the other groups are ethers or thioethers or a compound of Formula (II) where W is an aliphatic group of 2 to 6 carbons and R3 is an acid, amide or aromatic or heteroaromatic group and Z is exemplified by an alcohol or alcohol derivative.

Description

Method for Treating Multiple Sclerosis Field of Invention
The present invention relates to the use of certain compounds for treating multiple sclerosis. Background of the Invention
Multiple sclerosis (MS) is a disease in which there are patches of demyelination throughout the white matter of the central nervous system, sometimes extending into the gray matter. Typically the symptoms of lesions of the white matter are weakness, incoordination, paresthesias, speech disturbances, and visual complaints. The course of the disease is usually prolonged, with remissions and relapses over a period of many years. It is also called disseminated sclerosis and insular sclerosis.
The etiology of MS is unknown. Some work implicates an immunologic abnormality. Postulated causes include infection by a slow or latent virus, and myelinolysis by enzymes. IgG is usually elevated in the CSF, and elevated titers have been associated with a variety of viruses, including measles. The significance of these findings and of reported associations with HLA allotypes and altered number of T cells has not been clarified. Women are somewhat more often affected than men. The disease is more common in temperate climates that in the tropics. And while age of onset is usually between 20 and 40, MS has been linked to the geographic area where the patient spend his or hers first 15 years; it appears that relocation after the 15th birthday does not alter risk.
The pathology of MS can be summarized as follows: Plaques or islands of demyelination with destruction of oligodendroglia and perivascular inflammation are disseminated through the CNS, primarily in the white matter, with a predilection for the lateral and posterior columns, the optic nerve and periventricular areas. Tracts in the midbrain, pons, and cerebellum also are affected, and gray matter in both cerebrum and cord may be affected. Cell bodies and axons usually are preserved, especially in early lesions. Later, axons may be destroyed, especially in the long tracts, and a fibrous gliosis gives the tracts their "sclerotic" appearance.
Both early and late lesions may be found simultaneously. Chemical changes in lipid and protein constituents of myelin have been demonstrated in and around plaques.
The cellular pathophysiology of the disease is not clearly understood. However the weight of evidence suggests that it is an autoimmune disorder. As such, activation of immune and inflammatory cells, e.g. T cells, macrophages, and the generation of cytokines are likely to be involved. There exists a need for new forms of intervention in MS. The compounds detailed below provide one new form to meet this need.
Summary of the Invention This invention covers a method for treating MS by administering an effective amount of a compound of Formula (I) alone or in admixture with a pharmaceutically acceptable excipient wherein Formula (I) comprises:
Figure imgf000004_0001
wherein: Ri is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -
(CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 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 aryloxyCi-3 alkyl, indanyl, indenyl, C7-.11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by OH, 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydro thiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then Rβ is other than H in
-(CR4R5)nO(CR4R5)mR6;
X is YR2, halogen, nitro, NR4R5, or formyl amine; Y is O or S(O)m . m' is 0, 1, or 2; X2 is O or NR8; X3 is hydrogen or X;
Figure imgf000005_0001
X5 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8.
R2 is independently selected from the group consisting of -CH3 and - CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4;
R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo- substituted C1-4 alkyl, -CH=CR8'R8 . cyclopropyl optionally substituted by R8', CN, OR8, CH2OR8, NR8RlO, CH2NR8Rl0, C(Z*)H, C(O)OR8, C(O)NR8Rio, or C≡CR8';
Z' is O, NR9, NOR8, NCN, C(-CN)2, CR8CN, CR8NO2, CR8C(O)OR8, CR8C(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR8R8 ; Z is C(y)Ri4. C(O)ORi4, C(Y.NRιoRl4, C(NRιo)NRιoRl4, CN,
C(NOR8)Rl4. C(O)NR8NR8C(O)R8, C(O)NR8NRι0Rl4, C(NORι4)R8, C(NR8)NRιoRl4, C(NRi4)NR8R8, C(NCN)NRιoRl4, C(NCN)SR9, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[ 1,2,3]), (3- or 5-triazolyl[ 1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[ 1,2,4]), (2-oxadiazolyl[l,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-imidazolidinyl); wherein all of the heterocylic ring systems may be optionally substituted one or more times by R14; the dotted line in formula (a) represents a single or double bond; Y'is O or S;
R7 is -(CR4R5)qRi2 or C . alkyl wherein the R12 or C\. alkyl group is optionally substituted one or more times by Ci-2 alkyl optionally substituted by one to three fluorines, -F, -Br, -Cl, -NO2, -NRIQRH , -C(O)R8, -C(O)OR8, -ORS, -CN, -C(O)NRιoRl l, -OC(O)NRιoRl l, -OC(O)R8, -NRι0C(O)NRι0Rl l, -NRiθC(O)Rπ, -NRi0C(O)OR9, -NRi0C(O)Ri3, -C(NRi0)NRi0Rl l,
-C(NCN)NRιoRl l, -C(NCN)SR9, -NRioC(NCN)SR9 , -NRιoC(NCN)NRιoRl l, -NRιoS(O)2R9, -S(O)m'R9, -NRι0C(O)C(O)NRι0Rl l, -NRι0C(O)C(O)Rιo. thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is 0, 1, or 2; Rl2 is C3-7 cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2- imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl;
R8 is independently selected from hydrogen or R9; R8' is R8 or fluorine;
R9 is C -.4 alkyl optionally substituted by one to three fluorines;
Rlθ is OR8 or Rπ;
Rj j is hydrogen, or C1-.4 alkyl optionally substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S;
Rl3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two Cj_2 alkyl groups;
R]4 is hydrogen or R7; or when Rio and R 14 are as NR10R14 they 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; provided that: f) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N- piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1 ; or g) when X2R1 is OCF2H or OCF3, X is F, OCF2H or OCF3, X3 is H, s is zero, X5 is H, Z is C(O)ORi4 and R14 is Ci-7 unsubstituted alkyl, then R3 is other than H; or the pharmaceutically acceptable salts thereof.
