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WO1994024095A1 - Agents immunosuppresseurs - Google Patents

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Publication number
WO1994024095A1
WO1994024095A1 PCT/US1994/004045 US9404045W WO9424095A1 WO 1994024095 A1 WO1994024095 A1 WO 1994024095A1 US 9404045 W US9404045 W US 9404045W WO 9424095 A1 WO9424095 A1 WO 9424095A1
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Prior art keywords
cyano
isoxazole
methyl
carboxylic acid
amide
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PCT/US1994/004045
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English (en)
Inventor
Michael J. Coghlan
Jay R. Luly
Paul E. Wiedeman
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Abbott Laboratories
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Abbott Laboratories
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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Definitions

  • the present invention relates to novel chemical compounds having
  • the invention also relates to means for the preparation of and pharmaceutical compositions containing such compounds, as well as methods of treatment employing the same.
  • Certain cancer chemotherapy drugs such as methotrexate and cyclophosphamide have been found to have immunosuppressive activity.
  • azathioprine Another cancer chemotherapeutic agent
  • These compounds may not be ideal long-term immunosuppressive agents: Methotrexate is non-selective in its antiproliferative effects and shows no more potency on lymphocytes than other cell types (Jolivet et al., New End. J.
  • cyclosporine cyclosporin A, Borel et al. Immunol., 32:1017-1025 (1977)
  • Cyclosporine has found widespread use since its introduction in the fields of organ transplantation and immunomodulation and has brought about a significant increase in the success rate for transplantation procedures.
  • Cyclosporine has been found to be an inhibitor of cytokine production (reviewed by Schreiber et al., Immunology Today. 13(4):136-42 (1992) and Sigal et al., Ann. Rev. Immunol., 10:519-60 (1992)).
  • Leflunomide is readily converted in vivo to its ring-opened metabolite. Although this metabolite has a wide variety of physiological effects in vitro, the definitive mode of action is presently unclear. Isoxazole immunosuppressants also appear to be safer than their macrocyclic counterparts since none of the toxic effects associated with FK-506, cyclosporine or their analogs have been noted during the study of these new therapeutic agents.
  • one object of the invention is to provide novel isoxazoles, products derived from isoxazole ring opening (and analogs thereof), and their tautomers which possess the desired immunomodulatory activity but which may be found to minimize untoward side effects.
  • Another object of the present invention is to provide synthetic processes for the preparation of such compounds.
  • a further object of the invention is to provide pharmaceutical compositions containing, as an active ingredient, one of the above compounds.
  • Yet another object of the invention is to provide a method of treating a variety of disease states including resistance by a recipient patient to transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum ***, limb, muscle, nervus, duodenum, small-bowel, pancreatic-islet-cell, etc.; graft-versus-host diseases brought about by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis,
  • glomerulonephritis and the like; and further infectious diseases caused by pathogenic microorganisms.
  • Further uses may include the treatment and prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrheic dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia areata; various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis
  • renal diseases such as interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy
  • nervous diseases such as multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy
  • endocrine diseases such as hyperthyroidism and Basedow's disease
  • hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia
  • bone diseases such as osteoporosis
  • respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin disease such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesions of gingiva, periodontium, alveolar bone and substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern aleopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth; muscular dystrophy;
  • ischemic disease for example, thrombosis and cardiac infraction
  • intestinal diseases such as endotoxin-shock, pseudomembranous colitis and colitis caused by drug or radiation
  • renal diseases such as ischemic acute renal insufficiency and chronic renal insufficiency
  • pulmonary diseases such as toxinosis caused by lung-oxygen or drug (for example, paracort and bleomycins), lung cancer and pulmonary emphysema; ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring and corneal alkali burn; dermatitis such as erythema multiforme, linear IgA ballous dermatitis and cement dermatitis; and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (for example, air pollution), aging, carcinogenis, metastasis of carcinoma and hypobaropathy; disease caused by histamine or leukotriene-C 4 release;
  • Behcet's disease such as intestinal-, vasculo- or neuro-Behcet's disease, and also Behcet's which affects the oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on.
  • the compounds of the invention are useful for the treatment and prevention of hepatic disease such as immunogenic diseases (for example, chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g.
  • these ⁇ -cyano- ⁇ -hydroxy crotonyl analogs can be synthesized via an independent route.
  • the salts, esters and prodrugs of each of the above compounds are also included among the compounds of the invention.
