US20030171585A1 - Anti-inflammatory compounds - Google Patents

Anti-inflammatory compounds Download PDF

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US20030171585A1
US20030171585A1 US10/298,390 US29839002A US2003171585A1 US 20030171585 A1 US20030171585 A1 US 20030171585A1 US 29839002 A US29839002 A US 29839002A US 2003171585 A1 US2003171585 A1 US 2003171585A1
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hydrogen
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lower alkyl
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Malcolm Scott
Pauline Sanfilippo
Louis Fitzpatrick
Richard Cordova
Kevin Pan
Joseph Meschino
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Priority to US10/690,341 priority patent/US7141674B2/en
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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Definitions

  • This invention relates to triphenylpropanamide compounds which are useful in treating inflammations but which do not demonstrate the side effects normally associated with other anti-inflammatory treatments such as glucocorticoids
  • This invention also relates to methods for making and using the compounds of the invention.
  • Glucocorticoids are the only agents which reduce all the symptoms that are manifested in chronic adrenocortical disorder and hyperfunction, allergies, rheumatoid arthritis, lupus, inflammatory bowel disease, pneumonia, bronchial asthma, hematological disorders, dermatitis and eczema. Glucocorticoids also reduce immunological response in organ transplants. The undesired side effects of these agents include hypertension, atherosclerosis, diabetes, hyperglycemia, bone thinning and electrolyte imbalance.
  • glucocorticoids bind to the glucocorticoid receptor (GR) on the surface of leukocytes and the resulting glucocorticoid -GR complex migrates into the cell nucleus. There, the complex interacts with transcription factor AP-1 (activating protein-1), inhibiting its induction of genes that produce inflammatory cytokines and collagenase, thereby repressing the inflammatory process. However, the complex also activates GRE (glucocorticoid response element), a transcriptional activator of genes which are responsible for the undesirable side effects mentioned heretofore. The most desirable anti-inflammatory medication would inhibit AP-1 without activating GRE.
  • AP-1 transcription factor-1
  • GRE glucocorticoid response element
  • Steroids such as dexamethasone and prednisone have been found to exhibit potent antiinflammatory activity, but also exhibit the previously-mentioned side effects.
  • U.S. Pat. No. 3,941,833 (Gognaco) describes certain amino derivatives of 2,2-diarylcyclopropane. They are described as being useful for the treatment of disorders of the cardiovascular system. They are intended for systemic use. There is no indication in this patent that such compounds can or should be administered topically. Nor is there any indication that such compounds would be useful for treating inflammation of the skin.
  • German Patent No. 2,726,993 (Gognaco) describes 1-substituted 2,2-diphenylcyclopropanes. The patent indicates that they are useful as vasodilators and blood pressure lowering agents. They are intended for systemic use. There is no indication in this patent that such compounds can or should be administered topically. Nor is there any indication that such compounds would be useful for treating inflammation of the skin.
  • Falkenstein et al. describe certain phenylaziridine compounds in “Single electron transfer versus nucleophilic ring opening in reactions of cis-trans pairs of activated 2-phenylaziridines. Strong influence of nitrogen pyramid for N-benzoylaziridines.”, J. Org. Chem., 1993, 58, pp. 7377-7381.
  • Stamm et al. describe other aziridines in “Reactions with aziridines.53. Arene hydrides. 9. Intermediate substitution in the formation of a benzylic anion by an aromatic radical anion as observed with 1-benzoyl-2-phenylaziridine.” Chem. Ber., 1990, 123, pp. 2227-2230. Stamm et al. also described related aziridine structures in “Reductive ring opening of N-benzoylaziridine by anthracene hydride (anion of 9,10-dihydroanthracene) via base-induced fragmentation of the intermediate carbonyl adduct.” J. Org. Chem., 1989, 54, pp. 1603-1607. However, none of these publications describe the structures of this invention nor do they indicate that such compounds would be useful in treating inflammation.
  • Another object of this invention is to provide a method of treating inflammatory diseases in mammals by administration of the compounds of this invention.
  • This invention relates to novel non-steroidal small molecule organic compounds that exhibit the beneficial therapeutic properties of glucocorticoids, that may be free of glucocorticoid-like side effects, and which may have a high affinity for the human glucocorticoid receptor (hGR).
  • the compounds of this invention have the following structure (1):
  • X, R 1 , R 2 , R 3 , R 4 , R 5 , W, Y and Z are as defined hereinafter.
  • These compounds are useful in treating inflammatory diseases in humans and other mammals.
  • the compounds of the present invention may also be useful in the treatment of other disorders, such as chronic adrenocortical disorder and hyperfunction, allergies, rheumatoid arthritis, lupus, use as immunosuppressants in organ transplant, pneumonia, bronchial asthma, hematological disorders, dermatitis and eczema.
  • the present invention is also directed to pharmaceutical compositions containing the compounds of formula I and methods of treating inflammation and other conditions employing such compounds.
  • alkyl and alkoxy include straight and branched chains.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc.
  • Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Of course, if the alkyl or alkoxy substituent is branched there must be at least three carbon atoms in the group.
  • aryl as used herein along or in combination with other terms indicates aromatic hydrocarbon groups such as phenyl or naphthyl.
  • heteroaryl means aromatic groups, incorporating as part of the aromatic ring, 1 or 2 hetero atoms selected from any of S, O, or N.
  • substituents the term “independently” means that when more than one of such substituent is possible such substituents may be the same or different from each other.
  • X may be a single bond or is chosen from hydrogen, sulfur or NR 5 ; wherein R 5 is selected from the group consisting of: hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C 2 -C 6 ), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, or nitrile; phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile
  • X may further be selected from —(CH 2 ) n wherein n is an integer
  • R 1 is from one to three substituent groups each selected from the group consisting of lower alkyl (C 2 - C 6 ), lower alkoxy, hydroxy, halogen such as chlorine, fluorine, iodine or the like, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
  • R 2 is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C 2 - C 6 ), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; or a heteroaromatic ring such as substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or the like;
  • R 3 is chosen from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
  • Z is selected from the group consisting of carbonyl; carboxy; carbonylamino; or sulfone;
  • R 4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or the like or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole, pyridine or the like.
  • R 4 may be phenyl wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile.
  • the compounds of this invention have formula (I) above wherein X is hydrogen and Y is hydrogen. Also preferable are the compounds of this invention wherein R 1 is selected from the group consisting of hydrogen and halogen. More preferably, R 1 is fluorine.
  • the compounds of this invention have formula (I) above wherein X is hydrogen, Y is hydrogen, R 1 is selected from the group consisting of hydrogen and halogen and R 2 is selected from the group consisting of phenyl, halophenyl, or methylenedioxy. Most preferably, R 1 is fluorine or hydrogen and R 2 is 4-chlorophenyl, 4-Iodophenyl or 3,4-methylendioxyphenyl.
  • R 1 is selected from the group consisting of hydrogen and halogen
  • R 2 is selected from the group consisting of phenyl, halophenyl, or alkoxyphenyl
  • R 3 is selected from the group consisting of hydrogen and lower alkyl. Most preferably, R 3 is hydrogen.
  • R 1 is selected from the group consisting of hydrogen and halogen
  • R 2 is selected from the group consisting of phenyl and halophenyl
  • R 3 is selected from the group consisting of hydrogen and lower alkyl
  • Z is carbonyl.
  • R 4 is selected from the group consisting of straight-chain alkyl, phenyllower alkyl and heteroaromatic lower alkyl. Even more preferably R 4 is a heteroaromatic lower alkyl group. Most preferably, R 4 is 2-thiophenemethylene or 4-chlorophenylmethylene.
  • the compounds of this invention are useful in treating inflammatory diseases such as rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, dermatitis, and eczema. They may also be therapeutically beneficial in the treatment of other disorders including lupus, chronic adrenal disorder and hyperfunction, allergies, pneumonia, bronchial asthma, hematological disorders and as immunosuppressants in organ transplant. They may be administered topically or systemically.
  • the compounds of this invention have been found to bind to the hGR. However, because they differ in structure from glucocorticoids, they appear to bind selectively to the hGR, without binding to DNA and activating the GRE. This results in a potentially much lower incidence of side effects, and, consequently, longer periods of administration with greater overall efficacy and relief.
  • the compounds of this invention are optically active.
  • the beneficial therapeutic activity may reside with either enantiomer or they may be most active and advantageously utilized in racemic mixtures.
  • Examples of particularly preferred compounds include: 98, 29, 33, 72, 90, 96, 84, 80, 47, 97, 123, 127, 128, 132, 140, 141, 145, 147, 150, 153,165, 167, 173, 174, 175, 176, 177, 178, 179, and 180.
  • Exemplary compounds are as follows:
  • the compounds of this invention may also include the respective hydrates of compounds specifically identified herein.
  • Reaction Scheme 1 displays a method of making the compounds of formula 1, where R 1 -R 5 , W, X, Y and Z are as defined above.
  • a Reduction of A with LAH, NaBH 4 /BH 3 and the like leads to the formation of amines C.
  • nitrites of structure A when treated with diisobutylaluminum hydride (DiBAL), are converted to aldehydes of structure E.
  • DiBAL diisobutylaluminum hydride
  • Treatment of E with Rink resin affords resin-bound imines of structure F which are reduced with sodium triacetoxy borane to resin-bound imines of structure G.
  • Treatment of G with an appropriate acid in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (hereinafter referred to as “HATU”) and diisopropylethylamine (DIEA) affords compounds of structure I.
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • DIEA diisopropylethylamine
  • Compounds of structure I may also be prepared by the reaction of amines of structure H with appropriate carboxylic acids in the presence of resin-bound 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide which is prepared from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and Merrifield resin.
  • compositions of this invention one or more compounds or salts thereof of the invention, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
  • a pharmaceutical carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will preferably contain per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, from about 50 to about 100 mg of the active ingredient, although other unit dosages may be employed.
  • the compounds of this invention may also be applied or utilized topically.
  • the topically active composition of this invention may preferably be further composed of a pharmaceutically or cosmetically acceptable vehicle capable of functioning as a delivery system to enable the penetration of the topically active agent into the skin.
  • the topically active pharmaceutical or cosmetic composition may be optionally combined with other ingredients such as moisturizers, foaming agents, cosmetic adjuvants, anti-oxidants, surfactants, foaming agents, conditioners, humectants, fragrances, viscosifiers, buffering agents, preservatives, and the like in an amount which will not destroy the active ingredient in order to produce cosmetic or pharmaceutical products.
  • the topically active pharmaceutical or cosmetic composition should be applied in an amount effective to treat inflammation of mammalian skin.
  • amount effective shall mean an amount sufficient to ameliorate inflammation of mammalian skin.
  • a composition containing 0.001-10.0% of active agent is applied to the skin surface when amelioration of an inflammatory condition is desired.
  • a composition containing 0.05-5.0% of active agent is applied to the skin surface such that, based TABLE 1 Physical and Biological Properties of Triphenylpropylamine and Triphenylcyclopropyl amine Derivatives hPR hGR % inh cmp R 1 R 2 R 3 R 4 X Y Z mp, ° C.
  • 2,3,3-Triphenylpropionitrile (Hauser, C. R. et al., Formation and Preferential ⁇ -Alkylation of the Dicarbanion of 2,3,3-Triphenylpropionitrile by Means of Potassium Amide in Liquid Ammonia. J. Amer. Chem. Soc., 1959, 81, 4099-4102) was made as follows. A solution of phenylacetonitrile (1.00 g, 0.0086 mol) and THF (17 mL) was cooled to ⁇ 78° C.
  • 9H-(Fluoren-9-yl)phenylacetonitrile was prepared using the same procedure as that described in Example 1, however, 9-bromofluorene was substituted for diphenylmethylchloride. 9H-Fluoren-9-yl)phenylacetonitrile was obtained, having a melting point of 146-148.3° C.
  • 2-(2-Thienyl)-3,3-diphenylpropionitrile was made using the following procedure. To a mixture of 2-thiophenacetonitrile (16.30 g, 0.081 mol), benzyltriethylammonium chloride (0.185 g, 0.900081 mol), and 50% sodium hydroxide, diphenylmethylchloride (10.00 g, 0.081 mol) was added dropwise. This mixture was stirred for two hours at room temperature, heated at 40° C. for 30 minutes and then was treated with benzaldehyde (0,18 g, 0.0017 mol). The reaction mixture was poured into an ice-water mixture (200 ml) and extracted twice with dichloromethane.
  • 1,2,2-Triphenylcyclopropylnitrile was made using the procedure of C. R. Hauser, T. M. Harris, and T. G. Ledford [ J. Amer. Chem. Soc., 1959, 81, 4099-4102].
  • a solution of KNH 2 and liquid NH 3 was made by adding potassium (24.5 g, 0.63 mol) to liquid NH 3 (1500 ml).
  • 2,3,3-triphenylpropionitrile (87.5 g, 0.31 mol) was slowly added to the KNH 2 /NH 3 solution. After stirring for 10 minutes, this mixture was treated with a solution of dichloromethane (31.5 g, 0.37 mol) and diethyl ether (150 ml).
  • 2,3,3-Triphenylpropylamine was made according to the following procedure. A solution of 2,3,3-triphenylpropionitrile (10.00 g, 0.035 mol) and THF (80 ml) was added dropwise to a solution of LiAlH 4 (3.40 g, 0.089 mol) in THF (100 ml) at 0° C. The resulting mixture was stirred for 24 hours at room temperature and then refluxed for 24 hours. After cooling in an ice bath, the reaction mixture was treated with water (3.40 ml), 3N sodium hydroxide (10.20 ml) and water (3.4 ml) followed by the addition of magnesium sulfate.
  • 1,2,2-triphenylcyclopropylmethylamine was made using the procedure as set forth in Example 9, but substituting 1,2,2-Triphenylcyclopropylnitrile for 2,3,3-triphenylpropionitrile and diethyl ether for THF.
  • the end product was a white solid.
  • 2-(4-Iodophenyl)-3,3-diphenylpropylamine was made using the following procedure. A solution of TFA (3.30 g, 0.030 mol) and THF (10 ml) was slowly added to a slurry of sodium borohydrate (1.10 g, 0.029 mol) and THF (20 ml) at room temperature. After gas evolution ceased, the reaction was stirred for fifteen minutes and then treated dropwise with a solution of 2-(4-Iodophenyl)-3,3-diphenylpropionitrile (4,87 g, 0.012 mol) and THF (20 ml). After stirring overnight at room temperature, water was added slowly followed by dichloromethane (40 ml).
  • Compound 29 was made in accordance with the following procedure. A solution of thiopheneacetyl chloride (0.281 g, 0.0017 mol) and ethylene dichloride (8.0 ml) was added slowly to an icecooled mixture of 2,3,3-Triphenylpropylamine (0.50 g, 0.0017 mol), sodium acetate (0.18 g, 0.0022 mol) and ethylene chloride (8.0 ml). After stirring overnight at room temperature, water was added with thorough mixing. The resulting organic layer was separated, washed successively with 1N sodium hydroxide solution and 1N hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated to an oil which solidified. Two recrystallizations of this material afforded 0.410 g (59%) of 29 as a crystalline solid, having a melting point of 130-132° C.