In addition, this invention relates to a method for treating MS by administering an effective amount of a compound of Formula (II) to a mammal in need thereof, wherein Formula (II) is:
Figure imgf000006_0001
wherein: Rl is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties unsubstituted or substituted with one or more halogens; m is 0 to 2; n is 0 to 4; r is 0 to 6;
R4 and R5 are independently selected hydrogen or Ci-2 alkyl;
R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-.11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group, or an hydroxyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R is hydroxyl, then r is 2 to 6; or c) when Rβ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,
2-tetrahydrofuranyl,or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in
-(CR4R5)nO(CR4R5)mR6;
X is YR2, fluorine, NR4R5, or formyl amine; Y is O or S(O)m '; m' is 0, 1, or 2; X2 is O or NR8; X3 is hydrogen or X;
X4 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8; R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4;
W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms; R3 is COOR14, C(O)NR4Ri4 or R7;
Z is OR14, OR15, SR14, S(O)m'R7, S(O)2NRι0Rl4, NR10R14, NRι4C(O)R9, NRι0C(Y-)Rl4, NRι0C(O)OR7, NRι0C(Y')NRιoRl4, NRioS(O)2NRioRl4, NRι0C(NCN)NRι0Rl4, NRι0S(O)2R7, NRioC(CR4NO2)NRioRl4, NRioC(NCN)SR9, NRioC(CR4NO2)SR9, NRioC(NRιθ)NRi0Rl4, NRι0C(O)C(O)NRι0Rl4,or NRi0C(O)C(O)ORi4;
Y' is O or S; R7 is -(CR4R5)qRl2 or Cι_6 alkyl wherein the R12 or C\. alkyl group is unsubstituted or substituted one or more times by methyl or ethyl unsubstituted or substituted by 1-3 fluorines, -F, -Br, -Cl, -NO2, -NRIQRH , -C(O)R8, -CO2R8, -O(CH2)2-4θR8, -O(CH2)qR8, -CN, -C(O)NRι0Rl l. -O(CH2)qC(O)NRι0Rl l. - O(CH2)qC(O)R9, -NRiθC(O)NRlθRl l, -NRi0C(O)Rn, -NRi0C(O)OR9, -NRι0C(O)Ri3, -C(NRio)NRi0Rl l, -C(NCN)NRι0Rl l, -C(NCN)SR9, -NRιoC(NCN)SR9 , -NRι0C(NCN)NRιoRl l. -NRι0S(O)2R9, -S(O)m'R9, -NRιoC(O)C(O)NRιoRl l, -NRι0C(O)C(O)Rιo, or R13; q is 0, 1, or 2;
Rl2 is R13, C3-C7 cycloalkyl, or an unsubstituted or substituted aryl or heteroaryl group selected from the group consisting of (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, and phenyl;
R8 is independently selected from hydrogen or R9;
R9 is Cι_4 alkyl optionally substituted by one to three fluorines;
Figure imgf000008_0001
Rl 1 is hydrogen, or C 1.4 alkyl unsubstituted or substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S; R13 is a substituted or unsubstituted heteroaryl group selected from the group consisting of oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, and thiadiazolyl, and where R13 is substituted on R12 or R1 the rings are connected through a carbon atom and each second R1 ring may be unsubstituted or substituted by one or two C1-.2 alkyl groups unsubstituted or substituted on the methyl with 1 to 3 fluoro atoms;
Rl4 is hydrogen or R7; or when R8 and R 14 are as NR8Ri4 they may together with the nitrogen form a 5 to 7 membered ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S; R15 is C(O)R14, C(O)NR8R14, S(O)qNR8R14 or S(O)qR7 where q is 0, 1 or 2; provided that: (f) R7 is not Cι_4 alkyl unsubstituted or substituted by one to three fluorines; or the pharmaceutically acceptable salts thereof.
Detailed Description of the Invention This invention relates to the use of compounds of Formulas (I) and (II), and to pharmaceutical compositions comprising a compound of Formulas (I) and (II) and a pharmaceutically acceptable carrier or diluent, for treating MS.
Without being limited in any fashion, it is believed the mechanism of action may be one of the action of cells such as macrophages and lymphocytes and supressing the production of IL-2, TNF-α, TNF2, and other pro-inflammatory cytokines and mediators. Some reports indicate that rolipram, another regulator of TNF- is effective in treating experimental autoimmune encephalomyelitis (EAE) in animals. See for example Raine, C.S., Nature Medicine, Nol 1, No 3, pp211-214, 1995; Sommer, N. et al, Nature Medicine, Vol. 1, No. 3, pp. 244-248, 1995; Genin, C. P., et al, Proc. Natl. Acad. Sci., Vol. 92, pp. 3601-3605, April 1995; and Takusuka, N., et al, The J. of Immunology, 1995, 154: 4803-4812, 1995. Accordingly the compounds of Formulas (I) and (II) are useful in treating MS.