  • the substituent E in the above formulae is -R 14 , -NR 14 R 15 , -SR 14 , -OR 14 or -CR 14 R 15 R 16 , where R 14 , R 15 and R 16 are independently selected from
  • R 6 and R 7 in the above may be hydrogen, alkyl, alkenyl, acyl, aryl, heterocyclic, biaryl, cycloalkyl, arylalkyl, hydroxyalkyl or arylsulfonyl, where each radical other than hydrogen may be substituted with between one and three substituents
  • halogen independently selected from the group consisting of halogen, haloalkyl, haloalkoxy, -CHO, -CN, -C(O)OH, -C(O)O-(C 1 -to-C 6 alkyl), -N 3 , -NO 2 , -OH and oxo.
  • aryl, aryl', heterocyclic, heterocyclic' and biaryl are each independently substituted with X, Y and Z.
  • the substituent R 10 in the above is selected at each instance from among (i) halogen, (ii) haloalkyl, (iii) haloalkoxy, (iv) -OH, (v) -(CH) m NR 6 R 7 where m is zero to six, (vi) -CHO, (vii) -(CH 2 ) m OR 6 where m is zero to six, (viii) -CH(OR 12' )(OR 12" ) where R 12' and R 12" are independently -(C 1 -to-C 3 alkyl) or, taken together, form an ethylene or propylene bridge, (ix) -(CH 2 ) m -OC(O)R 6 , (x) -CN, (xi) -C(O)OH, (xii)-C(O)O-(C 1 -to-C 6 alkyl), (xiii) -C(O)NR 6 R 7 , (xiv)
  • R 11 in turn may be -P(O)(OH)O-M+ where M+ is a positively charged inorganic or organic counterion, -S(O) 2 O-M+ or -CO(CH 2 ) m C(O)O-M+.
  • the substituents X, Y, and Z in the above are each independently selected at each instance from among (a') hydrogen, (b') halogen, (c') haloalkyl, (d') -(C 1 -to-C 7 alkyl), (e') -(C 2 -to-C 6 alkenyl), (f)-(C 2 -to-C 6 alkynyl), (g') -(CH 2 ) m NR 6 R 7 , (h') -CN, (i') -CHO, (j') -(CH 2 ) m OR 6 where m is zero to six, (k') -(CH 2 ) m C(O)OR 6 , (1') -(CH 2 ) m OC(O)R 6 , (m') -CH(OR 12' )(OR 12" ) where R 12' and R 12" are independently -(C 1 -to-C 3 alkyl) or,
  • any two adjacent of X, Y and Z, taken together with the carbon atoms to which they are attached, may form a 5- to 7-membered ring which includes zero, one or two additional heteroatoms independently selected from among -O-, -S(O) s - and -N(R 8 )-.
  • X', Y' and Z' in the above are independently selected at each instance from the same groups comprised by X, Y and Z. Additionally, X', Y' and Z' may be chosen from among -(CH 2 ) m NR 6' R 7' , -(CH 2 ) m OR 6' , -(CH 2 ) m C(O)OR 6' ,
  • the substituents R 6' and R 7' in the above are independently selected at each instance from hydrogen, aryl substituted with X, Y and Z, heterocyclic substituted with X, Y and Z, and -(C 1 -to-C 10 alkyl), where -(C 1 -to-C 10 alkyl) is optionally substituted with one to six substituents selected from among R 10 , -NR 8 R 8' , -S(O) s R 8 , -S(O) t NR 8 R 8' , biaryl, -Q-aryl, -Q-heterocyclic, -Q-biaryl, -aryl-Q-aryr, -heterocyclic-Q-heterocyclic', -heterocyclic-Q-aryl and -aryl-Q-heterocyclic; each such aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X, Y
  • R 6' and R 7' and the nitrogen atom to which they are attached may form a 3- to 7-membered heterocyclic ring containing zero, one or two additional heteroatoms independently selected from -O-, -S(O) s - and -NR 8 -.
  • Each ring valency in the heterocyclic ring is substituted with a compatible radical which is -R 66 or -Q-R 66 , where R 66 is selected at each instance from the group consisting of hydrogen, R 10 ,-NR 8 R 8' , -S(O) s R 8 ,
  • each such aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X, Y and Z.
  • R 8 and R 8' in the above are independently selected at each instance from hydrogen; -R 10 other than halogen, -NO 2 or -N 3 ; -(C 1 -to-C 6 alkyl); -(C 2 -to-C 6 alkenyl) and -(C 3 -to-C 6 alkynyl).