  • Compound 80 was made using the following procedure: A solution of 2-chlorphenylacetic acid (0.289 g, 0.0017 mol), 1,1′-carbonyldiimidazole (0.271 g, 0.0017 mol) and acetonitrile (25 ml) was stirred for twenty minutes at room temperature and treated with 1,2,2-triphenylcyclopropylmethylamine (0.500 g, 0.0017 mol). After stirring for 24 hours, the reaction was evaporated and the residue dissolved in methylene dichloride. This solution was washed with water (10 ml), 1N HCl (10 ml), and water (10 ml). The organic layer was separated, dried over magnesium sulfate, filtered, and evaporated to an oil.
  • Compound 66 was made as follows: A solution of phenyl acetic acid (0.30 g, 0.0024 mol), 2-(9H-[Fluoren-9-yl])-2-(phenyl)ethylamine (0.70 g, 0.0024 mol), and ethylene dichloride (10 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbondiimide hydrochloride (0.55 g, 0.0029 mol). After stirring overnight, the reaction solution was washed with 3N sodium hydroxide, 6N HCl and saturated NaCl solution. The organic layer was separated, dried over magnesium sulfate and evaporated to a semi-solid.
  • Compound 52 was made in accordance with the following procedure: A solution of 2,3,3-Triphenylpropylamine (0.25 g, 0.0009 mol) and methylene dichloride (25 ml) was treated with 2-chlorophenyl isocyanate (0.13 g, 0 0009 mol) at room temperature. A solid formed which was filtered and recrystallized from methanol-hexane to give 0.14 g (75%) of 52 as a white crystalline solid having a melting point of 210-211° C.
  • Compound 40 was made as follows: An ice-cooled solution of 2,3,3-triphenylpropylamine (0.674 g, 0.0024 mol) and CHCl 3 (20 ml) was treated with 2-thiophenesulfonyl chloride (0.475 g, 0.0026 mol) followed by diisopropylethylamine (0.764 g, 0.0059 mol) and stirred at room temperature overnight. The reaction was washed with 1 N HCl (20 ml) and saturated NaCl solution. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated affording 0.660 g (66%) of 40 as a solid having a melting point of 169-170.9° C.
  • Compound 17 was made as follows: A mixture of N-[3,3-bis-(4-fluorophenyl)-2-phenylpropyl]-2-phenylacetamide [Compound 18] (0.84 g, 0.0019 mol), dimethylsulfate (0.37 g, 0.0029 mol), benzyltriethylammonium chloride (0.14 g, 0.00075 mol), 50% NaOH (30 ml) was stirred overnight at room temperature. Water was added and the mixture was extracted with ethylene dichloride.
  • Compound 98 was prepared as follows: A mixture of 2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine (18.0 g, 0.055 mol) and anhydrous THF (120 mL) at ⁇ 70° C. was treated dropwise with a 1.0M solution of DiBAL (100 mL, 0.110 mol). The reaction was stirred for 1 hour at ⁇ 70° C. and then at 25° C. for 1.5 hours. The reaction was cooled to 0° C. and treated with ethanol (20 mL) followed by 10% aqueous HCl (150 mL).
  • the resulting resin was shaken with NaBH(Oac) 3 (4.63 g, 0.022 mol), acetic acid (1.83 mL) and dichloroethane (60 mL) for two days.
  • the resulting resin was washed with methanol, methylene chloride, 10% acetic acid/methylene chloride, 10% triethylamine/methylene chloride, methylene chloride, and methanol.
  • This resin (0.235 g, 0.0001 mol) was shaken for 2 days with HATU (0.090 g, 0.00024 mol), diisopropylethylamine, (175 ⁇ L), 4-chlorophenylacetic acid (0.085 g, 0.0005 mol), and DMF (2 mL).
  • Compound 162 was prepared as follows: A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.67 g, 0.040 mol) and methylene chloride (300 mL) was washed with 10% NH 4 OH, dried over MgSO 4 , filtered and evaporated. The residue was dissolved in DMF (100 mL) and mixed with Merrifield resin (20.0 g, 0.020 mol) at 100° C. overnight. The mixture was filtered and the resin was washed with DMF, methanol, and methylene chloride.
  • a human glucocorticoid receptor binding assay was carried out to determine the extent to which the compounds of this invention have the ability to bind to human glucocorticoid receptors. This binding ability may be indicative of the antiinflammatory activity of the compound. The test was carried out as follows.
  • Human glucocorticoid receptors were prepared from either insect cells (Sf21) infected with baculovirus hGR or from a lymphoblast cell line which expresses high levels of endogenous hGR (IM9)
  • the receptor binding reactions, with or without test compounds, were set up in 96-well microtiter plates which were previously siliconized with SIGMACOTETM, a chlorinated organopolysiloxane in heptane.
  • the binding components, 3(H) Triamcinolone acetonide (TAA), glycerol/molybdate-containing buffer and unlabeled compounds were added to the wells using a combination of BIOMEK laboratory automation system and repeat pipettes.
  • TAA Triamcinolone acetonide
  • glycerol/molybdate-containing buffer unlabeled compounds
  • a human progesterone receptor binding assay was performed in order to determine selectivity of the compounds, as follows.
  • Human progesterone receptors were prepared from either insect cells (SF21) infected with baculovirus hPR A, or from a breast cancer cell line, T47D, which expresses high levels of endogenous hPR.
  • the receptor binding reactions, with or without test compounds, were set up in 96-well microtiter plates which were previously siliconized with SIGMACOTE.
  • the binding components 3(H) R5020 Promegestone, a high affinity ligand for the progesterone receptors, glycerol/molybdate-containing buffer and unlabeled compounds were added to the wells using a combination of BIOMEK laboratory automation system and repeat pipettes. After overnight incubation, the samples were precipitated with polyethylene glycol and filtered through Whatman GF/F paper using a TOMTEK cell harvester The filter mate with 96 samples were bound to a solidphase scintillant and directly counted in the BETAPLATE counter. Only those compounds that were active in the human glucocorticoid receptor assay set forth in Example 30 were used for progesterone receptor binding to determine cross-reactivity profiles, if any.
  • test compounds to displace 3(H) R5020 binding to hPR is expressed as percent inhibition at the two concentrations, 10 ⁇ 6 and 10 ⁇ 5 Molar. Those compounds that do not inhibit 3(H) TM binding by 50% at 10 ⁇ 5 M were not considered active. Surprisingly, the compounds of this invention selectively bind to the hGR but show little or no affinity for the hPR.
  • triphenylpropanamide compounds of this invention having varying affinities for the human glucocorticoid receptor, were tested for topical antiinflammatory activity in mouse ear inflammation models.
  • Compounds with low receptor affinity (IC 50 >20 nM) were weakly active or inactive at reducing ear inflammation induced by the contact sensitizer oxazolone.
  • Compounds having receptor affinities doser to hydrocortisone were as nearly active as hydrocortisone in suppressing mouse oxazolone-induced contact hypersensitization (MOCH) and phorbol ester-induced ear edema.
  • MOCH mouse oxazolone-induced contact hypersensitization
  • phorbol ester-induced ear edema The in vivo studies of this example were conducted as follows.
  • Albino male CD-1 mice 7-9 weeks old were used in this example.
  • a 0.005% (w/v) TPA or 20% (w/v) arachidonic acid (AA) solution was made in acetone.
  • a 20 ⁇ l volume of the TPA or M was applied to the dorsal left ear of the mouse.
  • Compounds of this invention were placed in a composition containing ethanol/propylene glycol at a ratio of 70:30 were applied to the left ear of each mouse in an amount of 20 ⁇ l immediately after application of the TPA or AA. The right ear was not treated.
  • mice were sacrificed by carbon dioxide inhalation 5.5 hours after administration of TPA and one hour after administration of AA, the left and right ears were removed and a 7 mm biopsy was removed from each ear and weighed. The difference in biopsy weights between the right and left ears was calculated. Antiinflammatory effects of compounds were evident as an inhibition of the increase in ear weight.
  • mice were sacrificed by carbon dioxide inhalation 24 hours after oxazolone challenge, the left and right ears were removed and a 7 mm biopsy was removed from each ear and weighed. The difference in biopsy weights between the right and left ears was calculated. Antiinflammatory effects of compounds were evident as an inhibition of the increase in ear weight.
  • triphenylpropanamides are topically active as antiinflammatory agents. Because of their selective effects on transcription factors, they should not cause the side effects known to be associated with classical glucocorticoids. In addition to inflammation, the triphenylpropanamides of this invention may be useful as therapeutics in other glucocorticoid-responsive skin conditions.

Abstract

This invention relates to anti-inflammatory compounds, methods of making such compounds and methods of using such compounds having the following structure:
Figure US20030171585A1-20030911-C00001

Description

    BACKGROUND OF THE INVENTION
  • 1. Field of Invention [0001]
  • This invention relates to triphenylpropanamide compounds which are useful in treating inflammations but which do not demonstrate the side effects normally associated with other anti-inflammatory treatments such as glucocorticoids This invention also relates to methods for making and using the compounds of the invention. [0002]
  • 2. Prior Art [0003]
  • Glucocorticoids are the only agents which reduce all the symptoms that are manifested in chronic adrenocortical disorder and hyperfunction, allergies, rheumatoid arthritis, lupus, inflammatory bowel disease, pneumonia, bronchial asthma, hematological disorders, dermatitis and eczema. Glucocorticoids also reduce immunological response in organ transplants. The undesired side effects of these agents include hypertension, atherosclerosis, diabetes, hyperglycemia, bone thinning and electrolyte imbalance. [0004]
  • Mechanistically, glucocorticoids bind to the glucocorticoid receptor (GR) on the surface of leukocytes and the resulting glucocorticoid -GR complex migrates into the cell nucleus. There, the complex interacts with transcription factor AP-1 (activating protein-1), inhibiting its induction of genes that produce inflammatory cytokines and collagenase, thereby repressing the inflammatory process. However, the complex also activates GRE (glucocorticoid response element), a transcriptional activator of genes which are responsible for the undesirable side effects mentioned heretofore. The most desirable anti-inflammatory medication would inhibit AP-1 without activating GRE. [0005]
  • Steroids, such as dexamethasone and prednisone have been found to exhibit potent antiinflammatory activity, but also exhibit the previously-mentioned side effects. [0006]
  • Heretofore, there has been no antiinflammatory agent found which does not cause side effects. Thus, new chemical agents are needed which would have the desired antiinflammatory effect without causing the side effects mentioned above. [0007]
  • Prior art compounds which relate to the triphenylcyclopropyl and triphenylpropyl compounds of the invention are as follows: U.S. Pat. No. 3,941,833 (Gognaco) describes certain amino derivatives of 2,2-diarylcyclopropane. They are described as being useful for the treatment of disorders of the cardiovascular system. They are intended for systemic use. There is no indication in this patent that such compounds can or should be administered topically. Nor is there any indication that such compounds would be useful for treating inflammation of the skin. [0008]
  • Gilbert, et al. in [0009] J. Med. Chem. 1983, 26, 693-699 report triphenylpropylidene amines and nitriles as inhibitors of prostaglandin synthetase
  • Blank et al. in [0010] J. Med. Chem. 1969, 12, 873-876 describe the inhibition by 2,3,3-triphenylpropylamines of the biosynthesis of aldosterone without altering deoxycorticosterone or corticosterone levels.
  • Schultz et al. in [0011] J. Med. Chem. 1967, 10, 717-724 describe diphenylpropanamides which are hypocholesteremic in rats and inhibit penicillin excretion in dogs.
  • Burch et al. in [0012] Proc. Natl. Acad. Sci. USA 1991, 88, 355-359 describe fluorenyl propanamides which inhibit localized inflammatory reactions in mice.
  • German Patent No. 2,726,993 (Gognaco) describes 1-substituted 2,2-diphenylcyclopropanes. The patent indicates that they are useful as vasodilators and blood pressure lowering agents. They are intended for systemic use. There is no indication in this patent that such compounds can or should be administered topically. Nor is there any indication that such compounds would be useful for treating inflammation of the skin. [0013]
  • Belgian patent No. BE 855689 (Hexachemie S. A. Fr.) describes 2,2-diphenylcyclopropylmethylamides with vasodilator activity. [0014]
  • Precigoux, et al. describe the compound 4,4′-(3-Acetemido-2-phenylpropylidene) diphenol diacetate in [0015] Acta Crystallogr., Sect. C: Cryst. Struct. Commun., C41 (8), 1985, pp. 1244-1246.
  • Falkenstein et al. describe certain phenylaziridine compounds in “Single electron transfer versus nucleophilic ring opening in reactions of cis-trans pairs of activated 2-phenylaziridines. Strong influence of nitrogen pyramid for N-benzoylaziridines.”, [0016] J. Org. Chem., 1993, 58, pp. 7377-7381.
  • Stamm et al. describe other aziridines in “Reactions with aziridines.53. Arene hydrides. 9. Intermediate substitution in the formation of a benzylic anion by an aromatic radical anion as observed with 1-benzoyl-2-phenylaziridine.”[0017] Chem. Ber., 1990, 123, pp. 2227-2230. Stamm et al. also described related aziridine structures in “Reductive ring opening of N-benzoylaziridine by anthracene hydride (anion of 9,10-dihydroanthracene) via base-induced fragmentation of the intermediate carbonyl adduct.” J. Org. Chem., 1989, 54, pp. 1603-1607. However, none of these publications describe the structures of this invention nor do they indicate that such compounds would be useful in treating inflammation.
  • Therefore, it is an object of this invention to provide one or more compounds capable of treating inflammatory diseases. [0018]
  • It is a further object of this invention to provide compounds capable of treating inflammatory diseases without causing side effects similar to those caused by glucocorticoids. [0019]
  • It is yet another object of this invention to provide a method of making compounds for treating inflammatory diseases. [0020]
  • Another object of this invention is to provide a method of treating inflammatory diseases in mammals by administration of the compounds of this invention. [0021]
    • SUMMARY OF THE INVENTION
  • This invention relates to novel non-steroidal small molecule organic compounds that exhibit the beneficial therapeutic properties of glucocorticoids, that may be free of glucocorticoid-like side effects, and which may have a high affinity for the human glucocorticoid receptor (hGR). The compounds of this invention have the following structure (1): [0022]
    Figure US20030171585A1-20030911-C00002
  • wherein X, R[0023] 1, R2, R3, R4, R5, W, Y and Z are as defined hereinafter. These compounds are useful in treating inflammatory diseases in humans and other mammals. The compounds of the present invention may also be useful in the treatment of other disorders, such as chronic adrenocortical disorder and hyperfunction, allergies, rheumatoid arthritis, lupus, use as immunosuppressants in organ transplant, pneumonia, bronchial asthma, hematological disorders, dermatitis and eczema. The present invention is also directed to pharmaceutical compositions containing the compounds of formula I and methods of treating inflammation and other conditions employing such compounds.