The preferred compounds for use in this invention are defined as follows: For compounds of Formula (I): 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 Cι_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-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl optionally substituted by OH, C7-11 polycycloalkyl, (3- or 4- cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl optionally substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)θ-2CH3, -(CH2)1-3O(CH2)0-2CH3, and -(CH2)2-4OH. When the Ri term contains the moiety (CR4R5), the R4 and R5 terms are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5)n or (CR4R5)m; 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. When R] is a C7-11 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0 >6]decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987, which disclosure is incorporated herein by reference in its entirety. Z is preferably C(O)R8, C(O)OR8, C(O)NR8R8, C(NR8)NR8R8, CN,
C(NOR8)R8, C(O)NR8NR8C(O)R8, C(NR8)NR8R8, C(NCN)NR8R8, C(NCN)SR9, (1-, 4- or 5-{R8}-2-imidazolyl), (1-, 4- or 5-{R8}-3-pyrazolyl), (1-, 2- or 5-{R8}-4-triazolyl[l,2,3]), (1-, 2-, 4- or 5-{R8}-3-triazolyl[l,2,4]), (1- or 2- {R8}-5-tetrazolyl), (4- or 5-{R8}-2-oxazolyl), (3- or 4-{R8}-5-isoxazolyl), (3- {R8}-5-oxadiazolyl[l,2,4]), (5-{R8}-3-oxadiazolyl[l,2,4]), (5- {R8}-2-oxadiazolyl[l,3,4]), (5-{R8}-2-thiadiazolyl[l,3,4]), (4- or 5-{R8}-2-thiazolyl), (4- or 5-{R8}-2-oxazolidinyl), (4- or 5-{R8 }-2-thiazolidinyl),(l-, 4- or 5-{R8}-2-imidazolidinyl); most preferred are those compounds wherein the R8 group of Z is R4. X5 is preferably hydrogen, Ci-2 alkyl optionally substituted by one to three fluorines, OR8, CN, C(O)R8, C(O)OR8, C(O)NRsR8, or NR8R8-
Preferred X groups for Formula (I) are those wherein X is YR2 and Y is oxygen. The preferred X2 group for Formula (I) is that wherein X2 is oxygen. The preferred X3 group for Formula (I) is that wherein X3 is hydrogen. Preferred R2 groups, where applicable, are Cι_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 and -CH3 moieties. Preferred R3 moieties are C(O)NH2, C≡CR8, CN, QZ^H, CH2OH, CH2F,
CF2H, and CF3. More preferred are -C≡CH and CN. Z' is preferably O or NOR8.
Preferred R7 moieties include optionally substituted -(CH2)l-2(cyclopropyl), -(CH2)0-2(cyclobutyl), -(CH2)0-2(cyclopentyl), -(CH2)0-2(cyclohexyl), -(CH2)0-2(2-, 3- or 4-pyridyl), -(CH2)l-2(2-imidazolyl), -(CH2)2(4-morpholinyl), -(CH2)2(4-piperazinyl), -(CH2)l-2(2-thienyl), -(CH2)l-2(4-thiazolyl), and -(CH2)0-2phenyl;
Preferred rings when Rio and Rl l in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 2-(R8)-l-imidazolyl, 1 -pyrazolyl,
3-(R8)-l -pyrazolyl, 1 -triazolyl, 2-triazolyl, 5-(R8)-l -triazolyl, 5-(R8)-2-triazolyl, 5-(R8)-l -tetrazolyl, 5-(R8)-2-tetrazolyl, 1 -tetrazolyl, 2-tetrazloyl, moφholinyl, piperazinyl, 4-(Rs)-l -piperazinyl, or pyrrolyl ring.
Preferred rings when Rio and R14 in the moiety -NR10R14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl, 1 -triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, moφholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I). Illustrations of such carbon substitutions includes, but are not limited to, 2-(R7)-l-imidazolyl,
4-(R7)-l-imidazolyl, 5-(R7)-l-imidazolyl, 3-(R7)-l -pyrazolyl, 4-(R7)-l -pyrazolyl, 5-(R7)-l -pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-l -triazolyl, 5-(R7)-l -triazolyl, 5-(R7)-l -tetrazolyl, and 5-(R7)-2-tetrazolyl. Applicable nitrogen substitution by R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l -tetrazolyl, 4-(R7)-l -piperazinyl. Where applicable, the ring may be substituted one or more times by R7.
Preferred groups for NR10R14 which contain a heterocyclic ring are 5- (Rl 4)- 1 -tetrazolyl, 2-(Ri4)-l-imidazolyl, 5-(Ri4)-2-tetrazolyl, or 4-(Rι_ -l- piperazinyl. Preferred rings for R13 include (2-, 4- or 5-imidazolyl), (3-, 4- or
5-pyrazolyl), (4- or 5-triazolyl[ 1,2,3]), (3- or 5-triazolyl[ 1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[l,2,4]), (2-oxadiazolyl[ 1,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl). When the R7 group is optionally substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be optionally substituted by R8 either on an available nitrogen or carbon atom, such as l-(R8)-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. Where applicable, the ring may be substituted one or more times by R8.
Preferred are those compounds of the Formula (I) wherein R is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl optionally substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Ci-2 alkyl optionally substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro- substituted alkyl, R3 is CN or C≡CRs; and X is YR2- Most preferred are those compounds wherein 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; and R2 is CF2H or methyl.