  • Radicals -(C 1 -to-C 6 alkyl), -(C 2 -to-C 6 alkenyl) and -(C 3 -to-C 6 alkynyl) may in turn be optionally substituted with one to three substituents R 55 chosen from among amino, aryl, guanidino, heterocyclic, monoalkylamino, dialkylamino, acylamino, alkoxycarbonylamino, arylalkyloxycarbonylamino, aryloxycarbonylamino, acylguanidino, arylsulfonylguanidino, alkoxycarbonylguanidino, arylalkyloxycarbonylguanidino, aryloxycarbonylguanidino, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, N-alkylcarboxamido, N,N-dialkylcarboxamido, N-aryl
  • R 8 and R 8' and the nitrogen atom to which they are attached may form an optionally substituted 3- to 7-membered heterocyclic ring which includes zero, one or two additional heteroatoms independently chosen from -O-, -S(O) s - where s is zero, one or two, and -NR 8 -.
  • substituents (IV) and (V), -(C 2 -to-C 10 alkenyl) (which includes branched, unbranched, cyclic and bicyclic alkenyl) and -(C 3 -to-C 10 alkynyl) (which includes branched and cyclic alkynyl), are each optionally substituted with one to six substituents independently selected at each instance from R 10 , R 10' , heterocyclic, biaryl, -Q-aryl, -Q-heterocyclic, -Q-biaryl, -aryl-Q-aryl', -heterocyclic-Q-heterocyclic', -heterocyclic-Q-aryl and
  • aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X, Y and Z.
  • each such aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X', Y' and Z'.
  • the substituent D in the above formulae is selected from hydrogen, loweralkyl, phenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2-chloro-4-fluorophenyl and -C(O)R 9 , where R 9 is (a) hydrogen, (b) -OH, (c) -O M+, (d) -(C 1 -to-C 4 alkyl) where alkyl includes branching alkyl, (e) -(C 1 -to-C 4 alkoxy) where alkoxy includes branching alkoxy,
  • R 4 and R 5 are independently selected from among -hydrogen, -(C 1 -to-C 4 hydroxyalkyl), (g) -(C 1 -to-C 4 thioalkyl), (h) -(CH 2 ) nn -(phenyl) where nn is zero to four, (i) -(CH 2 ) n -NR 4 R 5 , (j) -(CH 2 ) m -(morpholino), (k) -NR 4 R 5 , (1) -C(O)NR 4 R 5 , (m) -C(O)OR 4 , (n) phenyl substituted with X, Y and Z, (o) -O-phenyl where phenyl is substituted with X, Y and Z, (p) -O-(CH2) m -(morpholino) or (q) -S-(CH 2 ) nn -(phenyl).
  • R 4 and R 5 are independently
  • G may be -NR 24 R 25 , where R 24 and R 25 and the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring including zero, one or two additional heteroatoms independently selected from -O-, -S(O) s - and -NR 8 -.
  • each ring valency is substituted with a compatible radical independently selected at each instance from -R 66 , -Q-R 66 , -R 67 and -Q-R 67 , where R 67 at each instance is independently (i) -CH(OR 12' )(OR 12" ) or
  • alkoxycarbonyl arylalkoxycarbonyl, aryloxycarbonyl or alkylsulfonyl.
  • the substituent G must be other than R 77 where R 77 is (i) -(C 1 -to-C 6 alkyl) optionally substituted with halogen, (ii) phenyl, (iii) benzyl or (iv) -(C3-to-C6 cycloalkyl).
  • R 2 is chosen from among hydrogen, -(CH0-C4 alkyl), phenyl, and benzyl.
  • E When E is -S-phenyl or -O-phenyl where phenyl is substituted with X, Y and Z, the substituent G must be other than -(C 1 -to-C 4 alkyl).
  • the substituent G When E is phenyl substituted with X, Y and Z, the substituent G must be other than -(C 1 -to-C 6 alkyl) optionally substituted with halogen, -(C 1 -to-C 6 alkenyl) optionally substituted with halogen, -(C 5 -to-C 6 cycloalkenyl), -(C 3 -to-C 6 cycloalkyl), -(phenyl)-R 76 , -(benzyl)-R 76 or -C(O)OR 77 .