  • As used herein unless otherwise noted, alkyl and alkoxy, whether used along or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Of course, if the alkyl or alkoxy substituent is branched there must be at least three carbon atoms in the group. [0024]
  • The term “aryl” as used herein along or in combination with other terms indicates aromatic hydrocarbon groups such as phenyl or naphthyl. The term heteroaryl means aromatic groups, incorporating as part of the aromatic ring, 1 or 2 hetero atoms selected from any of S, O, or N. With reference to substituents, the term “independently” means that when more than one of such substituent is possible such substituents may be the same or different from each other. [0025]
    • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • The present invention is directed to compounds of the general formula I: [0026]
    Figure US20030171585A1-20030911-C00003
  • X may be a single bond or is chosen from hydrogen, sulfur or NR[0027] 5; wherein R5 is selected from the group consisting of: hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, or nitrile; phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile X may further be selected from —(CH2)n wherein n is an integer from 1 to 3; —HC═CH—; and —CHxW wherein W may be oxygen, sulfur or NF5. Of course when X is hydrogen, it does not represent a connection between the phenyl rings;
  • wherein R[0028] 1 is from one to three substituent groups each selected from the group consisting of lower alkyl (C2- C6), lower alkoxy, hydroxy, halogen such as chlorine, fluorine, iodine or the like, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
  • wherein R[0029] 2 is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C2- C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; or a heteroaromatic ring such as substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or the like;
  • wherein Y is —CH[0030] 2 or hydrogen;
  • wherein R[0031] 3 is chosen from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
  • wherein Z is selected from the group consisting of carbonyl; carboxy; carbonylamino; or sulfone; and [0032]
  • wherein R[0033] 4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or the like or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole, pyridine or the like. When X is hydrogen, S or NR5, R4 may be phenyl wherein said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile.
  • Preferably, the compounds of this invention have formula (I) above wherein X is hydrogen and Y is hydrogen. Also preferable are the compounds of this invention wherein R[0034] 1 is selected from the group consisting of hydrogen and halogen. More preferably, R1 is fluorine.
  • More preferably, the compounds of this invention have formula (I) above wherein X is hydrogen, Y is hydrogen, R[0035] 1 is selected from the group consisting of hydrogen and halogen and R2 is selected from the group consisting of phenyl, halophenyl, or methylenedioxy. Most preferably, R1 is fluorine or hydrogen and R2 is 4-chlorophenyl, 4-Iodophenyl or 3,4-methylendioxyphenyl.
  • Also preferable are compounds of formula (I) wherein X is hydrogen, Y is hydrogen, R[0036] 1 is selected from the group consisting of hydrogen and halogen, R2 is selected from the group consisting of phenyl, halophenyl, or alkoxyphenyl and R3 is selected from the group consisting of hydrogen and lower alkyl. Most preferably, R3 is hydrogen.
  • Another preferable group of compounds of formula (I) are those wherein X is hydrogen, Y is hydrogen, R[0037] 1 is selected from the group consisting of hydrogen and halogen, R2 is selected from the group consisting of phenyl and halophenyl, R3 is selected from the group consisting of hydrogen and lower alkyl and Z is carbonyl. Preferably, R4 is selected from the group consisting of straight-chain alkyl, phenyllower alkyl and heteroaromatic lower alkyl. Even more preferably R4 is a heteroaromatic lower alkyl group. Most preferably, R4 is 2-thiophenemethylene or 4-chlorophenylmethylene.
  • The compounds of this invention are useful in treating inflammatory diseases such as rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, dermatitis, and eczema. They may also be therapeutically beneficial in the treatment of other disorders including lupus, chronic adrenal disorder and hyperfunction, allergies, pneumonia, bronchial asthma, hematological disorders and as immunosuppressants in organ transplant. They may be administered topically or systemically. [0038]
  • The compounds of this invention have been found to bind to the hGR. However, because they differ in structure from glucocorticoids, they appear to bind selectively to the hGR, without binding to DNA and activating the GRE. This results in a potentially much lower incidence of side effects, and, consequently, longer periods of administration with greater overall efficacy and relief. [0039]
  • The compounds of this invention are optically active. The beneficial therapeutic activity may reside with either enantiomer or they may be most active and advantageously utilized in racemic mixtures. [0040]
  • Examples of particularly preferred compounds include: 98, 29, 33, 72, 90, 96, 84, 80, 47, 97, 123, 127, 128, 132, 140, 141, 145, 147, 150, 153,165, 167, 173, 174, 175, 176, 177, 178, 179, and 180. Exemplary compounds are as follows: [0041]
  • N-(2-thiophene)acetyl-2,3,3-triphenylpropylamine. [0042]
  • N-(5-methylthiophene)acetyl-2-phenyl-3,3-bis(4-fluorophenyl)propylamine. [0043]
  • N-(3-indolyl)acetyl-2,3,3-triphenylpropylamine. [0044]
  • N-(2-carbonyl-5methylthiophene)-2-(9H-fluoreny-9-yl)-2-phenylethylamine. [0045]
  • N-(2-chlorophenyl)acetyl-1,2,2-triphenylcyclopropylmethylamine. [0046]
  • N-(2-thienyl)carbonyl-1,2,2-triphenylcyclopropylmethylamine. [0047]
  • N-(phenyloxy)carbonyl-1,2,2-triphenylcyclopropylmethylamine. [0048]
  • N-(4-chlorophenyloxy)carbonyl-1,2,2-triphenylcyclopropylmethylamine. [0049]
  • N-(2-pyridine)acetyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine. [0050]
  • N-(4-n-butoxyphenyl)acetyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine. [0051]
  • N-(2,4-difluorophenyl)acetyl-2-(3,4methylenedioxyphenyl)-3,3-diphenylpropylamine. [0052]
  • N-(2-thiophene)carbonyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine. [0053]
  • N-(3-cyanophenyl)acetyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine. [0054]
  • N-(2,4-difluorophenyl)carbonyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine. [0055]
  • N-(4-fluorophenyl)acetyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine. [0056]
  • N-(4,5-dichlorophenyl)carbonyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine. [0057]
  • N-(phenyl)acetyl-2-(4-trifuoromethylphenyl)-3,3-diphenylpropylamine. [0058]
  • N-(5-chloro-2-benzothiophene)acetyl-2-(4-trifuoromethylphenyl)-3,3-diphenylpropylamine. [0059]
  • N-(2,4-difluorophenyl)carbonyl-2-(4-trifluoromethylphenyl)-3,3-diphenylpropylamine. [0060]
  • N-(4-trifuoromethylphenyl)acetyl-2-(4-trifluoromethylphenyl)-3,3-diphenylpropylamine. [0061]
  • N-(phenyl)acetyl-2-(4-trifluoromethylphenyl)-3,3-diphenylpropylamine. [0062]
  • N-(4-fluorophenyl)acetyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine. [0063]
  • N-(3,5-bis-trifluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine. [0064]
  • N-(4-chlorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine. [0065]
  • N-(3,4-dichlorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine. [0066]
  • N-(2-fluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine. [0067]
  • N-(2-fluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylamine. [0068]
  • N-(4-fluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine. [0069]
  • N-(4-trifluoromethylphenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine. [0070]
  • N-(3,5-bistrifluoromethylphenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine. [0071]
  • N-(2-thiophene)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine. [0072]
  • N-(5-methyl-2-thiophene)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine. [0073]
  • N-(4-chlorophenyl)carbonyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine. [0074]
  • N-(2-propyl)carbonyl-1,2,2-triphenylcyclopropylmethylamine.[0075]
  • The compounds of this invention may also include the respective hydrates of compounds specifically identified herein. [0076]
  • The compounds of formula I may be prepared according to the following reaction schemes. [0077]
  • Reaction Scheme 1 displays a method of making the compounds of formula 1, where R[0078] 1-R5, W, X, Y and Z are as defined above. Treatment of a suitable substituted or unsubstituted diphenyl methyl-, fluorenyl-, or 10,11-dihydro-5H-dibenzo[1,d]cyclohepten-4-yl chloride or bromide with an aryl- or heteroaryl acetonitrile using n-BuLi and the like or phase-transfer conditions, afford nitrile intermediates of structure A Reduction of A with LAH, NaBH4/BH3 and the like leads to the formation of amines C. Treatment of structure A with methylene chloride in the presence of potassium amide/liquid ammonia leads to the formation of structure B. Reduction of the nitrile group of structure B with LAH, NaBH4/BH3 and the like leads to an amine of structure D. By reacting C or D with acid chlorides as set forth below in Scheme I in combination with bases such as NaOAc and the like, organic acids in combination with activating agents such as 1,1′-carbonyldiimidazole and the like, sulfonyl chlorides, chloroformates, isocyanates, isothiocyanates, or a suitable organic sulfonyl chloride, compounds of structure I are obtained. Optionally, nitrites of structure A, when treated with diisobutylaluminum hydride (DiBAL), are converted to aldehydes of structure E. Treatment of E with Rink resin affords resin-bound imines of structure F which are reduced with sodium triacetoxy borane to resin-bound imines of structure G. Treatment of G with an appropriate acid in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (hereinafter referred to as “HATU”) and diisopropylethylamine (DIEA) affords compounds of structure I. Compounds of structure I may also be prepared by the reaction of amines of structure H with appropriate carboxylic acids in the presence of resin-bound 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide which is prepared from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and Merrifield resin.
    Figure US20030171585A1-20030911-C00004
    Figure US20030171585A1-20030911-C00005
  • To prepare the pharmaceutical compositions of this invention, one or more compounds or salts thereof of the invention, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations, such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will preferably contain per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, from about 50 to about 100 mg of the active ingredient, although other unit dosages may be employed. The compounds of this invention may also be applied or utilized topically. If the delivery parameters of the topically active pharmaceutical or cosmetic agent so require, the topically active composition of this invention may preferably be further composed of a pharmaceutically or cosmetically acceptable vehicle capable of functioning as a delivery system to enable the penetration of the topically active agent into the skin. In alternative embodiments, the topically active pharmaceutical or cosmetic composition may be optionally combined with other ingredients such as moisturizers, foaming agents, cosmetic adjuvants, anti-oxidants, surfactants, foaming agents, conditioners, humectants, fragrances, viscosifiers, buffering agents, preservatives, and the like in an amount which will not destroy the active ingredient in order to produce cosmetic or pharmaceutical products. [0079]
  • The topically active pharmaceutical or cosmetic composition should be applied in an amount effective to treat inflammation of mammalian skin. As used herein “amount effective” shall mean an amount sufficient to ameliorate inflammation of mammalian skin. A composition containing 0.001-10.0% of active agent is applied to the skin surface when amelioration of an inflammatory condition is desired. Preferably, a composition containing 0.05-5.0% of active agent is applied to the skin surface such that, based [0080]
    TABLE 1
    Physical and Biological Properties of Triphenylpropylamine
    and Triphenylcyclopropyl amine Derivatives