A preferred subgenus of the compounds of Formula (I) are the compounds of Formula (la)
Figure imgf000012_0001
wherein:
Rl is CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl optionally substituted by OH, C7 1 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl optionally substituted by 1 or more fluorines,-(CH2)l-3C(O)O(CH2)0-2CH3, -(CH2)l-3θ(CH2)0-2CH3, and -(CH2)2-4OH;
X is YR2, halogen, nitro, NR4R5, or formyl amine; X4 is
Figure imgf000012_0002
(a) (b)
X5 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8; Y is O or S(O)m'; m' is 0, l, or 2;
R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; R3 is hydrogen, -4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, CN, CH2OR8, C(Z')H, C(O)ORs, C(O)NRsRlθ, or C≡CR8; Z' is O or NOR8; Z is C(O)Ri4, C(O)ORi4, C(O)NRιoRl4, C(NRιo)NRιoRl4. CN,
C(NOR8)Ri4, C(O)NRsNR8C(O)R8, C(O)NR8NRιoRl4, C(NORi4)R8, C(NR8)NRιoRl4, C(NRi4)NR8R8, C(NCN)NRιoRl4, C(NCN)SR9, (1-, 4- or 5- {Rl4}-2-imidazolyl), (1-, 4- or 5-{Ri4}-3-pyrazolyl), (1-, 2- or 5- {Rl4}-4-triazolyl[l,2,3]), (1-, 2-, 4- or 5-{Ri4}-3-triazolyl[l,2,4]), (1- or 2- {Ri4}-5-tetrazolyl), (4- or 5-{Ri4}-2-oxazolyl), (3- or 4-{Ri4}-5-isoxazolyl), (3-{Ri4}-5-oxadiazolyl[l,2,4]), (5-{Ri4}-3-oxadiazolyl[l,2,4]), (5-{Ri4}-2-oxadiazolyl[l,3,4]), (5-{Ri4}-2-thiadiazolyl[l,3,4]), (4- or 5-{Rl4}-2-thiazolyl), (4- or 5-{Ri4}-2-oxazolidinyl), (4- or 5-{Ri4}-2-thiazolidinyl),(l-, 4- or 5-{Rl4}-2-imidazolidinyl);
R7 is -(CR4R5)qRi2 or Ci.g alkyl wherein the R12 or C\. alkyl group is optionally substituted one or more times by Cι_2 alkyl optionally substituted by one to three fluorines, -F, -Br, -Cl, -NO , -NR QRI 1, -C(O)R8, -C(O)OR8, -OR8, -CN, -C(O)NRιoRl l, -OC(O)NRιoRl l, -OC(O)R8, -NRι0C(O)NRι0Rl l, -NRiθC(O)Rn, -NRιoC(O)OR9, -NRlθC(O)Rι3, -C(NRio)NRi0Rl l, -C(NCN)NRιoRl l, -C(NCN)SR9, -NRiθC(NCN)SR9 , -NRioC(NCN)NRιoRl l, -NRιoS(O)2R9, -S(O)m'R9, -NRι0C(O)C(O)NRlθRl l, -NRlθC(O)C(O)Rι0, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is 0, 1, or 2;
Rl2 is C3-C7 cycloalkyl, (2-, 3- or 4-pyridyl), (1- or 2-imidazolyl), piperazinyl, moφholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl), or phenyl; the dotted line formula (a) represents a single or double bond; R8 is independently selected from hydrogen or R9;
R9 is C1-.4 alkyl optionally substituted by one to three fluorines;
Rlθ is OR8 or Rn;
Rl 1 is hydrogen or C1-.4 alkyl optionally substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S;
Rl3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C -.2 alkyl groups;
Rl4 is hydrogen or R7; or when Rio and R 14 are as NR10R14 they 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; provided that: a) when R12 is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, or N- moφholinyl, then q is not 1; or b) when Ri is CF2H or CF3, X is F, OCF2H, or OCF3, X5 is H, Z is C(O)ORi4 and R14 is Ci-7 unsubstituted alkyl, then R3 is other than H; or the pharmaceutically acceptable salts thereof. The most perferred compounds of Formula (I) are: methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex- 1 -ene- 1 - carboxylate; 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex- 1 -ene- 1 -carboxylic acid; methyl cw-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 - carboxylate]; methyl trαns-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane- 1 -carboxylate] ; methyl cis- [4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane- 1 - carboxylate]; methyl trans- [4-(3,4-bisdifluoromethoxyphenyl)-4- cyanocyclohexane- 1 -carboxylate] ; _ _?-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane-l -carboxylic acid]; cis-[4-cymo-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -carboxylate] , t (hydroxymethyl)ammonium methane salt; c _.-[4-(3,4- bisdifluoromethoxyphenyl)-4-cyanocyclohexane- 1 -carboxylic acid] ; tra«s-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-l- carboxylic acid]; _-[4-cyano-4-(3-cyclopropylmethoxy-4- methoxyphenyl)cyclohexane-l -carboxylic acid]; tran.y-[4-cyano-4-(3- cyclopropylmethoxy-4-methoxyphenyl)cyclohexane- 1 -carboxylic acid] ; methyl c._--[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-l- carboxylate]; methyl trαn_f-[4-cyano-4-(3-cyclopropylmethoxy-4- methoxyphenyl)cyclohexane- 1 -carboxylate] ; methyl c _,-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexane- 1 -carboxylate] ; methyl trans- [4-cyano-
4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-cyclohexane- 1 -carboxylate] ; cw-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexane-l -carboxylic acid]; tran_?-[4-cyano-4-(3- cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane- 1 -carboxylic acid] ; c/s-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-l- carboxamide] ; c 5,-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane- 1 - carboxamide]; trαns-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-l- carboxamide]; c 5-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-l- carbohydrazide] ; cis- [4-cyano-4-(3 ,4-bisdifluoromethoxyphenyl)cyclohexane- 1 -(2-acetylcarbohydrazide)] ; cis- { 4-(3,4-bisdifluoromethoxyphenyl)-4-cyano- 1 -(3- methyl[ 1 ,2,4]oxadiazol-5-yl)cyclohexane } ; cis- { 4-(3 ,4-bisdifluoromethoxyphenyl)- 4-cyano- 1 -(2-methyl [ 1 ,3,4] oxadiazol-5-yl)cyclohexane } ; cis- { 4-(3 ,4- bisdifluoromethoxyphenyl)-4-cyano-l-(2-methyl[l,3,4]thiadiazol-5- yl)cyclohexane } ; c -.-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - hydroxy- 1 -tris(methylthio)methylcyclohexane] ; methyl c _,-[4-cyano-4-(3- cyclopropylmethoxy-4-methoxyphenyl)- 1 -hydroxy-cyclohexane- 1 -carboxylate] ; cis -[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - hydroxycyclohexane- 1 -carboxylic acid] ; c _?-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - hydroxycyclohexane- 1 -carboxamide] ; methyl c/s-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - methoxy-cyclohexane- 1 -carboxylate] ; cw-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - methoxycyclohexane- 1 -carboxylic acid]; _>-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - methoxycyclohexane- 1 -carboxamide] ; tran.r-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l-hydroxy- cyclohexane- 1 -carboxaldehyde] ; methyl trans-[ 4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l- hydroxycyclohexane- 1 -carboxylate] ; trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - hydroxycyclohexane- 1 -carboxylic acid] ; methyl trα«s-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - methoxycyclohexane- 1 -carboxylate] ; tr «s-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - methoxycyclohexane- 1 -carboxylic acid] ; trαri5-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - methoxycyclohexane- 1 -carboxamide] ; cis- [4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 - carboxamic acid] ;
N-methyl- s-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -carboxamic acid]; cw-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-l-N-(2- cyanoethyl)carboxamide]; cis- [ 1 -(2-cyanoethyl)-5- { 4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexyl } tetrazole] ; and c _.-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-l-(tetrazol-5- yl)cyclohexane]. As regards the compounds of Formula (II), the preferred compounds are as follows: When Ri is an alkyl substituted by 1 or more halogens, the halogens are preferably fluorine and chlorine, more preferably a C1-.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 Formula (I) are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-.6 cycloalkyl unsubstituted or substituted with OHC7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or Ci-2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH2)l-3C(O)O(CH2)θ-2CH3, -(CH2)l-3O(CH2)0-2CH3, and -(CH2)2-4OH.