  • R 76 is selected from -C(O)R 77 , -CN, -NO 2 , halogen and -NR 78 R 79 , where R 78 and R 79 are -(C 1 -to-C 6 alkyl) radicals which may be the same or different.
  • Representative of the compounds of the present invention are those selected from the group consisting of
  • 5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(5,6-dehydro-exo-2-norbomyl)amide
  • 5-Methyl-isoxazole-4-carboxylic acid ( ⁇ -alanine t-butyl ester)amide
  • Cinnamyl 5-methylisoxazole-4-carboxylate Cinnamyl 5-methylisoxazole-4-carboxylate
  • Cinnamyl 2-cyano-3-hydroxycrotonate Cinnamyl 2-cyano-3-hydroxycrotonate
  • N-N-Dimethylaminoethyl-2-cyano-3-hydroxycrotonamide N-[2-(1-Cyclohexenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
  • 5-Methyl-isoxazole-4-carboxylic acid (7-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)amide
  • 5-Methyl-isoxazole-4-carboxylic acid (6-methyl-1,2,3,4-tetrahydroquinolinyl)amide
  • Cinnamyl 5-methylisoxazole-4-carboxylate Cinnamyl 5-methylisoxazole-4-carboxylate
  • Cinnamyl 2-cyano-3-hydroxycrotonate Cinnamyl 2-cyano-3-hydroxycrotonate
  • compositions which comprise a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier.
  • a method of producing immunosuppression in a patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of the invention.
  • Preferred compounds of the present invention include those in which D is hydrogen or -C(O)R 9 , where R 9 is as described above.
  • E is -NR 14 R 15 , -OR 14 or -SR 14 , and especially those where E is -NR 14 R 15 .
  • Particularly preferred among these compounds are those in which R 14 is X'-,Y'- and Z'-substituted aryl, heterocyclic,
  • R 15 is hydrogen, -(C 1 -to-C 6 alkyl) or -(C 1 -to-C 6 haloalkyl).
  • R 15 is hydrogen, -(C 1 -to-C 6 alkyl) or -(C 1 -to-C 6 haloalkyl).
  • Other preferred compounds of the invention include those compounds in which G is hydrogen, -(C 1 -to-C 6 alkyl), -(C 1 -to-C 6 haloalkyl) or X-, Y- and Z-substituted phenyl, and especially where G is methyl.
  • acyl refers to a carbonyl group to which is appended an alkyl, heterocyclic or aryl residue where aryl, heterocyclic and alkyl have the definitions specified below.
  • alkenyl and “loweralkenyl” as used herein refer to a branched or straight chain comprising two to ten carbon atoms which also comprises one or more carbon-carbon double bonds.
  • alkoxy and loweralkoxy refer to a loweralkyl group, as defined below, attached to the remainder of the molecule through an oxygen atom.
  • Alkoxy and loweralkoxy groups include, for example, methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, rm-butoxy and the like.
  • alkoxycarbonyl refers to an alkoxy group, as previously defined, attached to the parent molecular moiety through a carbonyl, -C(O)-.
  • Alkoxycarbonyl includes, but is not limited to, ethoxycarbonyl, methoxycarbonyl, isopropoxycarbonyl and the like.
  • alkyl refers to a monovalent straight chain or branched chain group of one to twelve carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, sec-butyl, isobutyl, tert-butyl and the like.
  • alkylamino and loweralkylamino refers to a group having the structure -NH-(loweralkyl), where the loweralkyl portion is as defined below.
  • Alkylamino and loweralkylamino groups include, for example, methylamino, ethylamino, isopropylamino and the like.
  • amidoalkyl refers to a group having the structure
  • R 101 C(O) R 102 appended to a loweralkyl group, as previously defined.
  • the groups R 101 and R 102 are independently selected from hydrogen, lower alkyl, aryl, arylalkyl, and halosubstituted alkyl. Additionally, R 101 and R 102 , taken together, may optionally be -(CH 2 ) aa - where aa is an integer of from two to six.
  • aminoalkyl refers to a group having the structure
  • R ⁇ 03 and R 104 are independently selected from hydrogen, lower alkyl, aryl and arylalkyl.
  • R 103 and R 104 taken together, may optionally be -(CH 2 ) bb- where bb is an integer of from two to six.