    Figure US20030171585A1-20030911-C00006
    hPR
    hGR % inh
    cmp R1 R2 R3 R4 X Y Z mp, ° C. IC50 (nM) 10 μM
    1 H Ph H PhCH2 H, H H, H CO 146.0-147.0 890 −0.2
    2 H Ph H 2-ClPhCH2 H, H H, H CO 140.5-141.2 134 −23
    3 H Ph H 4-ClPhCH2 H, H H, H CO 168.4-170.9 480 4
    4 H Ph H 4-MePhCH2 H, H H, H CO 142.3-143.6 528 12
    5 H Ph H 2-MeOPhCH2 H, H H, H CO 156.9-158.9 62%
    6 H Ph H 4-MeOPhCH2 H, H H, H CO 157-159 910
    7 H Ph H 3,4-MeOPhCH2 H, H H, H CO   123-124.5 910 11.6
    8 H Ph H 2,6-diClPhCH2 H, H H, H CO 165.2-166.5 340 3
    9 H Ph H 3,4-diClPhCH2 H, H H, H CO 65-68 1480
    10 H Ph H 2-CF3PhCH2 H ,H H, H CO   109-111.5 780 15
    11 H Ph H 3-CF3PhCH2 H, H H, H CO 108.8-111.3 830 20
    12 H Ph H 4-CF3PhCH2 H, H H, H CO 119.5-120.3 1500 15
    13 H Ph H Ph2CH H, H H, H CO 178.7-179.8 780
    14 H 4-ClPh H PhCH2 H, H H, H CO 151.5-152.7 72 18
    15 4-F Ph H PhCH2 H, H H, H CO 87.5-89.7 21
    16 4-F Ph H 2-ClPhCH2 H, H H, H CO 127.3-129.4 45
    17 4-F Ph Me PhCH2 H, H H, H CO 86.9-88.2
    18 H Ph H Ph H, H H, H CO 161.5-163   610 14.1
    19 H Ph H Ph(CH2)2 H, H H, H CO 107.4-109.0 141 24
    20 H Ph H 2-MeOPh(CH2)2 H, H H, H CO 137-140 58 9
    21 H 4-ClPh H 2-MeOPh(CH2)2 H, H H, H CO 122.2-123.5 57 21
    22 H Ph H 2-ClPh(CH2)2 H, H H, H CO 135.0-135.8 103
    23 4-F Ph H 2-MeOPh(CH2)2 H, H H, H CO 78.9-80.9 22
    24 H Ph H Ph(CH2)3 H, H H, H CO 78.1-81.0 670 10
    25 H Ph H PhCH2 H, H H, H SO2 172.9-174.2 210
    26 H Ph H 4-MePh H, H H, H SO2 139.7-142.1 175
    27 H Ph H PhSO2CH2 H, H H, H CO 186.9-187.5 67
    28 H Ph H 4-MePhSO2CH2 H, H H, H CO 190.3-191.9 57
    29 H Ph H 2-thiopheneCH2 H, H H, H CO 130-132 8 28.3
    (+) (+) 24
    (−) (−) >800
    30 H Ph H 5-Me-2-thiophene H, H H, H CO 183.5-185   50
    31 4-F Ph H 2-thiopheneCH2 H, H H, H CO 84.9-85.3 8
    32 4-F Ph H 5-Me-2- H, H H, H CO 127.9-128.9 7
    thiopheneCH2
    33 H 4-IPh H 2-thiopheneCH2 H, H H, H CO 127-130 8.6
    34 H 4-ClPh H 2-thiopheneCH2 H, H H, H CO 126.3-127.0 21 17
    35 H 4-ClPh H 3-thiopheneCH2 H, H H, H CO 126.4-127.9 54
    36 H Ph H 3-thiopheneCH2 H, H H, H CO 135-138 25 22
    37 H Ph H 2-thiophene(CH2)3 H, H H, H CO 105.5-106.9 500 4
    38 H Ph H 2-thio- H, H H, H CO 217.3-218.9 189
    pheneCH═CH(t)
    39 H Ph H 3- H, H H, H CO 204.8-206.5 727
    thiopheneCH═CH
    40 H Ph H 2-thiophene H, H H, H SO2 169.0-170.9 151 22
    41 H 4-ClPh H 2-thiophene H, H H, H SO2 180.4-181.9 491
    42 H Ph H 3-thiophene H, H H, H CO 153.5-154.7 68 18
    43 H Ph H 2-benzothiophene H, H H, H CO 218.3-218.8 495
    44 H Ph Me 2-thiopheneCH2 H, H H, H CO   107-109.3 133
    45 H Ph H 2-thiophene H, H H, H CO 139-142 31 5
    46 H 2-thio H 2-thiopheneCH2 H, H H, H CO 138.2-139.9 723
    47 H Ph H 3-indoleCH2 H, H H, H CO 89-93 416 17
    48 H Ph H 3-indole(CH2)2 H, H H, H CO 100-114 605 19
    49 H Ph H 2-pyridylCH2 H, H H, H CO 120.1-121.7 200 11
    50 H Ph H NHPh H, H H, H CO 205-206
    51 H Ph H 2-MeOPhNH H, H H, H CO 203-204 32%
    52 H Ph H 2-ClPhNH H, H H, H CO 210-211 273
    53 H Ph H 2-FPhNH H, H H, H CO 190-191 293
    54 H Ph H PhCH2NH H, H H, H CO 170-171 219
    55 H Ph H 2,4-diClPhCH2NH H, H H, H CO 166-167 121
    56 H Ph H PhO H, H H, H CO 128-129 310
    57 H Ph H 4-ClPhO H, H H, H CO 159-160 294
    58 H Ph H 4-FPhO H, H H, H CO 150-151 240
    59 H Ph H 2-NapthO H, H H, H CO 151-152 155
    60 H Ph H Pr H, H H, H CO 88-89 446
    61 H Ph H i-Pr H, H H, H CO 114-115 584
    62 H Ph H n-Bu H, H H, H CO 78-79 121
    63 H Ph H i-Bu H, H H, H CO 112-113 316
    64 H Ph H t-Bu H, H H, H CO 143-144 296
    65 H Ph H CH2CO2Et H, H H, H CO   103-105.5 937
    66 H Ph H PhCH2 SB H, H CO 148.7-150.8 888 18
    67 H Ph H 2-MeOPhCH2 SB H, H CO 159.4-161.1 23%
    68 H Ph H 2-ClPhCH2 SB H, H CO 162.4-184.2 46%
    69 H Ph H 2-CF3PhCH2 SB H, H CO 153.9-155   15%
    70 H Ph H 2-MeOPh(CH2)2 SB H, H CO 173.5-175.8 53%
    71 H Ph H 2-thiopheneCH2 SB H, H CO 128.7-130.5 820 16
    72 H Ph H 5-Me-2-thiophene SB H, H CO 158.3-180.5 33%
    73 H Ph H PhCH2 (CH2)2 H, H CO 172.7-174.8 770
    74 H Ph H 2-MeOPh(CH2)2 (CH2)2 H, H CO 134.3-136.8 388
    75 H Ph H 2-thiopheneCH2 (CH2)2 H, H CO   175-177.5 363
    76 H Ph H 3-thiopheneCH2 (CH2)2 H, H CO 167.3-169.3 571
    77 H Ph H 5-Me-2-thiophene (CH2)2 H, H CO 172.1-173   882
    78 H Ph H PhCH2 H, H CH2 CO 150-152 1200 6
    79 H Ph H 3,4-MeOPhCH2 H, H CH2 CO   131-133.5 1000 24.5
    80 H Ph H 2-ClPhCH2 H, H CH2 CO 128.5-130.5 955 −11
    81 H Ph H 2-MeOPh(CH2)2 H, H CH2 CO 187.5-189   709
    82 H Ph H CHPh2 H, H CH2 CO 166-169 510 −20.4
    83 H Ph H n-propyl H, H CH2 CO 149-150 573 45
    84 H Ph H i-propyl H, H CH2 CO 167-168 612 15.3
    85 H Ph H 2-Me-propyl H, H CH2 CO 142-143 68% 7.2s
    86 H Ph H t-butyl H, H CH2 CO 121-122 665 12.6
    87 H Ph H n-butyl H, H CH2 CO 122-123 681 19.8
    88 H Ph H 2-thiopheneCH2 H, H CH2 CO 135-137 425
    89 H Ph H 3-thiopheneCH2 H, H CH2 CO 130-135 570 22
    90 H Ph H 2-thiophene H, H CH2 CO 152.5-155   612
    91 H Ph H 5-Me-2-thiophene H, H CH2 CO   168-170.5 421
    92 H Ph H PhNH H, H CH2 CO 209-210 1488 −1
    93 H Ph H 2-FPhNH H, H CH2 CO 235-238 17% 33.9
    94 H Ph H 2-MeOPhNH H, H CH2 CO 246-247 13% −18.6
    95 H Ph H PhCH2NH H, H CH2 CO 231-232  4% −14.3
    96 H Ph H PhO H, H CH2 CO 146-147 927 9.9
    97 H Ph H 4-ClPhO H, H CH2 CO 171-172 157 12.5
    Molecular % Inhibition
    Cmpd R1 R2 R3 R4 X Y Z Mass Ion MOCH
    98 H 3,4-(OCH2O)Ph H 4-ClPhCH2 H, H H, H CO 484.0 486
    99 H 3,4-(OCH2O)Ph H 2-thiopheneCH2 H, H H, H CO 455.6 456 35
    100 H 3,4-(OCH2O)Ph H 3-Me-5-Cl-benzo- H, H H, H CO 554.1 554, 556 18
    thiophene-2-CH2
    101 H 3,4-(OCH2O)Ph H 5-Cl-benzo- H, H H, H CO 540.1 540, 542 26
    thiophene-2-CH2
    102 H 3,4-(OCH2O)Ph H 2-pyridineCH2 H, H H, H CO 450.5 451 51
    103 H 3,4-(OCH2O)Ph H 3-CF3phenylCH2 H, H H, H CO 517.5 518 37
    104 H 3,4-(OCH2O)Ph H 3,5-di-CF3phenylCH2 H, H H, H CO 585.5 586 52
    105 H 3,4-(OCH2O)Ph H 4-NO2phenylCH2 H, H H, H CO 494.5 495 24
    106 H 3,4-(OCH2O)Ph H 4-BuOphenylCH2 H, H H, H CO 521.7 522 52
    107 H 3,4-(OCH2O)Ph H 2-MeOphenylCH2 H, H H, H CO 479.6 480 28
    108 H 3,4-(OCH2O)Ph H 3,5-di-MeOphenylCH2 H, H H, H CO 509.6 510 38
    109 H 3,4-(OCH2O)Ph H phenylCH2 H, H H, H CO 449.5 450 22
    110 H 3,4-(OCH2O)Ph H 3-FphenylCH2 H, H H, H CO 467.5 468 20
    111 H 3,4-(OCH2O)Ph H 2,4-diF-phenylCH2 H, H H, H CO 485.5 486 60
    112 H 3,4-(OCH2O)Ph H 2,4-di-Cl-phenylCH2 H, H H, H CO 518.4 518, 520 36
    113 H 3,4-(OCH2O)Ph H 3,4-diCl-phenylCH2 H, H H, H CO 518.4 518, 520 31
    114 H 3,4-(OCH2O)Ph H phenylthioCH2 H, H H, H CO 481.6 482 41
    115 H 3,4-(OCH2O)Ph H 3-thiophene H, H H, H CO 441.5 442 28
    116 H 3,4-(OCH2O)Ph H 2-thiophene H, H H, H CO 441.5 442 62
    117 H 3,4-(OCH2O)Ph H phenyl H, H H, H CO 435.5 436 28
    118 H 3,4-(OCH2O)Ph H 2-MeO-phenyl H, H H, H CO 465.5 466 38
    119 H 3,4-(OCH2O)Ph H 2-Indole H, H H, H CO 474.6 475 31
    120 H 3,4-(OCH2O)Ph H 3,5-di-CF3phenyl H, H H, H CO 571.5 572 27
    121 H 3,4-(OCH2O)Ph H 3-NO2-phenyl H, H H, H CO 480.5 481 10
    122 H 3,4-(OCH2O)Ph H 3-NO2-4-Me-phenyl H, H H, H CO 494.5 495 33
    123 H 3,4-(OCH2O)Ph H 3-CN-phenyl H, H H, H CO 460.5 461 51
    124 H 3,4-(OCH2O)Ph H phenylethyl H, H H, H CO 463.6 464 35
    125 H 3,4-(OCH2O)Ph H 4-tBu-phenyl H, H H, H CO 491.6 492 31
    126 H 3,4-(OCH2O)Ph H 4-Me-phenyl H, H H, H CO 449.5 450 46
    127 H 3,4-(OCH2O)Ph H 2,4-diF-phenyl H, H H, H CO 471.5 472 61
    128 H 3,4-(OCH2O)Ph H 4-F-phenyl H, H H, H CO 453.5 454 54
    129 H 3,4-(OCH2O)Ph H 2-Cl-phenyl H, H H, H CO 470.0 470, 472 41
    130 H 3,4-(OCH2O)Ph H 4-Cl-phenyl H, H H, H CO 470.0 470, 472 37
    131 H 3,4-(OCH2O)Ph H 3,5-diCl-phenyl H, H H, H CO 504.4 504, 506 18
    132 H 3,4-(OCH2O)Ph H 4,5-diCl-phenyl H, H H, H CO 504.4 504, 506 69
    133 H 3,4-(OCH2O)Ph H 2-Me-phenyl H, H H, H CO 449.5 450 46
    134 H 3,4-(OCH2O)Ph H 4-biphenylCH2 H, H H, H CO 525.6 526 29
    135 H 4-CF3-Ph H 2-thiopheneCH2 H, H H, H CO 479.6 480 31
    136 H 4-CF3-Ph H 2-thiophene H, H H, H CO 465.5 466 38
    137 H 4-CF3-Ph H 2-Cl-phenyl H, H H, H CO 494 494, 496 45
    138 H 4-CF3-Ph H 3,4-diCl-phenylCH2 H, H H, H CO 542.4 542, 544 33
    139 H 4-CF3-Ph H 2,4-diCl-phenyl H, H H, H CO 528.4 528, 530 42
    140 H 4-CF3-Ph H 3-Me-phenylCH2 H, H H, H CO 487.6 488 57
    141 H 4-CF3-Ph H phenylCH2 H, H H, H CO 473.5 474 66
    142 H 4-CF3-Ph H 2-pyridineCH2 H, H H, H CO 474.5 475 39
    143 H 4-CF3-Ph H 4-MeS-phenylCH2 H, H H, H CO 519.6 520 19
    144 H 4-CF3-Ph H 2-MeO-4-Cl-phenyl H, H H, H CO 524 524, 526 33
    145 H 4-CF3-Ph H 5-Cl-benzo- H, H H, H CO 564.1 564, 565 54
    thiophene-2-CH2
    146 H 4-CF3-Ph H 2-Cl-phenylCH2 H, H H, H CO 508.0 508.2 39
    147 H 4-CF3-Ph H 2,4-diF-phenylCH2 H, H H, H CO 509.5 510.2 55
    148 H 4-CF3-Ph H 2-MeO-phenylCH2 H, H H, H CO 503.6 504 42
    149 H 4-CF3-Ph H 3,5-diMeO-phenylCH2 H, H H, H CO 533.6 534 42
    150 H 4-CF3-Ph H 4-CF3-phenylCH2 H, H H, H CO 541.5 542 61
    151 H 4-CF3-Ph H 3,5-diCF3-phenylCH2 H, H H, H CO 609.5 610 41
    152 H 4-CF3-Ph H 4-Me-phenylCH2 H, H H, H CO 487.6 488 41
    153 H 4-CF3-Ph H Ph2CH H, H H, H CO 549.6 550 69
    154 H 4-CF3-Ph H 4-NO2-phenylCH2 H, H H, H CO 518.5 519 34
    155 H 4-CF3-Ph H 4-(Me2N)-phenylCH2 H, H H, H CO 516.6 517 29
    156 H 4-CF3-Ph H 4-biphenylCH2 H, H H, H CO 549.6 550 19
    157 H 4-CF3-Ph H 2-naphthylCH2 H, H H, H CO 523.6 524 10
    158 H 4-CF3-Ph H 5-Cl-3-Me-benzo- H, H H, H CO 578.1 578, 580 16
    thiopheneCH2
    159 H 4-CF3-Ph H 4-(Me2N)- H, H H, H CO 528.6 529 12
    phenyl(CH)2
    160 H 4-CF3-Ph H 3,5-diCF3-phenyl H, H H, H CO 595.5 598 10
    161 H 4-I-Ph H 2-Cl-phenylCH2 H, H H, H CO 565.9 566, 568 42
    162 H 4-I-Ph H 4-Cl-phenylCH2 H, H H, H CO 565.9 566, 568 30
    163 H 4-I-Ph H 3,4-diCl-phenylCH2 H, H H, H CO 600.3 600 44
    164 H 4-I-Ph H 2-F-phenylCH2 H, H H, H CO 549.4 550 40
    165 H 4-I-Ph H 4-F-phenylCH2 H, H H, H CO 549.4 550 79
    166 H 4-I-Ph H 4-CF3-phenylCH2 H, H H, H CO 599.4 600 46
    167 H 4-I-Ph H 3,5-diCF3-phenylCH2 H, H H, H CO 667.4 668 63
    168 H 4-I-Ph H 2-MeO-phenylCH2 H, H H, H CO 561.5 562 32
    169 H 4-I-Ph H 3-MeO-phenylCH2 H, H H, H CO 561.5 562 45
    170 H 4-I-Ph H 4-MeO-phenylCH2 H, H H, H CO 561.5 562 25
    171 H 4-I-Ph H 3,5-diMeO-phenylCH2 H, H H, H CO 591.5 592 25
    172 H 4-I-Ph H 2-Cl-phenyl H, H H, H CO 551.9 552 32
    173 H 4-I-Ph H 4-Cl-phenyl H, H H, H CO 551.9 552 72
    174 H 4-I-Ph H 3,4-diCl-phenyl H, H H, H CO 586.3 587 50
    175 H 4-I-Ph H 2-F-phenyl H, H H, H CO 535.4 536 65
    176 H 4-I-Ph H 4-F-phenyl H, H H, H CO 535.4 536 68
    177 H 4-I-Ph H 4-CF3-phenyl H, H H, H CO 585.4 586 53
    178 H 4-I-Ph H 3,5-diCF3-phenyl H, H H, H CO 653.4 654 53
    179 H 4-I-Ph H 2-thiophene H, H H, H CO 523.4 524 53
    180 H 4-I-Ph H 5-Me-2-thiophene H, H H, H CO 537.5 538 57
    181 H 4-I-Ph H 2-MeO-phenyl H, H H, H CO 547.4 548 41
    182 H 4-I-Ph H 3-MeO-phenyl H, H H, H CO 547.4 548 15
    183 H 4-I-Ph H 3,5-diMeO-phenyl H, H H, H CO 577.5 578 42
  • upon a square cm of skin surface, from about 2 μl/cm[0081] 2 to about 8 μl/cm2 of topically active agent is present when amelioration of an inflammatory condition is desired.
  • The following examples are merely illustrative of the compounds, methods of making said compounds, compositions and methods of using said compounds and compositions, and do not serve to limit the scope of this invention.[0082]
    • EXAMPLE 1
  • 2,3,3-Triphenylpropionitrile, (Hauser, C. R. et al., Formation and Preferential β-Alkylation of the Dicarbanion of 2,3,3-Triphenylpropionitrile by Means of Potassium Amide in Liquid Ammonia. [0083] J. Amer. Chem. Soc., 1959, 81, 4099-4102) was made as follows. A solution of phenylacetonitrile (1.00 g, 0.0086 mol) and THF (17 mL) was cooled to −78° C. in a dry ice-acetone bath and treated dropwise with a solution of n-butyllithium in hexane (3.80 mL, 0.0095 mol). After stirring for 45 minutes at −78° C., a solution of diphenyl methylchloride (1.75 g, 0.0086 mol) and THF was added dropwise to give a light yellow solution. After stirring at room temperature overnight, water (20 mL) and diethyl ether (50 mL) were added with vigorous stirring. The organic layer was separated, dried over anhydrous magnesium sulfate (MgSO4), filtered, and evaporated to give an oil. This material was triturated and filtered to give 1,2,2-triphenylpropionitrile.