When Ri term contains the moiety (CR4R5), the R4 and R5 terms are independently hydrogen or alkyl. This allows for branching of the individual methylene units as (CR4R5)n or (CR4R5)m. 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 unsubstituted or be substituted by fluorine independent of each other to yield, for instance, the preferred Ri substitutions, as noted above.
When Ri is a C7.1 polycycloalkyl, examples are bicyclo[2.2.1]-heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.02>6]decyl, etc. additional examples of which are described in Saccamano et al., WO 87/06576, published 5 November 1987.
W is preferably alkyl, alkenyl or alkynyl of 3 to 5 carbon atoms, and where it is alkenyl or alkynyl, that one or two double or triple bonds be present. It is most preferred that W is ethynyl or 1,3-butadiynyl. Z is preferably OR14, OR15, SR14, S(O)m'R7, S(O)2NRιoRl4, NR10R14,
NRι4C(O)R9, NRlθC(O)Ri4, NRi0C(O)OR7, NRi0C(O)NRi0Rl4, NRιoS(O)2NRιoRl4. NRι0C(NCN)NRι0Rl4, NRι0S(O)2R7, NRioC(CR4NO2)NRioRl4, NRιoC(NCN)SR9, NRioC(CR4NO2)SR9, NRιoC(NRιo)NRιoRl4, NRioC(O)C(O)NRιoRl4, or NRιoC(O)C(O)ORi4. Preferred X groups for Formula (I) are those wherein X is YR2 and Y is oxygen. The preferred X2 group for Formula (I) is that wherein X2 is oxygen. The preferred X3 group for Formula (I) is that wherein X3 is hydrogen. Preferred R2 groups, where applicable, is a Ci-2 alkyl unsubstituted or 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 and -CH3 moieties. Preferred R7 moieties include unsubstituted or substituted -(CH2)0-2(2-, 3- or 4-pyridyl), (CH2)l-2(2-imidazolyl), (CH2)2(4-moφholinyl), (CH2)2(4- piperazinyl), (CH2)l-2(2-thienyl), (CH2)l-2(4-thiazolyl), unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH2)θ-2phenyl. Preferred rings when Rio and Rl l in the moiety -NRioRl 1 together with the nitrogen to which they are attached form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1 -imidazolyl, 2-(R8)-l -imidazolyl, 1 -pyrazolyl, 3-(R8)-l -pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R8)-l -triazolyl, 5-(R8)-2-triazolyl, 5-(R8)-l -tetrazolyl, 5-(R8)-2-tetrazolyl, 1 -tetrazolyl, 2-tetrazloyl, moφholinyl, piperazinyl, 4-(R8)-l -piperazinyl, or pyrrolyl ring.
Preferred rings when Rio and R14 in the moiety -NR10R14 together with the nitrogen to which they are attached may form a 5 to 7 membered ring comprised of carbon or carbon and at least one heteroatom selected from O, N, or S include, but are not limited to 1 -imidazolyl, 1 -pyrazolyl, 1 -triazolyl, 2-triazolyl, 1 -tetrazolyl, 2-tetrazolyl, moφholinyl, piperazinyl, and pyrrolyl. The respective rings may be additionally substituted, where applicable, on an available nitrogen or carbon by the moiety R7 as described herein for Formula (I). Illustrations of such carbon substitutions includes, but is not limited to, 2-(R7)-l -imidazolyl, 4-(R7)-l -imidazolyl, 5-(R7)-l -imidazolyl, 3-(R7)-l -pyrazolyl, 4-(R7)-l -pyrazolyl, 5-(R7)-l -pyrazolyl, 4-(R7)-2-triazolyl, 5-(R7)-2-triazolyl, 4-(R7)-l -triazolyl, 5-(R7)-l -triazolyl, 5-(R7)-l -tetrazolyl, and 5-(R7)-2-tetrazolyl. Applicable nitrogen substitution by R7 includes, but is not limited to, l-(R7)-2-tetrazolyl, 2-(R7)-l -tetrazolyl, 4-(R7)-l -piperazinyl. Where applicable, the ring may be substituted one or more times by R7.