  • aryl refers to substituted and unsubstituted carbocyclic aromatic groups including, but not limited to, phenyl, 1- or 2-naphthyl, fluorenyl,
  • arylalkyl refers to an aryl group, as previously defined, appended to an alkyl group including, but not limited to, benzyl, 1- and 2-naphthylmethyl, halobenzyl, alkoxybenzyl, hydroxybenzyl, aminobenzyl, nitrobenzyl, guanidinobenzyl, fluorenylmethyl, phenylmethyl(benzyl), 1-phenylethyl, 2-phenylethyl, 1-naphthylethyl and the like.
  • arylalkoxy refers to an arylalkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • Arylalkoxy includes, but is not limited to, benzyloxy, 2-phenethyloxy, 1-naphthylmethyloxy and the like.
  • arylalkoxycarbonyl refers to an arylalkyl group, as previously defined, attached to the parent molecular moiety through a carbonyl group, -C(O)-.
  • Arylalkoxycarbonyl includes, but is not limited to, benzyloxycarbonyl,
  • arylalkylamino refers to a group having the structure -NR 103 -(arylalkyl), where the arylalkyl portion is as previously defined.
  • arylalkylamino groups include benzylamino, 1-phenylethylamino and the like.
  • aryloxy refers to an aryl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • Aryloxy includes, but is not limited to, phenoxy, 1-naphthoxy, 2-naphthoxy and the like.
  • aryloxycarbonyl refers to an aryloxy group, as previously defined, attached to the parent molecular moiety through a carbonyl group, -C(O)-.
  • Aryloxycarbonyl includes, but is not limited to, phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like.
  • arylsulfonyl refers to an aryl group, as previously defined, attached to the parent molecular moiety through a sulfonyl group, -S(O)2-.
  • Arylsulfonyl includes, but is not limited to, benzenesulfonyl, 1- or 2-naphthylsulfonyl and the like.
  • biasing refers to a group where two substituted or unsubstituted aryl groups as defined above arc directly bound to each other including, but not limited to, biphenyl, 1-phenyl naphthyl, and the like.
  • bicycloalkyl refers to a ring system comprised of two fused cycloalkyl groups as defined below, including, but not limited to, norbornyl, norbornenyl and pinenyl.
  • (bicycloalkyl)alkyl refers to a bicycloalkyl group as defined above appended to a lower alkyl group including, but not limited to, norbomylmethyl and pinenylethyl .
  • carboxyalkyl refers to a carboxyl group, -CO 2 H, appended to a loweralkyl group, as previously defined.
  • cycloalkyl refers to cyclic groups of three to eight carbons including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • (cycloalkylalkyl) as used herein refers to a cycloalkyl group appended to a lower alkyl group including, but not limited to, cyclohexylmethyl and cyclohexylethyl.
  • R 105 , R 106 and R 107 are independently selected from hydrogen, lower alkyl, heterocyclic, aminoalkyl and aryl.
  • R 106 , and R 107 , taken together, may optionally be -(CH 2 ) cc - wherein cc is an integer of from two to six.
  • haloalkyl refers to alkyl groups as defined above containing one or more halogen atoms including, but not limited to, trifluoromethyl,
  • heterocyclic refers to any aromatic or non-aromatic 5-, 6- or 7-membered ring or a bi- or tricyclic group comprising fused five, six or seven-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds and each 6-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms as well as the carbon atoms may optionally be oxidized by unsaturation and/or introduction of hydroxy, thiol, oxo, thiooxo, (iii) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above heterocyclic rings may be fused to a benzene ring, and (v) Any carbon or heteroatom with suitable valence may bear a substituent.
  • heterocycles include, but are not limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, cytosinyl, thiocytosinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, xanthenyl, xanthonyl, xanthopterinyl, oxazoyl, oxazolidinyl, thiouracilyl, isoxazolyl, isoxazolidinyl, morpholinyl, indolyl, quinolinyl, uracilyl, urazolyl, uricyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl
  • ben-dmidazolyl benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl.
  • hydroxyalkyl and "hydroxyloweralkyl” as used herein refer to -OH appended to a loweralkyl group, as defined below.
  • hydroxy-protecting group refers to those groups which are known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable including, but not limited to, methylthiomethyl, tert-dimethylsilyl, tm-butyldiphenylsilyl, acyl substituted with an aromatic group and other groups found in Protective Groups in Organic Synthesis, 2nd Ed., Greene, T.W. John Wiley & Sons, New York, 1991.
  • loweralkyl refers to an alkyl group, as defined above, of one to eight carbon atoms.