    • EXAMPLE 2
  • 9H-(Fluoren-9-yl)phenylacetonitrile was prepared using the same procedure as that described in Example 1, however, 9-bromofluorene was substituted for diphenylmethylchloride. 9H-Fluoren-9-yl)phenylacetonitrile was obtained, having a melting point of 146-148.3° C. [0084]
    • EXAMPLE 3
  • (10,11-Dihydro-5H-dibenzo[1,d]cyclohepten-4-yl)phenylacetonitrile was made using the same procedure as described above in Example 1, with the exception that 5-chloro-10,11-dihydro-5-H-dibenzo[a,d]cycloheptene was substituted for diphenylmethylchloride. (10,11-Dihydro-5H-dibenzo[1,d]cycloheptenyl)phenylacetonitrile was obtained, having a melting point of 134.1-147.7° C. [0085]
    • EXAMPLE 4
  • 2-(4-Chlorophenyl)-3,3-diphenylpropionitrile was made using the same procedure as described for Example 1, but substituting 4-chlorophenylacetonitrile for phenylacetonitrile. The compound obtained had a melting point of 115.1-115.6° C. [0086]
    • EXAMPLE 5
  • 2-(2-Thienyl)-3,3-diphenylpropionitrile was made using the following procedure. To a mixture of 2-thiophenacetonitrile (16.30 g, 0.081 mol), benzyltriethylammonium chloride (0.185 g, 0.900081 mol), and 50% sodium hydroxide, diphenylmethylchloride (10.00 g, 0.081 mol) was added dropwise. this mixture was stirred for two hours at room temperature, heated at 40° C. for 30 minutes and then was treated with benzaldehyde (0,18 g, 0.0017 mol). The reaction mixture was poured into an ice-water mixture (200 ml) and extracted twice with dichloromethane. The organic layers were combined, washed with 2N hydrochloric acid (100 ml), water (100 ml), and saturated sodium chloride solution (100 ml), dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on flash silica to give a solid which was recrystallized three times from ethanol affording 17.45 g (74.3%) of 2-(2-Thienyl)-3,3-diphenylpropionitrile as a crystalline solid, having a melting point of 102.7-105.3° C. [0087]
    • EXAMPLE 6
  • 3,3-Bis-(4-fluorophenyl)-2-phenylpropionitrile was made using the same procedure as described in Example 5, but substituting phenylacetonitrile for 2-thiopheneacetonitrile and chlorobis(4-fluorophenyl)methane for diphenylmethylchloride. The end product had a melting point of 142.5-143.8° C. [0088]
    • EXAMPLE 7
  • 2-(4-Iodophenyl)-3,3-diphenylpropionitrile was made using the same procedure as described in Example 5, but substituting 4-iodophenylacetonitrile for 2-thiopheneacetonitrile. [0089]
    • EXAMPLE 8
  • 1,2,2-Triphenylcyclopropylnitrile was made using the procedure of C. R. Hauser, T. M. Harris, and T. G. Ledford [[0090] J. Amer. Chem. Soc., 1959, 81, 4099-4102]. A solution of KNH2 and liquid NH3 was made by adding potassium (24.5 g, 0.63 mol) to liquid NH3 (1500 ml). 2,3,3-triphenylpropionitrile (87.5 g, 0.31 mol) was slowly added to the KNH2/NH3 solution. After stirring for 10 minutes, this mixture was treated with a solution of dichloromethane (31.5 g, 0.37 mol) and diethyl ether (150 ml). After 1.5 hour, another portion of dichloromethane (6.0 g, 0.071 mol) and diethyl ether (25.0 ml) was added and the reaction mixture stirred for another hour at −78° C. Diethyl ether was added and the NH3 was allowed to evaporate. The ethereal solution was washed with water, 2N hydrochloric acid and water. The organic layer was separated, dried over potassium carbonate, filtered and evaporated to a solid residue. This material was recrystallized twice from methanol affording 47.0 g (51%) of 1,2,2-Triphenylcyclopropylnitrile as a crystalline solid.
    • EXAMPLE 9
  • 2,3,3-Triphenylpropylamine was made according to the following procedure. A solution of 2,3,3-triphenylpropionitrile (10.00 g, 0.035 mol) and THF (80 ml) was added dropwise to a solution of LiAlH[0091] 4 (3.40 g, 0.089 mol) in THF (100 ml) at 0° C. The resulting mixture was stirred for 24 hours at room temperature and then refluxed for 24 hours. After cooling in an ice bath, the reaction mixture was treated with water (3.40 ml), 3N sodium hydroxide (10.20 ml) and water (3.4 ml) followed by the addition of magnesium sulfate. The mixture was filtered and the filtrate was evaporated to an oil. This material was dissolved in diethyl ether (30 ml) and diethyl ether/anhydrous hydrochloric acid (25 ml, 0.025 mol) was added. A white solid was filtered and partitioned between diethyl ether and 3N sodium hydroxide. The organic layer was separated, dried over potassium carbonate, filtered, and evaporated affording 2,3,3-Triphenylpropylamine as a crystalline solid.
    • EXAMPLE 10
  • 2-(4-Chlorophenyl)-3,3-diphenylpropylamine was made using the same procedure as described in Example 9, but substituting 2-(4-Chlorophenyl)-3,3-diphenylpropionitrile for 2,3,3-triphenylpropionitrile. The end product had a melting point of 104.1-105.7° C. [0092]
    • EXAMPLE 11
  • 2-(9H-[Fluoren-9-yl])-2-(phenyl)ethylamine was made using the procedure as set forth in Example 9, but substituting 9H-(Fluoren-9yl)phenylacetonitrile for 2,3,3-triphenylpropionitrile and diethyl ether for THF. An oil was obtained. [0093]
    • EXAMPLE 12
  • 3,3-Bis-(4fluorophenyl)-2phenyl)propylamine was made using the procedure as set forth in Example 9, but substituting 3,3-bis-(4-fluorophenyl)-2-phenylpropionitrile for 2,3,3triphenylpropionitrile and diethyl ether for THF. The endproduct was a white solid. [0094]
    • EXAMPLE 13
  • 3,3-Diphenyl-2-(2-thienyl)propylamine was made using the procedure as set forth in Example 9, but substituting 2-(2-Thienyl)-3,3-diphenylprionitrile for 2,3,3-triphenylpropionitrile and diethyl ether for THF. The end product was a beige solid having a melting point greater than 200° C (decomposition). [0095]
    • EXAMPLE 14
  • 1,2,2-triphenylcyclopropylmethylamine was made using the procedure as set forth in Example 9, but substituting 1,2,2-Triphenylcyclopropylnitrile for 2,3,3-triphenylpropionitrile and diethyl ether for THF. The end product was a white solid. [0096]
    • EXAMPLE 15
  • 2-(4-Iodophenyl)-3,3-diphenylpropylamine was made using the following procedure. A solution of TFA (3.30 g, 0.030 mol) and THF (10 ml) was slowly added to a slurry of sodium borohydrate (1.10 g, 0.029 mol) and THF (20 ml) at room temperature. After gas evolution ceased, the reaction was stirred for fifteen minutes and then treated dropwise with a solution of 2-(4-Iodophenyl)-3,3-diphenylpropionitrile (4,87 g, 0.012 mol) and THF (20 ml). After stirring overnight at room temperature, water was added slowly followed by dichloromethane (40 ml). The organic layer was dried over potassium carbonate, filtered and evaporated to an oil. This material was dissolved in diethyl ether and treated with anhydrous hydrochloric acid/diethyl ether (10 ml). A white solid was filtered and partitioned between dichloromethane and 3N sodium hydroxide. The organic layer was separated, dried over potassium carbonate, filtered and evaporated to give 2-(4-Iodophenyl)-3,3-diphenylpropylamine as a solid. [0097]
    • EXAMPLE 16
  • 2-(10,11-Dihydro-5H-dibenzo[1,d]cyclohepten-4-yl)-2-(phenyl)ethylamine was made as follows. A solution of 1M BH[0098] 3-THF (24 ml, 0.024 mol) at room temperature was treated with a solution of (10,11-Dihydro-5H-dibenzo[1,d]cycloheptenyl)phenylacetonitrile (5.0 9, 0.016 mol) and THF (70 ml). The resulting solution was refluxed for 2 hours, cooled to 0° C. and treated with methanol (50 ml) followed by 6N hydrochloric acid (125 ml). The mixture was heated at 70° C. for 1 hour, cooled to 0° C., adjusted to pH 12 with 50% sodium hydroxide solution, and extracted two times with ethylacetate. The organic layers were combined, dried, filtered, and evaporated to a yellow oil. This material was triturated with hexane and filtered. The filtrate was evaporated and the residue was chromatographed on flash silica using ethylacetate:hexane (8:2) as the eluant to give a 2.29 g (46%) yield of 2-(10,11-Dihydro-5H-dibenzo[1,d]cycloheptenyl)-2-(phenyl)ethylamine as an oil.
    • EXAMPLE 17
  • Compound 29 was made in accordance with the following procedure. A solution of thiopheneacetyl chloride (0.281 g, 0.0017 mol) and ethylene dichloride (8.0 ml) was added slowly to an icecooled mixture of 2,3,3-Triphenylpropylamine (0.50 g, 0.0017 mol), sodium acetate (0.18 g, 0.0022 mol) and ethylene chloride (8.0 ml). After stirring overnight at room temperature, water was added with thorough mixing. The resulting organic layer was separated, washed successively with 1N sodium hydroxide solution and 1N hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated to an oil which solidified. Two recrystallizations of this material afforded 0.410 g (59%) of 29 as a crystalline solid, having a melting point of 130-132° C. [0099]
    • EXAMPLE 18
  • Other compounds may be obtained in accordance with the procedure set forth in Example 17, requiring the substitution for thiopheneacetyl chloride or 2,3,3-Triphenylpropylamine, such as compounds: 1, 6, 7, 18, 29, 78, 79, and 82. [0100]
    • EXAMPLE 19
  • Compound 80 was made using the following procedure: A solution of 2-chlorphenylacetic acid (0.289 g, 0.0017 mol), 1,1′-carbonyldiimidazole (0.271 g, 0.0017 mol) and acetonitrile (25 ml) was stirred for twenty minutes at room temperature and treated with 1,2,2-triphenylcyclopropylmethylamine (0.500 g, 0.0017 mol). After stirring for 24 hours, the reaction was evaporated and the residue dissolved in methylene dichloride. This solution was washed with water (10 ml), 1N HCl (10 ml), and water (10 ml). The organic layer was separated, dried over magnesium sulfate, filtered, and evaporated to an oil. This material was dissolved in ethylene dichloride and diethyl ether was added causing a crystalline solid to form. Filtration afforded 0.501 g (65%) of 80 as a crystalline solid with a melting point of 128.5-130.5° C. [0101]
    • EXAMPLE 20
  • Following the procedure of Example 19, substituting for the 2-chlorophenylacetic acid or 1,2,2-triphenylcyclopropylmethylamine equivalent amounts of the appropriate starting materials and substituting ethylene dichloride for the acetonitrile used therein, the following compounds may be obtained: 2, 3, 4, 5, 8, 9, 10,11, 12, 13, 14, 19, 20, 21, 22, 24, 25, 26, 27, 28, 30, 34, 37, 38, 39, 40, 41, 42, 43, 45, 46, 48, 49, 61, 62, 63, 64, 81, 83, 84, 85, 86, 87, 88, 89, and 90. [0102]
    • EXAMPLE 21
  • Compound 66 was made as follows: A solution of phenyl acetic acid (0.30 g, 0.0024 mol), 2-(9H-[Fluoren-9-yl])-2-(phenyl)ethylamine (0.70 g, 0.0024 mol), and ethylene dichloride (10 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbondiimide hydrochloride (0.55 g, 0.0029 mol). After stirring overnight, the reaction solution was washed with 3N sodium hydroxide, 6N HCl and saturated NaCl solution. The organic layer was separated, dried over magnesium sulfate and evaporated to a semi-solid. This material was triturated with diethyl ether and filtered to give a solid which was recrystallized from methanol affording 0.12 g (12%) of Compound 66 as a white crystalline solid having a melting point of 148.7-150.8° C. [0103]
    • EXAMPLE 22
  • Following the procedure of Example 21, substituting for the phenylacetic acid or 2-(9H-[Fluoren-9-yl])-2-(phenyl)ethylamine equivalent amounts of the appropriate starting materials, the following compounds may be obtained: 15, 16, 17, 23, 31, 32, 44, 65, 67, 68, 69, 70, 71, 72, 74, 75, 76, 77, and 91. [0104]
    • EXAMPLE 23
  • Compound 52 was made in accordance with the following procedure: A solution of 2,3,3-Triphenylpropylamine (0.25 g, 0.0009 mol) and methylene dichloride (25 ml) was treated with 2-chlorophenyl isocyanate (0.13 g, 0 0009 mol) at room temperature. A solid formed which was filtered and recrystallized from methanol-hexane to give 0.14 g (75%) of 52 as a white crystalline solid having a melting point of 210-211° C. [0105]
    • EXAMPLE 24
  • Following the procedure of Example 23, substituting for the chlorophenyl isocyanate or 2,3,3-Triphenylpropylamine used therein, equivalent amounts of the appropriate starting materials, the following compounds may be obtained: 50, 51, 53, 54, 55, 92, 93, 94, and 95 [0106]
    • EXAMPLE 25
  • Compound 40 was made as follows: An ice-cooled solution of 2,3,3-triphenylpropylamine (0.674 g, 0.0024 mol) and CHCl[0107] 3 (20 ml) was treated with 2-thiophenesulfonyl chloride (0.475 g, 0.0026 mol) followed by diisopropylethylamine (0.764 g, 0.0059 mol) and stirred at room temperature overnight. The reaction was washed with 1 N HCl (20 ml) and saturated NaCl solution. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated affording 0.660 g (66%) of 40 as a solid having a melting point of 169-170.9° C.
    • EXAMPLE 26
  • Following the procedure of Example 25, substituting for the 2,3,3-Triphenylpropylamine used therein an equivalent amount of 2-(4-chlorophenyl)-3,3-diphenylpropylamine, compound 41 may be obtained. [0108]
    • EXAMPLE 27
  • Compound 57 was made in accordance with the following procedure: To a solution of 2,3,3-Triphenylpropylamine (0.25 g, 00009 mol), triethylamine (0.09 g, 0.0009 mol) and CHCl[0109] 3 (25 ml) was added 4-fluorophenyl chloroformate (0.2 g, 0 0009 mol) and the resulting solution was stirred for 45 minutes. The reaction was then washed with 1N HCl, and brine. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated to white solid. This material was recrystallized form methanol/hexane to give 0.15 g (39%) of 57 as a white crystalline solid having a melting point of 150-151° C.
