[go: up one dir, main page]

WO1999034797A1 - Methode de traitement de la sclerose en plaques - Google Patents

Methode de traitement de la sclerose en plaques Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
cyano
methoxyphenyl
cyclohexane
cyclopropylmethoxy
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1999/000126
Other languages
English (en)
Inventor
Siegfried B. Christensen, Iv
Theodore Torphy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Priority to AU20262/99A priority Critical patent/AU2026299A/en
Priority to JP2000527246A priority patent/JP2002500187A/ja
Priority to CA002317548A priority patent/CA2317548A1/fr
Priority to EP99900751A priority patent/EP1043994A4/fr
Publication of WO1999034797A1 publication Critical patent/WO1999034797A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une méthode de traitement de la sclérose en plaques consistant à administrer aux patients souffrant de cette maladie des composés de la formule (I), dans laquelle X4 représente un groupe substitué par 1-cyclohexyle, les autres groupes représentant des éthers ou des thioéthers, ou un composé de la formule (II), dans laquelle W représente un groupe aliphatique de 2 ou 6 carbones et R3 représente un groupe acide, amide, ou aromatique ou hétéroaromatique, Z étant représenté par un alcool ou un dérivé d'alcool.
PCT/US1999/000126 1998-01-07 1999-01-06 Methode de traitement de la sclerose en plaques Ceased WO1999034797A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU20262/99A AU2026299A (en) 1998-01-07 1999-01-06 Method for treating multiple sclerosis
JP2000527246A JP2002500187A (ja) 1998-01-07 1999-01-06 多発性硬化症の治療方法
CA002317548A CA2317548A1 (fr) 1998-01-07 1999-01-06 Methode de traitement de la sclerose en plaques
EP99900751A EP1043994A4 (fr) 1998-01-07 1999-01-06 Methode de traitement de la sclerose en plaques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7067698P 1998-01-07 1998-01-07
US60/070,676 1998-01-07

Publications (1)

Publication Number Publication Date
WO1999034797A1 true WO1999034797A1 (fr) 1999-07-15

Family

ID=22096730

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/000126 Ceased WO1999034797A1 (fr) 1998-01-07 1999-01-06 Methode de traitement de la sclerose en plaques

Country Status (5)

Country Link
EP (1) EP1043994A4 (fr)
JP (1) JP2002500187A (fr)
AU (1) AU2026299A (fr)
CA (1) CA2317548A1 (fr)
WO (1) WO1999034797A1 (fr)

Cited By (3)

* 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
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5552438A (en) * 1992-04-02 1996-09-03 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10511398A (ja) * 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−（二置換）シクロヘキサン−１−カルボキシレート単量体および関連する化合物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Also Published As

Publication number Publication date
AU2026299A (en) 1999-07-26
CA2317548A1 (fr) 1999-07-15
EP1043994A4 (fr) 2002-09-11
JP2002500187A (ja) 2002-01-08
EP1043994A1 (fr) 2000-10-18

Similar Documents

Publication Publication Date Title
AP519A (en) Pharmaceutical compositions containing novel compounds and their use in treating allergic and inflamatory diseases.
JPH07508263A (ja) 炎症疾患の治療および腫瘍壊死因子の産生阻害に有用な化合物
JPH09501420A (ja) ３−シアノ−３−（３，４−二置換）フェニルシクロヘキシル−１−カルボキシレート類
JPH01299289A (ja) 血糖降下剤としてのチアゾリジンジオン誘導体
WO1999034798A1 (fr) Procede pour le traitement de la bronchopneumopathie chronique obstructive
WO1999034797A1 (fr) Methode de traitement de la sclerose en plaques
TWI330630B (en) 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
US20020147206A1 (en) Combination treatment of multiple sclerosis (MS), other demyelinating conditions and peripheral neuropathy, especially painful neuropathies and diabetic neuropathy
JPH023626A (ja) リシルオキシダーゼの抑制剤
JPH10511391A (ja) ３，３−（二置換）シクロヘキサン−１−オール二量体および関連化合物
JP2873090B2 (ja) アレルギーおよび炎症疾患の治療用化合物
MXPA00006704A (en) Method for treating copd
HK1033551B (en) Method for treating copd
CZ20002530A3 (cs) Farmaceutický prostředek, způsob profylaxe, použití pro výrobu léčiva, způsob jeho výroby a léčivo
JPS63277672A (ja) 置換された１，３‐ジオキソランおよび１，３‐ジオキサン誘導体、その製法と使用
SI9300167A (sl) Nove spojine, ki so uporabne pri posredovanju ali inhibiciji encimske aktivnosti fosfodiesteraze IV (PDE IV)
JPH10511661A (ja) １，３，３−（三置換）シクロヘキサ−１−エン二量体および関連化合物
JPH10511662A (ja) １，４，４−（三置換）シクロヘキサン二量体および関連化合物
JPH10511659A (ja) １，４，４−（三置換）シクロヘキサン単量体および関連する化合物
JPH10511389A (ja) ４，４−（二置換）シクロヘキサン−１−オール二量体および関連化合物
JPH10511390A (ja) １，４，４−（三置換）シクロヘクス−１−エンダイマーおよび関連化合物
AU1563902A (en) Novel use of compounds for anti-pruritic activity

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AU BA BB BG BR CA CN CZ EE GE GH GM HR HU ID IL IN IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 09582740

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2317548

Country of ref document: CA

Ref country code: CA

Ref document number: 2317548

Kind code of ref document: A

Format of ref document f/p: F

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 527246

Kind code of ref document: A

Format of ref document f/p: F

NENP Non-entry into the national phase

Ref country code: KR

WWE Wipo information: entry into national phase

Ref document number: 1999900751

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1999900751

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1999900751

Country of ref document: EP