  • thioalkoxy and thioloweralkoxy refer to a loweralkyl group, as previously defined, attached to the remainder of the molecule through a sulfur atom.
  • thioalkoxy and thioloweralkoxy groups include, but are not limited to, thiomethoxy, thioethoxy, thioisopropoxy, n-thiobutoxy, s-thiobutoxy, isothiobutoxy, f-thiobutoxy and the like.
  • thioalkoxyalkyl refers to a thioalkoxy group, as defined above, appended to a loweralkyl group.
  • thioarylalkoxy refers to an arylalkyl group, as previously defined, attached to the remainder of the molecule through a sulfur atom.
  • thioaryloxy refers to an aryl group, as defined above, attached to the remainder of the molecule through a sulfur atom.
  • salts refers to those carboxylate salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like
  • nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
  • ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like See, for example S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (1977) which is incorporated herein by reference.)
  • esters of the compounds of this invention include C 1 to C 6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C 5 -to-C 7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C 1 -to-C 6 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
  • Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C 1 -to-C 6 alkyl amines and secondary C 1 -to-C 6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 -to-C 3 alkyl primary amides and C 1 -to -C 2 dialkyl secondary amides are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • prodrugs of derivatives of compounds of the present invention may be prepared by any suitable method.
  • the condensation of the amino group with amino acids and peptides may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC (dicyclohexylcarbodiimede) method, the active ester method (p -nitrophenyl ester method, N-hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the DCC-HOBT (1-hydroxy-benzotriazole) method and the like.
  • Classical methods for amino acid condensation reactions are described in "Peptide Synthesis” Second Edition, M. Bodansky, Y.S. Klausner and M.A. Ondetti (1976).
  • the compounds of the invention possess immunomodulatory activity in animals.
  • immunosuppressants the compounds are expected to be useful in the treatment and/or prevention of rejection of transplanted organs or tissues, such as kidney, heart, lung, bone marrow, skin or cornea transplants, and also in the treatment or prevention of autoimmune, inflammatory, proliferative, and hypeiproliferative diseases, such as rheumatoid arthritis, lupus
  • erythematosus erythematosus, sytemic lupus erythematosus, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, Hashimoto's thyroiditis, nephrotic syndrome, psoriasis, atopical dermatitis, contact dermatitis, seborrheic dermatitis, graft-versus-host diseases by medulla ossium transplantation, vernal keratocojunctivitis, eczematous dermatises, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, alopecia areata and the like.
  • the compounds of this invention are also expected to find use in the treatment of reversible obstructive airways disease. Further, the compounds of this invention may be indicated in the treatment of diseases caused by intestinal inflammations and allergies, such as Coeliac disease, gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, and the like; and food-related allergic diseases which have symptoms remote from the gastrointestinal tract, as for example migraine, rhinitis, and eczema.
  • diseases caused by intestinal inflammations and allergies such as Coeliac disease, gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, and the like
  • food-related allergic diseases which have symptoms remote from the gastrointestinal tract, as for example migraine, rhinitis, and eczema.
  • Aqueous liquid compositions of the present invention may be particularly useful for the treatment and prevention of various diseases of the eye such as autoimmune diseases (including, for example, conical cornea, keratitis, dysophia epithelialis comeae, leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy) and rejection of corneal
  • autoimmune diseases including, for example, conical cornea, keratitis, dysophia epithelialis comeae, leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy
  • a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
  • the compound may be administered as pharmaceutical compositions containing the compound of interest in combination with one or more pharmaceutically acceptable excipients.
  • a "therapeutically effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat gastrointestinal disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder, activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • compositions of the present invention comprise a compound of the invention and a pharmaceutically acceptable carrier or excipient, which may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
  • pharmaceutically acceptable carrier is meant a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and mtraarticular injection and infusion.
  • compositions of this invention for parenteral injection include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • the absorption of the drug in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parcnterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,
  • polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye.
  • Compositions for topical administration may be prepared as a dry powder which may be pressurized or non-pressurized.
  • the active ingredient in finely divided form may be used in adinixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter.
  • suitable inert carriers include sugars such as lactose.
  • at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • the composition may be pressurized and contain a compressed gas, such as nitrogen or a liquified gas propellant.
  • a compressed gas such as nitrogen or a liquified gas propellant.
  • the liquified propellant medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent
  • the pressurized composition may also contain a surface active agent.
  • the surface active agent may be a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent It is preferred to use the solid anionic surface active agent in the form of a sodium salt.