    • EXAMPLE 28
  • Following the procedure of Example 27, but substituting for the 2,3,3-Triphenylpropylamine and 4-fluorophenyl chloroformate used therein, equivalent amounts of the appropriate starting materials, the following compounds may be obtained: 56, 58, 59, 96, and 97. [0110]
    • EXAMPLE 29
  • Compound 17 was made as follows: A mixture of N-[3,3-bis-(4-fluorophenyl)-2-phenylpropyl]-2-phenylacetamide [Compound 18] (0.84 g, 0.0019 mol), dimethylsulfate (0.37 g, 0.0029 mol), benzyltriethylammonium chloride (0.14 g, 0.00075 mol), 50% NaOH (30 ml) was stirred overnight at room temperature. Water was added and the mixture was extracted with ethylene dichloride. The organic layer was separated, dried over potassium carbonate, filtered and evaporated to an oil which was crystallized from diethyl ether-hexane affording 0.080 g (9%) of 17 as a yellow crystalline solid having a melting point of 86.9-88.2° C. [0111]
    • EXAMPLE 30
  • Compound 98 was prepared as follows: A mixture of 2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine (18.0 g, 0.055 mol) and anhydrous THF (120 mL) at −70° C. was treated dropwise with a 1.0M solution of DiBAL (100 mL, 0.110 mol). The reaction was stirred for 1 hour at −70° C. and then at 25° C. for 1.5 hours. The reaction was cooled to 0° C. and treated with ethanol (20 mL) followed by 10% aqueous HCl (150 mL). Extraction with ethyl acetate, drying over anhydrous MgSO[0112] 4, evaporation and purification by flash chromatography (silica gel) afforded 2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropionaldehyde a solid. A mixture of this material (8.0 g, 0.024 mol), Rink amine resin (8.73 g, 0.0044 mol), and trimethylorthoformate (60 mL) was shaken for 4 days, filtered and washed twice with trimethylorthoformate, methylene chloride, and dichloroethane. The resulting resin was shaken with NaBH(Oac)3 (4.63 g, 0.022 mol), acetic acid (1.83 mL) and dichloroethane (60 mL) for two days. The resulting resin was washed with methanol, methylene chloride, 10% acetic acid/methylene chloride, 10% triethylamine/methylene chloride, methylene chloride, and methanol. This resin (0.235 g, 0.0001 mol) was shaken for 2 days with HATU (0.090 g, 0.00024 mol), diisopropylethylamine, (175 μL), 4-chlorophenylacetic acid (0.085 g, 0.0005 mol), and DMF (2 mL). The resin was filtered and washed three times each with DMF, methylene chloride, and methanol and dried. The dried resin was treated with 10% TFA/methylene chloride and filtered. The filtrate was blown dry with nitrogen to afford 0.042 g (87%) of compound 98, electrospray mass spectrometry m/e=484.
    • EXAMPLE 31
  • Following the procedure of Example 30, but substituting for the 4-chlorophenylacetic acid and 2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine used therein, equivalent amounts of the appropriate starting materials, the following compounds may be obtained: 99-161, 164, 168, 173, 174, 176-178, 180, and 182. [0113]
    • EXAMPLE 32
  • Compound 162 was prepared as follows: A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.67 g, 0.040 mol) and methylene chloride (300 mL) was washed with 10% NH[0114] 4OH, dried over MgSO4, filtered and evaporated. The residue was dissolved in DMF (100 mL) and mixed with Merrifield resin (20.0 g, 0.020 mol) at 100° C. overnight. The mixture was filtered and the resin was washed with DMF, methanol, and methylene chloride. A mixture of this resin (0.48 g, 0.00048 mol), 4-chlorophenylacetic acid (0.0205 g, 0.00012 mol), 2-(4-iodophenyl)-3,3 diphenylpropylamine (0.0413 g, 0.0001 mol), and CHCl3 (2.0 mL) was agitated for 2 days, filtered, and washed with CHCl3. The filtrate was blown dry with nitrogen affording compound 163, 0.0425 g. (88%), CI mass spectrometry m/e=483.99.
    • EXAMPLE 33
  • Following the procedure of Example 32, but substituting for the 4-chlorophenylacetic acid used therein, equivalent amounts of the appropriate starting materials, the following compounds may be obtained: 163, 165-167, 169-172, 175, 179, 181, and 183. [0115]
    • EXAMPLE 34
  • A human glucocorticoid receptor binding assay was carried out to determine the extent to which the compounds of this invention have the ability to bind to human glucocorticoid receptors. This binding ability may be indicative of the antiinflammatory activity of the compound. The test was carried out as follows. [0116]
  • Human glucocorticoid receptors were prepared from either insect cells (Sf21) infected with baculovirus hGR or from a lymphoblast cell line which expresses high levels of endogenous hGR (IM9) The receptor binding reactions, with or without test compounds, were set up in 96-well microtiter plates which were previously siliconized with SIGMACOTE™, a chlorinated organopolysiloxane in heptane. The binding components, 3(H) Triamcinolone acetonide (TAA), glycerol/molybdate-containing buffer and unlabeled compounds were added to the wells using a combination of BIOMEK laboratory automation system and repeat pipettes. After four hours of incubation, the samples were precipitated with polyethylene glycol and filtered through Whatman GF/F paper using a TOMTEK cell harvester. The filter mate with 96 samples were bound to a solidphase scintillant and directly counted in a BETAPLATE counter. The IC[0117] 50 values were determined based on competition of 3H TM with the test compounds at 6-8 concentrations ranging from 10−10-10−5 M and calculated using the Chung-Prusoff equation. The activity of test compounds to displace 3(H) TAA binding to hGR is also expressed as percent inhibition at 1 μM. The results of this test are set forth in Table 1 below.
    • EXAMPLE 35
  • A human progesterone receptor binding assay was performed in order to determine selectivity of the compounds, as follows. Human progesterone receptors were prepared from either insect cells (SF21) infected with baculovirus hPR A, or from a breast cancer cell line, T47D, which expresses high levels of endogenous hPR. The receptor binding reactions, with or without test compounds, were set up in 96-well microtiter plates which were previously siliconized with SIGMACOTE. The binding components, 3(H) R5020 Promegestone, a high affinity ligand for the progesterone receptors, glycerol/molybdate-containing buffer and unlabeled compounds were added to the wells using a combination of BIOMEK laboratory automation system and repeat pipettes. After overnight incubation, the samples were precipitated with polyethylene glycol and filtered through Whatman GF/F paper using a TOMTEK cell harvester The filter mate with 96 samples were bound to a solidphase scintillant and directly counted in the BETAPLATE counter. Only those compounds that were active in the human glucocorticoid receptor assay set forth in Example 30 were used for progesterone receptor binding to determine cross-reactivity profiles, if any. The activity of test compounds to displace 3(H) R5020 binding to hPR is expressed as percent inhibition at the two concentrations, 10[0118] −6 and 10−5 Molar. Those compounds that do not inhibit 3(H) TM binding by 50% at 10−5 M were not considered active. Surprisingly, the compounds of this invention selectively bind to the hGR but show little or no affinity for the hPR.
    • EXAMPLE 36
  • Several triphenylpropanamide compounds of this invention, having varying affinities for the human glucocorticoid receptor, were tested for topical antiinflammatory activity in mouse ear inflammation models. Compounds with low receptor affinity (IC[0119] 50>20 nM) were weakly active or inactive at reducing ear inflammation induced by the contact sensitizer oxazolone. Compounds having receptor affinities doser to hydrocortisone were as nearly active as hydrocortisone in suppressing mouse oxazolone-induced contact hypersensitization (MOCH) and phorbol ester-induced ear edema. The in vivo studies of this example were conducted as follows.
  • Albino male CD-1 mice, 7-9 weeks old were used in this example. A 0.005% (w/v) TPA or 20% (w/v) arachidonic acid (AA) solution was made in acetone. A 20 μl volume of the TPA or M was applied to the dorsal left ear of the mouse. Compounds of this invention were placed in a composition containing ethanol/propylene glycol at a ratio of 70:30 were applied to the left ear of each mouse in an amount of 20 μl immediately after application of the TPA or AA. The right ear was not treated. The mice were sacrificed by carbon dioxide inhalation 5.5 hours after administration of TPA and one hour after administration of AA, the left and right ears were removed and a 7 mm biopsy was removed from each ear and weighed. The difference in biopsy weights between the right and left ears was calculated. Antiinflammatory effects of compounds were evident as an inhibition of the increase in ear weight. [0120]
  • In determining the MOCH using the compounds of this invention, albino male CD-1 mice, 7-9 weeks old were induced on the shaved abdomen with 50 μl of 3% oxazolone in acetone/corn oil (Day 0). On Day 5, a 20 μl volume of 2% oxazolone in acetone was applied to the dorsal left ear of the mouse. Compounds (made in ethanol/propylene glycol, 70:30) were applied to the left ear in 20 μl volume, one hour after oxazolone challenge. The right ear was not treated. The mice were sacrificed by carbon dioxide inhalation 24 hours after oxazolone challenge, the left and right ears were removed and a 7 mm biopsy was removed from each ear and weighed. The difference in biopsy weights between the right and left ears was calculated. Antiinflammatory effects of compounds were evident as an inhibition of the increase in ear weight. [0121]
  • The results of the foregoing in vivo testing is set forth in the following Table 2. [0122]
    TABLE 2
    Oxazolone Ear Swelling (MOCH)
    Compound No. % inhibition vs. Vehicle at 1 mg
     2 4
     4 1
     5 13
     6 38
     9 18
    10 19
    11 33
    12 36
    13 10
    14 11
    15 47
    16 46
    19 2
    20 32
    22 15
    23 41
    24 21
    25 9
    26 −5
    27 20
    28 28
    29 83
    30 21
    31 14
    32 83
    33 74
    34 29
    35 36
    36 13
    37 25
    38 13
    39 24
    40 15
    41 3
    42 27
    43 47
    44 3
    45 31
    46 4
    47 51
    48 22
    49 20
    50 30
    53 24
    54 10
    55 18
    56 38
    57 13
    58 16
    60 27
    61 17
    62 36
    63 3
    64 26
    65 13
    66 20
    68 28
    69 43
    72 50
    74 18
    75 26
    76 23
    77 41
    79 18
    80 54
    81 22
    82 23
    83 −4
    84 54
    85 16
    87 22
    88 29
    89 16
    90 65
    91 13
    92 42
    93 26
    94 35
    95 16
    96 52
    97 50
    98 85
    hydrocortisone 75-85
  • In accordance with the foregoing table, for example, compounds 23, 15, and 16 had moderate topical activity whereas compounds 29, 32, and 98 were equiactive with hydrocortisone. Compounds 29 and 32 were tested for dose-related activity in the oxazolone model. As shown below in Table 3, both compounds inhibited ear swelling in a dose-dependent manner. [0123]
    TABLE 3
    Oxazolone
    Ear Swelling % Inhibition vs. Vehicle
    Treatment Dose (%) Experiment 1 Experiment 2
    Hydrocortisone
    1 78.9 58.2
    Compound 29
    3 66.5 —
    1 49.9 —
    0.3 34.7 —
    0.1 4.3 —
    Compound 32
    3 — 36.5
    1 — 31.45
    0.3 — 18.95
    0.1 — 11.2
  • Both compounds were also tested in a TPA-induced ear edema model, which also shows effect of glucocorticoids. At equivalent doses, the two non-steroidal compounds were only slightly less active than hydrocortisone, as set forth in Table 4 below. [0124]
    TABLE 4
    % Inhibition of TPA Ear
    Treatment Dose (%) Edema vs. Vehicle
    Hydrocortisone 1 80.6
    Compound 29 1 64.9
    Compound 32 1 60.0
  • These tests demonstrate that the compounds of this invention (triphenylpropanamides) are topically active as antiinflammatory agents. Because of their selective effects on transcription factors, they should not cause the side effects known to be associated with classical glucocorticoids. In addition to inflammation, the triphenylpropanamides of this invention may be useful as therapeutics in other glucocorticoid-responsive skin conditions. [0125]

Claims (105)

What is claimed is:
1. A compound having the formula:
Figure US20030171585A1-20030911-C00007
wherein X is a single bond, hydrogen, sulfur or NR5, (CH2)n wherein n is an integer from 1 to 3; —HC═CH—; and —CHxW wherein W may be oxygen, sulfur or NR5;
R1 is from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sufonamido or nitrile;
R2 is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, or pyridine.
Y is —CH2— or hydrogen,
R3 is chosen from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
Z is selected from the group consisting of carbonyl; carboxy; carbonylamino; or sulfone;
R4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole or pyridine; and
R5 is selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, or nitrile; phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile
2. A compound according to claim 1 wherein R1 is selected from the group consisting of hydrogen and halo group.
3. A compound according to claim 2 wherein R1 is hydrogen
4. A compound according to claim 2 wherein R1 is halogen.
5. A compound according to claim 4 wherein R1 is fluorine.
6. A compound according to claim 1 wherein X is hydrogen.
7. A compound according to claim 1 wherein Y is hydrogen.
8. A compound according to claim 1 wherein R2 is selected from the group consisting of phenyl and halophenyl.
9. A compound according to claim 8 wherein R2 is phenyl.
10. A compound according to claim 8 wherein R2 is halophenyl.
11. A compound according to claim 10 wherein R2 is chlorophenyl.
12. A compound according to claim 1 wherein R3 is selected from the group consisting of hydrogen and lower alkyl.
13. A compound according to claim 12 wherein R3 is hydrogen.
14. A compound according to claim 1 wherein R4 is selected from the group consisting of straight-chain alkyl, phenyllower alkyl and heteroaromatic lower alkyl.
15. A compound according to claim 14 wherein R4 is heteroaromatic lower alkyl.
16. A compound according to claim 15 wherein R4 is thiophene.
17. A compound according to claim 1 wherein Z is carbonyl.
18. A compound having the formula:
Figure US20030171585A1-20030911-C00008
wherein X is hydrogen;
R1 is selected from the group consisting of hydrogen and halogen group;
R2 is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C2- C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, or pyridine;
Y is hydrogen;
R3 is chosen from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl, alkynyl, phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrite; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
Z is selected from the group consisting of carbonyl; carboxy, carbonylamino; or sulfone; and
R4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole or pyridine.
19. A compound according to claim 18 wherein R1 is hydrogen.
20. A compound according to claim 18 wherein R1 is halogen.
21. A compound according to claim 20 wherein R1 is fluorine.
22. A compound according to claim 18 wherein R2 is selected from the group consisting of phenyl, halophenyl and thio.
23. A compound according to claim 22 wherein R2 is phenyl.
24. A compound according to claim 23 wherein R2 is halophenyl.
25. A compound according to claim 24 wherein R2 is chlorophenyl.
26. A compound according to claim 18 wherein R3 is selected from the group consisting of hydrogen and lower alkyl.
27. A compound according to claim 26 wherein R3 is hydrogen.
28. A compound according to claim 18 wherein R4 is selected from the group consisting of straight-chain alkyl, phenyllower alkyl and heteroaromatic lower alkyl.
29. A compound according to claim 28 wherein R4 is heteroaromatic lower alkyl.
30. A compound according to claim 29 wherein R4 is thiophene.
31. A compound having the formula:
Figure US20030171585A1-20030911-C00009
wherein X is hydrogen;
Y is hydrogen,
R1 is selected from hydrogen and halogen;
R2 is selected from phenyl and halophenyl;
R3 is chosen from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
Z is selected from the group consisting of carbonyl; carboxy; carbonylamino; or sulfone; and
R4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted-or unsubstituted thiophene, furan, pyrrol, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole or pyridine.