Preferred groups for NR10R14 which contain a heterocyclic ring are 5- (R 14)- 1 -tetrazolyl, 2-(R 14)- 1 -imidazolyl, 5-(Ri4)-2-tetrazolyl, 4-(Ri4)-l- piperazinyl, or 4-(Rι 5)- 1 -piperazinyl.
Preferred rings for R13 include (2-, 4- or 5 -imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[ 1,2,3]), (3- or 5 -triazolyl [1,2, 4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[ 1,2,4]), (2-oxadiazolyl[ 1,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).
When the R7 group is unsubstituted or substituted by a heterocyclic ring such as imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, the heterocyclic ring itself may be unsubstituted or substituted by R8 on an available nitrogen or carbon atom, such as l-(R8)-2-imidazolyl, l-(R8)-4-imidazolyl, l-(R )-5-imidazolyl, l-(R8)-3-pyrazolyl, l-(R8)-4-pyrazolyl, l-(R8)-5-pyrazolyl, l-(R8)-4-triazolyl, or l-(R8)-5-triazolyl. Where applicable, the ring may be substituted one or more times by R8.
Preferred are those compounds of Formula (II) wherein Ri is -CH2- cyclopropyl, -CH2-C5-6 cycloalkyl, -C4-6 cycloalkyl unsubstituted or substituted by OH, tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -Cχ2 alkyl unsubstituted or substituted by 1 or more fluorines, and -(CH2)2-4 OH; R2 is methyl or fluoro-substituted alkyl, W is ethynyl or 1,3-butadiynyl; R3 is R7 where R7 is an unsubstituted or substituted aryl or heteroaryl ring, X is YR2, and Z is OR14, ORi5? NR10R14, or NRi4C(O)R9.
Most preferred are those compounds of Formula (II) wherein Ri is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; X3 is hydrogen; and R2 is CF2H or methyl, W is ethynyl or 1,3-butadiynyl, and R3 is a substituted or unsubstituted pyrimidinyl ring. The most preferred compounds of Formula (II) are: c._.-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -ol] , s-[4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-cyclohexan- 1 -ol] , trα«_.-[4-(2-acetamidopyrimidin-5-ylethynyl)-4-(3-cyclopentyloy-4- methoxyphenyl)cyclohexan- 1 -ol] , trαn5-[4-(2-aminopyrimidin-5-yl-ethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-cyclohexan- 1 -ol, ci_f-[4-(2-methylaminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -ol] , c/_-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-4- ylethynyl)cyclohexan- 1 -ol] , c._.-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2- ylethynyl)cyclohexan- 1 -ol] , c _f-[4-(4-cyanothien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)- cyclohexan-1-ol], c _.-[4-(thiazol-2-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan- 1 -ol] , c _>-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[4-(5-methyl- [l,2,4]oxadiazol-2-yl)thien-2-ylethynyl] cyclohexan-1-ol], c._.-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(3- methyl[l,2,4]oxadiazol-5-yl)phenyl]ethynyl)cyclohexan-l-ol], cz-.-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5- methyl [ 1 ,3 ,4] oxadiazol-2-yl)phenyl]ethynyl)cyclohexan- 1 -ol] , c._.-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-[3-(5- methylf 1 ,2,4]oxadiazol-3-yl)phenyl]ethynyl)cyclohexan- 1 -ol] , c 5,-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-trifluoromethyl-
[ 1 ,2,4]oxadiazol-3-yl)phenylethynyl)cyclohexan- 1 -ol, cw-4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[3-(5-methyl-[l,3,4]thiadiazol- 2-yl)phenylethynyl]cyclohexan- 1 -ol, trαn-?-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2- ylethynyl)cyclohexyl- 1 -amine] , tra«j,-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2- ylethynyl)cyclohexyl- 1 -formamide] , trαns-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl- [l,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-l-amine], cyclohexylsulfamate salt c/s-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2- ylethynyl)cyclohexyl- 1 -amine] , s-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(pyrid-2- ylethynyl)cyclohexyl- 1 -formamide] , cw-[4-(3-cyclopentyloxy-4-methoxyphenyl)-4-[5-(5-methyl-
[l,2,4]oxadiazol-2-yl)thien-2-ylethynyl]cyclohexyl-l-amine], cyclohexylsulfamate salt, trfl7i-f-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexyl-l -amine], cyclohexylsulfamate salt, or cw-[4-(2-aminopyrimidin-5-ylethynyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexyl-l -amine], cyclohexylsulfamate salt.
Some compounds of Formula (I) and Formula (II) may exist in both racemic and optically active forms; some may also exist in distinct diastereomeric forms possessing distinct physical and biological properties. All of these compounds are considered to be within the scope of the present invention. Therefore another aspect of the present invention is the administration of either a racemate, a single enantiomeric form, a single diastereomeric form, or mixtures thereof.
The terms cis and trans denote stereochemistry at the C-l position of the cyclohexane ring relative to the R3 group at the C-4 position. The terms"Cι_3 alkyl", "Cμ alkyl", "Cι_6 alkyl" or "alkyl" include 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, tert-butyl, and the like. "Alkenyl" includes 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" includes 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. Preferably the aryl is monocyclic, i.e, phenyl. The alkyl chain includes both straight or branched chain radicals of 1 to 4 carbon atoms. "Heteroaryl" as used herein, is meant an aromatic ring system containing one or more heteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl. "Halo" as used herein is meant all halogens, i.e., chloro, fluoro, bromo, or iodo.
The phrase "down regulating or inhibiting the production of TNF" means: a) a decrease of excessive in vivo 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; b) a down regulation, at the translational or transcriptional level, of excessive in vivo 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 TNF levels as a postranslational event.
All of the compounds of Formula (I) are useful in the method of treating MS; the mechanism of which may be that of inhibiting or down regulating the production of TNF, preferably by macrophages, monocytes or macrophages and monocytes, in a mammal. Mammals includes humans.