  • a further form of topical administration is to the eye, as for the treatment of immune-mediated conditions of the eye such as automimmune diseases, allergic or inflammatory conditions, and comeal transplants.
  • the compound of the invention is delivered in a pharmaceutically acceptable ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the comeal and internal regions of the eye, as for example the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, choroid/retina and sclera.
  • the pharmaceutically acceptable ophthalmic vehicle may, for example, be an ointment, vegetable oil or an encapsulating material.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV, Academic Press, New York, N.Y. 0976), p. 33 et seq.
  • the compounds where E is -NR 14 R 15 or -OR 14 may be prepared via condensation of the corresponding isoxazole-4-carboxylic acid or activated derivative with commercially available amines or alcohols thereby providing the respective amide or ester analogs. Many of these materials are prepared from the corresponding isoxazole acid chloride with two equivalents of amine or with an alcohol and a base used as an acid scavenger. Isoxazole-4-carboxylic acids are prepared from commercially available ⁇ -dicarbonyl compounds according to published methods involving homologation of the active methvlene followed by hydroxylamine-mediated cyclization (Schenone etal.
  • Cleavage of the isoxazoles (I) to ring opened analogues (II) may be routinely done using an excess of aqueous sodium hydroxide in a hydroxylic solvent such as methyl or ethyl alcohol at temperatures ranging from ambient to reflux.
  • a hydroxylic solvent such as methyl or ethyl alcohol
  • the resulting hydroxycyanoacrylic acid derivatives are then purified, as for example via recrystallization or flash
  • reaction Scheme I Representative of the processes of the invention is reaction Scheme I presented below.
  • a ⁇ -dicarbonyl compound 1 is reacted with a trialkylorthoformate such as triethylorthoformate in acetic anhydride to give the alkoxymethylene-dicarbonyl compound 2.
  • a trialkylorthoformate such as triethylorthoformate in acetic anhydride
  • Treatment of 2 with hydroxylamine hydrochloride in an alcoholic solution gives the isoxazole carboxylic acid ethyl ester 3.
  • the desired regioisomer is separated, and the purified ester is hydrolyzed under acidic conditions to give the carboxylic acid 4.
  • the acid is activated, for example as the acid chloride 5 using thionyl chloride.
  • Compound 5 is then reacted with the appropriate amines to give carboxamides 6 or the appropriate alcohols to give esters 7.
  • Scheme III shows the ring opening of the isoxazole with base, for example, sodium hydroxide in an alcoholic solution to give the hydroxycyanoacrylic acid derivative 12.
  • 12 can be prepared by reaction of the corresponding cyanoacetyl precursor 14 with activated acid derivatives (e.g. an acid chloride) 13.
  • activated acid derivatives e.g. an acid chloride
  • Step B 5-Methyl-isoxazole-4-carboxylic acid 2-(4-trifluoromethylphenyl)ethylamide:
  • Cinnamyl 5-methylisoxazole-4- oil 69.12 5.39 5.76 69.15 5.48 5.53 carboxylate
  • Step A 4-(2-Methoxyethyl) isoxazole-4-carboxylic acid
  • Step B 4-(2-Methoxyethyl) isoxazole-4-carboxylic acid chloride
  • Step C N-(4-Trifluoromethylphenyl)-5-(2-methoxyethyl)isoxazole-4-carboxamide
  • HMLR human mixed lymphocyte reaction
  • the in vitro immunosuppressant activity of the compounds of the present invention was also determined in a one way allogeneic mixed leukocyte response (MLR) assay using rat lymph node and spleen cells, conducted as follows: Responder cells were obtained from the lymph nodes of Brown Norway rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) and the stimulator cells were isolated from the spleens of Lewis rats (Harlan Sprague Dawley, Inc., Indianapolis, IN). 200-250 gram rats were sacrificed by asphyxiation with CO 2 and the popliteal and mesenteric lymph nodes or spleen were removed by sterile dissection.
  • MLR mixed leukocyte response
  • the tissue was placed in RPMI 1640 supplemented with 10 % heat-inactivated fetal bovine serum, 2 mM L-glutamine, 50 ⁇ M 2-mercaptoethanol, 50 units/mL penicillin G, and 50 ⁇ g/mL streptomycin (complete RPMI medium). After mechanically disrupting the tissue and allowing debris to settle at 1 ⁇ g, the suspended cells were aspirated. The cell suspensions were centrifuged 10 min at 400 ⁇ g and the responder cells resuspended in complete RPMI medium at 2 X 10 6 cells/mL.