32. A compound according to claim 31 wherein R3 is selected from the group consisting of hydrogen and lower alkyl.
33. A compound according to claim 32 wherein R3 is hydrogen.
34. A compound according to claim 31 wherein R4 is selected from the group consisting of straight-chain alkyl, phenyllower alkyl and heteroaromatic lower alkyl.
35. A compound according to claim 34 wherein R4 is heteroaromatic lower alkyl.
36. A compound according to claim 35 wherein R4 is thiophene.
37. A compound according to claim 31 wherein Z is carbonyl.
38. A compound having the formula:
Figure US20030171585A1-20030911-C00010
wherein X is hydrogen;
Y is hydrogen;
R1 is selected from hydrogen and halogen;
R2 is selected from phenyl and halophenyl;
R3 is selected from hydrogen and lower alkyl;
Z is selected from the group consisting of carbonyl; carboxy; carbonylamino; or sulfone; and
R4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrite: a heteroaromatic ring such as substituted-or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole or pyridine.
39. A compound according to claim 38 wherein R3 is hydrogen.
40. A compound according to claim 38 wherein R3 is methyl.
41. A compound according to claim 38 wherein R4 is selected from the group consisting of straight-chain alkyl, phenyllower alkyl and heteroaromatic lower alkyl.
42. A compound according to claim 41 wherein R4 is heteroaromatic lower alkyl.
43. A compound according to claim 42 wherein R4 is thiophene.
44. A compound according to claim 38 wherein Z is carbonyl.
45. A compound having the formula:
Figure US20030171585A1-20030911-C00011
wherein X is hydrogen;
Y is hydrogen;
R1 is selected from hydrogen and halogen;
R2 is selected from phenyl and halophenyl;
R3 is selected from hydrogen and lower alkyl,
Z is carbonyl; and
R4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrite; a heteroaromatic ring such as substituted-or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole or pyridine.
46. A compound according to claim 45 wherein R4 is selected from the group consisting of straight-chain alkyl, phenyllower alkyl and heteroaromatic lower alkyl.
47. A compound according to claim 46 wherein R4 is heteroaromatic lower alkyl.
48. A compound according to claim 47 wherein R4 is thiophene.
49. An antiinflammatory composition comprising a pharmaceutically acceptable carrier and an antiinflammatory-effective amount of a compound having the formula.
Figure US20030171585A1-20030911-C00012
wherein X is a single bond, hydrogen, sulfur or NR5, (CH2)n wherein n is an integer from 1 to 3, —HC═CH—; and —CHxW wherein W may be oxygen, sulfur or NR5;
R1 is from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
R2 is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, or pyridine;
Y is —CH2— or hydrogen;
R3 is chosen from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
Z is selected from the group consisting of carbonyl; carboxy; carbonylamino; or sulfone;
R4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted-or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole or pyridine; and
R5 is selected from the group consisting of: hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, or nitrile; phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile.
50. A composition according to claim 49 wherein R1 is selected from the group consisting of hydrogen and halo group.
51. A compound according to claim 50 wherein R1 is hydrogen.
52. A compound according to claim 50 wherein R1 is halogen.
53. A compound according to claim 52 wherein R1 is fluorine.
54. A compound according to claim 49 wherein X is hydrogen.
55. A compound according to claim 49 wherein Y is hydrogen.
56. A compound according to claim 49 wherein R2 is selected from the group consisting of phenyl and halophenyl.
57. A compound according to claim 56 wherein R2 is phenyl.
58. A compound according to claim 57 wherein R2 is halophenyl.
59. A compound according to claim 58 wherein R2 is chlorophenyl.
60. A compound according to claim 49 wherein R3 is selected from the group consisting of hydrogen and lower alkyl.
61. A compound according to claim 60 wherein R3 is hydrogen.
62. A compound according to claim 49 wherein R4 is selected from the group consisting of straight-chain alkyl, phenyllower alkyl and heteroaromatic lower alkyl.
63. A compound according to claim 62 wherein R4 is heteroaromatic lower alkyl.
64. A compound according to claim 63 wherein R4 is thiophene.
65. A compound according to claim 49 wherein Z is carbonyl.
66. A method of making a compound having the formula:
Figure US20030171585A1-20030911-C00013
wherein X is a single bond, hydrogen, sulfur or NR5, (CH2)n wherein n is an integer from 1 to 3; —HC═CH—; and —CHxW wherein W may be oxygen, sulfur or NR5;
R1 is from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
R2 is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, or pyridine;
Y is —CH2— or hydrogen;
R3 is chosen from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
Z is selected from the group consisting of carbonyl; carboxy; carbonylamino; or sulfone
R4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sufonamido or nitrile; a heteroaromatic ring such as substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole or pyridine; and
R5 is selected from the group consisting of: hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, or nitrile; phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile comprising the steps of
(1) reacting R2CH2CN with a compound having the formula (II) in the presence of nBuLI:
Figure US20030171585A1-20030911-C00014
to obtain a compound having the formula (III)
Figure US20030171585A1-20030911-C00015
(2) reacting said compound of formula (III) with LAH to form a compound of formula (IV):
Figure US20030171585A1-20030911-C00016
and
(3) reacting said compound of formula (IV) with compound selected from the group consisting of (a) sodium acetate and R4COCl, (b) CDI and R4CO2H, (c) EtN═C═N(CH2)3NMe2·HCl; (d) R4CO2H; (e) ClCO2R4, (f) ClC═O(NHR4), and (g) R4SO2Cl to obtain a compound of formula (I)
67. A method of making a compound having the formula:
Figure US20030171585A1-20030911-C00017
wherein X is a single bond, hydrogen, sulfur or NR5 , (CH2)n wherein n is an integer from 1 to 3; —HC═CH—; and —CHxW wherein W may be oxygen, sulfur or NR5;
R1 is from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
R2 is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, or pyridine,
R3 is chosen from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
Z is selected from the group consisting of carbonyl; carboxy; carbonylamino; or sulfone;
R4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted-or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole or pyridine; and
R5 is selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sufonamido, or nitrile; phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile comprising the steps of
(1) reacting R2CH2CN with a compound having the formula (II) in the presence of nBuLI;
Figure US20030171585A1-20030911-C00018
to obtain a compound having the formula (III)
Figure US20030171585A1-20030911-C00019
(2) reacting said compound of formula (III) with CH2Cl2 in the presence of KNH2 and liquid NH3 to obtain a compound having formula (V):
Figure US20030171585A1-20030911-C00020
(3) reacting said compound of formula (V) with LAH to form a compound of formula (VI):
Figure US20030171585A1-20030911-C00021
and
(4) reacting said compound of formula (VI) with compound selected from the group consisting of: (a) sodium acetate and R4COCl; (b) CDl and R4CO2H; (c) EtN═C═N(CH2)3NMe2·HCl; (d) R4CO2H; (e) ClCO2R4; (f) ClC═O(NHR4), and (g) R4SO2Cl to obtain a compound of formula (I)
68. A method of making a compound having the formula:
Figure US20030171585A1-20030911-C00022
wherein X is a single bond, hydrogen, sulfur or NR5, (CH2)n wherein n is an integer from 1 to 3, —HC═CH—; and —CHnW wherein W may be oxygen, sulfur or NR5;
R1 is from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
R2 is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, or pyridine;
wherein Y is —CH2— or hydrogen;
R3 is hydrogen;
Z is selected from the group consisting of carbonyl; carboxy; carbonylamino; or sulfone:
R4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole or pyridine; and
R5 is selected from the group consisting of: hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, or nitrile; phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile comprising the steps of
(1) reacting DiBAL with a compound having the formula (VII)
Figure US20030171585A1-20030911-C00023
to obtain a compound having the formula (VIII)
Figure US20030171585A1-20030911-C00024
(2) reacting said compound of formula (VIII) with Rink resin to give a resin-bound compound of formula (IX).
Figure US20030171585A1-20030911-C00025
(3) reacting said compound of formula (IX) with sodium triacetoxyborohydride to form a compound of formula (X):
Figure US20030171585A1-20030911-C00026
(4) reacting said compound of formula (X) with R4CO2H in the presence of HATU and DIEA followed by treatment with TFA to form a compound of formula (I):
69. A method of making a compound having the formula:
Figure US20030171585A1-20030911-C00027
wherein X is a single bond, hydrogen, sulfur or NR5, (CH2)n wherein n is an integer from 1 to 3; —HC═CH—; and —CHxW wherein W may be oxygen, sulfur or NR5;
R1 is from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile;
R2 is a phenyl group in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl(C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile, a heteroaromatic ring selected from the group consisting of substituted- or unsubstituted thiophene, furan, pyrrole, or pyridine;
wherein Y is —CH2— or hydrogen;
R3 is hydrogen;
Z is selected from the group consisting of carbonyl; carboxy; carbonylamino; or sulfone;
R4 is straight- or branched-chain alkyl having from 2 to 12 carbon atoms; phenylloweralkyl in which said phenyl group is substituted with hydrogen or with one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile; a heteroaromatic ring such as substituted- or unsubstituted thiophene, furan, pyrrole, pyridine, or a heteroaromatic ring connected by a lower alkyl chain wherein said heteroaromatic ring is chosen from substituted-or unsubstituted thiophene, furan, pyrrole or pyridine; and
R5 is selected from the group consisting of: hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; phenyl, in which said phenyl group is substituted with hydrogen or from one to three substituent groups each selected from the group consisting of lower alkyl (C2-C6), lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido, or nitrile; phenyl lower alkyl in which said phenyl group is substituted with hydrogen or with from one to three substituent groups each selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halo, carboxy, carboalkoxy, amino, amido, sulfonamido or nitrile comprising the steps of
(1) reacting said compound of formula (XII) with Merrifield resin to form a compound of formula (XIII):
Figure US20030171585A1-20030911-C00028
to obtain a compound of formula XIII
Figure US20030171585A1-20030911-C00029
(2) reacting said compound of formula XIII with a compound of formula XIV and an appropriate acid R4CO2H
Figure US20030171585A1-20030911-C00030
to obtain a compound of formula (I)
70. A method of treating inflammatory conditions comprising applying to the skin of a mammal a compound formula (I).
71. A compound according to claim 1, having the name N-(2-thiophene)acetyl-2,3,3-triphenylpropylamine.
72. A compound according to claim 1, having the name N-(5-methylthiophene)acetyl-2-phenyl-3,3-bis (4-fluorophenyl)propylamine.
73. A compound according to claim 1, having the name N-(3-indolyl) acetyl-2,3,3-triphenylpropylamine.
74. A compound according to claim 1, having the name N-(2-carbonyl-5-methylthiophene)-2-(9H-fluoreny-9-yl)-2-phenylethylamine.
75. A compound according to claim 1, having the name N-(2-chlorophenyl)acetyl-1,2,2-triphenylcyclopropylmethylamine.
76 A compound according to claim 1, having the name N-(2-thienyl)carbonyl-1,2,2-triphenylcyclopropylmethylamine.
77. A compound according to claim 1, having the name N-(phenyloxy)carbonyl-1,2,2-triphenylcyclopropylmethylamine.
78. A compound according to claim 1, having the name N-(4-chlorophenyloxy)carbonyl-1,2,2-triphenylcyclopropylmethylamine.
79 A compound according to claim 1, having the name N-(2-pyridine)acetyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine.
80 A compound according to claim 1, having the name N-(4-n-butoxyphenyl)acetyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine.
81 A compound according to claim 1, having the name N-(2,4-difluorophenyl)acetyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine.
82 A compound according to claim 1, having the name N-(2-thiophene)carbonyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine.
83 A compound according to claim 1, having the name N-(3-cyanophenyl)acetyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine.
84 A compound according to claim 1, having the name N-(2,4-difluorophenyl)carbonyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine.
85 A compound according to claim 1, having the name N-(4-fluorophenyl)acetyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine.
86 A compound according to claim 1, having the name N-(4,5-dichlorophenyl)carbonyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine.
87 A compound according to claim 1, having the name N-(3-methylphenyl)acetyl-2-(4-trifluoromethylphenyl)-3,3-diphenylpropylamine.
88 A compound according to claim 1, having the name N-(phenyl)acetyl-2-(4-trifluoromethylphenyl)-3,3-diphenylpropylamine.
89 A compound according to claim 1, having the name N-(5-chloro-2-benzothiophene)acetyl-2-(4-trifluoromethylphenyl)-3,3-diphenylpropylamine.
90 A compound according to claim 1, having the name N-(2,4-difluorophenyl)carbonyl-2-(4-trifluoromethylphenyl)-3,3-diphenylpropylamine.
91 A compound according to claim 1, having the name N-(4-trifluoromethylphenyl)acetyl-2-(4-trifluoromethylphenyl)-3,3-diphenylpropylamine.
92 A compound according to claim 1, having the name N-(phenyl)acetyl-2-(4-trifluoromethylphenyl)-3,3-diphenylpropylamine.
93 A compound according to claim 1, having the name N-(4-fluorophenyl)acetyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine.
94 A compound according to claim 1, having the name N-(3,5-bis-trifluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine.
95 A compound according to claim 1, having the name N-(4-chlorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine.
96 A compound according to claim 1, having the name N-(3,4-dichlorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine.
97 A compound according to claim 1, having the name N-(2-fluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine.
98 A compound according to claim 1, having the name N-(2-fluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine.
99 A compound according to claim 1, having the name N-(4-fluorophenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine.
100 A compound according to claim 1, having the name N-(4-trifluoromethylphenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine.
101 A compound according to claim 1, having the name N-(3,5-bistrifluoromethylphenyl)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine.
102 A compound according to claim 1, having the name N-(2-thiophene)carbonyl-2-(4-iodomethylphenyl-3,3-diphenylpropylamine.
103 A compound according to claim 1, having the name N-(5-methyl-2-thiophene)carbonyl-2-(4-iodomethylphenyl)-3,3-diphenylpropylamine.
104 A compound according to claim 1, having the name N-(4-chlorophenyl)carbonyl-2-(3,4-methylenedioxyphenyl)-3,3-diphenylpropylamine.
105 A compound according to claim 1, having the name N-(2-propyl)carbonyl-1,2,2-triphenylcyclopropylmethylamine.
US10/298,390 1997-12-29 2002-11-18 Anti-inflammatory compounds Abandoned US20030171585A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040220153A1 (en) * 2002-09-24 2004-11-04 Jost-Price Edward Roydon Methods and reagents for the treatment of diseases and disorders associated with increased levels of proinflammatory cytokines
WO2005051293A2 (en) 2003-11-21 2005-06-09 Combinatorx, Incorporated Methods and reagents for the treatment of inflammatory disorders
WO2006051477A2 (en) 2004-11-10 2006-05-18 Nicholas Piramal India Limited Fused tricyclic compounds as inhibitors of tumor necrosis factor-alpha
EP2070550A1 (en) 2003-10-15 2009-06-17 Combinatorx, Incorporated Use of combinations comprising a corticosteroid and a pyrimidopyrimidine in the treatment of inflammatory diseases
US20100092479A1 (en) * 2008-08-18 2010-04-15 Combinatorx (Singapore) Pte. Ltd. Compositions and methods for treatment of viral diseases
EP2218442A1 (en) 2005-11-09 2010-08-18 CombinatoRx, Inc. Methods, compositions, and kits for the treatment of ophthalmic disorders

Families Citing this family (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1201660B1 (en) 2000-10-30 2005-08-31 Pfizer Products Inc. Glucocorticoid receptor modulators
AU2003214879B2 (en) 2002-01-22 2008-02-07 The Regents Of The University Of California Non-steroidal ligands for the glucocorticoid receptor, compositions and uses thereof
ES2298508T3 (en) 2002-03-26 2008-05-16 Boehringer Ingelheim Pharmaceuticals Inc. GLUCOCORTICOID MIMETICS, METHODS TO PREPARE THEM, PHARMACEUTICAL COMPOSITIONS AND THEIR USES.