No unacceptable toxic effects are expected when these compounds are administered in accordance with the present invention.
METHODS OF PREPARATION: The preparation of compounds of Formula (I) is fully set forth in U.S. patent 5,552,438 issued 3 September 1996. This patent is incoφorated herein in its entirety by reference as if fully set out herein. The compounds of Formula (II) are known compound and can be prepared by the methods set out in published PCT application PCT/US95/16711 published as WO96/19988 on 4 July 1996. The whole contents of this published PCT application is incoφorated herein by reference as if fully set forth herein. METHODS OF TREATMENT In order to use a compound of Formula (I) and (II) or a pharmaceutically acceptable salt thereof for the treatment of MS, it will be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. The compounds of Formula (I) and (II) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylatic or therapeutic treatment of MS.
The pharmaceutical composition of the present invention will comprise an effective, non-toxic amount of a compound of Formula (I) or (II) and a pharmaceutically acceptable carrier or diluent. The compounds of Formula (I) and (II) are administered in conventional dosage forms prepared by combining a compound of Formula (I) and (II) 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. 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 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 incoφorated 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 flavoring or coloring agent.
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) and (II) or a pharmaceutically acceptable salt thereof calculated as the free base. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity.
While it is possible for an active ingredient to be administered neat, it is preferable to present it as a pharmaceutical formulation. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of 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 Formulation.
Formulations of the present invention comprise an active ingredient together with one or more acceptable carrier(s) thereof and optionally any other therapeutic ingredient(s). The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of Formulation and not deleterious to the recipient thereof.
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 well-known variables.

Claims

What is claimed is:
1. A method for treating multiple sclerosis, which method comprises administering to a mammal suffering from multiple sclerosis an effective amount of a compound of Formula (I):
Figure imgf000023_0001
wherein:
Rl is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, - (CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 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 aryloxyCi-3 alkyl, indanyl, indenyl, C7.11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by OH, 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R is other than H in
-(CR4R5)nO(CR4R5)mR6;
X is YR2, halogen, nitro, NR4R5, or formyl amine;
Y is O or S(O)m'; m' is 0, 1, or 2;
X2 is O or NR8;
X3 is hydrogen or X;
X4 is
Figure imgf000024_0001
(a) (b)
X5 is H, R9, OR8, CN, C(O)R8, C(O)OR8, C(O)NR8R8, or NR8R8;
R2 is independently selected from the group consisting of -CH3 and - CH2CH3 optionally substituted by 1 or more halogens; s is 0 to 4;
R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo- substituted C1-4 alkyl, -CH=CR8'R8'. cyclopropyl optionally substituted by R8', CN, OR8, CH2OR8, NR8Rlθ, CH2NR8RlO, QZ^H, C(O)OR8, C(O)NR8Rl0, or C≡CRg';
Z' is O, NR9, NOR8, NCN, C(-CN)2, CRδCN, CR8NO2, CR8C(O)OR8, CR8C(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NR8R8 ;
Z is C(Y Rl4, C(O)ORi4, C(Y NRιoRl4, C(NRιo)NRι0Rl4, CN, C(NOR8)Rl4, C(O)NR8NR8C(O)R8, C(O)NR8NRioRl4, C(NORi4)R8, C(NR8)NRιoRl4, C(NRi4)NRsR8 C(NCN)NRιoRl4, C(NCN)SR9, (2-, 4- or 5 -imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[ 1,2,3]), (3- or 5-triazolyl[ 1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[ 1,2,4]), (2-oxadiazolyl[ 1,3,4]), (2-thiadiazolyl[ 1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocylic ring systems may be optionally substituted one or more times by R14; the dotted line in formula (a) represents a single or double bond;
Y' is O or S;
R7 is -(CR4R5)qRi2 or Cι_6 alkyl wherein the R 2 or Cι_6 alkyl group is optionally substituted one or more times by C 1-2 alkyl optionally substituted by one to three fluorines, -F, -Br, -Cl, -NO2, -NRioRπ. -C(O)R8, -C(O)OR8, -OR8, -CN, -C(O)NRιoRl l, -OC(O)NRιoRl l, -OC(O)R8, -NRιoC(O)NRιoRl l, -NRιoC(O)Rn, -NRioC(O)OR9, -NRi0C(O)Rι3, -C(NRιo)NRι0Rl l, -C(NCN)NRιoRn, -C(NCN)SR9, -NRιoC(NCN)SR9 , -NRιoC(NCN)NRιoRl l, -NRioS(O) R9, -S(O)m'R9, -NRι0C(O)C(O)NRι0Rl l, -NRι0C(O)C(O)Rio, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is 0, 1, or 2;
Rl2 is C3-C7-cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2- imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, moφholinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl; R8 is independently selected from hydrogen or R9;
R ' is R8 or fluorine;
R9 is C1.4 alkyl optionally substituted by one to three fluorines;
Rlθ is OR8 or Rn;
Rl is hydrogen, or C1-.4 alkyl optionally substituted by one to three fluorines; or when Rio and Ri 1 are as NRioRl 1 they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O/N/or S;
Rl3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two Cj_2 alkyl groups;
Rl4 is hydrogen or R7; or when Rio and R14 are as NR10 14 they 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; provided that: f) when R12 is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N- piperazinyl, N-piperidinyl, or N-moφholinyl, then q is not 1; or g) when X2R1 is OCF2H or OCF3, X is F, OCF2H or OCF3, X3 is H, s is zero, X5 is H, Z is C(O)ORi4 and R14 is C1-.7 unsubstituted alkyl, then R3 is other than H; or the pharmaceutically acceptable salts thereof.