  • the spleen cells were suspended in 0.14 M NH4CI/0.017 M Tris-HCl lysing buffer, pH 7.4, for 2 minutes, mixed with RPMI 1640, and centrifuged as before. The spleen cells were subsequendy washed three times by centrifugation in RPMI 1640. To inhibit their ability to proliferate, spleen cells were suspended at 1 ⁇ 10 7 cells/mL in complete RPMI medium and incubated in the presence of 25 ⁇ g/mL of mitomycin C for 30 minutes at 37 °C. The mitomycin C-treated spleen cells were washed three times by centrifugation in RPMI 1640 before being suspended in complete RPMI medium at 4 ⁇ 10 6 cells/mL.
  • the cells were labeled with 0.5 ⁇ Ci per well of tritiated thymidine ( 3 H-TdR; DuPont NEN Research Products, Boston, MA). The cells were harvested by vacuum filtration onto glass fiber filters and the filter radioactivity measured with a MATRIX 9600 direct beta counter (Packard Instrument Company, Meriden, CT).

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Abstract

L'invention concerne des composés représentés par une formule choisie dans le groupe constitué de (I), (a) et (III) et leurs sels, esters et promédicaments pharmaceutiquement acceptables, dans laquelle E est choisi dans le groupe composé de -R?14, -NR14, -NR14R15, -SR14, -OR14¿, et -CR?14R15R16 et R14, R15 et R16¿ étant choisi parmi (I) hydrogène, (II) -NR6R7, (III) -(alkyle C¿1? à 10) substitué, (IV) -(alcényl C2 à C10) substitué, (V) -(alkynyle C3 à C10) substitué, (VI) aryle substitué, (VII) hétérocycle substitué, (VII) hétérocycle substitué, (VIII) biaryle substitué, (IX) aryle-hétérocylce substitué, (X) aryle-hétérocycle substitué, (X) Q-aryle substitué, (XI) Q-hétérocyle substitué, (XII) Q-biaryle substitué, (XIII) aryle-Q-aryle substitué, (XIV) hétérocycle -Q-hétérocyle substitué, (XV) hétérocycle -Q-aryle substitué et (XVI) aryle-Q-hétérocyle substitué ainsi que des compositions pharmaceutiques contenant lesdits composés et des méthodes d'utilisation thérapeutiques de ces derniers.
PCT/US1994/004045 1993-04-16 1994-04-14 Agents immunosuppresseurs Ceased WO1994024095A1 (fr)

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US5773476A (en) * 1994-03-07 1998-06-30 Sugen, Inc. Methods and compositions for inhibiting cell proliferative disorders
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US6387934B1 (en) 1996-09-12 2002-05-14 Aventis Pharma Deutschland Gmbh 2-Cyano-3,5-dihydroxyhex-2-enecarboxamide derivatives
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US6121316A (en) * 1996-09-12 2000-09-19 Hoechst Aktiengesellschaft 2-cyano-3,5-dihydroxyhex-2-enecarboxamide derivatives
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US6569874B1 (en) 1996-12-23 2003-05-27 Bristol-Myers Squibb Company Thiazoles as factor Xa inhibitors
US6187797B1 (en) * 1996-12-23 2001-02-13 Dupont Pharmaceuticals Company Phenyl-isoxazoles as factor XA Inhibitors
EP0946528B1 (fr) * 1996-12-23 2003-04-09 Bristol-Myers Squibb Pharma Company OXYGENE OU SOUFRE CONTENANT 5-COMPOSES DE HETERO-AROMATIQUES UTILISES COMME INHIBITEURS DU FACTEUR Xa
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EP0859000A1 (fr) * 1997-01-28 1998-08-19 Hoechst Aktiengesellschaft Dérivés d'isoxazole amide et d'amide crotonique, leur utilisation comme médicament et en diagnostic
WO1999037291A3 (fr) * 1998-01-23 1999-09-10 Bayer Ag Utilisation de sulfonamides substitues comme agents antiviraux et nouvelles substances
JP2003523309A (ja) * 1998-03-11 2003-08-05 オハイオ ステイト ユニバーシティ リサーチ ファウンデーション レフルノミド産物の抗ウイルス用途
US7691890B2 (en) 1998-03-11 2010-04-06 James W. Williams Anti-viral uses of leflunomide products
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