GB0207637D0 (en) * 2002-04-02 2002-05-15 Karobio Ab Novel compound
US7186864B2 (en) 2002-05-29 2007-03-06 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7074806B2 (en) 2002-06-06 2006-07-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
TW200400816A (en) 2002-06-26 2004-01-16 Lilly Co Eli Tricyclic steroid hormone nuclear receptor modulators
UY28526A1 (en) 2003-09-24 2005-04-29 Boehringer Ingelheim Pharma GLUCOCORTICOID MIMETICS, METHODS OF PREPARATION PHARMACEUTICAL COMPOSITIONS AND USES OF THE SAME
US8655755B2 (en) * 2003-10-22 2014-02-18 Scottrade, Inc. System and method for the automated brokerage of financial instruments
US7482344B2 (en) 2003-12-19 2009-01-27 Eli Lilly And Company Tricyclic steroid hormone nuclear receptor modulators
EP1697350B1 (en) 2003-12-19 2008-06-25 Eli Lilly And Company Tricyclic steroid hormone nuclear receptor modulators
US7795272B2 (en) 2004-03-13 2010-09-14 Boehringer Ingelheim Pharmaceutical, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
US8017395B2 (en) 2004-12-17 2011-09-13 Lifescan, Inc. Seeding cells on porous supports
JP2008525525A (en) 2004-12-27 2008-07-17 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Glucocorticoid mimetic, its production, pharmaceutical composition and use
AU2006202209B2 (en) * 2005-05-27 2011-04-14 Lifescan, Inc. Amniotic fluid derived cells
CN101484575B (en) * 2005-06-08 2013-10-02 森托科尔公司 Cellular therapy for ocular degeneration
AU2006282767A1 (en) 2005-08-26 2007-03-01 The Regents Of The University Of California Non-steroidal antiandrogens
US7790770B2 (en) 2005-11-23 2010-09-07 Bristol-Myers Squibb Company Heterocyclic CETP inhibitors
US20070122448A1 (en) * 2005-11-28 2007-05-31 Alireza Rezania Compositions and methods to create a vascularized environment for cellular transplantation
EP1960351B1 (en) * 2005-12-09 2013-06-19 F.Hoffmann-La Roche Ag Propionamide compounds as antiinflammatory agents
US8741643B2 (en) 2006-04-28 2014-06-03 Lifescan, Inc. Differentiation of pluripotent stem cells to definitive endoderm lineage
CA2984541C (en) 2006-04-28 2022-04-12 Lifescan, Inc. Differentiation of human embryonic stem cells
US7390772B2 (en) 2006-05-18 2008-06-24 International Flavor & Fragrances Inc. 1-phenyl-spiro[2.5]octane-1-carbonitrile analogues their use in fragrance formulations
EA014695B1 (en) 2006-07-14 2010-12-30 Эли Лилли Энд Компани Modulator of receptors of glucocorticosteroids and the use thereof
US8034940B2 (en) 2006-08-09 2011-10-11 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
TW200829578A (en) 2006-11-23 2008-07-16 Astrazeneca Ab Chemical compounds 537
KR20090097908A (en) 2006-12-06 2009-09-16 베링거 인겔하임 인터내셔날 게엠베하 Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
JO2754B1 (en) 2006-12-21 2014-03-15 استرازينكا ايه بي Indazolyl amide derivatives for the treatment of glucocorticoid receptor mediated disorders
US9175260B2 (en) * 2007-01-30 2015-11-03 TheUniversity of Georgia Research Foundation, Inc. Early mesoderm cells, a stable population of mesendoderm cells that has utility for generation of endoderm and mesoderm lineages and multipotent migratory cells (MMC)
US9080145B2 (en) * 2007-07-01 2015-07-14 Lifescan Corporation Single pluripotent stem cell culture
JP2010532172A (en) 2007-07-01 2010-10-07 ライフスキャン・インコーポレイテッド Single cell pluripotent stem cell culture
CN105176919A (en) 2007-07-18 2015-12-23 生命扫描有限公司 Differentiation Of Human Embryonic Stem Cells
CN101952415B (en) 2007-07-31 2017-06-27 生命扫描有限公司 The differentiation of human embryo stem cell
CN107574142B (en) 2007-11-27 2021-07-06 生命扫描有限公司 Differentiation of human embryonic stem cells
TWI431010B (en) 2007-12-19 2014-03-21 Lilly Co Eli Mineralocorticoid receptor antagonists and methods of use
EA017288B1 (en) 2008-01-11 2012-11-30 Эли Лилли Энд Компани (E)-N-{3-[1-(8-FLUORO-11H-10-OXA-1-AZADIBENZO[a,d]CYCLOHEPTEN-5-YLIDENE)PROPYL]PHENYL}METHANESULFONAMIDE AS GLUCOCORTICOID RECEPTOR MODULATOR FOR THE TREATMENT OF RHEUMATOID
WO2009105570A2 (en) 2008-02-21 2009-08-27 Centocor Ortho Biotech Inc. Methods, surface modified plates and compositions for cell attachment, cultivation and detachment
US20090220995A1 (en) * 2008-02-28 2009-09-03 Sachs David H Multiple administrations of umbilicus derived cells
US8623648B2 (en) 2008-04-24 2014-01-07 Janssen Biotech, Inc. Treatment of pluripotent cells
US8211930B2 (en) 2008-05-20 2012-07-03 Astrazeneca Ab Phenyl and benzodioxinyl substituted indazoles derivatives
SI2300472T1 (en) 2008-06-06 2012-05-31 Boehringer Ingelheim Int Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
JP5734183B2 (en) 2008-06-30 2015-06-17 ヤンセン バイオテツク，インコーポレーテツド Differentiation of pluripotent stem cells
CN102165058B (en) 2008-07-25 2015-07-01 佐治亚大学研究基金会 Compositions for mesoderm derived ISLl1+ multipotent cells (IMPs), epicardial progenitor cells (EPCs) and multipotent CXCR4+CD56+ cells (C56Cs) and methods of use
US20110305672A1 (en) 2008-07-25 2011-12-15 University Of Georgia Research Foundation, Inc. COMPOSITIONS FOR MESODERM DERIVED ISL1+ MULTIPOTENT CELLS (IMPs), EPICARDIAL PROGENITOR CELLS (EPCs) AND MULTIPOTENT CD56C CELLS (C56Cs) AND METHODS OF PRODUCING AND USING SAME
US20100028307A1 (en) * 2008-07-31 2010-02-04 O'neil John J Pluripotent stem cell differentiation
BRPI0919885A2 (en) * 2008-10-31 2015-08-11 Centocor Ortho Biotech Inc Differentiation of human embryonic stem cells into pancreatic endocrine lineage
CA2742267C (en) * 2008-10-31 2019-06-04 Centocor Ortho Biotech Inc. Differentiation of human embryonic stem cells to the pancreatic endocrine lineage
AU2009316583B2 (en) * 2008-11-20 2016-04-21 Janssen Biotech, Inc. Methods and compositions for cell attachment and cultivation on planar substrates
RU2555538C2 (en) 2008-11-20 2015-07-10 Сентокор Орто Байотек Инк. Culture of pluripotent stem cells on microcarriers
GB2485113B (en) 2009-07-20 2016-12-28 Janssen Biotech Inc Differentiation of human embryonic stem cells into cells of the pancreatic endoderm lineage
RU2540021C2 (en) * 2009-07-20 2015-01-27 Янссен Байотек, Инк. Differentiating human embryonic stem cells
EP2456862A4 (en) 2009-07-20 2013-02-27 Janssen Biotech Inc Differentiation of human embryonic stem cells
AU2010280323A1 (en) 2009-07-31 2012-03-08 Cadila Healthcare Limited Novel compounds as modulators of glucocorticoid receptors
PL2494035T3 (en) * 2009-10-29 2018-07-31 Janssen Biotech, Inc. Pluripotent stem cells
CN102741395B (en) 2009-12-23 2016-03-16 詹森生物科技公司 The differentiation of human embryo stem cell
RU2586506C2 (en) * 2009-12-23 2016-06-10 Янссен Байотек, Инк. Differentiation of human embryonic stem cells
AU2011223900A1 (en) 2010-03-01 2012-09-13 Janssen Biotech, Inc. Methods for purifying cells derived from pluripotent stem cells
MX351515B (en) 2010-05-12 2017-10-17 Janssen Biotech Inc Differentiation of human embryonic stem cells.
JP2013533319A (en) 2010-08-12 2013-08-22 ヤンセン バイオテツク，インコーポレーテツド Treatment of diabetes with pancreatic endocrine precursor cells
CA2809305C (en) 2010-08-31 2019-06-11 Janssen Biotech, Inc. Differentiation of pluripotent stem cells
AU2011296381B2 (en) 2010-08-31 2016-03-31 Janssen Biotech, Inc. Differentiation of human embryonic stem cells
US9528090B2 (en) 2010-08-31 2016-12-27 Janssen Biotech, Inc. Differentiation of human embryonic stem cells
CA2816495C (en) 2010-12-15 2020-10-13 Kadimastem Ltd. Insulin producing cells derived from pluripotent stem cells
AU2012355698B2 (en) 2011-12-22 2018-11-29 Janssen Biotech, Inc. Differentiation of human embryonic stem cells into single hormonal insulin positive cells
KR20140131999A (en) 2012-03-07 2014-11-14 얀센 바이오테크 인코포레이티드 Defined Media for Expansion and Maintenance of Pluripotent Stem Cells
CN102603544A (en) * 2012-04-06 2012-07-25 南京大学 Anti-inflammatory compound, preparation and use thereof
CN108103006A (en) 2012-06-08 2018-06-01 詹森生物科技公司 Differentiation of the human embryo stem cell to pancreatic endocrine cell
US10370644B2 (en) 2012-12-31 2019-08-06 Janssen Biotech, Inc. Method for making human pluripotent suspension cultures and cells derived therefrom
KR102036780B1 (en) 2012-12-31 2019-10-25 얀센 바이오테크 인코포레이티드 Differentiation of human embryonic stem cells into pancreatic endocrine cells using hb9 regulators
KR102084561B1 (en) 2012-12-31 2020-03-04 얀센 바이오테크 인코포레이티드 Culturing of human embryonic stem cells at the air-liquid interface for differentiation into pancreatic endocrine cells
JP6529440B2 (en) 2012-12-31 2019-06-12 ヤンセン バイオテツク，インコーポレーテツド Suspension and clustering of human pluripotent cells for differentiation to pancreatic endocrine cells
US10500231B2 (en) 2013-03-13 2019-12-10 University Of Miami Method for isolation and purification of microvesicles from cell culture supernatants and biological fluids
CA2949056A1 (en) 2014-05-16 2015-11-19 Janssen Biotech, Inc. Use of small molecules to enhance mafa expression in pancreatic endocrine cells
EP3384286B1 (en) 2015-11-30 2023-04-19 Kadimastem Ltd. Methods for differentiating and purifying pancreatic endocrine cells
MA45479A (en) 2016-04-14 2019-02-20 Janssen Biotech Inc DIFFERENTIATION OF PLURIPOTENT STEM CELLS IN ENDODERMAL CELLS OF MIDDLE INTESTINE
JP2023538109A (en) 2020-08-21 2023-09-06 ユニバーシティ オブ マイアミ Compositions and methods of treatment using microvesicles from bone marrow-derived mesenchymal stem cells
US20230390341A1 (en) 2022-04-19 2023-12-07 University Of Miami Methods and compositions for prevention and treatment of graft versus host disease

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3507919A (en) * 1967-04-27 1970-04-21 Smithkline Corp Triphenylpropyl amines
PT66589B (en) 1976-06-16 1978-10-23 Hexachimie PROCESS FOR THE PREPARATION OF 1-SUBSTITUTED DIPHENYL-2,2 CYCLOPROPANE DERIVATIVES
US4822780A (en) 1987-07-08 1989-04-18 Otsuka Pharmaceutical Factory, Inc. Carboxamide compounds
AU7947594A (en) 1993-10-27 1995-05-22 Merck Sharp & Dohme Limited Substituted amides as tachykinin antagonists
US5736578A (en) * 1995-06-06 1998-04-07 Bristol-Myers Squibb Company Ethylamido fluorenes and improved method of making same
US6028112A (en) * 1997-05-23 2000-02-22 Bristol-Myers Squibb Company Spirocyclopropyl fluorenes as melatonergic agents

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040220153A1 (en) * 2002-09-24 2004-11-04 Jost-Price Edward Roydon Methods and reagents for the treatment of diseases and disorders associated with increased levels of proinflammatory cytokines
EP2070550A1 (en) 2003-10-15 2009-06-17 Combinatorx, Incorporated Use of combinations comprising a corticosteroid and a pyrimidopyrimidine in the treatment of inflammatory diseases
EP2301628A1 (en) 2003-10-15 2011-03-30 Zalicus Inc. Methods and reagents for the treatment of immunoinflammatory disorders
WO2005051293A2 (en) 2003-11-21 2005-06-09 Combinatorx, Incorporated Methods and reagents for the treatment of inflammatory disorders
WO2006051477A2 (en) 2004-11-10 2006-05-18 Nicholas Piramal India Limited Fused tricyclic compounds as inhibitors of tumor necrosis factor-alpha
US7834052B2 (en) 2004-11-10 2010-11-16 Piramal Life Sciences Limited Fused tricyclic compounds as inhibitors of tumor necrosis factor-alpha
US20100305094A1 (en) * 2004-11-10 2010-12-02 Piramal Life Sciences Limited Fused tricyclic compounds as inhibitors of tumor necrosis factor-alpha
US20100324026A1 (en) * 2004-11-10 2010-12-23 Piramal Life Sciences Limited Fused tricyclic compounds as inhibitors of tumor necrosis factor-alpha
US7964631B2 (en) 2004-11-10 2011-06-21 Piramal Life Sciences Limited Fused tricyclic compounds as inhibitors of tumor necrosis factor-α
US8163730B2 (en) 2004-11-10 2012-04-24 Piramal Life Sciences Limited Fused tricyclic compounds as inhibitors of tumor necrosis factor-alpha
EP2218442A1 (en) 2005-11-09 2010-08-18 CombinatoRx, Inc. Methods, compositions, and kits for the treatment of ophthalmic disorders
US20100092479A1 (en) * 2008-08-18 2010-04-15 Combinatorx (Singapore) Pte. Ltd. Compositions and methods for treatment of viral diseases

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