2. The method of claim 1 in which the compound used is : methyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex- 1 -ene- 1 - carboxylate;
4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex- 1 -ene- 1 -carboxylic acid; methyl cis- [4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 - carboxylate]; methyl trαn.y-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -carboxylate]; methyl cis- [4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane- 1 - carboxylate] ; methyl trans- [4-(3 ,4-bisdifluoromethoxyphenyl)-4- cyanocyclohexane-1 -carboxylate]; _-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane-l -carboxylic acid]; cw-[4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -carboxylate] , tra(hydroxymethyl)ammonium methane salt; cis - [4-(3 ,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane- 1 -carboxylic acid]; trαns-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-l- carboxylic acid]; c 5-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-l- carboxylic acid]; trαn5-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-l- carboxylic acid]; methyl cw-[4-cyano-4-(3-cyclopropylmethoxy-4- methoxyphenyl)cyclohexane- 1 -carboxylate] ; methyl tra/M-[4-cyano-4-(3-cyclopropylmethoxy-4- methoxyphenyl)cyclohexane- 1 -carboxylate] ; methyl c/.s-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexane- 1 -carboxylate] ; methyl trαns-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)- cyclohexane- 1 -carboxylate] ; c s-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexane- 1 -carboxylic acid] ; trøn.s-[4-cyano-4-(3-cyclopropylmethoxy-4- difluoromethoxyphenyl)cyclohexane- 1 -carboxylic acid] ; cis- [4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 - carboxamide]; α'_-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-l -carboxamide]; trans- [4-cyano-4-(3 ,4-bisdifluoromethoxyphenyl)cyclohexane- 1 - carboxamide]; cis- [4-cyano-4-(3 ,4-bisdifluoromethoxyphenyl)cyclohexane- 1 - carbohydrazide]; cw-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-l-(2- acetylcarbohydrazide)] ; cis- { 4-(3 ,4-bisdifluoromethoxyphenyl)-4-cyano- 1 -(3- methyl[ 1 ,2,4]oxadiazol-5-yl)cyclohexane } ; cis- { 4-(3 ,4-bisdifluoromethoxyphenyl)-4-cyano- 1 -(2- methyl[l,3,4]oxadiazol-5-yl)cyclohexane}; cis- { 4-(3 ,4-bisdifluoromethoxyphenyl)-4-cyano- 1 -(2- methyl[ 1 ,3,4]thiadiazol-5-yl)cyclohexane } ; c/.s-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l-hydroxy-l- tris(methylthio)methylcyclohexane]; methyl c «-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 -hydroxycyclohexane- 1 -carboxylate] ; c._.-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyph.enyl)- 1 - hydroxycyclohexane- 1 -carboxylic acid] ; cώ-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - hydroxycyclohexane- 1 -carboxamide] ; methyl ds-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - methoxy-cyclohexane- 1 -carboxylate] ; cw-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l- methoxycyclohexane- 1 -carboxylic acid] ; c ->-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l- methoxycyclohexane- 1 -carboxamide] ; trα«s-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l-hydroxy- cyclohexane- 1 -carboxaldehyde] ; methyl trans-[ 4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l- hydroxycyclohexane- 1 -carboxylate] ; trαn.s-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - hydroxycyclohexane- 1 -carboxylic acid] ; methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l- methoxycyclohexane- 1 -carboxylate] ; trαns-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)- 1 - methoxycyclohexane- 1 -carboxylic acid] ; trαn_»-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-l- methoxycyclohexane- 1 -carboxamide] ; s-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-l- carboxamic acid];
N-methyl-cw-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -carboxamic acid]; s-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-l-N-(2- cyanoethyl)carboxamide] ; c _?-[l-(2-cyanoethyl)-5-{4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexyl } tetrazole] ; or s-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-l-(tetrazol-5- yl)cyclohexane].
3. A method for treating multiple sclerosis, which method comprises administering to a mammal suffering from multiple sclerosis an effective amount of a compound of Formula (II) as defined herein above.
PCT/US1999/000126 1998-01-07 1999-01-06 Method for treating multiple sclerosis Ceased WO1999034797A1 (en)

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CA002317548A CA2317548A1 (en) 1998-01-07 1999-01-06 Method for treating multiple sclerosis
EP99900751A EP1043994A4 (en) 1998-01-07 1999-01-06 THERAPY OF MULTIPLE Sclerosis

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US6555572B2 (en) 2000-03-16 2003-04-29 Inflazyme Pharmaceuticals Ltd. Benzylated PDE4 inhibitors
US7514457B2 (en) 2005-05-31 2009-04-07 Pfizer Inc. Substituted aryloxymethyl bicyclicmethyl acetamide compounds
US8076324B2 (en) 2007-06-05 2011-12-13 Sanofi-Aventis Di(hetero)arylcyclohexane derivatives, their preparation, their use and pharmaceutical compositions comprising them

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US5552438A (en) * 1992-04-02 1996-09-03 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases

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JPH10511398A (en) * 1994-12-23 1998-11-04 スミスクライン・ビーチャム・コーポレイション 4,4- (disubstituted) cyclohexane-1-carboxylate monomers and related compounds

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US5552438A (en) * 1992-04-02 1996-09-03 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6555572B2 (en) 2000-03-16 2003-04-29 Inflazyme Pharmaceuticals Ltd. Benzylated PDE4 inhibitors
US7446129B2 (en) 2000-03-16 2008-11-04 Biolipox Ab Benzylated PDE4 inhibitors
US7459479B2 (en) 2000-03-16 2008-12-02 Biolipox Ab Benzylated PDE4 inhibitors
US7514457B2 (en) 2005-05-31 2009-04-07 Pfizer Inc. Substituted aryloxymethyl bicyclicmethyl acetamide compounds
US8076324B2 (en) 2007-06-05 2011-12-13 Sanofi-Aventis Di(hetero)arylcyclohexane derivatives, their preparation, their use and pharmaceutical compositions comprising them

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